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PREVIOUS LITERATURE IN DR-TB

From our November 2023 Newsletter

1. Identifying patients with multidrug-resistant tuberculosis who may benefit from shorter durations of treatment.
 
PLoS One. 2023 Oct 5;1
8(10):e0292106. doi: 10.1371/journal.pone.0292106. eCollection 2023.
 
Winters N(1), Schnitzer ME(1)(2)(3), Campbell JR(4)(5)(6), Ripley S(1), Winston C(7), Savic R(8)(9), Ahmad N(10), Bisson G(11), Dheda K(12), Esmail A(12), Gegia M(13), Monedero I(14), Dalcolmo MP(15), Rodrigues D(16), Singla R(17), Yim JJ(18), Menzies D(1)(5).
 
OBJECTIVE: Studying treatment duration for rifampicin-resistant and multidrug-resistant tuberculosis (MDR/RR-TB) using observational data is methodologically challenging. We aim to present a hypothesis generating approach to identify factors associated with shorter duration of treatment.
 
STUDY DESIGN AND SETTING: We conducted an individual patient data meta-analysis among MDR/RR-TB patients restricted to only those with successful treatment outcomes. Using multivariable linear regression, we estimated associations and their 95% confidence intervals (CI) between the outcome of individual deviation in treatment duration (in months) from the mean duration of their treatment site and patient characteristics, drug resistance, and treatments used.
 
RESULTS: Overall, 6702 patients with successful treatment outcomes from 84 treatment sites were included. We found that factors commonly associated with poor treatment outcomes were also associated with longer treatment durations, relative to the site mean duration. Use of bedaquiline was associated with a 0.51 (95% CI: 0.15, 0.87) month decrease in duration of treatment, which was consistent across subgroups, while MDR/RR-TB with fluoroquinolone resistance was associated with 0.78 (95% CI: 0.36, 1.21) months increase.
 
CONCLUSION: We describe a method to assess associations between clinical factors and treatment duration in observational studies of MDR/RR-TB patients, that may help identify patients who can benefit from shorter treatment.
 
DOI: 10.1371/journal.pone.0292106
PMCID: PMC10553332
PMID: 37797071

 
2. Pretomanid resistance: An update on emergence, mechanisms and relevance for clinical practice.
 
Int J Antimicrob Agents. 2023 Oct;62(4):106953. doi: 10.1016/j.ijantimicag.2023.106953. Epub 2023 Aug 16.
 
Nguyen TVA(1), Nguyen QH(1), Nguyen TNT(2), Anthony RM(3), Vu DH(2), Alffenaar JC(4).
 
Pretomanid (PA-824), a novel anti-tuberculosis (TB) nitroimidazoxazine, has been approved for multi-drug-resistant TB treatment for a few years. Pretomanid has been demonstrated to be highly active against Mycobacterium tuberculosis when combined with other anti-TB drugs. This review provides an update of the current knowledge on the modes of action, resistance mechanisms, emergence of drug resistance, and status of antimicrobial susceptibility testing for pretomanid and its relevance for clinical practice. Pretomanid resistance has been reported in in-vitro and animal models but not yet in clinical trials. Pretomanid-resistance-associated mutations have been reported in the fbiA, fbiB, fbiC, fbiD, ddn and fgd1 genes. However, understanding of in-vivo molecular resistance mechanisms remains limited, and complicates the development of accurate antimicrobial susceptibility testing methods for pretomanid. As such, no reference method for antimicrobial susceptibility testing of pretomanid has been established to guide clinical use. Further studies linking specific mutations, in-vitro susceptibility, drug exposure and resistance mechanisms to treatment failure with pretomanid should be prioritized.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.ijantimicag.2023.106953
PMID: 37595848 [Indexed for MEDLINE]

 
3. Designing molecular diagnostics for current tuberculosis drug regimens.
 
Emerg Microbes Infect. 2023 Dec;12(1):2178243. doi: 10.1080/22221751.2023.2178243.
 
Georghiou SB(1), de Vos M(1), Velen K(1), Miotto P(2), Colman RE(1)(3), Cirillo DM(2), Ismail N(4), Rodwell TC(1)(3), Suresh A(1), Ruhwald M(1).
 
Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option 
exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and 
evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.Trial registration: ClinicalTrials.gov identifier: NCT05117788..
 
DOI: 10.1080/22221751.2023.2178243
PMCID: PMC9980415
PMID: 36752055 [Indexed for MEDLINE]

4. Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.
 
Nat Commun. 2023 Oct 4;14(1):6182. doi: 10.1038/s41467-023-41937-9.
 
Menzies NA(1)(2), Allwood BW(#)(3), Dean AS(#)(4), Dodd PJ(#)(5), Houben RMGJ(#)(6)(7), James LP(#)(8)(9), Knight GM(#)(10), Meghji J(#)(11), Nguyen LN(#)(4), Rachow A(#)(12)(13)(14), Schumacher SG(#)(4), Mirzayev F(4), Cohen T(15).
 
In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.
 
© 2023. Springer Nature Limited.
 
DOI: 10.1038/s41467-023-41937-9
PMCID:
PMC10550952
PMID: 37794037 [Indexed for MEDLINE]

From our October 2023 Newsletter

1. Community perspective on child-friendly medications for drug-resistant TB: importance, priorities and advocacy.
 
Int J Tuberc Lung Dis. 2023 Sep 1;27(9):655-657. doi: 10.5588/ijtld.23.0164.
 
Viljoen L(1), Acaba J(2), Agbassi YJP(3), Beko B(4), Goslett C(5),
Hoddinott G(1), Kumar B(6), Kumar RG(7), McKenna L(8), Moses G(3), Sachs T(1), Seidel 
S(9), von Delft A(10).
 
DOI: 10.5588/ijtld.23.0164
PMCID: PMC10443785
PMID: 37608482 [Indexed for MEDLINE]
 
2. Successful outcomes for patients with drug-resistant tuberculosis despite civil unrest and COVID-19 in Haiti.

PLOS Glob Public Health. 2023 Sep 12;3(9):e0002356. doi: 10.1371/journal.pgph.0002356. eCollection 2023.
 
Vilbrun SC(1), Souroutzidis A(2), Walsh KF(3)(4), Ellis J(5), Guiteau C(1), Delva S(1), Joissaint G(1), Joseph P(1), Pape JW(1)(3), Koenig SP(6).
 
Globally, treatment outcomes for people with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) are sub-optimal, with MDR/RR-TB programs further weakened due to the COVID-19 pandemic, and in Haiti, by severe civil unrest. We assessed the impact of these disruptions on treatment outcomes at GHESKIO, in 
Port-au-Prince, Haiti. We conducted a retrospective analysis including all adults (age ≥18 years) who initiated MDR/RR-TB treatment at GHESKIO from 2010 to 2020. We assessed predictors of poor treatment outcome using multivariable logistic regression, adjusting for baseline characteristics and year of treatment. 453 patients initiated treatment for MDR/RR-TB at GHESKIO. Median age was 31 (IQR: 25, 40), 233 (51.4%) were male, and 100 (22.1%) were living with HIV. Three hundred sixty-nine patients (81.5%) achieved cure, 42 (9.3%) died, 40 (8.8%) were lost to follow-up and 2 (<1%) failed treatment. HIV status was associated with poor treatment outcome (aRR: 1.65 (95% CI: 1.09, 2.48)) but there was no difference by year of treatment initiation. Outcomes for patients with MDR/RR-TB remained outstanding, even during the COVID-19 pandemic and severe civil unrest in Haiti. We attribute this resilience in care to the adaptability of program staff and provision of economic and psychosocial support.
 
Copyright: © 2023 Vilbrun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
DOI: 10.1371/journal.pgph.0002356
PMCID: PMC10497149
PMID: 37698996
 
3. 1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.
 
Clin Infect Dis. 2023 Sep 18;77(6):892-900. doi: 10.1093/cid/ciad301.
 
Krishnan S(1), Wu X(2), Kim S(3), McIntire K(1), Naini L(4), Hughes MD(2), Dawson R(5), Mave V(1)(6), Gaikwad S(6), Sanchez J(7), Mendoza-Ticona A(8), Gonzales P(9), Comins K(8), Shenje J(10), Fontain SN(11), Omozoarhe A(12), Mohapi L(13), Lalloo UG(14), Garcia Ferreira AC(15), Mugah C(16), Harrington M(17), Shah NS(18), Hesseling AC(19), Churchyard G(20)(21)(22), Swindells S(23), Gupta A(1)(6); AIDS Clinical Trials Group A5300/International Maternal Pediatric Adolescent AIDS Clinical Trials I2003 Protecting Households on Exposure to Newly Diagnosed Index Multidrug-resistant Tuberculosis Patients Feasibility Study Team* (Additional study group members are listed in the Acknowledgment section).
 
BACKGROUND: Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups.
 
METHODS: We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, 
diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations.
 
RESULTS: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT.
 
CONCLUSIONS: TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups.
 
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciad301
PMID: 37227925 [Indexed for MEDLINE]

From our September 2023 Newsletter

1. Surveillance of multidrug-resistant tuberculosis in sub-Saharan Africa through wastewater-based epidemiology.
 
Heliyon. 2023 Jul 21;9(8):e18302. doi: 10.1016/j.heliyon.2023.e18302. eCollection 2023 Aug.
 
Mtetwa HN(1)(2), Amoah ID(1)(3), Kumari S(1), Bux F(1), Reddy P(1)(2).
 
The spread of multidrug-resistant tuberculosis (MDR-TB) is a serious public health issue, particularly in developing nations. The current methods of monitoring drug-resistant TB (DR-TB) using clinical diagnoses and hospital records are insufficient due to limited healthcare access and underreporting. This study proposes using Wastewater-Based Epidemiology (WBE) to monitor DR-TB in six African countries (Ghana, Nigeria, Kenya, Uganda, Cameroon, and South Africa) and examines the impact of treated wastewater on the spread of TB drug-resistant genes in the environment. Using droplet-digital polymerase chain reaction (ddPCR), the study evaluated untreated and treated wastewater samples in selected African countries for TB surveillance. There was a statistically significant difference in concentrations of genes conferring resistance to TB drugs in wastewater samples from the selected countries (p-value<0.05); South African samples exhibited the highest concentrations of 4.3(±2,77), 4.8(±2.96), 4.4(±3,10) and 4.7(±3,39) log copies/ml for genes conferring resistance to first-line TB drugs (katG, rpoB, embB and pncA respectively) in untreated wastewater. This may be attributed to the higher prevalence of TB/MDR-TB in SA compared to other African countries. Interestingly, genes conferring resistance to second-line TB drugs such as delamanid (ddn gene) and bedaquiline (atpE gene) were detected in relatively high concentrations (4.8(±3,67 and 3.2(±2,31 log copies/ml for ddn and atpE respectively) in countries, such as Cameroon, where these drugs are not part of the MDR-TB treatment regimens, perhaps due to migration or the unapproved use of these drugs in the country. The gene encoding resistance to streptomycin (rrs gene) was abundant in all countries, perhaps due to the common use of this antibiotic for infections other than TB. These results highlight the need for additional surveillance and monitoring, such as WBE, to gather data at a community level. Combining WBE with the One Health strategy and current TB surveillance systems can help prevent the spread of DR-TB in populations.
 
© 2023 The Authors.
 
DOI: 10.1016/j.heliyon.2023.e18302
PMCID: PMC10412881
PMID: 37576289
 
2. Fluoroquinolone-resistant latent tuberculosis infection: A literature review and case series of 5 patients treated with linezolid monotherapy.
 
J Clin Tuberc Other Mycobact Dis. 2023 May 18;32:100376. doi: 10.1016/j.jctube.2023.100376. eCollection 2023 Aug.
 
Baker JJ(1), Nahar R(2), Petroelje BK(1), Goswami ND(3), Lardizabal AA(4).
 
Latent tuberculosis infection (LTBI) constitutes an important public health problem because of risk of progression to TB disease. Effective treatment of multi-drug resistant (MDR) LTBI would prevent progression to MDR TB disease, which would improve patient and public health outcomes. The majority of MDR LTBI treatment studies have focused on the use of fluoroquinolone-based antibiotic regimens. Options for and experience in the treatment of fluoroquinolone-resistant MDR LTBI are limited in the published literature and not comprehensively addressed in current guidelines. In this review, we share our experience with the treatment of fluoroquinolone-resistant MDR LTBI with linezolid. We discuss treatment options for MDR TB that provide context for predicting effective MDR LTBI treatment, with a focus on the microbiologic and pharmacokinetic properties of linezolid that support its use. We then summarize the evidence for treatment of MDR LTBI. Finally, we present our experiences treating fluoroquinolone-resistant MDR LTBI with linezolid with an emphasis on dosing considerations to optimize efficacy and minimize potential toxicities.
 
© 2023 The Authors.
 
DOI: 10.1016/j.jctube.2023.100376
PMCID: PMC10209533
PMID: 37252368
 
3. Nutritional support for adult patients with microbiologically confirmed pulmonary tuberculosis: outcomes in a programmatic cohort nested within the RATIONS trial in Jharkhand, India.

 
Lancet Glob Health. 2023 Sep;11(9):e1402-e1411. doi: 10.1016/S2214-109X(23)00324-8. Epub 2023 Aug 8.
 
Bhargava A(1), Bhargava M(2), Meher A(3), Teja GS(4), Velayutham B(3), Watson B(3), Benedetti A(5), Barik G(3), Singh VP(3), Singh D(3), Madhukeshwar AK(6), Prasad R(7), Pathak RR(8), Chadha V(9), Joshi R(10).
 
BACKGROUND: Undernutrition is a common comorbidity of tuberculosis in countries with a high tuberculosis burden, such as India. RATIONS is a field-based, cluster-randomised controlled trial evaluating the effect of providing nutritional support to household contacts of adult patients with microbiologically confirmed pulmonary tuberculosis in Jharkhand, India, on tuberculosis incidence. The patient cohort in both groups of the trial was provided with nutritional support. In this study, we assessed the effects of nutritional support on tuberculosis mortality, treatment success, and other outcomes in the RATIONS patient cohort.

METHODS: We enrolled patients (aged 18 years or older) with microbiologically confirmed pulmonary tuberculosis across 28 tuberculosis units. Patients received nutritional support in the form of food rations (1200 kcal and 52 g of protein per day) and micronutrient pills. Nutritional support was for 6 months for drug-susceptible tuberculosis and 12 months for multidrug-resistant tuberculosis; patients with drug-susceptible tuberculosis could receive an extension of up to 6 months if their BMI was less than 18·5 kg/m2 at the end of treatment. We recorded BMI, diabetes status, and modified Eastern Cooperative Oncology Group (ECOG) performance status at baseline. Clinical outcomes (treatment success, tuberculosis mortality, loss to follow-up, and change in performance status) and weight gain were recorded at 6 months. We assessed the predictors of tuberculosis mortality with Poisson and Cox regression using adjusted incidence rate ratios (IRRs) and adjusted hazard ratios (HRs). The RATIONS trial is registered with the Clinical Trials Registry of India (CTRI/2019/08/020490).

FINDINGS: Between Aug 16, 2019, and Jan 31, 2021, 2800 patients (mean age 41·5 years [SD 14·5]; 1979 [70·7%] men and 821 [29·3%] women) were enrolled. At enrolment, 2291 (82·4%) patients were underweight (BMI <18·5 kg/m2), and 480 (17·3%) had a BMI of less than 14 kg/m2. The mean weight and BMI were 42·6 kg (SD 7·8) and 16·4 kg/m2 (2·6) in men and 36·1 kg (7·3) and 16·2 kg/m2 (2·9) in women. During the 6-month follow-up, treatment was successful in 2623 (93·7%) patients, 108 (3·9%) tuberculosis deaths occurred, 28 (1·0%) patients were lost to follow-up, and treatment failure was experienced by five (0·2%) patients. The median weight gain was 4·6 kg (IQR 2·8-6·8), but 1441 (54·8%) of 2630 patients remained underweight. At 2 months, 1444 (54·0%) of 2676 patients gained at least 5% of baseline weight. Baseline weight (adjusted IRR 0·95, 95% CI 0·90-0·99), BMI (0·88, 0·76-1·01), poor performance status (ECOG categories 3-4; 5·33, 2·90-9·79), diabetes (3·30, 1·65-6·72), and haemoglobin (0·85, 0·71-1·00) were predictors of tuberculosis mortality. A reduced hazard of death (adjusted HR 0·39, 95% CI 0·18-0·86) was associated with a 5% weight gain at 2 months.

INTERPRETATION: In this study, nutritional support was provided to a cohort with a high prevalence of severe undernutrition. Weight gain, particularly in the first 2 months, was associated with a substantially decreased hazard of tuberculosis mortality. Nutritional support needs to be an integral component of patient-centred care to improve treatment outcomes in such settings.

FUNDING: India Tuberculosis Research Consortium, Indian Council of Medical Research.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S2214-109X(23)00324-8
PMID: 37567210 [Indexed for MEDLINE]

4. Linezolid optic neuropathy.
 
Curr Opin Ophthalmol. 2023 Aug 22. doi: 10.1097/ICU.0000000000000995. Online ahead of print.
 
Miller HV(1), Cao AA(2), McClelland CM(1)(3), Lee MS(1)(3).
 
PURPOSE OF REVIEW: In this article, we reviewed 67 reported cases of linezolid optic neuropathy and describe the common characteristics and expectations for recovery with an emphasis on recent findings in the literature.

RECENT FINDINGS: Linezolid classically causes a reversible, duration-dependent optic neuropathy. However, in our review, we found only 66.7% of patients recovered complete visual function. Vision loss most commonly affected visual acuity followed by visual field and color vision. We also found patients taking higher doses of linezolid experienced full recovery less often, suggesting a dose-dependent component of linezolid optic neuropathy. Linezolid use has increased in frequency and duration, especially in the treatment of drug-resistant tuberculosis, and data indicate that these patients experience lower rates of complete vision recovery compared with patients taking linezolid for other indications.

SUMMARY: Linezolid is an effective medication for treating drug-resistant infections; however, it may result in optic neuropathy. It is reasonable for patients on linezolid to undergo screening examinations, especially those on higher doses or for prolonged duration of therapy.
 
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
 
DOI: 10.1097/ICU.0000000000000995
PMID: 37603423
 
5. Pregnancy and Birth Outcomes in Patients With Multidrug-Resistant Tuberculosis Treated With Regimens That Include New and Repurposed Drugs.
 
Clin Infect Dis. 2023 Aug 22:ciad445. doi: 10.1093/cid/ciad445. Online ahead of print.
 
Lotia Farrukh I(1), Lachenal N(2), Adenov MM(3), Ahmed S(1), Algozhin Y(4), Coutisson S(2), Garavito ES(5), Hewison C(6), Holtzman D(7), Huerga H(8), Janmohamed A(1), Khan PY(1)(9), Jacques GL(10), Lomtadze N(11), Melikyan N(12), Mitnick CD(13)(14), Mussabekova G(3), Osso E(13), Perea S(15), Putri FA(16), Rashidov M(4), Rich ML(14)(17), Sakhabutdinova Y(4), Seung KJ(14)(17), Stambekova A(4), Vásquez DV(18), Franke MF(13), Khan U(1).
 
Among 43 pregnant women receiving multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment with bedaquiline and/or delamanid, 98% had favorable treatment outcomes. Of 31 continued pregnancies, 81% had live births with no reported malformations, and 68% of neonates had normal birth weights. Effective MDR/RR-TB treatment during pregnancy can improve maternal outcomes without harming neonates.
 
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciad445
PMID: 37606512

6. Pretomanid resistance: an update on emergence, mechanisms and relevance for clinical practice.
 
Int J Antimicrob Agents. 2023 Aug 16:106953. doi: 10.1016/j.ijantimicag.2023.106953. Online ahead of print.
 
Nguyen TVA(1), Nguyen QH(1), Nguyen TNT(2), Anthony RM(3), Vu DH(2), Alffenaar JC(4).
 
Pretomanid (PA-824), a novel anti-tuberculosis nitroimidazoxazine, has been approved for multidrug-resistant tuberculosis treatment for a few years. Pretomanid has been demonstrated to be highly active against Mycobacterium tuberculosis when combined with other anti-tuberculosis drugs. This review provides an update of the current knowledge on the modes of action, resistance mechanisms, emergence of drug resistance, status of antimicrobial susceptibility testing for pretomanid and their relevance for clinical practice. Pretomanid resistance has been reported in in vitro and animal models but not yet in clinical trials. Pretomanid resistance-associated mutations have been reported in fbiA, fbiB, fbiC, fbiD, ddn and fgd1 genes. However, understanding of in vivo molecular resistance mechanisms remains limited and complicates the development of accurate antimicrobial susceptibility testing methods for pretomanid. Hence, no reference method for antimicrobial susceptibility testing of pretomanid has been established to guide clinical use. Further studies linking specific mutations, in vitro susceptibility, drug exposure and resistance mechanisms to treatment failure with pretomanid should be prioritized.
 
Copyright © 2023. Published by Elsevier Ltd.
 
DOI: 10.1016/j.ijantimicag.2023.106953
PMID: 37595848

From our August 2023 Newsletter


1. QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.
 
Antimicrob Agents Chemother. 2023 Jul 18;67(7):e0144822. doi: 10.1128/aac.01448-22. Epub 2023 Jun 26.
 
Ali AM(1)(2), Radtke KK(1), Hesseling AC(3), Winckler J(3), Schaaf HS(3), Draper HR(3), Solans BP(1), van der Laan L(3), Hughes J(3), Fourie B(3), Nielsen J(4), Garcia-Prats AJ(#)(3)(5), Savic RM(#)(1).
 
Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.
 
DOI: 10.1128/aac.01448-22
PMCID: PMC10353402
PMID: 37358463 [Indexed for MEDLINE]
 
2. To Test or Not? Xpert MTB/RIF as an Alternative to Smear Microscopy to Guide Line Probe Assay Testing for Drug-Resistant Tuberculosis.
 

J Clin Microbiol. 2023 Jul 20;61(7):e0001723. doi: 10.1128/jcm.00017-23. Epub 2023 Jun 27.
 
Pillay S(1)(2), de Vos M(1), Sohn H(3), Ghebrekristos Y(2), Dolby T(2), Warren RM(1), Theron G(1).
 
Xpert MTB/RIF (Xpert) revolutionized tuberculosis (TB) diagnosis. Laboratory decision making on whether widely-used reflex drug susceptibility assays (MTBDRplus, first-line resistance; MTBDRsl, second-line) are conducted is based on smear status, with smear-negative specimens often excluded. We performed receiver operator characteristic (ROC) curve analyses using bacterial load information (smear microscopy grade, Xpert-generated semi-quantitation categories and minimum cycle threshold [CTmin] values) from Xpert 
rifampicin-resistant sputum for the prediction of downstream line probe assay results as "likely non-actionable" (no resistance or susceptible results generated). We evaluated actionable-to-non-actionable result ratios and pay-offs with missed resistance versus LPAs done universally. Smear-negatives were more likely than smear-positive specimens to generate a non-actionable MTBDRplus (23% [133/559] versus 4% [15/381]) or MTBDRsl (39% [220/559] versus 12% [47/381]) result. However, excluding smear-negatives would result in missed rapid diagnoses (e.g., only 49% [264/537] of LPA-diagnosable isoniazid resistance would be detected if smear-negatives were omitted). Testing smear-negatives with a semi-quantitation category ≥ "medium" had a high ratio of actionable-to-non-actionable results (12.8 or a 4-fold improvement versus testing all using MTBDRplus, 4.5 or 3-fold improvement for MTBDRsl), which would still capture 64% (168/264) and 77% (34/44) of LPA-detectable smear-negative resistance, respectively. Use of CTmins permitted optimization of this ratio with higher specificity for non-actionable results but decreased resistance detected. Xpert quantitative information permits identification of a smear-negative subset in whom the payoffs of the ratio of actionable-to-non-actionable LPA results with missed resistance may prove acceptable to laboratories, depending on context. Our findings permit the rational expansion of direct DST to certain smear-negative sputum specimens.
 
DOI: 10.1128/jcm.00017-23
PMID: 37367228

3. Linezolid resistance in patients with drug-resistant TB.
 
Int J Tuberc Lung Dis. 2023 Jul 1;27(7):567-569. doi: 10.5588/ijtld.22.0632.
 
Vengurlekar D(1), Walker C(2), Mahajan R(3), Dalal A(4), Chavan V(1), Galindo MA(1), Iyer A(1), Mansoor H(1), Silsarma A(1), Isaakidis P(5), Spencer H(6).
 
DOI: 10.5588/ijtld.22.0632
PMCID: PMC10321363
PMID: 37353865 [Indexed for MEDLINE]

4. Estimating the prevalence of poor-quality anti-TB medicines: a neglected risk for global TB control and resistance.
 
BMJ Glob Health. 2023 Jul;8(7):e012039. doi: 10.1136/bmjgh-2023-012039.
 
Tabernero P(1)(2)(3)(4), Newton PN(2)(3)(4).
 
OBJECTIVES: Tuberculosis (TB) remains a major global public health problem, especially with the recent emergence of multidrug-resistant TB and extensively drug-resistant TB. There has been little consideration of the extent of substandard and falsified (SF) TB medicines as drivers of resistance. We assessed the evidence on the prevalence of SF anti-TB medicines and discussed their public health impact.

MATERIALS/METHODS: We searched Web of Science, Medline, Pubmed, Google Scholar, WHO, US Pharmacopeia and Medicines Regulatory Agencies websites for publications on anti-TB medicines quality up to 31 October 2021. Publications reporting on the prevalence of SF anti-TB drugs were evaluated for quantitative analysis.

RESULTS: Of the 530 screened publications, 162 (30.6%) were relevant to anti-TB medicines quality; of those, 65 (40.1%) described one or more TB quality surveys in a specific location or region with enough information to yield an estimate of the local prevalence of poor-quality TB medicines. 7682 samples were collected in 22 countries and of those, 1170 (15.2%) failed at least one quality test. 14.1% (879/6255) of samples failed in quality surveys, 12.5% (136/1086) in bioequivalence studies and 36.9% (87/236) in accelerated biostability studies. The most frequently assessed were rifampicin monotherapy (45 studies, 19.5%) and isoniazid monotherapy (33, 14.3%), rifampicin-isoniazid-pyrazinamide-ethambutol fixed dose combinations (28, 12.1%) and rifampicin-isoniazid (20, 8.6%). The median (IQR) number of samples collected per study was 12 (1-478).

CONCLUSIONS: SF, especially substandard, anti-TB medicines are present worldwide. However, TB medicine quality data are few and are therefore not generalisable that 15.2% of global anti-TB medicine supply is SF. The evidence available suggests that the surveillance of the quality of TB medicines needs to be an integral part of treatment programmes. More research is needed on the development and evaluation of rapid, affordable and accurate portable devices to empower pharmacy inspectors to screen for anti-TB medicines.
 
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
 
DOI: 10.1136/bmjgh-2023-012039
PMCID: PMC10347509
PMID: 37433693 [Indexed for MEDLINE]

5. Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis.
 
Lancet Infect Dis. 2023 Jul;23(7):778-780. doi: 10.1016/S1473-3099(23)00349-3. Epub 2023 May 25.
 
Garcia-Prats AJ(1), Hoddinott G(2), Howell P(3), Hughes J(2), Jean-Philippe P(4), Kim S(5), Palmer M(2), Schaaf HS(2), Seddon JA(6), Svensson E(7), Hesseling AC(2).
 
DOI: 10.1016/S1473-3099(23)00349-3
PMID: 37245523 [Indexed for MEDLINE]
 

6. Making the Case for All-Oral, Shorter Regimens for Children with Drug-Resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2023 Jul 15;208(2):130-131. doi: 10.1164/rccm.202304-0670VP.
 
Patankar S(1), Cruz AT(2), Douglas-Jones B(3), Garcia-Prats A(3)(4), Kay A(2), Reuter A(5), Schaaf HS(3), Seddon JA(3)(6), Sharma S(7), Starke J(2), Tommasi M(8), Triasih R(9), Furin JJ(10).
 
DOI: 10.1164/rccm.202304-0670VP
PMID: 37276531 [Indexed for MEDLINE]

From our July 2023 Newsletter

1. Long-term treatment outcomes in patients with multidrug-resistant tuberculosis.
 
Clin Microbiol Infect. 2023 Jun;29(6):751-757. doi: 10.101
6/j.cmi.2023.02.013. Epub 2023 Feb 25.
 
Maier C(1), Chesov D(2), Schaub D(1), Kalsdorf B(1), Andres S(3), Friesen I(3), Reimann M(1), Lange C(4).
 
OBJECTIVES: To describe long-term treatment outcomes in patients with  multi-drug-resistant/rifampicin resistant tuberculosis (MDR/RR-TB) and validate  established outcome definitions for MDR/RR-TB treatment.

METHODS: Among patients with MDR/RR-TB admitted to a German MDR/RR-TB referral centre from 1 September 2002 to 29 February 2020, we compared long-term treatment outcomes derived from individual patient follow-up with treatment outcomes defined by WHO-2013, WHO-2021 and the Tuberculosis Network European Trials Group-2016.

RESULTS: In a total of 163 patients (mean age, 35 years; standard deviation, 13 years; 14/163 [8.6%] living with HIV; 109/163 [66.9%] men, 149/163 [91.4%] migrating to Germany within 5 years), the treatment of culture-confirmed MDR/RR-TB was initiated. Additional drug resistance to a fluoroquinolone or a  second-line injectable agent was present in 15 of the 163 (9.2%) Mycobacterium tuberculosis strains; resistance against both the drug classes was present in 29 of the 163 (17.8%) strains. The median duration of MDR/RR-TB treatment was 20 months (interquartile range, 19.3-21.6 months), with a medium of five active drugs included. The median follow-up time was 4 years (47.7 months; interquartile range, 21.7-65.8 months). Among the 163 patients, cure was achieved in 25 (15.3%), 82 (50.3%) and 95 (58.3%) patients according to the outcome definitions of WHO-2013, WHO-2021, and the Tuberculosis Network European Trials Group-2016, respectively. The lost to follow-up rate was 17 of 163 (10.4%). Death was more likely in patients living with HIV (hazard ratio, 4.28; 95% confidence interval, 1.26-12.86) and older patients (hazard ratio, 1.08; 95% confidence interval, 1.05-1.12; increment of 1 year). Overall, 101/163 (62.0%) patients experienced long-term, relapse-free cure; of those, 101/122 (82.8%) patients with a known status (not lost to-follow-up or transferred out) at follow-up.

CONCLUSION: Under optimal management conditions leveraging individualized treatment regimens, long-term, relapse-free cure from MDR/RR-TB is substantially higher than cure rates defined by current treatment outcome definitions.
 
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.cmi.2023.02.013
PMID: 36842637 [Indexed for MEDLINE]
 
2. Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

Int J Tuberc Lung Dis. 2023 Jun 1;27(6):451-457. doi: 10.5588/ijtld.22.0613.
 
Rich ML(1), Khan U(2), Zeng C(3), LaHood A(3), Franke MF(3), Atwood S(4), Bastard M(5), Burhan E(6), Danielyan N(7), Dzhazibekova PM(8), Gadissa D(9), Ghafoor A(10), Hewison C(11), Islam MS(12), Kazmi E(13), Khan PY(14), Lecca L(15), Maama LB(16), Melikyan N(17), Naing YY(18), Philippe K(19), Saki NA(20), Seung KJ(1), Skrahina A(21), Tefera GB(9), Varaine F(11), Vilbrun SC(22), Võ L(23), Mitnick CD(24), Huerga H(5).
 
BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.

METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.

RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.

CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.
 
DOI: 10.5588/ijtld.22.0613
PMCID: PMC10237267
PMID: 37231598 [Indexed for MEDLINE]

3. Operationalising targeted next-generation sequencing for routine diagnosis of drug-resistant TB.

Public Health Action. 2023 Jun 21;13(2):43-49. doi: 10.5588/pha.22.0041.
 
Iyer A(1), Ndlovu Z(2)(3), Sharma J(1), Mansoor H(1), Bharati M(1), Kolan S(1), Morales M(1), Das M(1), Issakidis P(2), Ferlazzo G(2), Hirani N(4), Joshi A(4), Tipre P(5), Sutar N(5), England K(6).
 
BACKGROUND: Phenotypic drug susceptibility testing (pDST) for Mycobacterium tuberculosis can take up to 8 weeks, while conventional molecular tests identify a limited set of resistance mutations. Targeted next generation sequencing (tNGS) offers rapid results for predicting comprehensive drug resistance, and this study sought to explore its operational feasibility within a public health laboratory in Mumbai, India.

METHODS: Pulmonary samples from consenting patients testing Xpert MTB-positive were tested for drug resistance by conventional methods and using tNGS. Laboratory operational and logistical implementation experiences from study team members are shared below.

RESULTS: Of the total number of patients tested, 70% (113/161) had no history of previous TB or treatment; however, 88.2% (n = 142) had rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB). There was a high 
concordance between resistance predictions of tNGS and pDST for most drugs, with tNGS more accurately identifying resistance overall. tNGS was integrated and adapted into the laboratory workflow; however, batching samples caused significantly longer result turnaround time, fastest at 24 days. Manual DNA extraction caused inefficiencies; thus protocol optimisations were performed. Technical expertise was required for analysis of uncharacterised mutations and interpretation of report templates. tNGS cost per sample was US$230, while for pDST this was US$119.

CONCLUSIONS: Implementation of tNGS is feasible in reference laboratories. It can rapidly identify drug resistance and should be considered as a potential alternative to pDST.
 
© 2023 The Union.
 
DOI: 10.5588/pha.22.0041
PMCID: PMC10290261
PMID: 37359066

4. Effectiveness of Bedaquiline Use beyond Six Months in Patients with Multidrug-Resistant Tuberculosis.

Am J Respir Crit Care Med. 2023 Jun 1;207(11):1525-1532. doi: 10.1164/rccm.202211-2125OC.
 
Trevisi L(1), Hernán MA(2), Mitnick CD(1)(3)(4), Khan U(5), Seung KJ(1)(3)(4), Rich ML(1)(3)(4), Bastard M(6), Huerga H(6), Melikyan N(6), Atwood SA(3), Avaliani Z(7), Llanos F(8)(9), Manzur-Ul-Alam M(10), Zarli K(11), Binegdie AB(12), Adnan S(13), Melikyan A(14), Gelin A(15), Isani AK(16), Vetushko D(17), Daugarina Z(18), Nkundanyirazo P(19), Putri FA(5), Vilbrun C(20), Khan M(21), Hewison C(22), Khan PY(23), Franke MF(1).
 
Comment in Am J Respir Crit Care Med. 2023 Jun 1;207(11):1423-1424.
 
Rationale: Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ.

Objectives: We emulated a target trial to estimate the effect of three BDQ duration treatment strategies (6, 7-11, and ⩾12 mo) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis.

Methods: To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse probability weighting. Measurements and Main

Results: The 1,468 eligible individuals received a median of 4 (interquartile range, 4-5) likely effective drugs. In 87.1% and 77.7% of participants, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment was 0.85 (95% confidence interval [CI], 0.81-0.88) for 6 months of BDQ, 0.77 (95% CI, 0.73-0.81) for 7-11 months, and 0.86 (95% CI, 0.83-0.88) for ⩾12 months. Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI, 0.85-0.96) for 7-11 months and 1.01 (95% CI, 0.96-1.06) for ⩾12 months. Naive analyses that did not account for bias revealed a higher probability of successful treatment with ⩾12 months (ratio, 1.09 [95% CI, 1.05-1.14]). 

Conclusions: BDQ use beyond 6 months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time bias can influence estimates of the effects of treatment duration. Future analyses should explore the effect of treatment duration of BDQ and other drugs in subgroups with advanced disease and/or receiving less potent regimens.
 
DOI: 10.1164/rccm.202211-2125OC
PMCID: PMC10263131
PMID: 36802336 [Indexed for MEDLINE]

5. Post-tuberculosis lung impairment: systematic review and meta-analysis of spirometry data from 14 621 people.

Eur Respir Rev. 2023 Apr 19;32(168):220221. doi: 10.1183/16000617.0221-2022. Print 2023 Jun 30.
 
Ivanova O(1)(2)(3), Hoffmann VS(4)(3), Lange C(5)(6)(7)(8), Hoelscher M(9)(2), Rachow A(9)(2).
 
BACKGROUND: A substantial proportion of tuberculosis patients remain with pulmonary symptoms and reduced physical capacity despite successful treatment. We performed a systematic review to analyse the burden of post-tuberculosis lung impairment measured by lung function testing.

METHODS: We searched the PubMed database for articles published between database inception and November 2020 and performed meta-analyses to estimate the prevalence, type and severity of lung impairment among drug-susceptible and multidrug-resistant tuberculosis survivors. Methodological quality of included studies was assessed using the Newcastle-Ottawa scale.

RESULTS: 54 articles were included in this review. For subjects with former drug-susceptible tuberculosis, the combined estimated mean was 76.6% (95% CI 71.6-81.6) of predicted for forced expiratory volume in 1 s (FEV1) and 81.8% (95% CI 77.4-86.2) for forced vital capacity (FVC). In former patients with multidrug-resistant tuberculosis, it was 65.9% (95% CI 57.1-74.7) for FEV1 and 76.0% (95% CI 66.3-85.8) for FVC, respectively. The analysis of impairment types in former patients with drug-susceptible and multidrug-resistant tuberculosis showed that 22.0% versus 19.0% had obstructive, 23.0% versus 22.0% restrictive and 15.0% versus 43.0% had mixed impairment type, respectively. In the majority of studies, at least 10-15% of tuberculosis survivors had severe lung impairment.

CONCLUSIONS: This systematic review showed long-term abnormal spirometry results in a significant proportion of tuberculosis survivors.
 
Copyright ©The authors 2023.
 
DOI: 10.1183/16000617.0221-2022
PMCID: PMC10113954
PMID: 37076175 [Indexed for MEDLINE]

From our June 2023 Newsletter

1. Achieving universal access to rapid tuberculosis diagnostics.

BMJ Glob Health. 2023 May;8(5):e012666. doi: 10.1136/bmjgh-2023-012666.
 
Ismail N(1), Nathanson CM(2), Zignol M(2), Kasaeva T(2).

The first WHO-recommended rapid diagnostic (WRD), endorsed by WHO in 2010, revolutionised the diagnosis of TB. It was simple to perform, produced results in under 2 hours and could detect resistance to rifampicin, one of the most potent drugs to treat TB. Over the years, evidence has shown WRDs are highly accurate, reduce time to treatment initiation, impact patient-important outcomes and are cost-effective.2 In the past decade, WHO has endorsed several WRDs, including products suited to different contexts.2

The WHO End TB Strategy adopted by all countries calls for all people with TB to be diagnosed with a WRD as an initial test by 2025.3 However, in 2021, only 38% of people with TB were tested with a WRD as an initial test,1 while only 25% of all TB diagnostic testing sites had access to WRDs.4 Lack of access and insufficient use of WRDs contribute to the large gap in the detection of TB and drug resistance. Most people with TB still undergo a smear microscopy test as the initial TB test or do not receive any bacteriological diagnosis. Smear microscopy has several limitations, the most notable being very low sensitivity and inability to detect drug resistance. Furthermore, patient pathway analyses and work on diagnostic cascades highlight the importance of a holistic and decentralised approach to improve timely access to WRDs at the primary healthcare level, where over 80% of people with TB first seek care.5–7 The lack of access to WRDs needs to be rapidly addressed, and plans to switch to WRDs should be accelerated in all high-TB burden countries.

DOI: 10.1136/bmjgh-2023-012666
PMID: 37230547 [Indexed for MEDLINE]

2. Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an 
in-vitro and in-silico data analysis.

Lancet Microbe. 2023 May;4(5):e358-e368. doi: 10.1016/S2666-5247(23)00002-2. 
Epub 2023 Mar 29.
 
Sonnenkalb L(1), Carter JJ(2), Spitaleri A(3), Iqbal Z(4), Hunt M(5), Malone 
KM(4), Utpatel C(1), Cirillo DM(6), Rodrigues C(7), Nilgiriwala KS(8), Fowler 
PW(9), Merker M(10), Niemann S(11); Comprehensive Resistance Prediction for 
Tuberculosis: an International Consortium.
 
BACKGROUND: Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data.

METHODS: For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations.

FINDINGS: We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5-MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand.

INTERPRETATION: Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments.

FUNDING: Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie Skłodowska-Curie Actions.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open 
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All 
rights reserved.
 
DOI: 10.1016/S2666-5247(23)00002-2
PMCID: PMC10156607
PMID: 37003285 [Indexed for MEDLINE]

3. Residual respiratory disability after successful treatment of pulmonary 
tuberculosis: a systematic review and meta-analysis.

EClinicalMedicine. 2023 May 8;59:101979. doi: 10.1016/j.eclinm.2023.101979. 
eCollection 2023 May.
 
Taylor J(1), Bastos ML(1)(2), Lachapelle-Chisholm S(1), Mayo NE(3)(4), Johnston 
J(5), Menzies D(1)(2)(3).
 
BACKGROUND: Pulmonary tuberculosis (PTB) can result in long-term health consequences, even after successful treatment. We conducted a systematic review and meta-analysis to estimate the occurrence of respiratory impairment, other disability states, and respiratory complications following successful PTB treatment.

METHODS: We identified studies from January 1, 1960, to December 6, 2022, describing populations of all ages that successfully completed treatment for active PTB and had been assessed for at least one of the following outcomes: occurrence of respiratory impairment, other disability states, or respiratory complications following PTB treatment. Studies were excluded if they reported on participants with self-reported TB, extra-pulmonary TB, inactive TB, latent TB, or if participants had been selected on the basis of having more advanced disease. Study characteristics and outcome-related data were abstracted. Meta-analysis was performed using a random effects model. We adapted the Newcastle Ottawa Scale to evaluate the methodological quality of the included studies. Heterogeneity was assessed using the I2 statistic and prediction intervals. Publication bias was assessed using Doi plots and LFK indices. This study is registered with PROSPERO (CRD42021276327).

FINDINGS: 61 studies with 41,014 participants with PTB were included. In 42 studies reporting post-treatment lung function measurements, 59.1% (I2 = 98.3%) of participants with PTB had abnormal spirometry compared to 5.4% (I2 = 97.4%) of controls. Specifically, 17.8% (I2 = 96.6%) had obstruction, 21.3% (I2 = 95.4%) restriction, and 12.7% (I2 = 93.2%) a mixed pattern. Among 13 studies with 3179 participants with PTB, 72.6% (I2 = 92.8%) of participants with PTB had a Medical Research Council dyspnoea score of 1-2 and 24.7% (I2 = 92.2%) a score of 3-5. Mean 6-min walk distance in 13 studies was 440.5 m (I2 = 99.0%) in all participants (78.9% predicted, I2 = 98.9%) and 403.0 m (I2 = 95.1%) among MDR-TB participants in 3 studies (70.5% predicted, I2 = 97.6%). Four studies reported data on incidence of lung cancer, with an incidence rate ratio of 4.0 (95% CI 2.1-7.6) and incidence rate difference of 2.7 per 1000 person-years (95% CI 1.2-4.2) when compared to controls. Quality assessment indicated overall low-quality evidence in this field, heterogeneity was high for pooled estimates of nearly all outcomes of interest, and publication bias was considered likely for almost all outcomes.

INTERPRETATION: The occurrence of post-PTB respiratory impairment, other disability states, and respiratory complications is high, adding to the potential benefits of disease prevention, and highlighting the need for optimised management after successful treatment.

FUNDING: Canadian Institutes of Health Research Foundation Grant.
 
© 2023 The Author(s).
 
DOI: 10.1016/j.eclinm.2023.101979
PMCID: PMC10189364
PMID: 37205923

4. One-year incidence of tuberculosis infection and disease among household 
contacts of rifampin- and multi-drug resistant tuberculosis.

Clin Infect Dis. 2023 May 25:ciad301. doi: 10.1093/cid/ciad301. Online ahead of 
print.
 
Krishnan S(1), Wu X(2), Kim S(3), McIntire K(1), Naini L(4), Hughes MD(2), 
Dawson R(5), Mave V(1)(6), Gaikwad S(6), Sanchez J(7), Mendoza-Ticona A(8), 
Gonzales P(7), Comins K(8), Shenje J(9), Nerette Fontain S(10), Omozoarhe A(11), 
Mohapi L(12), Lalloo UG(13), Garcia Ferreira AC(14), Mugah C(15), Harrington 
M(16), Shah NS(17), Hesseling AC(18), Churchyard G(19)(20)(21), Swindells S(22), 
Gupta A(1)(6); AIDS Clinical Trials Group (ACTG) A5300/International Maternal 
Pediatric Adolescent AIDS Clinical Trials (IMPAACT) I2003 Protecting Households 
on Exposure to Newly Diagnosed Index Multidrug-resistant Tuberculosis Patients 
(PHOENIx) Feasibility Study Team.
 

Collaborators: Chaisson RE, Johnson D, Siberry GK, Smith E, Demers AM, Kanade S, Nicotera J, Anthony P, Lane C, Kadam UA, Ssenyonga R, Shahkolahi A, Jones L, 
Heckman B, Manzella A.

 
BACKGROUND: Tuberculosis infection (TBI) and tuberculosis disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant tuberculosis exposure. We sought to characterize TBI and TBD incidence at one-year in HHCs and to evaluate tuberculosis preventive therapy (TPT) use in high-risk groups.

METHODS: We previously conducted a cross-sectional study of HHCs of rifampin-/multidrug-resistant tuberculosis in 8 high-burden countries and re-assessed TBI (interferon-gamma release assay, HHCs ≥5 years) and TBD (HHCs all ages) at one-year. Incidence was estimated across age and risk groups (age <5 years; age ≥5 years, HIV-positive; age ≥5 years, HIV-negative/unknown, baseline TBI positive) by logistic or log-binomial regression fitted using generalized estimating equations.

RESULTS: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median: 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a one-year 21.6% (95% CI 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n=5), probable (n=3) or possible (n=8) TBD, yielding a 2.3% (95% CI 1.4-3.8) one-year cumulative incidence (1.1% [95% CI 0.5-2.2] for confirmed/probable TBD). TBD relative risk was 11.5 (95% CI 1.7-78.7), 10.4 (95% CI 2.4-45.6), and 2.9 (95% CI 0.5-17.8) fold higher in age <5 years, HIV+, and baseline TBI high-risk groups, respectively, versus not high-risk group (p=0.0015). By one-year, 4% (21 of 553) high-risk HHCs received TPT.

CONCLUSIONS: TBI and TBD incidence continued through one-year in rifampin-/multidrug-resistant tuberculosis HHCs. Low TPT coverage emphasizes need for evidence-based prevention and scale-up, particularly among high-risk groups.
 
© The Author(s) 2023. Published by Oxford University Press on behalf of 
Infectious Diseases Society of America. All rights reserved. For permissions, 
please e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciad301
               PMID: 37227925               

              

From our May 2023 Newsletter

1. Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis.

Antibiotics (Basel). 2023 Apr 6;12(4):714. doi: 10.3390/antibiotics12040714.

Padmapriyadarsini C(1), Solanki R(2), Jeyakumar SM(1), Bhatnagar A(3), Muthuvijaylaksmi M(1), Jeyadeepa B(1), Reddy D(1), Shah P(2), Sridhar R(4), Vohra V(5), Bhui NK(6).

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal 2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

DOI: 10.3390/antibiotics12040714
PMCID: PMC10135341
PMID: 37107075

2. The relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot.

Nat Commun. 2023 Apr 8;14(1):1988. doi: 10.1038/s41467-023-37719-y.

Loiseau C(#)(1)(2), Windels EM(#)(3)(4), Gygli SM(1)(2), Jugheli L(1)(2)(5), Maghradze N(1)(2)(5), Brites D(1)(2), Ross A(1)(2), Goig G(1)(2), Reinhard M(1)(2), Borrell S(1)(2), Trauner A(1)(2), Dötsch A(1)(2), Aspindzelashvili R(5), Denes R(6), Reither K(1)(2), Beisel C(6), Tukvadze N(1)(2)(5), Avaliani Z(5), Stadler T(6)(7), Gagneux S(8)(9).

Multidrug-resistant tuberculosis (MDR-TB) is among the most frequent causes of death due to antimicrobial resistance. Although only 3% of global TB cases are MDR, geographical hotspots with up to 40% of MDR-TB have been observed in countries of the former Soviet Union. While the quality of TB control and patient-related factors are known contributors to such hotspots, the role of the pathogen remains unclear. Here we show that in the country of Georgia, a known hotspot of MDR-TB, MDR Mycobacterium tuberculosis strains of lineage 4 (L4) transmit less than their drug-susceptible counterparts, whereas most MDR strains of L2 suffer no such defect. Our findings further indicate that the high transmission fitness of these L2 strains results from epistatic interactions between the rifampicin resistance-conferring mutation RpoB S450L, compensatory mutations in the RNA polymerase, and other pre-existing genetic features of L2/Beijing clones that circulate in Georgia. We conclude that the transmission fitness of MDR M. tuberculosis strains is heterogeneous, but can be as high as drug-susceptible forms, and that such highly drug-resistant and transmissible strains contribute to the emergence and maintenance of hotspots of MDR-TB. As these strains successfully overcome the metabolic burden of drug resistance, and given the ongoing rollout of new treatment regimens against MDR-TB, proper surveillance should be implemented to prevent these strains from acquiring resistance to the additional drugs.

© 2023. The Author(s).
DOI: 10.1038/s41467-023-37719-y
PMCID: PMC10082831
PMID: 37031225 [Indexed for MEDLINE]

3. Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

PLOS Glob Public Health. 2023 Apr 28;3(4):e0000818. doi: 10.1371/journal.pgph.0000818. eCollection 2023.

Rodriguez CA(1)(2), Lodi S(3), Horsburgh CR(1)(3)(4)(5), Mitnick CD(2)(6)(7), Bastard M(8), Huerga H(8), Khan U(9), Rich M(6)(7), Seung KJ(6)(7), Atwood S(2), Manzur-Ul-Alam M(10), Melikyan N(8), Mpinda S(11), Myint Z(12), Naidoo Y(13),
Petrosyan O(14), Salahuddin N(15), Sarfaraz S(15), Vilbrun SC(16), Yae K(17), Achar J(18), Ahmed S(19), Algozhina E(20), Beauchamp J(21), de Guadelupe Perea Moreno S(22), Gulanbaeva M(23), Gergedava M(24), Indah Sari CY(25), Hewison C(26), Khan P(9), Franke MF(2).

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Copyright: © 2023 Rodriguez et al. 
DOI: 10.1371/journal.pgph.0000818
PMCID: PMC10146539
PMID: 37115740

4. A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum.

mBio. 2023 Apr 25;14(2):e0059823. doi: 10.1128/mbio.00598-23. Epub 2023 Apr 5.

Sarathy JP(1), Xie M(1), Jones RM(2), Chang A(3), Osiecki P(1), Weiner D(4)(5), Tsao WS(1), Dougher M(1), Blanc L(6), Fotouhi N(7), Via LE(4)(5), Barry CE 3rd(4)(8), De Vlaminck I(3), Sherman DR(2), Dartois VA(1)(9).

Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. An in vitro model that recapitulates the major features of Mycobacterium tuberculosis (Mtb) in caseum would accelerate the identification of compounds with treatment-shortening potential. We have developed a caseum surrogate model consisting of lysed and denatured foamy macrophages. Upon inoculation of Mtb from replicating cultures, the pathogen adapts to the lipid-rich matrix and gradually adopts a nonreplicating state. We determined that the lipid composition of ex vivo caseum and the surrogate matrix are similar. We also observed that Mtb in caseum surrogate accumulates intracellular lipophilic inclusions (ILI), a distinctive characteristic of quiescent and drug-tolerant Mtb. Expression profiling of a representative gene subset revealed common signatures between the models. Comparison of Mtb drug susceptibility in caseum and caseum surrogate revealed that both populations are similarly tolerant to a panel of TB drugs. By screening drug candidates in the surrogate model, we determined that the bedaquiline analogs TBAJ876 and TBAJ587, currently in clinical development, exhibit superior bactericidal against caseum-resident Mtb, both alone and as substitutions for bedaquiline in the bedaquiline-pretomanid-linezolid regimen approved for the treatment of multidrug-resistant TB. In summary, we have developed a physiologically relevant nonreplicating persistence model that reflects the distinct metabolic and drug-tolerant state of Mtb in caseum. IMPORTANCE M. tuberculosis (Mtb) within the caseous core of necrotic granulomas and cavities is extremely drug tolerant and presents a significant hurdle to treatment success and relapse prevention. Many in vitro models of nonreplicating persistence have been developed to characterize the physiologic and metabolic adaptations of Mtb and identify compounds active against this treatment-recalcitrant population. However, there is little consensus on their relevance to in vivo infection. Using lipid-laden macrophage lysates, we have designed and validated a surrogate matrix that closely mimics caseum and in which Mtb develops a phenotype similar to that of nonreplicating bacilli in vivo. The assay is well suited to screen for bactericidal compounds against caseum-resident Mtb in a medium-throughput format, allowing for reduced reliance on resource intensive animal models that present large necrotic lesions and cavities. Importantly, this approach will aid the identification of vulnerable targets in caseum Mtb and can accelerate the development of novel TB drugs with treatment-shortening potential.

DOI: 10.1128/mbio.00598-23
PMCID: PMC10127596
PMID: 37017524 [Indexed for MEDLINE]

5. Next-Generation Diarylquinolines Improve Sterilizing Activity of Regimens with Pretomanid and the Novel Oxazolidinone TBI-223 in a Mouse Tuberculosis Model.

Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0003523. doi: 10.1128/aac.00035-23. Epub 2023 Mar 15.

Li SY(1), Converse PJ(1), Betoudji F(1), Lee J(1), Mdluli K(2), Upton A(2)(3), Fotouhi N(2), Nuermberger EL(1).

A regimen comprised of bedaquiline (BDQ, or B), pretomanid, and linezolid (BPaL)is the first oral 6-month regimen approved by the U.S. Food and Drug Administration and recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis. We used a well-established BALB/c mouse model of tuberculosis to evaluate the treatment-shortening potential of replacing bedaquiline with either of two new, more potent diarylquinolines, TBAJ-587 and TBAJ-876, in early clinical trials. We also evaluated the effect of replacing linezolid with a new oxazolidinone, TBI-223, exhibiting a larger safety margin with respect to mitochondrial toxicity in preclinical studies. Replacing bedaquiline with TBAJ-587 at the same 25-mg/kg dose significantly reduced the proportion of mice relapsing after 2 months of treatment, while replacing linezolid with TBI-223 at the same 100-mg/kg dose did not significantly change the proportion of mice relapsing. Replacing linezolid or TBI-223 with sutezolid in combination with TBAJ-587 and pretomanid significantly reduced the proportion of mice relapsing. In combination with pretomanid and TBI-223, TBAJ-876 at 6.25 mg/kg was equipotent to TBAJ-587 at 25 mg/kg. We conclude that replacement of bedaquiline with these more efficacious and potentially safer diarylquinolines and replacement of linezolid with potentially safer and at least as efficacious oxazolidinones in the clinically successful BPaL regimen may lead to superior regimens capable of treating both drug-susceptible and drug-resistant TB more effectively and safely.

DOI: 10.1128/aac.00035-23
PMCID: PMC10112056
PMID: 36920217 [Indexed for MEDLINE]

6. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Lancet Infect Dis. 2023 Apr;23(4):e122-e137. doi: 10.1016/S1473-3099(22)00875-1. Epub 2023 Feb 28.

Domínguez J(1), Boeree MJ(2), Cambau E(3), Chesov D(4), Conradie F(5), Cox V(6), Dheda K(7), Dudnyk A(8), Farhat MR(9), Gagneux S(10), Grobusch MP(11), Gröschel MI(12), Guglielmetti L(13), Kontsevaya I(14), Lange B(15), van Leth F(16), Lienhardt C(17), Mandalakas AM(18), Maurer FP(19), Merker M(20), Miotto P(21), Molina-Moya B(22), Morel F(13), Niemann S(23), Veziris N(13), Whitelaw A(24), Horsburgh CR Jr(25), Lange C(18); TBnet and RESIST-TB networks.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00875-1
PMID: 36868253 [Indexed for MEDLINE]

From our April 2023 Newsletter

1. Update of drug-resistant tuberculosis treatment guidelines: A turning point.

Int J Infect Dis. 2023 Mar 12:S1201-9712(23)00089-9. doi: 10.1016/j.ijid.2023.03.013. Online ahead of print.

Vanino E(1), Granozzi B(2), Akkerman OW(3), Munoz-Torrico M(4), Palmieri F(5), Seaworth B(6), Tiberi S(7), Tadolini M(8).

In December 2022 World Health Organization released a new treatment for multidrug resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9 month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively
drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2023.03.013
PMID: 36918080

2. Prevalence and factors associated with reported adverse-events among patients on multi-drug-resistant tuberculosis treatment in two referral hospitals in Uganda.

BMC Infect Dis. 2023 Mar 10;23(1):149. doi: 10.1186/s12879-023-08085-3.

Ategyeka PM(1), Muhoozi M(2)(3), Naturinda R(2), Kageni P(4), Namugenyi C(5), Kasolo A(6), Kisaka S(2)(7)(8), Kiwanuka N(2).

BACKGROUND: Multi-drug-resistant tuberculosis (MDR-TB) treatment involves toxic drugs that cause adverse events (AEs), which are life-threatening and may lead to death if not well managed. In Uganda, the prevalence of MDR-TB is increasingly high, and about 95% of the patients are on treatment. However, little is known about the prevalence of AEs among patients on MDR-TB medicines. We therefore estimated the prevalence of reported adverse events (AEs) of MDR-TB drugs and factors associated with AEs in two health facilities in Uganda.
METHODS: A retrospective cohort study of MDR-TB was conducted among patients enrolled at Mulago National Referral and Mbarara Regional Referral hospitals in Uganda. Medical records of MDR-TB patients enrolled between January 2015 and December 2020 were reviewed. Data on AEs, which were defined as irritative reactions to MDR-TB drugs, were extracted and analyzed. To describe reported AEs, descriptive statistics were computed. A modified Poisson regression analysis was used to determine factors associated with reported AEs.
RESULTS: Overall, 369 (43.1%) of 856 patients had AEs, and 145 (17%) of 856 had more than one. Joint pain (244/369, or 66%), hearing loss (75/369, or 20%), and vomiting (58/369, or 16%) were the most frequently reported effects. Patients started on the 24-month regimen (adj. PR = 1.4, 95%; 1.07, 1.76) and individualized regimens (adj. PR = 1.5, 95%; 1.11, 1.93) were more likely to suffer from AEs. Lack of transport for clinical monitoring (adj. PR = 1.9, 95%; 1.21, 3.11); alcohol consumption (adj. PR = 1.2, 95%; 1.05, 1.43); and receipt of directly observed therapy from peripheral health facilities (adj. PR = 1.6, 95%; 1.10, 2.41) were significantly associated with experiencing AEs. However, patients who received food supplies (adj. PR = 0.61, 95%; 0.51, 0.71) were less likely to suffer from AEs.
CONCLUSION: The frequency of adverse events reported by MDR-TB patients is considerably high, with joint pain being the most common. Interventions such as the provision of food supplies, transportation, and consistent counseling on alcohol consumption to patients at initiation treatment facilities may contribute to a reduction in the rate of occurrence of AEs.

© 2023. The Author(s).
DOI: 10.1186/s12879-023-08085-3
PMCID: PMC9999637
PMID: 36899299 [Indexed for MEDLINE]

3. Impact of COVID-19 on diagnosis of TB, MDR-TB and on mortality in 11 countries in Europe, Northern America and Australia. A Global Tuberculosis Network study.

Int J Infect Dis. 2023 Mar 7:S1201-9712(23)00076-0. doi: 10.1016/j.ijid.2023.02.025. Online ahead of print.

Nalunjogi J(1), Mucching-Toscano S(2), Sibomana JP(3), Centis R(4), D&#39;Ambrosio L(5), Alffenaar JW(6), Denholm J(7), Blanc FX(8), Borisov S(9), Danila E(10), Duarte R(11), García-García JM(12), Goletti D(13), Ong CWM(14), Rendon A(15), Thomas TA(16), Tiberi S(17), van den Boom M(18), Sotgiu G(19), Migliori GB(20); Global Tuberculosis Network.

OBJECTIVE: Although evidence is growing on the overall impact of the COVID-19 pandemic on tuberculosis (TB) services, global studies based on national data are needed to better quantify the extent of the impact and the countries&#39; preparedness to tackle the two diseases. The aim of this study was to compare the number of people with new diagnosis or recurrence of TB disease, the number of drug-resistant (DR)-TB, and the number of TB deaths in 2020 versus 2019 in 11 countries in Europe, Northern America and Australia.
METHODS: TB managers or directors of national reference centres of the selectedcountries provided the agreed-upon variables through a validated questionnaire on a monthly basis. A descriptive analysis compared incidence of TB and drug-resistant TB and mortality of the pre-COVID-19 year (2019) versus the first year of the COVID-19 pandemic (2020).
RESULTS: Comparing 2020 vs 2019, lower number of TB cases (new diagnosis or recurrence) was notified in all countries (except USA-Virginia and Australia), and less DR-TB notifications (apart from France, Portugal and Spain). The deaths among TB cases were higher in 2020 compared to 2019 in most countries with three countries (France, Netherlands, USA-Virginia) reporting minimal TB-related mortality.

Copyright © 2023. Published by Elsevier Ltd.
DOI: 10.1016/j.ijid.2023.02.025
PMCID: PMC9991328
PMID: 36893943

4. Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household.

PLoS One. 2023 Mar 17;18(3):e0283290. doi: 10.1371/journal.pone.0283290. eCollection 2023.

Kim S(1), Hesseling AC(2), Wu X(3), Hughes MD(3), Shah NS(4), Gaikwad S(5), Kumarasamy N(6), Mitchell E(7), Leon M(8), Gonzales P(9), Badal-Faesen S(10), Lourens M(11), Nerette S(12), Shenje J(13), de Koker P(2), Nedsuwan S(14), Mohapi L(15), Chakalisa UA(16), Mngqbisa R(17), Escada RODS(18), Ouma S(19), Heckman B(20), Naini L(21), Gupta A(22), Swindells S(23), Churchyard G(24); ACTG A5300/IMPAACT 2003 PHOENIx Feasibility Study Team.

BACKGROUND: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations.
METHODS: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated centrally. We fitted logistic regression models using generalized estimating equations.
RESULTS: Seven hundred twelve HHCs age ≥15 years enrolled from 279 households in eight high-TB burden countries were a median age of 34 years, 63% female, 22% current smokers and 8% previous smokers, 8% HIV-positive, and 11% previously treated for TB. Of 686 with determinate IGRA results, 471 tested IGRA positive (prevalence 68.8% (95% Confidence Interval: 64.6%, 72.8%)). Multivariable modeling showed IGRA positivity was more common in HHCs aged 25-49 years; reporting prior TB treatment; reporting incarceration, substance use, and/or a period of daily alcohol use in the past 12 months; sharing a sleeping room or more evenings spent with the index participant; living with smokers; or living in a home of materials typical of low socioeconomic status. Forty-six (6.5% (95% Confidence Interval: 4.6%, 9.0%)) HHCs age ≥15 years had prevalent TB disease. Multivariable modeling showed higher prevalence of TB disease among HHCs aged ≥50 years; reporting current or previous smoking; reporting a period of daily alcohol use in the past 12 months; and reporting prior TB treatment.
CONCLUSION: We identified overlapping and distinct characteristics associated with Mycobacterium tuberculosis infection and TB disease that may be useful for those conducting household TB investigations.

DOI: 10.1371/journal.pone.0283290
PMCID: PMC10022776
PMID: 36930628 [Indexed for MEDLINE]

5. Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field.

Int J Tuberc Lung Dis. 2023 Mar 1;27(3):189-194. doi: 10.5588/ijtld.22.0440.

Taneja R(1), Nahata MC(2), Scarim J(3), Pande PG(1), Scarim A(3), Hoddinott G(4), Fourie CL(5), Jew RK(6), Schaaf HS(4), Garcia-Prats AJ(7), Hesseling AC(4).

BACKGROUND: Bedaquiline (BDQ) tablets are indicated as part of a combination regimen for the treatment of multidrug-resistant TB in adults, adolescents and children. A dispersible tablet formulation is now approved but is not currently available in all settings. The aim of this study was to develop stable extemporaneous liquid formulations of BDQ that can be stored at room temperature or 30°C for several weeks, to support pragmatic pediatric dosing in the field and reduce wastage.
METHODS: BDQ tablets were suspended in simple syrup and a sugar-free vehicle. Each 20 mg/mL formulation was stored at room temperature or 30°C for 30 days in amber dispensing bottles. Appearance, BDQ potency, pH and microbial counts were determined on Days 0, 15 and 30.
RESULTS: The BDQ potency in both formulations remained at 98-101% of the theoretical concentration for 30 days. The appearance, pH and microbial count of sugar-free formulation did not change during the 30-day storage. The simple syrup formulation was stable for 15 days as microbial growth was observed on Day 30.
CONCLUSIONS: BDQ may be prepared in syrup or sugar-free suspensions: syrup suspensions can be stored for 15 days at room temperature and 30C, whereas sugar-free suspensions can be stored for 30 days at room temperature and 30C. This information will support practical BDQ dosing for children in the field.

DOI: 10.5588/ijtld.22.0440
PMCID: PMC9983625
PMID: 36855042 [Indexed for MEDLINE]

From our March 2023 Newsletter

1. Designing molecular diagnostics for current tuberculosis drug regimens.

Emerg Microbes Infect. 2023 Feb 8:2178243. doi: 10.1080/22221751.2023.2178243. Online ahead of print.

Georghiou SB(1), de Vos M(1), Velen K(1), Miotto P(2), Colman RE(1)(3), Cirillo DM(2), Ismail N(4), Rodwell TC(1)(3), Suresh A(1), Ruhwald M(1).

Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets. ClinicalTrials.gov identifier: NCT05117788.

DOI: 10.1080/22221751.2023.2178243
PMID: 36752055

2. Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

PLoS One. 2023 Feb 13;18(2):e0281097. doi: 10.1371/journal.pone.0281097. eCollection 2023.

Pietersen E(1), Anderson K(1)(2), Cox H(3), Dheda K(1)(4), Bian A(5), Shepherd BE(5), Sterling TR(6)(7), Warren RM(8), van der Heijden YF(6)(7)(9).

BACKGROUND: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates.
METHODS: We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model.
RESULTS: Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%)
patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P&lt;0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations.
CONCLUSION: We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

DOI: 10.1371/journal.pone.0281097
PMCID: PMC9925007
PMID: 36780443 [Indexed for MEDLINE]

3. Non-actionable Results, Accuracy, and Effect of First- and Second-line Line Probe Assays for Diagnosing Drug-Resistant Tuberculosis, Including on Smear-Negative Specimens, in a High-Volume Laboratory.

Clin Infect Dis. 2023 Feb 8;76(3):e920-e929. doi: 10.1093/cid/ciac556.

Pillay S(1)(2), de Vos M(1), Derendinger B(1), Streicher EM(1), Dolby T(2), Scott LA(1), Steinhobel AD(1), Warren RM(1), Theron G(1).

BACKGROUND: Rapid tuberculosis (TB) drug susceptibility testing (DST) is crucial. Genotype MTBDRsl is a widely deployed World Health Organization (WHO)-endorsed assay. Programmatic performance data, including non-actionable results from smear-negative sputum, are scarce.
METHODS: Sputa from Xpert MTB/RIF individuals (n = 951) were routinely-tested using Genotype MTBDRplus and MTBDRsl (both version 2). Phenotypic DST was the second-line drug reference standard. Discrepant results underwent Sanger sequencing.
FINDINGS: 89% (849 of 951) of individuals were culture-positive (56%, 476 of 849 smear-negative). MTBDRplus had at least 1 nonactionable result (control and/or TB-detection bands absent or invalid, precluding resistance reporting) in 19%
(92 of 476) of smear-negatives; for MTBDRsl, 40% (171 of 427) were nonactionable (28%, 120 of 427 false-negative TB; 17%, 51 of 427 indeterminate). In smear-negatives, MTBDRsl sensitivity for fluoroquinolones was 84% (95% confidence interval, 67%-93), 81% (54%-95%) for second-line injectable drugs, and 57% (28%-82%) for both. Specificities were 93% (89%-98%), 88% (81%-93%), and 97% (91%-99%), respectively. Twenty-three percent (172 of 746) of Xpert
rifampicin-resistant specimens were MTBDRplus isoniazid-susceptible. Days-to-second-line-susceptibility reporting with the programmatic advent of MTBDRsl improved (6 [5-7] vs 37 [35-46]; P &lt; .001).
CONCLUSIONS: MTBDRsl did not generate a result in 4 of 10 smear-negatives, resulting in substantial missed resistance. However, if MTBDRsl generates an actionable result, that is accurate in ruling-in resistance. Isoniazid DST remains crucial. This study provides real-world, direct, second-line susceptibility testing performance data on non-actionable results (that, if unaccounted for, cause an overestimation of test utility), accuracy, and care cascade impact.

DOI: 10.1093/cid/ciac556
PMCID: PMC7614164
PMID: 35788278 [Indexed for MEDLINE]

4. Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

Clin Infect Dis. 2023 Feb 8;76(3):497-505. doi: 10.1093/cid/ciac511.

Heysell SK(1), Mpagama SG(2)(3), Ogarkov OB(4), Conaway M(5), Ahmed S(6), Zhdanova S(4), Pholwat S(1), Alshaer MH(7), Chongolo AM(2), Mujaga B(3), Sariko M(3), Saba S(6), Rahman SMM(6), Uddin MKM(6), Suzdalnitsky A(8), Moiseeva E(8), Zorkaltseva E(9), Koshcheyev M(8), Vitko S(1), Mmbaga BT(3), Kibiki GS(3), Pasipanodya JG(10), Peloquin CA(7), Banu S(6), Houpt ER(1).

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome.
METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug&#39;s area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures.
RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P= .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR &gt;1.0, P &lt; .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion.
CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.
© The Author(s) 2022. Published by Oxford University Press on behalf of
Infectious Diseases Society of America.

DOI: 10.1093/cid/ciac511
PMCID: PMC9907514
PMID: 35731948 [Indexed for MEDLINE]

5. Long-term treatment outcomes in multidrug-resistant tuberculosis.

Clin Microbiol Infect. 2023 Feb 24:S1198-743X(23)00083-6. doi: 10.1016/j.cmi.2023.02.013. Online ahead of print.

Maier C(1), Chesov D(2), Schaub D(1), Kalsdorf B(1), Andres S(3), Friesen I(3), Reimann M(1), Lange C(4).

OBJECTIVES: We describe long-term treatment outcomes in patients with multidrug-resistant/rifampicin-resistant (MDR/RR)-tuberculosis (TB) and validate established MDR/RR-TB treatment outcome definitions.
METHODS: Among patients with MDR/RR-TB admitted to a German MDR/RR-TB referral center from 01.09.2002-29.02.2020, we compared long-term treatment outcomes derived from individual patient follow-up with treatment outcomes defined by WHO-2013, WHO-2021 and TBnet-2016.
RESULTS: In total 163 patients (mean age 35 ± standard deviation 13 years, 14/163 [8.6%] living with HIV, 109/163 [66.9%] male, 149/163 [91.4%] migrating to Germany within five years) initiated treatment for culture confirmed MDR/RR-TB. Additional drug resistance to a fluoroquinolone or a second-line injectable agent was present in 15/163 (9.2%) of Mycobacterium tuberculosis strains; resistance against both drug classes was present in 29/163 (17.8%) of strains. Median duration of MDR/RR-TB treatment was 20 months (interquartile range [IQR] 19.3-21.6) with a medium of 5 active drugs included. Median follow-up time was 4 years (47.7 months; IQR 21.7-65.8 months). Cure was
achieved in 25/163 (15.3%), 82/163 (50.3%) and 95/163 (58.3%) of patients according to WHO-2013, WHO-2021, and TBnet-2016 outcome definitions, respectively. The lost to follow-up rate was 17/163 (10.4%). Death was more likely in patients living with HIV (hazard ratio [HR]=4.28, 95% confidence interval [CI] 1.26-12.86) and older patients (HR=1.08, 95%CI 1.05-1.12, increment of one year). Overall, 101/163 (62.0%) patients experienced long-term, relapse-free cure; of those, 101/122 (82.8%) patients with a known status (not lost to-follow-up or transferred out) at follow-up.
CONCLUSIONS: Under optimal management conditions leveraging individualized
treatment regimens, long-term relapse-free cure from MDR/RR-TB is substantially
higher than cure rates as defined by current treatment outcome definitions.

Copyright © 2023 European Society of Clinical Microbiology and Infectious
Diseases. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cmi.2023.02.013
PMID: 36842637

6. Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Antimicrob Agents Chemother. 2023 Feb 6:e0142622. doi: 10.1128/aac.01426-22. Online ahead of print.

Chirehwa MT(#)(1), Resendiz-Galvan JE(#)(1), Court R(1), De Kock M(2), Wiesner L(1), de Vries N(3), Harding J(4), Gumbo T(5), Warren R(2), Maartens G(1), Denti P(#)(1), McIlleron H(#)(1)(6).

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of &gt;53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

DOI: 10.1128/aac.01426-22
PMID: 36744891

7. Association Between Increased Linezolid Plasma Concentrations and the Development of Severe Toxicity in Multidrug-Resistant Tuberculosis Treatment.

Clin Infect Dis. 2023 Feb 8;76(3):e947-e956. doi: 10.1093/cid/ciac485.
 
Eimer J(1), Fréchet-Jachym M(2), Le Dû D(2), Caumes E(3), El-Helali N(4), Marigot-Outtandy D(2)(5), Mechai F(6)(7), Peytavin G(8), Pourcher V(3), Rioux C(9), Yazdanpanah Y(9), Robert J(1)(10), Guglielmetti L(1)(10); LZDM group.

BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity.
METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or
myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates.
RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P &lt; .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk.
CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.

© The Author(s) 2022. Published by Oxford University Press on behalf of
Infectious Diseases Society of America. All rights reserved. For permissions,
please e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciac485
PMID: 35717636 [Indexed for MEDLINE]

From our February 2023 Newsletter

1. Feasibility, Ease-of-Use, and Operational Characteristics of World Health Organization-Recommended Moderate-Complexity Automated Nucleic Acid Amplification Tests for the Detection of Tuberculosis and Resistance to Rifampicin and Isoniazid.

 

J Mol Diagn. 2023 Jan;25(1):46-56. doi: 10.1016/j.jmoldx.2022.10.001. Epub 2022 Oct 13.

 

David A(1), de Vos M(2), Scott L(3), da Silva P(4), Trollip A(2), Ruhwald M(2), Schumacher S(2), Stevens W(5).

Four moderate-complexity automated nucleic acid amplification tests for the diagnosis of tuberculosis are reported as having laboratory analytical and clinical performance similar to that of the Cepheid Xpert MTB/RIF assay. These assays are the Abbott RealTime MTB and RealTime MTB RIF/INH Resistance, Becton Dickinson MAX MDR-TB, the Hain Lifescience/Bruker FluoroType MTBDR, and the Roche cobas MTB and MTB RIF/INH assays. The study compared feasibility, ease of use, and operational characteristics of these assays/platforms. Manufacturer input was obtained for technical characteristics. Laboratory operators were requested to complete a questionnaire on the assays & ease of use. A time-in-motion analysis was also undertaken for each platform. For ease-of-use and operational requirements, the BD MAX MDR-TB assay achieved the highest scores (86% and 90%) based on information provided by the user and manufacturer, respectively, followed by the cobas MTB and MTB-RIF/INH assay (68% and 86%), the FluoroType MTBDR assay (67% and 80%), and the Abbott RT-MTB and RT MTB RIF/INH assays (64% and 76%). The time-in-motion analysis revealed that for 94 specimens, the RealTime MTB assay required the longest processing time, followed by the cobas MTB assay and the FluoroType MTBDR assay. The BD MAX MDR-TB assay required 4.6 hours for 22 specimens. These diagnostic assays exhibited different strengths and weaknesses that should be taken into account, in addition to affordability, when considering placement of a new platform.

Copyright © 2023 Association for Molecular Pathology and American Society for
Investigative Pathology. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jmoldx.2022.10.001
PMCID: PMC9830532
PMID: 36243289 [Indexed for MEDLINE]

2. Population pharmacokinetics and dose evaluations of linezolid in the treatment of multidrug-resistant tuberculosis.

 

Front Pharmacol. 2023 Jan 9;13:1032674. doi: 10.3389/fphar.2022.1032674. eCollection 2022.

 

Zhang H(1), He Y(2), Davies Forsman L(3)(4), Paues J(5)(6), Werngren J(7), Niward K(5)(6), Schön T(5)(6)(8), Bruchfeld J(3)(4), Alffenaar JW(9)(10)(11), Hu Y(1).

 

Background: The pharmacokinetic/pharmacodynamics (PK/PD) target derived from the hollow-fiber system model for linezolid for treatment of the multidrug-resistant tuberculosis (MDR-TB) requires clinical validation. Therefore, this study aimed to develop a population PK model for linezolid when administered as part of a standardized treatment regimen, to identify the PK/PD threshold associated with successful treatment outcomes and to evaluate currently recommended linezolid doses.
Method: This prospective multi-center cohort study of participants with laboratory-confirmed MDR-TB was conducted in five TB designated hospitals. The population PK model for linezolid was built using nonlinear mixed-effects modeling using data from 168 participants. Boosted classification and regression tree analyses (CART) were used to identify the ratio of 0- to 24-h area under the concentration-time curve (AUC0-24h) to the minimal inhibitory concentration(MIC) threshold using the BACTEC MGIT 960 method associated with successful treatment outcome and validated in multivariate analysis using data from a different and prospective cohort of 159 participants with MDR-TB. Furthermore, based on the identified thresholds, the recommended doses were evaluated by the probability of target attainment (PTA) analysis.
Result: Linezolid plasma concentrations (1008 samples) from 168 subjects treated with linezolid, were best described by a 2-compartment model with first-order absorption and elimination. An AUC0-24h/MIC &gt; 125 was identified as a threshold for successful treatment outcome. Median time to sputum culture conversion between the group with AUC0-24h/MIC above and below 125 was 2 versus 24 months; adjusted hazard ratio (aHR), 21.7; 95% confidence interval (CI), (6.4, 72.8). The boostedCART-derived threshold and its relevance to the final treatment outcome was comparable to the previously suggested target of AUC0-24h/MIC (119) using MGITMICs in a hollow fiber infection model. Based on the threshold from the present study, at a standard linezolid dose of 600 mg daily, PTA was simulated to achieve 100% at MGIT MICs of ≤ .25 mg which included the majority (81.1%) of isolates in the study.
Conclusion: We validated an AUC0-24h/MIC threshold which may serve as a target for dose adjustment to improve efficacy of linezolid in a bedaquiline-containing treatment. Linezolid exposures with the WHO-recommended dose (600 mg daily) was sufficient for all the M. tb isolates with MIC ≤.25 mg/L.

Copyright © 2023 Zhang, He, Davies Forsman, Paues, Werngren, Niward, Schön, Bruchfeld, Alffenaar and Hu.
DOI: 10.3389/fphar.2022.1032674
PMCID: PMC9868619
PMID: 36699070
 
3. Implementation challenges and lessons learned from the STREAM clinical trial-a survey of trial sites.

 

Trials. 2023 Jan 23;24(1):51. doi: 10.1186/s13063-023-07068-8.

 

Patel LN(1), Gurumurthy M(2), Bronson G(3), Sanders K(4), Rusen ID(3).

BACKGROUND: Design and implementation of multi-country clinical trials for multidrug-resistant tuberculosis (MDR-TB) are complex for several reasons, including trial duration, varying levels of experience and infrastructure across settings, and different regulatory requirements. STREAM was an MDR-TB clinical trial that recruited over 1000 participants. We documented challenges and best practices/lessons learned from the site perspective to improve implementation of future trials.
METHODS: We conducted a voluntary survey of trial staff at all sites to obtain information on challenges encountered and best practices/lessons learned from implementation of the STREAM trial. Respondents were asked to identify substantive aspects of trial implementation from a list that included: trial administration, laboratory strengthening/infrastructure, pharmacy and supply chain management, community engagement, regulatory and ethics requirements, health economics, and other (respondent designated) about which a practical guide would be useful to improve future trial implementation. For each aspect of trial implementation selected, respondents were asked to report challenges and best practices/lessons learned during STREAM. Lastly, respondents were asked to list up to three things they would do differently when implementing future trials. Summary statistics were generated for quantitative data and thematic analysis was undertaken for qualitative data.
RESULTS: Of 67 responses received from 13 of 15 sites, 47 (70%) were included in the analyses, after excluding duplicate or incomplete responses. Approximately half the respondents were investigators or trial coordinators. The top three aspects of trial implementation identified for a best practices/lessons learned practical guide to improve future trial implementation were: trial administration, community engagement, and laboratory strengthening/infrastructure. For both challenges and best practices/lessons learned, three common themes were identified across different aspects of trial implementation. Investment in capacity building and ongoing monitoring; investment in infrastructure and well-designed trial processes; and communication and coordination between staff and meaningful engagement of stakeholders were all thought to be critical to successful trial implementation.
CONCLUSIONS: Existing practices for clinical trial implementation should be reevaluated. Sponsors should consider the local context and the need to increase upfront investment in the cross-cutting thematic areas identified to improve trial implementation.

© 2023. The Author(s).
DOI: 10.1186/s13063-023-07068-8
PMCID: PMC9869607
PMID: 36691098 [Indexed for MEDLINE]

4. Large-scale genomic analysis of Mycobacterium tuberculosis reveals extent of target and compensatory mutations linked to multi-drug resistant tuberculosis.

 

Sci Rep. 2023 Jan 12;13(1):623. doi: 10.1038/s41598-023-27516-4.

 

Napier G(1), Campino S(1), Phelan JE(#)(2), Clark TG(#)(3)(4).

 

Resistance to isoniazid (INH) and rifampicin (RIF) first-line drugs in Mycobacterium tuberculosis (Mtb), together called multi-drug resistance, threatens tuberculosis control. Resistance mutations in katG (for INH) and rpoB (RIF) genes often come with fitness costs. To overcome these costs, Mtb compensatory mutations have arisen in rpoC/rpoA (RIF) and ahpC (INH) loci. By leveraging the presence of known compensatory mutations, we aimed to detect novel resistance mutations occurring in INH and RIF target genes. Across ~ 32 k Mtb isolates with whole genome sequencing (WGS) data, there were 6262 (35.7%) with INH and 5435 (30.7%) with RIF phenotypic resistance. Known mutations in katG and rpoB explained ~ 99% of resistance. However, 188 (0.6%) isolates had ahpC compensatory mutations with no known resistance mutations in katG, leading to the identification of 31 putative resistance mutations in katG, each observed in at least 3 isolates. These putative katG mutations can co-occur with other INH variants (e.g., katG-Ser315Thr, fabG1 mutations). For RIF, there were no isolates with rpoC/rpoA compensatory mutations and unknown resistance mutations. Overall, using WGS data we identified putative resistance markers for INH that could be used for genotypic drug-resistance profiling. Establishing the complete repertoire of Mtb resistance mutations will assist the clinical management of tuberculosis.

© 2023. The Author(s).
DOI: 10.1038/s41598-023-27516-4
PMCID: PMC9837068
PMID: 36635309 [Indexed for MEDLINE]

5. Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial.

 

Lancet Glob Health. 2023 Feb;11(2):e265-e277. doi: 10.1016/S2214-109X(22)00498-3. Epub 2022 Dec 21.

 

Rosu L(1), Madan JJ(2), Tomeny EM(3), Muniyandi M(4), Nidoi J(5), Girma M(6), Vilc V(7), Bindroo P(8), Dhandhukiya R(9), Bayissa AK(10), Meressa D(11), Narendran G(4), Solanki R(9), Bhatnagar AK(8), Tudor E(7), Kirenga B(5), Meredith SK(12), Nunn AJ(12), Bronson G(13), Rusen ID(13), Squire SB(3), Worrall E(3); STREAM Study Health Economic Evaluation Collaborators.

 

BACKGROUND: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens.
METHODS: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631.
FINDINGS: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India.
INTERPRETATION: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable.
FUNDING: USAID and Janssen Research & Development.
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..
All rights reserved.
DOI: 10.1016/S2214-109X(22)00498-3
PMID: 36565704 [Indexed for MEDLINE]

From our January 2023 Newsletter

1. Economic burden of multidrug-resistant tuberculosis on patients and households: a global systematic review and meta-analysis.

Sci Rep. 2023 Dec 15;13(1):22361. doi: 10.1038/s41598-023-47094-9.
 
Akalu TY(1)(2)(3), Clements ACA(4)(5), Wolde HF(6)(4)(7), Alene KA(6)(4).
 
Multidrug-resistant tuberculosis (MDR-TB) is a major health threat worldwide, causing a significant economic burden to patients and their families. Due to the longer duration of treatment and expensive second-line medicine, the economic burden of MDR-TB is assumed to be higher than drug-susceptible TB. However, the costs associated with MDR-TB are yet to be comprehensively quantified. We conducted this systematic review and meta-analysis to determine the global burden of catastrophic costs associated with MDR-TB on patients and their 
households. We systematically searched five databases (CINHAL, MEDLINE, Embase, Scopus, and Web of Science) from inception to 2 September 2022 for studies reporting catastrophic costs on patients and affected families of MDR-TB. The primary outcome of our study was the proportion of patients and households with catastrophic costs. Costs were considered catastrophic when a patient spends 20% or more of their annual household income on their MDR-TB diagnosis and care. The pooled proportion of catastrophic cost was determined using a random-effects meta-analysis. Publication bias was assessed using visualization of the funnel 
plots and the Egger regression test. Heterogeneity was assessed using I2, and sub-group analysis was conducted using study covariates as stratification variables. Finally, we used the Preferred Reporting Items for Reporting Systematic Review and Meta-Analysis-20 (PRISMA-20). The research protocol was registered in PROSPERO (CRD42021250909). Our search identified 6635 studies, of which 11 were included after the screening. MDR-TB patients incurred total costs ranging from $USD 650 to $USD 8266 during treatment. The mean direct cost and indirect cost incurred by MDR-TB patients were $USD 1936.25 (SD ± $USD 1897.03) and $USD 1200.35 (SD ± $USD 489.76), respectively. The overall burden of catastrophic cost among MDR-TB patients and households was 81.58% (95% Confidence Interval (CI) 74.13-89.04%). The catastrophic costs incurred by MDR-TB patients were significantly higher than previously reported for DS-TB patients. MDR-TB patients incurred more expenditure for direct costs than indirect costs. Social protection and financial support for patients and affected families are needed to mitigate the catastrophic economic consequences of MDR-TB.
 
© 2023. The Author(s).
 
DOI: 10.1038/s41598-023-47094-9
PMCID: PMC10724290
PMID: 38102144 [Indexed for MEDLINE]


2. Designing molecular diagnostics for current tuberculosis drug regimens.
 
Emerg Microbes Infect. 2023 Dec;12(1):2178243. doi: 10.1080/22221751.2023.2178243.
 
Georghiou SB(1), de Vos M(1), Velen K(1), Miotto P(2), Colman RE(1)(3), Cirillo DM(2), Ismail N(4), Rodwell TC(1)(3), Suresh A(1), Ruhwald M(1).
 
Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option 
exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.
Trial registration: ClinicalTrials.gov identifier: NCT05117788..
 
DOI: 10.1080/22221751.2023.2178243
PMCID: PMC9980415
PMID: 36752055 [Indexed for MEDLINE]


3. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
 
Lancet Microbe. 2023 Dec;4(12):e972-e982. doi: 10.1016/S2666-5247(23)00172-6. Epub 2023 Nov 3.
 
Derendinger B(1), Dippenaar A(2), de Vos M(3), Huo S(4), Alberts R(1), Tadokera R(1), Limberis J(5), Sirgel F(1), Dolby T(6), Spies C(1), Reuter A(7), Folkerts M(8), Allender C(8), Lemmer D(8), Van Rie A(9), Gagneux S(10), Rigouts L(11), Te Riele J(12), Dheda K(13), Engelthaler DM(8), Warren R(1), Metcalfe J(5), Cox H(14), Theron G(15).
 
BACKGROUND: Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment.
 
METHODS: We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL).Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done.
 
FINDINGS: In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred.
 
INTERPRETATION: Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed.
 
FUNDING: Doris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust.
 
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S2666-5247(23)00172-6
PMID: 37931638 [Indexed for MEDLINE]

4. Determinants of catastrophic costs among households affected by multi-drug resistant tuberculosis in Ho Chi Minh City, Viet Nam: a prospective cohort study.
 
BMC Public Health. 2023 Dec 3;23(1):2372. doi: 10.1186/s12889-023-17078-5.
 
Pham TAM(1), Forse R(2)(3), Codlin AJ(1)(4), Phan THY(5), Nguyen TT(5), Nguyen N(4), Vo LNQ(5), Dat PT(6), Minh HDT(6), Nguyen LH(6), Nguyen HB(7), Nguyen NV(7)(8), Bodfish M(9), Lönnroth K(1), Wingfield T(1)(10)(11), Annerstedt KS(1).
 
BACKGROUND: Globally, most people with multidrug-resistant tuberculosis (MDR-TB) and their households experience catastrophic costs of illness, diagnosis, and care. However, the factors associated with experiencing catastrophic costs are poorly understood. This study aimed to identify risk factors associated with catastrophic costs incurrence among MDR-TB-affected households in Ho Chi Minh City (HCMC), Viet Nam.
 
METHODS: Between October 2020 and April 2022, data were collected using a locally-adapted, longitudinal WHO TB Patient Cost Survey in ten districts of HCMC. Ninety-four people with MDR-TB being treated with a nine-month TB regimen were surveyed at three time points: after two weeks of treatment initiation, completion of the intensive phase and the end of the treatment (approximately five and 10 months post-treatment initiation respectively). The catastrophic costs threshold was defined as total TB-related costs exceeding 20% of annual pre-TB household income. Logistic regression was used to identify variables associated with experiencing catastrophic costs. A sensitivity analysis examined the prevalence of catastrophic costs using alternative thresholds and cost estimation approaches.

RESULTS: Most participants (81/93 [87%]) experienced catastrophic costs despite the majority 86/93 (93%) receiving economic support through existing social protection schemes. Among participant households experiencing and not experiencing catastrophic costs, median household income was similar before MDR-TB treatment. However, by the end of MDR-TB treatment, median household income was lower (258 [IQR: 0-516] USD vs. 656 [IQR: 462-989] USD; p = 0.003), and median income loss was higher (2838 [IQR: 1548-5418] USD vs. 301 [IQR: 0-824] USD; p < 0.001) amongst the participant households who experienced catastrophic costs. Being the household's primary income earner before MDR-TB treatment (aOR = 11.2 [95% CI: 1.6-80.5]), having a lower educational level (aOR = 22.3 [95% CI: 1.5-344.1]) and becoming unemployed at the beginning of MDR-TB treatment (aOR = 35.6 [95% CI: 2.7-470.3]) were associated with experiencing catastrophic costs.
 
CONCLUSION: Despite good social protection coverage, most people with MDR-TB in HCMC experienced catastrophic costs. Incurrence of catastrophic costs was independently associated with being the household's primary income earner or being unemployed. Revision and expansion of strategies to mitigate TB-related catastrophic costs, in particular avoiding unemployment and income loss, are urgently required.
 
© 2023. The Author(s).
 
DOI: 10.1186/s12889-023-17078-5
PMCID: PMC10693707
PMID: 38042797 [Indexed for MEDLINE]


5. Addressing the needs of people with extensively drug-resistant TB through pre-approval access to drugs and research.
 
Public Health Action. 2023 Dec;13(4):126-129. doi: 10.5588/pha.23.0033. Epub 2023 Dec 7.
 
Stillo J(1)(2), Frick M(2)(3), Galarza J(2)(4), Kondratyuk S(2), Makone A(2)(5), McKenna L(2)(3), Vandevelde W(2)(6), Winarni P(2), Agbassi P(2).
 
Multiple therapeutic options exist for people with drug-resistant TB (DR-TB), but there is an urgent need to improve access to novel compounds and regimens for people with difficult to treat forms of TB. In additional to formal research studies and clinical trials, other mechanisms of accessing promising new TB compounds need to be introduced as soon as these drugs have shown efficacy and safety in phase II trials. Pre-approval access programs for newer TB drugs such as bedaquiline, delamanid, and pretomanid all suffered from shortcomings. These can be addressed for the next generation of new TB drugs through a series of concerted actions by stakeholders at multiple levels. In this viewpoint, we advocate for transparent, accessible pre-approval access as a core element of person-centered care for DR-TB.
 
© 2023 The Union.
 
DOI: 10.5588/pha.23.0033
PMCID: PMC10703140
PMID: 38077718

From our December 2022 Newsletter
1. Availability and costs of medicines for the treatment of tuberculosis in Europe.

Clin Microbiol Infect. 2023 Jan;29(1):77-84. doi: 10.1016/j.cmi.2022.07.026. Epub 2022 Aug 10.

Günther G(1), Guglielmetti L(2), Leu C(3), Lange C(4), van Leth F(5); Tuberculosis Network European Trials group.

OBJECTIVES: To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries.
METHODS: We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries.
RESULTS: Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem
was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible-tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 

6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum-maximum, €15-152), €764 (minimum-maximum, €542-15152), and €8709 (minimum-maximum, €7965-11759) in middle-income countries (n = 12) and €280 (minimum-maximum, €78-1084), €29765 (minimum-maximum, €11116-40584), and €217591 (minimum-maximum, €82827-320146) in high-income countries (n = 29), respectively.
DISCUSSION: In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.cmi.2022.07.026
PMCID: PMC9801521
PMID: 35961488 [Indexed for MEDLINE]

2. Ultrasensitive Detection of Multidrug-Resistant Mycobacterium tuberculosis Using SuperSelective Primer-Based Real-Time PCR Assays.

Int J Mol Sci. 2022 Dec 12;23(24):15752. doi: 10.3390/ijms232415752.

Narang A(1), Marras SAE(1), Kurepina N(2), Chauhan V(3), Shashkina E(2), Kreiswirth B(2), Varma-Basil M(3), Vinnard C(4), Subbian S(1).

The emergence of drug-resistant tuberculosis is a significant global health issue. The presence of heteroresistant Mycobacterium tuberculosis is critical to developing fully drug-resistant tuberculosis cases. The currently available molecular techniques may detect one copy of mutant bacterial genomic DNA in the presence of about 1-1000 copies of wild-type M. tuberculosis DNA. To improve the limit of heteroresistance detection, we developed SuperSelective primer-based real-time PCR assays, which, by their unique assay design, enable selective and exponential amplification of selected point mutations in the presence of abundant wild-type DNA. We designed SuperSelective primers to detect genetic mutations associated with M. tuberculosis resistance to the anti-tuberculosis drugs isoniazid and rifampin. We evaluated the efficiency of our assay in detecting heteroresistant M. tuberculosis strains using genomic DNA isolated from laboratory strains and clinical isolates from the sputum of tuberculosis patients. Results show that our assays detected heteroresistant mutations with a specificity of 100% in a background of up to 104 copies of wild-type M. tuberculosis genomic DNA, corresponding to a detection limit of 0.01%. Therefore, the SuperSelective primer-based RT-PCR assay is an ultrasensitive tool that can efficiently diagnose heteroresistant tuberculosis in clinical specimens and contributes to understanding the drug resistance mechanisms. This approach can improve the management of antimicrobial resistance in tuberculosis and other infectious diseases.

DOI: 10.3390/ijms232415752
PMCID: PMC9779475
PMID: 36555395 [Indexed for MEDLINE]
 
3. Paediatric formulations for the treatment of drug resistant TB: closing the gaps.

Int J Tuberc Lung Dis. 2022 Dec 1;26(12):1097-1100. doi: 10.5588/ijtld.22.0498.

Alffenaar JWC(1), Marais BJ(2), Touw DJ(3).

DOI: 10.5588/ijtld.22.0498
PMCID: PMC9728946
PMID: 36447327 [Indexed for MEDLINE]

4. High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates.

Emerg Microbes Infect. 2022 Dec;11(1):1857-1866. doi: 10.1080/22221751.2022.2099304.

Trisakul K(1)(2), Nonghanphithak D(1)(2), Chaiyachat P(1)(2), Kaewprasert O(1)(2), Sakmongkoljit K(3), Reechaipichitkul W(1)(2), Chaiprasert A(4), Blair D(5), Clark TG(6), Faksri K(1)(2).

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of Rv0678 and Rv1979c were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%)
for clofazimine resistance with additional mmpL5 mutations. Mutations conferring resistance to delamanid were detected in fbiB and ddn genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the ddn gene for 3/513 isolates (0.6%). Nineteen mutations of pykA, cycA, ald, and alr genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.

DOI: 10.1080/22221751.2022.2099304
PMCID: PMC9336503
PMID: 35792049 [Indexed for MEDLINE]

5. A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166.

Nyang&#39;wa BT(1), Berry C(1), Kazounis E(1), Motta I(1), Parpieva N(1), Tigay Z(1), Solodovnikova V(1), Liverko I(1), Moodliar R(1), Dodd M(1), Ngubane N(1), Rassool M(1), McHugh TD(1), Spigelman M(1), Moore DAJ(1), Ritmeijer K(1), du Cros P(1), Fielding K(1); TB-PRACTECAL Study Collaborators.

Comment in N Engl J Med. 2022 Dec 22;387(25):2380-2381.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.
METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The non-inferiority margin was 12 percentage points.
RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk
difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).
CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2117166
PMID: 36546625 [Indexed for MEDLINE]

From our June 2022 Newsletter

1. 25 years of surveillance of drug-resistant tuberculosis: achievements,
challenges, and way forward.

 
Lancet Infect Dis. 2022 Jul;22(7):e191-e196. doi: 10.1016/S1473-3099(21)00808-2.
Epub 2022 Mar 3.
 
Dean AS(1), Tosas Auguet O(2), Glaziou P(2), Zignol M(2), Ismail N(2), Kasaeva
T(2), Floyd K(2).
 
Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.
 
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168

 
2. Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis.
 
Clin Infect Dis. 2022 May 30;74(10):1736-1747. doi: 10.1093/cid/ciab699.
 
Imperial MZ(1), Nedelman JR(2), Conradie F(3), Savic RM(1).
 
BACKGROUND: We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis.
METHODS: A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table.
RESULTS: Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%-22% vs 5%, 4%-7%) and severe anemia (15%, 12%-17% vs 1%, 0%-2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%-72%) of severe anemia.
CONCLUSIONS: Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious
Diseases Society of America.
 
DOI: 10.1093/cid/ciab699
PMCID: PMC9155613
PMID: 34604901 [Indexed for MEDLINE]
 
3. Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study.
 
Lancet Infect Dis. 2022 Jul;22(7):1042-1051. doi: 10.1016/S1473-3099(21)00811-2.
Epub 2022 May 2.
 
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), Hughes
J(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9),
Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
 
BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable
group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
 
This is an Open Access article published under the CC BY 3.0 IGO license which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. In any use of this article, there should be
no suggestion that WHO endorses any specific organisation, products or services.
The use of the WHO logo is not permitted. This notice should be preserved along
with the article's original URL.
 
DOI: 10.1016/S1473-3099(21)00811-2
PMID: 35512718
 
4. Global availability of susceptibility testing for second-line anti-tuberculosis agents.
 
Int J Tuberc Lung Dis. 2022 Jun 1;26(6):524-528. doi: 10.5588/ijtld.21.0420.
 
Lazarchik A(1), Nyaruhirira AU(2), Chiang CY(3), Wares F(4), Horsburgh CR(5).
 
BACKGROUND: The continued development of new anti-TB agents brings with it a demand for accompanying treatment regimens to prevent the development of resistance. Effectively meeting this demand requires an understanding of the pathogen´s susceptibility to various treatment options, which in turn makes access to antibiotic susceptibility testing (AST) a paramount consideration in the global treatment of TB.
METHODS: A 12-question, quantitative and qualitative survey was developed to gauge global capacity and access to AST. The survey was disseminated to members of the Global Laboratory Initiative, Global Drug-resistant TB Initiative, and the TB section of the International Union Against Tuberculosis and Lung Disease to solicit responses from pertinent stakeholders.
RESULTS: A total of 323 complete responses representing 84 countries and all WHO Regions were collected. AST capacity for fluoroquinolones and second-line injectables was high in all WHO Regions. AST capacity for the new and repurposed drugs is highest in the European Region, Region of the Americas and the Western Pacific Region, but quite limited in the African and Eastern Mediterranean Regions. The AST turnaround time for second-line drugs was delayed compared to that for first-line drugs as samples needed to be sent farther for analysis. Common barriers to AST for second-line drugs were lack of specimen transportation infrastructure, high costs, and lack of specialised laboratory workers and specialised laboratory facilities.
CONCLUSION: Without expanding global access to AST, the growing availability of new treatment options will likely be threatened by accompanying increase in resistance. There is an earnest and pressing need to improve capacity and access to AST alongside treatment options.
 
DOI: 10.5588/ijtld.21.0420
PMID: 35650708 [Indexed for MEDLINE]

5. Keeping up with the guidelines: design changes to the STREAM stage 2 randomised controlled non-inferiority trial for rifampicin-resistant tuberculosis.
 
Trials. 2022 Jun 7;23(1):474. doi: 10.1186/s13063-022-06397-4.
 
Goodall RL(1), Sanders K(2), Bronson G(3), Gurumurthy M(4), Torrea G(5),
Meredith S(2), Nunn A(2), Rusen ID(3); STREAM Trial Team.
 
Collaborators: Bronson G, Gurumurthy M, Komrska J, Patel L, Qawiy I, Rusen ID,
Ali S, Bellenger K, Bennet D, Bennet R, Dodds W, Goodall R, Meredith S, Murphy
B, Nunn A, Roach C, Sanders K, Whitney J, Van Deun A, Torrea G, Chiang CY, Rosu
L, Squire B, Madan J.
 
Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial's design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally. Trial registration: ISRCTN ISRCTN18148631. Registered 10 February
2016.
 
© 2022. The Author(s).
 
DOI: 10.1186/s13063-022-06397-4
PMCID: PMC9171092
PMID: 35672833 [Indexed for MEDLINE]
 
Conflict of interest statement: The authors declare that they have no competing
interests.

From Our May 2022 Newsletter​

Cost of TB prevention and treatment in the Philippines in 2017

Int J Tuberc Lung Dis. 2022 May 1;26(5):392-398. doi: 10.5588/ijtld.21.0622.

Capeding TPJ(1), Rosa JD(1), Lam H(1), Gaviola DG(2), Garfin AMC(2), Hontiveros C(2), Cunnama L(3), Laurence YV(4), Kitson N(4), Vassall A(4), Sweeney S(4), Garcia-Baena I(5).

BACKGROUND: The Philippines aims to accelerate TB reduction through the provision of universally accessible and affordable services. The objectives of this paper are to estimate the costs of TB services and interventions using a health systems´ perspective, and to explore cost differences in service delivery via primary care facilities or hospitals.
METHODS: Data were collected from a multi-stage stratified random sampling of 28 facilities in accordance with Global Health Cost Consortium costing standards and analysis tools. Unit costs (in US$) estimated using top-down (TD) and bottom-up (BU) approaches, are summarised following Value TB reporting standards and by broad facility type.
RESULTS: Cost of delivering 32 TB services and eight interventions varied by costing method and delivery platform. Average BU costs ranged from US$0.38 for treatment support visits, US$2.5 for BCG vaccination, US$19.48 for the Xpert® MTB/RIF test to US$3,677 for MDR-TB treatment using the long regimen. Delivering TB care in hospitals was generally more costly than in primary care facilities, except for TB prevention in children and MDR-TB treatment using the long regimen.
CONCLUSION: Comprehensive costing data for TB care in the Philippines are now available to aid in the design, planning, and prioritisation of delivery models to End TB.

DOI: 10.5588/ijtld.21.0622
PMCID: PMC9067429
PMID: 35505478 [Indexed for MEDLINE]
 
Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children
 
Clin Infect Dis. 2022 Apr 28;74(8):1372-1381. doi: 10.1093/cid/ciab641.

Radtke KK(1), Hesseling AC(2), Winckler JL(2), Draper HR(2), Solans BP(1), Thee S(2)(3), Wiesner L(4), van der Laan LE(2), Fourie B(2), Nielsen J(5), Schaaf HS(2), Savic RM(1), Garcia-Prats AJ(2)(6).

BACKGROUND: Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB.
METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing.
RESULTS: Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children.
CONCLUSIONS: Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

DOI: 10.1093/cid/ciab641
PMCID: PMC9049278
PMID: 34286843 [Indexed for MEDLINE]
 
Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial
 
Antimicrob Agents Chemother. 2022 May 17;66(5):e0214421. doi:10.1128/aac.02144-21. Epub 2022 Apr 11.
 
Garcia-Prats AJ(1), Frias M(2), van der Laan L(1), De Leon A(3), Gler MT(2), Schaaf HS(1), Hesseling AC(1), Malikaarjun S(4), Hafkin J(4).
 
Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- (n = 7), 6- to 11- (n = 6), and 3- to 5-year-olds (n = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID). Exposures in 0- to 2-year-olds (n = 12) following a weight-based dosing regimen (5 mg once daily [QD] to 10 mg BID) were lower than predicted from pharmacokinetic modeling of the older three age groups and below target exposures in adults. Overall, the safety profile of delamanid in children 0 to 17 years of age was similar to the adult profile. At 24 months after the first delamanid dose, 33/37 children (89.2%) had favorable treatment outcomes, as defined by the World Health Organization (15/37 [40.5%] cured and 18/37 [48.6%] completed treatment). A new pediatric delamanid formulation used in 0- to 2-year-olds and 3- to 5-year-olds was palatable per child/parent and nurse/investigator reports. Data from initial phase I/II studies inform our understanding of delamanid use in children and support its further assessment in the setting of pediatric MDR-TB. (This study has been registered at ClinicalTrials.gov under identifiers NCT01856634 [phase I trial] and NCT01859923 [phase II trial].).
 
DOI: 10.1128/aac.02144-21
PMCID: PMC9112969
PMID: 35404075 [Indexed for MEDLINE]
 
Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis
 
Pediatr Infect Dis J. 2022 May 1;41(5):401-404. doi: 
10.1097/INF.0000000000003486.

Shah I(1), Antony S(1), Jaiswal A(1), Bodhanwala M(2), Shah D(3), Tipre P(3), 
Salve J(4), Parmar M(4)(5), Sachdeva KS(6).

INTRODUCTION: The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.
OBJECTIVES: To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.
DESIGN AND METHODS: Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.
RESULTS: Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 
5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.

CONCLUSIONS: Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

DOI: 10.1097/INF.0000000000003486
PMID: 35153288 [Indexed for MEDLINE]

Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views

Cochrane Database Syst Rev. 2022 Apr 26;4(4):CD014877. doi: 10.1002/14651858.CD014877.pub2.

Engel N(1), Ochodo EA(2)(3), Karanja PW(4), Schmidt BM(5), Janssen R(1), Steingart KR(6), Oliver S(7)(8).

Update of doi: 10.1002/14651858.CD014877.

BACKGROUND: Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need.
OBJECTIVES: To synthesize end-user and professional user perspectives and experiences with low-complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity.
SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009.
SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low-complexity NAATs to diagnose tuberculosis and drug-resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug-resistant tuberculosis (including multidrug-resistant (MDR-TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR-TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first-line drugs used to treat tuberculosis.
DATA COLLECTION AND ANALYSIS: We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate.
MAIN RESULTS: We found 32 studies. All studies were conducted in low- and middle-income countries. Twenty-seven studies were conducted in high-tuberculosis burden countries and 21 studies in high-MDR-TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low-complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic-associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low-complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low-complexity NAATs compared to sputum microscopy, and increased staff satisfaction. Challenges reported to realizing those values People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR-TB) due to fears, stigma, or cost concerns. Thus, low-complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low-complexity NAATs; increased workload; inefficient work and patient flows; over-reliance on low-complexity NAAT results in lieu of clinical judgement; and lack of data-driven and inclusive implementation processes. These challenges were reported to lead to underutilization.  Concerns for access and equity The reported concerns included sustainable funding and maintenance and equitable use of resources to access low-complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low-complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered access to prompt and accurate testing and treatment. This was particularly the case for vulnerable groups, such as children, people with MDR-TB, or people with limited ability to pay. We had high confidence in most of our findings.
AUTHORS' CONCLUSIONS: Low-complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings. Implementation of new diagnostic 
technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

DOI: 10.1002/14651858.CD014877.pub2
PMCID: PMC9038447
PMID: 35470432 [Indexed for MEDLINE]

Treatment outcomes 24 months after initiating short, all-oralbedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study
 
Lancet Infect Dis. 2022 May 2:S1473-3099(21)00811-2. doi:10.1016/S1473-3099(21)00811-2. Online ahead of print.
 
Ndjeka N(1), Campbell JR(2), Meintjes G(3), Maartens G(3), Schaaf HS(4), HughesJ(4), Padanilam X(5), Reuter A(6), Romero R(7), Ismail F(8), Enwerem M(9), Ferreira H(10), Conradie F(11), Naidoo K(12), Menzies D(2).
 
BACKGROUND: There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).
METHODS: Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of
treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus
death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.
FINDINGS: Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.
INTERPRETATION: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.
FUNDING: WHO Global TB Programme.
TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
 
This is an Open Access article published under the CC BY 3.0 IGO license which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. In any use of this article, there should be
no suggestion that WHO endorses any specific organisation, products or services.
The use of the WHO logo is not permitted. This notice should be preserved along
with the article's original URL.
 
DOI: 10.1016/S1473-3099(21)00811-2
PMID: 35512
718

From Our April 2022 Newsletter

Disadvantage and the Experience of Treatment for Multidrug-Resistant Tuberculosis (MDR-TB).
 
SSM Qual Res Health. 2022 Dec;2:100042. doi: 10.1016/j.ssmqr.2022.100042. Epub 2022 Jan 28.
 
Taylor HA(1), Dowdy DW(2), Searle AR(3), Stennett AL(3), Dukhanin V(1), Zwerling AA(4), Merritt MW(5).

In the present research, we aimed to demonstrate how exploring patients’ treatment experiences may help decision makers better understand and pay attention to social impacts of health interventions. We take multi-drug-resistant tuberculosis (MDR-TB) as a paradigm case of a disease that disproportionately affects people already living with disadvantage and for which treatment itself is extremely burdensome. We conducted a total of 140 in-depth interviews with 53 patients, 56 health care providers, and 31 community members.We found that the burdens of MDR-TB treatment described by respondents fell into two categories: those related to managing the medications (n=77) and those related to other aspects of completing treatment (n=52). Respondents also identified social support (n=121), access to essential goods and services (n=74), personal motivation (n=52), and patient knowledge about the relationship between treatment completion and potential cure (n=44) as factors that may either lighten treatment burdens and facilitate completion or add to treatment burdens and inhibit completion. When asked specifically about preferences for MDR-TB treatment advances, respondents favored a shorter course of treatment (n=52) and fewer pills (n=51) over fewer side effects (n=18). According a pattern analysis applied across the data using the core dimensions of social justice we found that experiencing the side effects of MDR-TB treatment tends uniformly to erode all three dimensions. Our findings demonstrate how systematic collection of data about patients’ lived experience can inform decision-making regarding the social impacts of health interventions in at-risk community living with a high-burden of disease from the perspective of disadvantage.
 
DOI: 10.1016/j.ssmqr.2022.100042
PMCID: PMC8896740
PMID: 35252955

Investigation of Clofazimine Resistance and Genetic Mutations in Drug-Resistant Mycobacterium tuberculosis Isolates.
 
J Clin Med. 2022 Mar 30;11(7):1927. doi: 10.3390/jcm11071927.
 
Park S(1), Jung J(1), Kim J(1), Han SB(2), Ryoo S(1).
 
Recently, as clofazimine (CFZ) showed a good therapeutic effect in treating multi-drug-resistant tuberculosis (MDR-TB), the anti-tuberculosis activity and resistance were re-focused. Here, we investigated the CFZ resistance and genetic mutations of drug-resistant Mycobacterium tuberculosis (DR-Mtb) isolates to improve the diagnosis and treatment of drug-resistant TB patients. The minimal inhibitory concentration (MIC) of CFZ was examined by resazurin microtiter assay (REMA) with two reference strains and 122 clinical isolates from Korea. The cause of CFZ resistance was investigated in relation to the therapeutic history of patients. Mutations of Rv0678, Rv1979c and pepQ of CFZ resistant isolates were analyzed by PCR and DNA sequencing. The rate of CFZ resistance with MIC &gt; 1 mg/L was 4.1% in drug-resistant Mtb isolates. The cause of CFZ resistance was not related to treatment with CFZ or bedaquiline. A CFZ susceptibility test should be conducted regardless of dugs use history. The four novel mutation sites were identified in the Rv0678 and pepQ genes related to CFZ resistance in this study.
 
DOI: 10.3390/jcm11071927
PMCID: PMC9000149
PMID: 35407536
 
Delamanid or pretomanid? A Solomonic judgement!
 
J Antimicrob Chemother. 2022 Mar 31;77(4):880-902. doi: 10.1093/jac/dkab505.
 
Mudde SE(1), Upton AM(2), Lenaerts A(3), Bax HI(1)(4), De Steenwinkel JEM(1).
 
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
 
DOI: 10.1093/jac/dkab505
PMCID: PMC8969540
PMID: 35089314 [Indexed for MEDLINE]
 
Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study.
 
J Antimicrob Chemother. 2022 Mar 31;77(4):1146-1154. doi: 10.1093/jac/dkac019.
 
Wasserman S(1)(2), Brust JCM(3), Abdelwahab MT(4), Little F(5), Denti P(4), Wiesner L(4), Gandhi NR(6)(7), Meintjes G(1)(8), Maartens G(1)(4).
 
BACKGROUND: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescribers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated.
PATIENTS AND METHODS: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifampicin-resistant TB in South Africa. Linezolid exposures were estimated from a population  pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes.
RESULTS: One hundred and fifty one participants, 63% HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21%) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14%) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95% CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin >2 g/dL. Trough 
linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and treatment-emergent anaemia (adjusted OR 2.9; 95% CI 1.3-6.8). SNPs 2706A > G and 3010G > A in mitochondrial DNA were not associated with linezolid toxicity.
CONCLUSIONS: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkac019
PMCID: PMC7612559
PMID: 35134182 [Indexed for MEDLINE]
 
Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment.
 
Eur Respir J. 2022 Apr 14;59(4):2200166. doi: 10.1183/13993003.00166-2022. Print 2022 Apr.
 
Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti- TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.
 
DOI: 10.1183/13993003.00166-2022
PMID: 35422426 [Indexed for MEDLINE]

Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.
 
Lancet Infect Dis. 2022 Apr;22(4):496-506. doi: 10.1016/S1473-3099(21)00470-9. Epub 2021 Nov 12.
 
Ismail NA(1), Omar SV(2), Moultrie H(3), Bhyat Z(3), Conradie F(4), Enwerem M(5), Ferreira H(6), Hughes J(7), Joseph L(3), Kock Y(8), Letsaolo V(3), Maartens G(9), Meintjes G(9), Ngcamu D(3), Okozi N(3), Padanilam X(10), Reuter A(11), Romero R(12), Schaaf S(7), Te Riele J(13), Variava E(14), van der Meulen M(3), Ismail F(15), Ndjeka N(8).
 
BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated 
with bedaquiline resistance, using data from South Africa (2015-19).
METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.
FUNDING: National Institute for Communicable Diseases of South Africa.
 
Copyright © 2022 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00470-9
PMID: 34780706 [Indexed for MEDLINE]

From Our March 2022 Newsletter

25 years of surveillance of drug-resistant tuberculosis: achievements, challenges, and way forward.
 

Lancet Infect Dis. 2022 Mar 3:S1473-3099(21)00808-2. doi: 10.1016/S1473-3099(21)00808-2. Online ahead of print.
 
Dean AS(1), Tosas Auguet O(2), Glaziou P(2), Zignol M(2), Ismail N(2), Kasaeva T(2), Floyd K(2).
 
Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.
 
Copyright © 2022 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00808-2
PMCID: PMC8893725
PMID: 35248168
 
Treatment outcomes among childhood extensively drug-resistant tuberculosis patients in Pakistan.
 

ERJ Open Res. 2022 Feb 21;8(1):00551-2021. doi: 10.1183/23120541.00551-2021. eCollection 2022 Jan.
 
Abubakar M(1), Ahmad N(1), Atif M(2), Hayat Khan A(3), Ghafoor A(4).
 
Treatment outcomes of childhood XDR-TB patients in Pakistan are better than in adult patients but still disappointing https://bit.ly/3rkQ9sw.
 
Copyright ©The authors 2022.
 
DOI: 10.1183/23120541.00551-2021
PMCID: PMC8859504
PMID: 35198629
 
Safety and effectiveness outcomes from a 14-country cohort of patients with multi-drug resistant tuberculosis treated concomitantly with bedaquiline, delamanid and other second-line drugs.
 
Clin Infect Dis. 2022 Mar 4:ciac176. doi: 10.1093/cid/ciac176. Online ahead of print.
 
Huerga H(1), Khan U(2), Bastard M(1), Mitnick CD(3)(4)(5), Lachenal N(6), Khan PY(2)(7), Seung KJ(3)(4)(5), Melikyan N(1), Ahmed S(8), Rich ML(3)(4)(5), Varaine F(9), Osso E(3)(6), Rashitov M(10), Salahuddin N(11), Salia G(12), Sánchez E(13), Serobyan A(14), Siddiqui MR(15), Tefera DG(16), Vetushko D(17), Yeghiazaryan L(18), Holtzman D(19), Islam S(20), Kumsa A(21), Leblanc GJ(22), Leonovich O(23), Mamsa S(20), Manzur-Ul-Alam M(24), Myint Z(25), Padayachee S(26), Franke MF(3), Hewison C(9); endTB study observational study team.
 
BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet, this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died and 7.2% experienced treatment failure.
CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciac176
PMID: 35243494
 
Bedaquiline adherence measured by electronic dose monitoring predicts clinical outcomes in the treatment of patients with multidrug-resistant tuberculosis and HIV/AIDS.
 
J Acquir Immune Defic Syndr. 2022 Feb 21. doi: 10.1097/QAI.0000000000002940. Online ahead of print.
 
O'Donnell MR(1), Padayatchi N, Wolf A, Zelnick J, Daftary A, Orrell C, Nimmo C, Baldwin M, Boodhram R, Maharaj B, Amico KR, Naidoo K, Friedland G.
 
BACKGROUND: Novel regimens have revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment; however, medication adherence remains challenging and poorly characterized. We hypothesized that bedaquiline adherence, measured using electronic dose monitoring, would predict MDR-TB treatment outcomes.
SETTING: Prospective cohort study in KwaZulu-Natal, South Africa.
METHODS: Adults with MDR-TB and HIV initiating bedaquiline and on antiretroviral therapy (ART) were eligible. Separate electronic dose monitoring devices measured bedaquiline and ART adherence through six months, calculated as observed versus expected doses. Whole genome sequencing was performed to identify bedaquiline resistance-associated variants.
RESULTS: From November 2016 through February 2018, 199 participants with MDR-TB and HIV were enrolled and followed through treatment completion (median 17.2 months IQR 12.2-19.6). Median bedaquiline adherence was higher than ART adherence (97 vs. 89%, p<0.001), but correlated (r2=0.68, p<0.001). High bedaquiline adherence (≥90%) compared to lower adherence was associated with improved rates of end of treatment successful outcome (83.4% vs. 46.3%, p<0.001), decreased mortality (11.0% vs. 29.6% p=0.004), and improved retention in care through end of treatment (94.5% vs. 79.6% p=0.002). Modelling identified a highly significant, but linear association between bedaquiline adherence and outcome. On multivariable analysis, bedaquiline adherence was independently associated with mortality and outcome. Bedaquiline resistance-associated variants were seen in 12% (7/57) of sequenced isolates (7% baseline, 5% emergent) with only 28.6% experiencing successful treatment outcome.
CONCLUSIONS: Bedaquiline adherence through 6-months independently predicted end of MDR-TB treatment outcome, but a specific bedaquiline adherence threshold was not identified. Interventions to optimize bedaquiline adherence are urgently needed to improve MDR-TB HIV treatment outcomes.
 
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
 
DOI: 10.1097/QAI.0000000000002940
PMID: 35195572

From Our February 2022 Newsletter

 

Delamanid or pretomanid? A Solomonic judgement!
 
J Antimicrob Chemother. 2022 Jan 28:dkab505. doi: 10.1093/jac/dkab505. Online 
ahead of print.
 
Mudde SE(1), Upton AM(2), Lenaerts A(3), Bax HI(1)(4), De Steenwinkel JEM(1).
 
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
 
© The Author(s) 2022. Published by Oxford University Press on behalf of British 
Society for Antimicrobial Chemotherapy.
 
DOI: 10.1093/jac/dkab505
PMID: 35089314

Model-Based Efficacy and Toxicity Comparisons of Moxifloxacin for Multidrug-Resistant Tuberculosis.

Open Forum Infect Dis. 2021 Dec 29;9(3):ofab660. doi: 10.1093/ofid/ofab660. 
eCollection 2022 Mar.
 
Yun HY(1), Chang V(2), Radtke KK(2), Wang Q(2), Strydom N(2), Chang MJ(3)(4)(5), Savic RM(2).
 
BACKGROUND: Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integrative model-based approaches in MDR-TB patients.
METHODS: In total, 113 MDR-TB patients from 5 different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients.
RESULTS: The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400-mg, twice-daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800-mg once-daily dosing regimen, because of the narrow fluctuation of concentrations.
CONCLUSIONS: Our results suggest that a 400-mg, twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.
 
© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
 
DOI: 10.1093/ofid/ofab660
PMCID: PMC8825669
PMID: 35146045
 
Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.
 

Open Forum Infect Dis. 2021 Dec 23;9(2):ofab615. doi: 10.1093/ofid/ofab615. 
eCollection 2022 Feb.
 
Tornheim JA(1), Udwadia ZF(2), Arora PR(3), Gajjar I(3), Sharma S(3), Karane 
M(3), Sawant N(3), Kharat N(3), Blum AJ(4), Shivakumar SVBY(5), Gupte AN(1), 
Gupte N(1)(5), Mullerpattan JB(2), Pinto LM(2), Ashavaid TF(3), Gupta A(1)(6), 
Rodrigues C(7).
 
BACKGROUND: Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.
METHODS: We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.
RESULTS: Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]).
CONCLUSIONS: In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.
 
© The Author(s) 2021. Published by Oxford University Press on behalf of 
Infectious Diseases Society of America.
 
DOI: 10.1093/ofid/ofab615
PMCID: PMC8794589
PMID: 35097152

An All-Oral 6-Month Regimen for Multidrug-Resistant TB (the NExT Study): A Multicenter, Randomized Controlled Trial.
 
Am J Respir Crit Care Med. 2022 Feb 17. doi: 10.1164/rccm.202107-1779OC. Online ahead of print.
 
Esmail A(1)(2), Oelofse S(3)(2), Lombard C(4)(5), Perumal R(3)(2), Mbuthini 
L(3), Goolam Mahomed A(6), Variava E(7)(8), Black J(9), Oluboyo P(10), Gwentshu 
N(11), Ngam E(11), Ackerman T(12), Marais L(13), Mottay L(3)(2), Meier S(14)(2), 
Pooran A(3)(2), Tomasicchio M(3)(15), Te Riele J(16), Derendinger B(17), Ndjeka 
N(18), Maartens G(19), Warren R(20), Martinson N(21)(22), Dheda K(23)(2)(24).
 
Rationale/objectives: Improving treatment outcomes, reducing drug toxicity, avoiding injectable agents, and shortening the treatment duration to 6-months (approximating that of rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB).
METHODS: We conducted a multicentre randomised controlled trial in adults with MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a ~6-month all-oral regimen that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥ 9-month WHO-approved injectable-based regimen. The primary endpoint was a favourable WHO-defined treatment outcome 24 months after treatment initiation.
MAIN RESULTS: 93 of 111 participants randomised were included in the modified intention-to-treat analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/mL). Participants in the intervention arm were 2.2 times more likely to experience a favourable 24-month outcome than participants in the standard-of-care arm [RR 2.2 (1.2-4.1); p=0.006]. Toxicity-related drug substitution occurred more frequently in the standard-of-care arm [(65·9% (29/44) versus 36·7% (18/49), p= 0·001)]; 79.3% (23/29) due to kanamycin (mainly hearing loss; replaced by bedaquiline) in the standard-of-care arm, and 83·3% (15/18) due to linezolid (mainly anaemia) in the interventional arm. Culture conversion was significantly better in the intervention arm [HR 2.6 (1.4-4.9); p= 0.003] after censoring those with bedaquiline replacement in the standard-of-care arm.
CONCLUSIONS: An all-oral 6-month levofloxacin, bedaquiline and linezolid-containing MDR/RR-TB regimen was associated with significantly improved 24-month treatment outcomes compared with traditional injectable-containing regimens. However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02454205.
 
DOI: 10.1164/rccm.202107-1779OC
PMID: 35175905
 
Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.
 

Pediatr Infect Dis J. 2022 Feb 10. doi: 10.1097/INF.0000000000003486. Online 
ahead of print.
 
Shah I(1), Antony S, Jaiswal A, Bodhanwala M, Shah D, Tipre P, Salve J, Parmar 
M, Sachdeva KS.
 
INTRODUCTION: The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.
OBJECTIVES: To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.
DESIGN AND METHODS: Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.
RESULTS: Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.
CONCLUSIONS: Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.
 
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
 
DOI: 10.1097/INF.0000000000003486
PMID: 35153288

From Our December 2021 Newsletter

Between Curing and Torturing: Burden of Adverse Reaction in Drug- Resistant Tuberculosis Therapy.

Patient Prefer Adherence. 2021 Nov 23;15:2597-2607. doi: 10.2147/PPA.S333111. eCollection 2021.

Ausi Y(1)(2), Santoso P(3), Sunjaya DK(4), Barliana MI(1)(5).

Drug-resistant tuberculosis (DR-TB) requires prolonged and complex therapy which is associated with several adverse drug reactions (ADR). The burden of ADR can affect the quality of life (QoL) of patients that consists of physical, mental, and social well-being, and influences the beliefs and behaviors of patient related to treatment. This article reviews the burden of ADR and its association with QoL and adherence. We used PubMed to retrieve the relevant original research articles written in English from 2011 to 2021. We combined the following keywords: "tuberculosis," "Drug-resistant tuberculosis," "Side Effect," "Adverse Drug Reactions," "Adverse Event," "Quality of Life," "Adherence," "Non-adherence," "Default," and "Loss to follow-up." Article selection process was unsystematic. We included 12 relevant main articles and summarized into two main topics, namely, 1) ADR and QoL (3 articles), and 2) ADR and therapy adherence (9 articles). The result showed that patients with ADR tend to have low QoL, even in the end of treatment. Although it was torturing, the presence of ADR does not always result in non- adherence. It is probably because the perception about the benefit of the treatment dominates the perceived barrier. In conclusion, burden of ADR generally tends to degrade QoL of patients and potentially influence the adherence. A comprehensive support from family, community, and healthcare provider is required to help patients in coping with the burden of ADR. Nevertheless, the regimen safety and efficacy improvement are highly needed.

© 2021 Ausi et al.

DOI: 10.2147/PPA.S333111 PMCID: PMC8627322 PMID: 34848950

 Emergence of additional drug resistance during treatment of multidrug- resistant tuberculosis in China: a prospective cohort study.

Clin Microbiol Infect. 2021 Dec;27(12):1805-1813. doi: 10.1016/j.cmi.2021.04.001. Epub 2021 Apr 23.

Hu Y(1), Zheng X(1), Davies Forsman L(2), Ning Z(3), Chen C(4), Gao Y(1), Zhang Z(3), Lu W(4), Werngren J(5), Bruchfeld J(2), Hoffner S(6), Xu B(7).

OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment.
METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance.
RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03- 5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance.
CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.

Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.cmi.2021.04.001 PMID: 33895338

 Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug- Resistant Tuberculosis: A Prospective Cohort Study.

Clin Infect Dis. 2021 Dec 6;73(11):2083-2092. doi: 10.1093/cid/ciab335.

Brust JCM(1), Gandhi NR(2)(3), Wasserman S(4), Maartens G(4)(5), Omar SV(6) (7), Ismail NA(6)(7), Campbell A(2), Joseph L(1), Hahn A(1), Allana
S(2), Hernandez-Romieu AC(3), Zhang C(1), Mlisana K(8), Viljoen CA(9), Zalta B(10), Ebrahim I(4), Franczek M(2), Master I(11), Ramangoaela L(12), Te Riele J(13), Meintjes G(4).

BACKGROUND: Bedaquiline improves treatment outcomes in patients with rifampin- resistant (RR) tuberculosis but prolongs the QT interval and carries a black-box warning from the US Food and Drug Administration. The World Health Organization recommends that all patients with RR tuberculosis receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac
safety has not been published.
METHODS: We conducted an observational cohort study of patients with
RR tuberculosis from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, which included obtaining electrocardiograms in triplicate at 4 time points during bedaquiline therapy. Participants were followed up until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT interval prolongation (QT prolongation), defined as any QT interval corrected by the Fridericia method (QTcF) >500 ms or an absolute change from baseline (ΔQTcF) >60 ms.
RESULTS: We enrolled 195 eligible participants, of whom 40% had extensively drug- resistant tuberculosis. Most participants (97%) received concurrent clofazimine. Of the participants, 74% were cured or successfully completed treatment, and outcomes did not differ by human immunodeficiency virus status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase
(standard deviation) of 23.7 (22.7) ms from baseline to month 6. Four participants experienced a QTcF >500 ms and 19 experienced a ΔQTcF >60 ms. Older age was independently associated with QT prolongation. QT prolongation was neither more common nor more severe in participants receiving concurrent lopinavir-ritonavir. CONCLUSIONS: Severe QT prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close monitoring of the QT interval may be advisable in older patients.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Value of routine whole genome sequencing for Mycobacterium tuberculosis drug resistance detection.

Int J Infect Dis. 2021 Dec;113 Suppl 1:S48-S54. doi: 10.1016/j.ijid.2021.03.033. Epub 2021 Mar 19.

Lam C(1), Martinez E(2), Crighton T(2), Furlong C(3), Donnan E(3), Marais BJ(4), Sintchenko V(5).

Routine whole genome sequencing (WGS) of pathogens is becoming more feasible as sequencing costs decrease and access to benchtop sequencing equipment and bioinformatics pipelines increases. This study examined the added value gained from implementing routine WGS of all Mycobacterium tuberculosis isolates in New South Wales, Australia. Drug resistance markers inferred from WGS data were compared to commercial genotypic drug susceptibility testing (DST) assays and conventional phenotypic DST in all isolates sequenced between 2016 and 2019. Of the 1107 clinical M. tuberculosis isolates sequenced, 29 (2.6%) were multi- drug resistant (MDR); most belonged to Beijing (336; 30.4%) or East-African Indian (332; 30%) lineages. Compared with conventional phenotypic DST, WGS identified an additional 1% of isolates which were likely drug resistant, explained by mutations previously associated with treatment failure and mixed bacterial populations. However, WGS provided a 20% increase in drug resistance detection in comparison with commercial genotypic assays by identifying mutations outside of the classic resistance determining regions in rpoB, inhA, katG, pncA and embB genes. Gains in drug resistance detection were significant (p = 0.0137, paired t-test), but varied substantially for different phylogenetic lineages. In
low incidence settings, routine WGS of M. tuberculosis provides better guidance for person-centered management of drug resistant tuberculosis than commercial genotypic assays.

Copyright © 2021. Published by Elsevier Ltd.

DOI: 10.1016/j.ijid.2021.03.033 PMID: 33753222

A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial.

Am J Respir Crit Care Med. 2021 Dec 1;204(11):1327-1335. doi: 10.1164/rccm.202103-0534OC.

Gausi K(1), Ignatius EH(2), Sun X(3), Kim S(4), Moran L(5), Wiesner L(1),
von Groote-Bidlingmaier F(6), Hafner R(7), Donahue K(8), Vanker N(6), Rosenkranz SL(3), Swindells S(9), Diacon AH(6), Nuermberger EL(2), Dooley KE(2), Denti P(1).

Rationale: There is accumulating evidence that higher-than-standard doses
of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains

of Mycobacterium tuberculosis, but the optimal dose remains unknown. Objectives: To characterize the association between isoniazid

pharmacokinetics (standard or high dose) and early bactericidal activity against M. tuberculosis (drug sensitive and inhA mutated) and N-acetyltransferase 2 status. Methods: ACTG (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal activity study with isoniazid at a normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary tuberculosis received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (cfu) on solid culture and time to positivity in liquid culture were jointly analyzed using nonlinear mixed-effects modeling. Measurements and Main
Results: Fifty-nine adults were included in this analysis. A decline in sputum cfu was described by a one-compartment model, whereas an exponential bacterial growth model was used to interpret time-to-positivity data. The model found that bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship (a model linking the drug concentration to the observed effect). The model predicted lower potency but similar maximum kill of isoniazid against inhA-mutated compared with drug-sensitive isolates. Based on simulations from the pharmacokinetics-pharmacodynamics model, to achieve a drop in bacterial load comparable to 5 mg/kg against drug-sensitive tuberculosis, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg.
Conclusions: Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

DOI: 10.1164/rccm.202103-0534OC PMID: 34403326

 Evaluation of the performance of the BD MAX MDR-TB test in the diagnosis of Mycobacterium tuberculosis complex in extrapulmonary and pulmonary samples.

Expert Rev Mol Diagn. 2021 Dec;21(12):1361-1367. doi: 10.1080/14737159.2021.1997594. Epub 2021 Nov 16.

Sağıroğlu P(1), Atalay MA(1).

BACKGROUND: The BD MAX MDR-TB is a recently marketed molecular test for detecting Mycobacterium tuberculosis complex (MTC), rifampin, and isoniazid drug resistance.
RESEARCH DESIGN AND METHODS: This study aimed to evaluate the BD MAX MDR-TB test performance in 933 extrapulmonary and 774 pulmonary samples.

RESULTS: Test MTC detecting sensitivity was 90.6%, 82.5%, and the specificity was 98.5%, 98.9%, in pulmonary and extrapulmonary samples, respectively. In smear- positive samples, sensitivity, and specificity were 100% for all samples. However, in smear-negative samples, the test's sensitivity and specificity were 82.3%, 98.5% in pulmonary samples, and 76.7%, 98.9% in extrapulmonary samples. Test sensitivity in detecting isoniazid resistance was 71.4%, specificity 96.8%, and in detecting rifampin resistance was 100%, specificity 93.9%, respectively.

CONCLUSIONS: BD MAX MDR-TB is a reliable, rapid, user-friendly test for detecting MTC in extrapulmonary and pulmonary samples and its resistance toward isoniazid and rifampin. It can be used as an alternative to the Xpert system assays.

DOI: 10.1080/14737159.2021.1997594 PMID: 34689662

Exposure-safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis.

CPT Pharmacometrics Syst Pharmacol. 2021 Dec;10(12):1538-1549. doi: 10.1002/psp4.12722. Epub 2021 Oct 22.

Tanneau L(1), Svensson EM(1)(2), Rossenu S(3), Karlsson MO(1).

Bedaquiline (BDQ) has shown great value in the treatment of multidrug- resistant tuberculosis (MDR-TB) in recent years. However, exposure-safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels in patients with MDR-TB using the approved dose regimen. Data from 429 patients with MDR-TB from two phase IIb studies were analyzed via nonlinear mixed-effects modeling. Individual model-predicted concentrations and summary PK metrics were evaluated, respectively, in the QTcF interval and transaminase level exposure-response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug-related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to a critical QTcF interval increase. No exposure-safety relationship could be described with transaminase levels despite previous reports of higher levels in patients treated with BDQ. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase level elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.

© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by

Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

DOI: 10.1002/psp4.12722 PMID: 34626526

 

From Our November 2021 Newsletter

One Step Forward: Successful End-of-Treatment Outcomes of Patients With Drug-Resistant Tuberculosis Who Received Concomitant Bedaquiline and Delamanid in Mumbai, India.

 
Clin Infect Dis. 2021 Nov 2;73(9):e3496-e3504. doi: 10.1093/cid/ciaa1577.
 
Das M(1), Dalal A(2), Laxmeshwar C(1), Ravi S(1), Mamnoon F(1), Meneguim AC(1), Paryani R(1), Mathur T(1), Singh P(1), Mansoor H(1), Kalon S(1), Hossain FN(1), Lachenal N(3), Coutisson S(3), Ferlazzo G(4), Isaakidis P(4).
 
BACKGROUND: The Médecins Sans Frontières Clinic in Mumbai, India, has been providing concomitant bedaquiline (BDQ) and delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment.
METHODS: This was a retrospective cohort study based on routinely collected program data. In clinic, treatment regimens are designed based on culture drug sensitivity test patterns and previous drug exposures, and are provided for 20-22 months. BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February 2016-February 2018 were included.
RESULTS: Of the 70 patients included, the median age was 25 (interquartile range [IQR], 22-32) years and 56% were females. All except 1 were fluoroquinolone resistant. The median duration of exposure to BDQ and DLM was 77 (IQR, 43-96) weeks. Thirty-nine episodes of SAEs were reported among 30 (43%) patients, including 5 instances of QTc prolongation, assessed as possibly related to BDQ and/or DLM. The majority (69%) had culture conversion before 24 weeks of treatment. In 61 (87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49 (70%) patients.
CONCLUSIONS: The successful treatment outcomes of this cohort show that regimens including concomitant BDQ and DLM for longer than 24 weeks are effective and can be safely administered on an ambulatory basis. National TB programs globally should scale up access to life-saving DR-TB regimens with new drugs.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious 
Diseases Society of America.
 
DOI: 10.1093/cid/ciaa1577
PMID: 33079176 [Indexed for MEDLINE]

 
Evaluation of the performance of the BD MAX MDR-TB test in the diagnosis of Mycobacterium tuberculosis complex in extrapulmonary and pulmonary samples.

 
Expert Rev Mol Diagn. 2021 Nov 16:1-7. doi: 10.1080/14737159.2021.1997594. Online ahead of print.
 
Sağıroğlu P(1), Atalay MA(1).
 
BACKGROUND: The BD MAX MDR-TB is a recently marketed molecular test for detecting Mycobacterium tuberculosis complex (MTC), rifampin, and isoniazid drug resistance.
RESEARCH DESIGN AND METHODS: This study aimed to evaluate the BD MAX MDR-TB test performance in 933 extrapulmonary and 774 pulmonary samples.
RESULTS: Test MTC detecting sensitivity was 90.6%, 82.5%, and the specificity was 98.5%, 98.9%, in pulmonary and extrapulmonary samples, respectively. In smear-positive samples, sensitivity, and specificity were 100% for all samples. However, in smear-negative samples, the test's sensitivity and specificity were 82.3%, 98.5% in pulmonary samples, and 76.7%, 98.9% in extrapulmonary samples. Test sensitivity in detecting isoniazid resistance was 71.4%, specificity 96.8%, and in detecting rifampin resistance was 100%, specificity 93.9%, respectively.
CONCLUSIONS: BD MAX MDR-TB is a reliable, rapid, user-friendly test for detecting MTC in extrapulmonary and pulmonary samples and its resistance toward isoniazid and rifampin. It can be used as an alternative to the Xpert system assays.
 
DOI: 10.1080/14737159.2021.1997594
PMID: 34689662

 
Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis.
 

Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0138121. doi: 
10.1128/AAC.01381-21. Epub 2021 Sep 20.
 
Abdelwahab MT(1), Wasserman S(1)(2)(3), Brust JCM(4), Dheda K(5)(6)(7), Wiesner L(1), Gandhi NR(8)(9), Warren RM(10), Sirgel FA(10), Meintjes G(2), Maartens G(1)(2), Denti P(1).
 
Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimization, we aimed to characterize the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV coinfection, on drug exposure. Data were obtained from pharmacokinetic substudies in a randomized controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using nonlinear mixed-effects modeling and performed simulations to estimate attainment of putative efficacy and toxicity targets. A total of 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and their median weight was 56 kg (interquartile range [IQR], 50 to 63). In the final model, typical values for clearance and central volume were 3.57 liters/h and 40.2 liters, respectively. HIV coinfection had no significant effect on linezolid exposure. Simulations showed that 600-mg dosing achieved the efficacy target (area under the concentration-time curve for the free, unbound fraction of the drug [[Formula: see text] at a MIC level of 0.5 mg/liter) with 96% probability but had 56% probability of exceeding safety target ([Formula: see text]. The 300-mg dose did not achieve adequate efficacy exposures. Our model characterized population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600-mg daily dose with safety monitoring.
 
DOI: 10.1128/AAC.01381-21
PMID: 34543098

 
A Comprehensive Evaluation of GeneLEAD VIII DNA Platform Combined to Deeplex Myc-TB(®) Assay to Detect in 8 Days Drug Resistance to 13 Antituberculous Drugs and Transmission of Mycobacterium tuberculosis Complex Directly From Clinical Samples.
 
Front Cell Infect Microbiol. 2021 Oct 29;11:707244. doi: 
10.3389/fcimb.2021.707244. eCollection 2021.
 
Bonnet I(1)(2)(3), Enouf V(4), Morel F(1)(2)(3), Ok V(1)(2)(3), Jaffré 
J(1)(2)(3), Jarlier V(1)(2), Aubry A(1)(2)(3), Robert J(1)(2)(3), Sougakoff 
W(1)(2)(3).
 
The GeneLEAD VIII (Diagenode, Belgium) is a new, fully automated, 
sample-to-result precision instrument for the extraction of DNA and PCR detection of Mycobacterium tuberculosis complex (MTBC) directly from clinical samples. The Deeplex Myc-TB® assay (Genoscreen, France) is a diagnostic kit based on the deep sequencing of a 24-plexed amplicon mix allowing simultaneously the detection of resistance to 13 antituberculous (antiTB) drugs and the determination of spoligotype. We evaluated the performance of a strategy combining the both mentioned tools to detect directly from clinical samples, in 8 days, MTBC and its resistance to 13 antiTB drugs, and identify potential transmission of strains from patient-to-patient. Using this approach, we screened 112 clinical samples (65 smear-negative) and 94 MTBC cultured strains. The sensitivity and the specificity of the GeneLEAD/Deeplex Myc-TB approach for MTBC detection were 79.3% and 100%, respectively. One hundred forty successful Deeplex Myc-TB results were obtained for 46 clinical samples and 94 strains, a total of 85.4% of which had a Deeplex Myc-TB susceptibility and resistance prediction consistent with phenotypic drug susceptibility testing (DST). Importantly, the Deeplex Myc-TB assay was able to detect 100% of the multidrug-resistant (MDR) MTBC tested. The lowest concordance rates were for pyrazinamide, ethambutol, streptomycin, and ethionamide (84.5%, 81.5%, 73%, and 55%, respectively) for which the determination of susceptibility or resistance is generally difficult with current tools. One of the main difficulties of Deeplex Myc-TB is to interpret the non-synonymous uncharacterized variants that can represent up to 30% of the detected single nucleotide variants. We observed a good level of concordance between Deeplex Myc-TB-spoligotyping and MIRU-VNTR despite a lower discriminatory power for spoligotyping. The median time to obtain complete results from clinical samples was 8 days (IQR 7-13) provided a high-throughput NGS sequencing platform was available. Our results highlight 
that the GeneLEAD/Deeplex Myc-TB approach could be a breakthrough in rapid diagnosis of MDR TB in routine practice.
 
Copyright © 2021 Bonnet, Enouf, Morel, Ok, Jaffré, Jarlier, Aubry, Robert and 
Sougakoff.
 
DOI: 10.3389/fcimb.2021.707244
PMCID: PMC8586210
PMID: 34778100

 
Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.
 

Lancet Infect Dis. 2021 Nov 12:S1473-3099(21)00470-9. doi: 
10.1016/S1473-3099(21)00470-9. Online ahead of print.
 
Ismail NA(1), Omar SV(2), Moultrie H(3), Bhyat Z(3), Conradie F(4), Enwerem M(5), Ferreira H(6), Hughes J(7), Joseph L(3), Kock Y(8), Letsaolo V(3), Maartens G(9), Meintjes G(9), Ngcamu D(3), Okozi N(3), Padanilam X(10), Reuter A(11), Romero R(12), Schaaf S(7), Te Riele J(13), Variava E(14), van der Meulen M(3), Ismail F(15), Ndjeka N(8).
 
BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19).
METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.
FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.
INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.
FUNDING: National Institute for Communicable Diseases of South Africa.
 
Copyright © 2021 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00470-9
PMID: 34780706


Comparative Efficacy of the Novel Diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis.
 
Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0141221. doi: 
10.1128/AAC.01412-21. Epub 2021 Sep 27.
 
Almeida D(1), Converse PJ(1), Li SY(1), Upton AM(2), Fotouhi N(2), Nuermberger EL(1)(3).
 
Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for 
treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB. However, the emergence of BDQ resistance, primarily due to inactivating mutations in the Rv0678 gene encoding a repressor of the MmpS5-MmpL5 transporter, threatens to undermine the efficacy of new BDQ-containing regimens. Since the shift in MIC due to these mutations is relatively small (2-8×), safer, and more potent, diarylquinoline analogues may be more effective than BDQ. TBAJ-876, which is in phase 1 trials, has more potent in vitro activity and a superior pre-clinical safety profile than BDQ. Using a murine model of TB, we evaluated the dose-dependent activity of TBAJ-876 compared to BDQ against the wild-type H37Rv strain and an isogenic Rv0678 loss-of-function mutant. Although the mutation affected the MIC of both drugs, the MIC of TBAJ-876 against the mutant was 10-fold lower than that of BDQ. TBAJ-876 at doses ≥6.25 mg/kg had greater efficacy against both strains compared to BDQ at 25 mg/kg, when administered alone or in combination with pretomanid and linezolid. Likewise, no selective amplification of BDQ-resistant bacteria was observed at TBAJ-876 doses ≥6.25 mg/kg. These results indicate that replacing BDQ with TBAJ-876 may shorten the duration of TB treatment and be more effective in treating and preventing infections caused by Rv0678 mutants.
 
DOI: 10.1128/AAC.01412-21
PMID: 34570644

From our November 2022 Newsletter

1. Adherence trajectory as an on-treatment risk indicator among drug-resistant TB patients in the Philippines

PLoS One. 2022 Nov 8;17(11):e0277078. doi: 10.1371/journal.pone.0277078.
eCollection 2022.
 
Huddart S(1)(2), Geocaniga-Gaviola DM(3), Crowder R(1)(2), Lim AR
(3), Lopez E(3), Valdez CL(3), Berger CA(1)(2), Destura R(4), Kato-Maeda M(1)(2), Cattamanchi A(1)(2), Garfin AMC(3).
 
INTRODUCTION: High levels of treatment adherence are critical for achieving
optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.
METHODS: We conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of
treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.
RESULTS: Of 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%)
extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n = 483), a moderate adherence group (n = 93) and a low adherence group (n = 20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90-6.12) and final (aOR 2.71, 95% 1.73-4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9% vs. 65.4% correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).
CONCLUSIONS: Adherence patterns are strongly predictive of DR TB treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.
 
Copyright: © 2022 Huddart et al.
 
DOI: 10.1371/journal.pone.0277078
PMCID: PMC9642894
PMID: 36346814 [Indexed for MEDLINE]

2. Effectiveness and Safety of Bedaquiline-based, Modified All-oral 9-11-month Treatment Regimen for Rifampicin-Resistant Tuberculosis in Vietnam.
 
Int J Infect Dis. 2022 Nov 10:S1201-9712(22)00592-6. doi: 10.1016/j.ijid.2022.11.007. Online ahead of print.
 
Mai Phuong NT(1), Hai Minh LT(1), Collette Merle CS(2), Pedrazzoli D(3), Linh NN(3), Decroo T(4), Hoa NB(1), Thuy HTT(1), Nhung NV(5).
 
BACKGROUND: WHO recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR).
METHODS: Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid, clofazimine and/or pyrazinamide) for RR-TB patients
without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021.
RESULTS: One hundred eight patients were enrolled. Sixty-three of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, 6 (6%) were lost-to-follow-up, 1 (1%) died and 4 (4%) had
treatment failure, including 3 with permanent regimen change due to adverse events (AE) and 1 with culture reversion. Thirty-two (30% of 108) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening or death). The median time to AE was 3 months (IQR:2-5). Twenty-six AEs led to regimen adaptation: either dose reduction (N=1), drug temporary interruption (N=19), or drug permanent discontinuation (N=6, 4 attributed to linezolid).
CONCLUSION: The high treatment success 5-drug mSTR may replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using linezolid throughout.
 
Copyright © 2022. Published by Elsevier Ltd.
 
DOI: 10.1016/j.ijid.2022.11.007
PMID: 36372364
 
3. Selection bias in multidrug-resistant tuberculosis cohort studies assessing  sputum culture conversion.

PLoS One. 2022 Nov 10;17(11):e0276457. doi: 10.1371/journal.pone.0276457. 
eCollection 2022.

Rodriguez CA(1)(2), Lodi S(3), Horsburgh CR(1), Bastard M(4), Hewison C(5), 
Huerga H(4), Khan M(6), Khan PY(7)(8), Khan U(7), Oyewusi L(9), Padayachee S(6), Mitnick CD(2), Franke MF(2).

BACKGROUND: Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.
METHODS: We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.
RESULTS: In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.
CONCLUSION: Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

Copyright: © 2022 Rodriguez et al. 

DOI: 10.1371/journal.pone.0276457
PMCID: PMC9648724
PMID: 36355658 [Indexed for MEDLINE]

4. In silico evaluation of WHO-endorsed molecular methods to detect drug resistant tuberculosis.

Sci Rep. 2022 Oct 22;12(1):17741. doi: 10.1038/s41598-022-21025-6.

Brankin A(1)(2), Seifert M(2)(3), Georghiou SB(2), Walker TM(1)(4), Uplekar S(2), Suresh A(2), Colman RE(5)(6).

Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.

© 2022. The Author(s).

DOI: 10.1038/s41598-022-21025-6
PMCID: PMC9587982
PMID: 36273016 [Indexed for MEDLINE]
 
5. Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

Clin Infect Dis. 2022 Nov 14;75(10):1772-1780. doi: 10.1093/cid/ciac252.

Hughes JA(1), Solans BP(2), Draper HR(1), Schaaf HS(1), Winckler JL(1), van der Laan L(1), Radtke KK(2), Fourie B(3), Wiesner L(4), Hesseling AC(1), Savic 
RM(2), Garcia-Prats AJ(1)(5).

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We 
described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care.
METHODS: In this observational cohort study, children aged 6-17 years receiving 
bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described.
RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation.
CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

© The Author(s) 2022. Published by Oxford University Press for the Infectious 
Diseases Society of America. All rights reserved. For permissions, e-mail: 
journals.permissions@oup.com.

DOI: 10.1093/cid/ciac252
PMCID: PMC9662178
PMID: 35377434 [Indexed for MEDLINE]

6. Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial

BACKGROUND: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen.
METHODS: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631.
FINDINGS: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9–19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1–31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss.
INTERPRETATION: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss.
FUNDING: USAID and Janssen Research & Development.
 
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S0140-6736(22)02078-5
PMID: 36368336 [Indexed for MEDLINE]

From our October 2022 Newsletter

Mutation detection and minimum inhibitory concentration determination against linezolid and clofazimine in confirmed XDR-TB clinical isolates. 

BMC Microbiol. 2022 Oct 3;22(1):236. doi: 10.1186/s12866-022-02622-x. 

Singh K(1), Sharma S(1), Banerjee T(1), Gupta A(2), Anupurba S(3).
 
BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates.
RESULTS: A total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC50 and MIC90 for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene.
CONCLUSION: REMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively.
 
© 2022. The Author(s).
 
DOI: 10.1186/s12866-022-02622-x
PMCID: PMC9531458
PMID: 36192704 [Indexed for MEDLINE]

2. Caregiver willingness to give TPT to children living with drug-resistant TB patients. 

Int J Tuberc Lung Dis. 2022 Oct 1;26(10):949-955. doi: 10.5588/ijtld.21.0760.
 
Rouzier V(1), Murrill M(2), Kim S(3), Naini L(4), Shenje J(5), Mitchell E(6), Raesi M(7), Lourens M(8), Mendoza A(9), Conradie F(10), Suryavanshi N(11), Hughes M(12), Shah S(13), Churchyard G(14), Swindells S(15), Hesseling A(16), Gupta A(1).
 
BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.
METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.
RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27-48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3-11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2-23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6-12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6-12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1-14.3), and willingness to take TPT oneself (OR 35.1, 95% CI 11.0-112.8).
CONCLUSIONS A high percentage of caregivers living with MDR- or rifampicin-resistant TB patients were willing to give children a hypothetical MDR TPT. These results provide important evidence for the potential uptake of effective MDR TPT when implemented.
 
DOI: 10.5588/ijtld.21.0760
PMCID: PMC9524515
PMID: 36163664 [Indexed for MEDLINE]
 
3. Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. 

Clin Infect Dis. 2022 Sep 29;75(6):1006-1013. doi: 10.1093/cid/ciac019.
 
Hewison C(1), Khan U(2), Bastard M(3), Lachenal N(4), Coutisson S(4), Osso E(5), Ahmed S(6), Khan P(2), Franke MF(5), Rich ML(5)(7), Varaine F(1), Melikyan N(3), Seung KJ(5)(7), Adenov M(8), Adnan S(9), Danielyan N(10), Islam S(11), Janmohamed A(6), Karakozian H(12), Kamene Kimenye M(13), Kirakosyan O(14), Kholikulov B(15), Krisnanda A(16), Kumsa A(17), Leblanc G(18), Lecca L(19), Nkuebe M(20), Mamsa S(9), Padayachee S(21), Thit P(22), Mitnick CD(5)(7), Huerga H(3).
 
Comment in doi: 10.1093/cid/ciac347.
 
BACKGROUND: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.
METHODS: Multicentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.
RESULTS: Among 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.
CONCLUSIONS: AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations.
CLINICAL TRIALS REGISTRATION: NCT02754765.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciac019
PMCID: PMC9522425
PMID: 35028659 [Indexed for MEDLINE]
 
4. Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial. 

Trials. 2022 Oct 8;23(1):864. doi: 10.1186/s13063-022-06793-w.
 
Van Rie A(1), De Vos E(2), Costa E(3), Verboven L(2), Ndebele F(4), Heupink TH(2), Abrams S(2); SMARTT team, Fanampe B(5), Van der Spoel Van Dyk A(6), Charalambous S(4), Churchyard G(4), Warren R(3).
 
Collaborators: Maraba N, Makkan H, Beattie T, Sibeko ZR, Bohlela S, Segwaba P, Ogunbayo EA, Mhlambi N, Wells F, Rigouts L, Maartens G, Conradie F, Black J, Potgieter S.
 
BACKGROUND: Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition.
METHODS: This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective.
DISCUSSION: This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.
 
© 2022. The Author(s).
 
DOI: 10.1186/s13063-022-06793-w
PMCID: PMC9548157
PMID: 36209235 [Indexed for MEDLINE]
 
5. Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus. 

BMC Health Serv Res. 2022 Sep 30;22(1):1217. doi: 10.1186/s12913-022-08525-x.
 
Harrison RE(1), Shyleika V(1), Falkenstein C(1), Garsevanidze E(1), Vishnevskaya O(1), Lonnroth K(2), Sayakci Ö(1), Sinha A(3), Sitali N(4), Skrahina A(5), Stringer B(3), Tan C(6), Mar HT(1), Venis S(3), Vetushko D(5), Viney K(2)(7), Vishneuski R(1), Carrion Martin AI(8).
 
BACKGROUND: Tuberculosis (TB) often concentrates in groups of people with complex health and social issues, including alcohol use disorders (AUD). Risk of TB, and poor TB treatment outcomes, are substantially elevated in people who have AUD. Médecins sans Frontières and the Belarus Ministry of Health have worked to improve treatment adherence in patients with multi-drug or rifampicin resistant (MDR/RR)-TB and harmful use of alcohol. In 2016, a person-centred, multidisciplinary, psychosocial support and harm reduction programme delivered
by TB doctors, counsellors, psychiatrists, health-educators, and social workers was initiated. In 2020, we described patient and provider experiences within the programme as part of a wider evaluation.
METHODS: We recruited 12 patients and 20 health-care workers, using purposive sampling, for in-depth individual interviews and focus group discussions. We used a participant-led, flexible, exploratory approach, enabling participants and the interviewer to shape topics of conversation. Qualitative data were coded manually and analysed thematically. As part of the analysis process, identified themes were shared with health-care worker participants to enable their reflections to be incorporated into the findings.
RESULTS: Key themes related to the patients' and practitioners experience of having and treating MDRTB with associated complex health and social issues were: fragility and despair and guidance, trust and health. Prejudice and marginalisation were global to both themes. Counsellors and other health workers built a trusting relationship with patients, enabling guidance through a multi-disciplinary approach, which supported patients to achieve their vision of health. This guidance was achieved by a team of social workers, counsellors, doctors and health-educators who provided professional and individualised help for patients' illnesses, personal or interpersonal problems, administrative tasks, and job searches.
CONCLUSIONS: Patients with MDR/RR-TB and harmful use of alcohol faced complex issues during treatment. Our findings describe how person-centred, multi-disciplinary, psychosocial support helped patients in this setting to cope with these challenges and complete the treatment programme. We recommend that these findings are used to: i) inform programmatic changes to further boost the person-centred care nature of this program; and ii) advocate for this type of person-centred care approach to be rolled out across Belarus, and in contexts that face similar challenges.
 
© 2022. The Author(s).
 
DOI: 10.1186/s12913-022-08525-x
PMCID: PMC9523183
PMID: 36180873 [Indexed for MEDLINE]
 
6. Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs. 

Clin Infect Dis. 2022 Oct 12;75(8):1307-1314. doi: 10.1093/cid/ciac176.
 
Huerga H(1), Khan U(2), Bastard M(1), Mitnick CD(3)(4)(5), Lachenal N(6), Khan PY(2)(7), Seung KJ(3)(4)(5), Melikyan N(1), Ahmed S(8), Rich ML(3)(4)(5), Varaine F(9), Osso E(3)(6), Rashitov M(10), Salahuddin N(11), Salia G(12), Sánchez E(13), Serobyan A(14), Rafi Siddiqui M(15), Grium Tefera D(16), Vetushko D(17), Yeghiazaryan L(18), Holtzman D(19), Islam S(11), Kumsa A(20), Jacques Leblanc G(21), Leonovich O(22), Mamsa S(11), Manzur-Ul-Alam M(23), Myint Z(24), Padayachee S(25), Franke MF(3), Hewison C(9).
 
BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.
METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.
RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure.
CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.
 
© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.
 
DOI: 10.1093/cid/ciac176
PMCID: PMC9555840
PMID: 35243494 [Indexed for MEDLINE]

 
From our September 2022 Newsletter

1. High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates

Emerg Microbes Infect. 2022 Dec;11(1):1857-1866. doi: 10.1080/22221751.2022.2099304.

Trisakul K(1)(2), Nonghanphithak D(1)(2), Chaiyachat P(1)(2), Kaewprasert O(1)(2), Sakmongkoljit K(3), Reechaipichitkul W(1)(2), Chaiprasert A(4), Blair D(5), Clark TG(6), Faksri K(1)(2).

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of Rv0678 and Rv1979c were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%)
for clofazimine resistance with additional mmpL5 mutations. Mutations conferring resistance to delamanid were detected in fbiB and ddn genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the ddn gene for 3/513 isolates (0.6%). Nineteen mutations of pykA, cycA, ald, and alr genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.

DOI: 10.1080/22221751.2022.2099304
PMCID: PMC9336503
PMID: 35792049 [Indexed for MEDLINE]
 
2. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Lancet Microbe. 2022 Sep;3(9):e672-e682. doi: 10.1016/S2666-5247(22)00116-1. Epub 2022 Jul 27.

Finci I(1), Albertini A(2), Merker M(3), Andres S(4), Bablishvili N(5), Barilar I(6), Cáceres T(7), Crudu V(8), Gotuzzo E(7), Hapeela N(9), Hoffmann H(10), Hoogland C(2), Kohl TA(6), Kranzer K(11), Mantsoki A(2), Maurer FP(12), Nicol MP(13), Noroc E(8), Plesnik S(14), Rodwell T(15), Ruhwald M(2), Savidge T(16), Salfinger M(17), Streicher E(18), Tukvadze N(5), Warren R(18), Zemanay W(9), Zurek A(19), Niemann S(6), Denkinger CM(20).

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.
METHODS: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.
FINDINGS: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1%
[95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.
INTERPRETATION: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).
FUNDING: Bill &amp; Melinda Gates Foundation, German Centre for Infection Research,

German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG. Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2666-5247(22)00116-1
PMCID: PMC9436784
PMID: 35907429 [Indexed for MEDLINE]
 
3. Pharmacokinetics and Safety of WHO-Recommended Dosage and Higher Dosage of Levofloxacin for Tuberculosis Treatment in Children: a Pilot Study.

Int J Infect Dis. 2022 Sep;122:603-608. doi: 10.1016/j.ijid.2022.07.029. Epub
2022 Jul 13.

Jantarabenjakul W(1), Suntarattiwong P(2), Wacharachaisurapol N(3), Supradish Na Ayudhya P(2), Phaisal W(4), Tawan M(5), Moonwong J(5), Sudjaritruk T(6), Chariyavilaskul P(4), Puthanakit T(7).

OBJECTIVES: To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage.
METHODS: Children aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100.
RESULTS: The median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events.
CONCLUSION: Levofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2022.07.029
PMID: 35842213 [Indexed for MEDLINE] 

4. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.

Conradie F(1), Bagdasaryan TR(1), Borisov S(1), Howell P(1), Mikiashvili L(1), Ngubane N(1), Samoilova A(1), Skornykova S(1), Tudor E(1), Variava E(1), Yablonskiy P(1), Everitt D(1), Wills GH(1), Sun E(1), Olugbosi M(1), Egizi E(1), Li M(1), Holsta A(1), Timm J(1), Bateson A(1), Crook AM(1), Fabiane SM(1), Hunt R(1), McHugh TD(1), Tweed CD(1), Foraida S(1), Mendel CM(1), Spigelman M(1); ZeNix Trial Team.
Collaborators: Bagdasaryan T, Conradie F, Ngubane N, Howell P, Borisov S,
Mikiashvili L, Variava E, Samoilova A, Yablonskiy P, Tudor E, Skornyakov S,
Thompson L, Canseco JO, Paleckyte A, Solanki P, Choo L, Witney AA.

Comment in N Engl J Med. 2022 Sep 1;387(9):842-843.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.
METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.
RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.
CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2119430
PMID: 36053506 [Indexed for MEDLINE]

From our August 2022 Newsletter

1. Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline.

Clin Pharmacokinet. 2022 Aug;61(8):1177-1185. doi: 10.1007/s40262-022-01133-2. Epub 2022 Jun 7.

Tanneau L(1), Karlsson MO(1), Diacon AH(2), Shenje J(3), De Los Rios J(4), Wiesner L(5), Upton CM(2), Dooley KE(6), Maartens G(5), Svensson EM(7)(8).

BACKGROUND AND OBJECTIVE: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered.

METHODS: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.

RESULTS: Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV).
CONCLUSIONS: This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

© 2022. The Author(s).

DOI: 10.1007/s40262-022-01133-2
PMCID: PMC9349160
PMID: 35668346 [Indexed for MEDLINE]
 
2. Integrative analysis of clinical health records, imaging and pathogen genomics identifies personalized predictors of disease prognosis in tuberculosis.

medRxiv. 2022 Jul 21:2022.07.20.22277862. doi: 10.1101/2022.07.20.22277862. Preprint.

Sambarey A, Smith K, Chung C, Arora HS, Yang Z, Agarwal P, Chandrasekaran S.

Tuberculosis (TB) afflicts over 10 million people every year and its global burden is projected to increase dramatically due to multidrug-resistant TB (MDR-TB). The Covid-19 pandemic has resulted in reduced access to TB diagnosis and treatment, reversing decades of progress in disease management globally. It is thus crucial to analyze real-world multi-domain information from patient health records to determine personalized predictors of TB treatment outcome and drug resistance. We conduct a retrospective analysis on electronic health records of 5060 TB patients spanning 10 countries with high burden of MDR-TB including Ukraine, Moldova, Belarus and India available on the NIAID-TB portals database. We analyze over 200 features across multiple host and pathogen modalities representing patient social demographics, disease presentations as seen in cChest X rays and CT scans, and genomic records with drug susceptibility features of the pathogen strain from each patient. Our machine learning model, built with diverse data modalities outperforms models built using each modality alone in predicting treatment outcomes, with an accuracy of 81% and AUC of 0.768. We determine robust predictors across countries that are associated with unsuccessful treatmentclinical outcomes, and validate our predictions on new patient data from TB Portals. Our analysis of drug regimens and drug interactions suggests that synergistic drug combinations and those containing the drugs Bedaquiline, Levofloxacin, Clofazimine and Amoxicillin see more success in treating MDR and XDR TB. Features identified via chest imaging such as percentage of abnormal volume, size of lung cavitation and bronchial obstruction are associated significantly with pathogen genomic attributes of drug resistance. Increased disease severity was also observed in patients with lower BMI and with comorbidities. Our integrated multi-modal analysis thus revealed significant associations between radiological, microbiological, therapeutic, and demographic data modalities, providing a deeper understanding of personalized responses to aid in the clinical management of TB.

DOI: 10.1101/2022.07.20.22277862
PMCID: PMC9327630
PMID: 35898335

 
3. A data compendium associating the genomes of 12,289 Mycobacterium tuberculosis isolates with quantitative resistance phenotypes to 13 antibiotics.

PLoS Biol. 2022 Aug 9;20(8):e3001721. doi: 10.1371/journal.pbio.3001721. eCollection 2022 Aug.

The CRyPTIC Consortium.

Comment in
    Genome-wide association studies of global Mycobacterium tuberculosis resistance to thirteen antimicrobials in 10,228 genomes identify new resistance mechanisms.

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

DOI: 10.1371/journal.pbio.3001721
PMCID: PMC9363010
PMID: 35944069 [Indexed for MEDLINE]
 

4. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Lancet Microbe. 2022 Jul 27:S2666-5247(22)00116-1. doi: 10.1016/S2666-5247(22)00116-1. Online ahead of print.

Finci I(1), Albertini A(2), Merker M(3), Andres S(4), Bablishvili N(5), Barilar I(6), Cáceres T(7), Crudu V(8), Gotuzzo E(7), Hapeela N(9), Hoffmann H(10), Hoogland C(2), Kohl TA(6), Kranzer K(11), Mantsoki A(2), Maurer FP(12), Nicol MP(13), Noroc E(8), Plesnik S(14), Rodwell T(15), Ruhwald M(2), Savidge T(16), Salfinger M(17), Streicher E(18), Tukvadze N(5), Warren R(18), Zemanay W(9), Zurek A(19), Niemann S(6), Denkinger CM(20).

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.
METHODS: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.
FINDINGS: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.
INTERPRETATION: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M 
tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).
FUNDING: Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open 
Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All 
rights reserved.

DOI: 10.1016/S2666-5247(22)00116-1
PMID: 35907429

From our July 2022 Newsletter

1. Spatial heterogeneity of extensively drug resistant-tuberculosis in Western Cape Province, South Africa.

 

Sci Rep. 2022 Jun 27;12(1):10844. doi: 10.1038/s41598-022-14581-4.

Sy KTL(1), Leavitt SV(2), de Vos M(3), Dolby T(4), Bor J(1)(2), Horsburgh CR Jr(1)(2)(5)(6), Warren RM(3), Streicher EM(3), Jenkins HE(2), Jacobson KR(7).

 

Tuberculosis (TB) remains a leading infectious disease killer globally. Treatment outcomes are especially poor among people with extensively drug-resistant (XDR) TB, until recently defined as rifampicin-resistant (RR) TB with resistance to an aminoglycoside (amikacin) and a fluoroquinolone (ofloxacin). We used laboratory TB test results from Western Cape province, South Africa between 2012 and 2015 to identify XDR-TB and pre-XDR-TB (RR-TB with resistance to one second-line drug) spatial hotspots. We mapped the percentage and count of individuals with RR-TB that had XDR-TB and pre-XDR-TB across the province and in Cape Town, as well as amikacin-resistant and ofloxacin-resistant TB. We found the percentage of pre-XDR-TB and the count of XDR-TB/pre-XDR-TB highly heterogeneous with geographic hotspots within RR-TB high burden areas, and found hotspots in both percentage and count of amikacin-resistant and ofloxacin-resistant TB. The spatial distribution of percentage ofloxacin-resistant TB hotspots was similar to XDR-TB hotspots, suggesting that fluoroquinolone-resistace is often the first step to additional resistance. Our work shows that interventions used to reduce XDR-TB incidence may need to be targeted within spatial locations of RR-TB, and further research is required to understand underlying drivers of XDR-TB transmission in these locations.

 

© 2022. The Author(s).

DOI: 10.1038/s41598-022-14581-4

PMCID: PMC9237070

PMID: 35760977 [Indexed for MEDLINE] 

 

2. Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis.

 

Clin Infect Dis. 2022 Jun 29:ciac528. doi: 10.1093/cid/ciac528. Online ahead of print.

 

Padmapriyadarsini C(1), Vohra V(2), Bhatnagar A(3), Solanki R(4), Sridhar R(5), Anande L(6), Muthuvijaylakshmi M(1), Bhatia M(2), Jeyadeepa B(1), Taneja G(3), Balaji S(1), Shah P(4), Saravanan N(1), Chauhan V(6), Kumar H(1), Ponnuraja C(1), Livchits V(7), Bahl M(8), Alavadi U(7), Sachdeva KS(9), Swaminathan S(10)(11); for BEAT India Team.

 

BACKGROUND: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+).

METHODS: We prospectively determined the effectiveness and safety of combining two new drugs with two repurposed drugs - Bedaquiline, Delamanid, Linezolid, and Clofazimine for 24-36 weeks in adults with pulmonary MDR-TBFQ+ or/and MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as two consecutive negative cultures taken four weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during treatment period.

RESULTS: Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: four deaths, seven treatment changes, two bacteriological failures, and one withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500msec. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority.

CONCLUSION: After 24-36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

 

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

DOI: 10.1093/cid/ciac528

PMID: 35767251 

 

3. Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB.

 

Int J Tuberc Lung Dis. 2022 Jul 1;26(7):671-677. doi: 10.5588/ijtld.21.0678.

 

Kambili C(1), Rossenu S(2), Hoetelmans RMW(2), Birmingham E(3), Bakare N(4).

 

SETTING: The recommended dosing regimen for bedaquiline (BDQ), consisting of a 2-week loading phase (400 mg/day), followed by a maintenance phase (200 mg three times/week), might pose challenges when treatment is interrupted and needs to be reinitiated. Guidance on BDQ treatment re-initiation is, therefore, needed.

OBJECTIVE: This pharmacokinetic-based simulation study aimed to provide recommendations for re-initiating BDQ following treatment interruptions.

DESIGN: Simulations of treatment interruptions, defined as any time a patient misses ≥2 consecutive BDQ doses for up to 56 consecutive days (2 months), were assessed using the BDQ population-pharmacokinetic model.

RESULTS: Any treatment interruption lasting ≤28 days prior to completing the 14-day loading phase can be managed by completing the remaining loading doses. Scenarios when it is sufficient to simply restart maintenance dosing are discussed. In some scenarios, treatment interruptions require reloading for 1 week prior to restarting maintenance dosing.

CONCLUSIONS: This simulation study provided recommendations for managing BDQ treatment interruptions and underscores the importance of having a robust population-pharmacokinetic model for TB drugs to inform clinical guidance. Such recommendations are valuable to help ensure optimal treatment with BDQ for treating multidrug-resistant TB.

 

DOI: 10.5588/ijtld.21.0678

PMCID: PMC9272739

PMID: 35768912 [Indexed for MEDLINE] 

4. Practical and psychosocial challenges faced by caregivers influence the acceptability of multidrug-resistant tuberculosis preventive therapy for young children.

 

PLoS One. 2022 Jul 14;17(7):e0268560. doi: 10.1371/journal.pone.0268560. eCollection 2022.

 

Wademan DT(1), Hoddinott G(1), Purchase SE(1), Seddon JA(1)(2), Hesseling AC(1), Garcia-Prats AJ(1)(3), Reis R(4)(5)(6), Reynolds LJ(7)(8).

 

Drug-resistant (DR) strains of Mycobacterium tuberculosis (M. tb) are increasingly recognised as a threat to global tuberculosis (TB) control efforts. Identifying people with DR-TB exposure/ infection and providing TB preventive therapy (TPT) is a public health priority. TB guidelines advise the evaluation of household contacts of newly diagnosed TB cases, with the provision of TPT to vulnerable populations, including young children (<5 years). Many children become infected with TB through exposure in their household. Levofloxacin is under evaluation as TPT in children exposed to M. tb strains with resistance to rifampicin and isoniazid (multidrug-resistant TB; MDR-TB). Prior to opening a phase 3 prevention trial in children <5 years exposed to MDR-TB, the pharmacokinetics and safety of a novel formulation of levofloxacin given daily was evaluated as part of a lead-in study. We conducted an exploratory qualitative study of 10 caregivers' experiences of administering this formulation. We explored how the acceptability of levofloxacin as TPT is shaped by the broader impacts of MDR-TB on the overall psychological, social, and financial wellbeing of caregivers, many of whom also had experienced MDR-TB. Caregivers reported that the novel levofloxacin formulation was acceptable. However, caregivers described significant psychosocial challenges in the process of incorporating TPT administration to their children into their daily lives, including financial instability, withdrawal of social support and stigma. When caregivers themselves were sick, these challenges became even more acute. Although new child-friendly formulations can ameliorate some of the pragmatic challenges related to TPT preparation and administration, the overall psychosocial burden on caregivers responsible for administering TPT remains a major determinant of effective MDR-TB prevention in children.

 

DOI: 10.1371/journal.pone.0268560

PMCID: PMC9282439

PMID: 35834509 [Indexed for MEDLINE]

 

5. The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study.

 

Lancet Glob Health. 2022 Jul;10(7):e1034-e1044. doi: 10.1016/S2214-109X(22)00113-9. Epub 2022 May 18.

 

Dodd PJ(1), Mafirakureva N(2), Seddon JA(3), McQuaid CF(4).Comment in Lancet Glob Health. 2022 Jul;10(7):e942-e943.

 

BACKGROUND: Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done.

METHODS: We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy.

FINDINGS: Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000-252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940-2790), costing an additional US$63 million (74-95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540-6890) and an additional 1240 deaths (970-1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin.

INTERPRETATION: HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally.

FUNDING: UK Medical Research Council.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2214-109X(22)00113-9

PMCID: PMC9197775

PMID: 35597248 [Indexed for MEDLINE]

 

From Our October 2021 Newsletter

Design of Multidrug-Resistant Tuberculosis Treatment Regimens Based on DNA Sequencing.
 
Clin Infect Dis. 2021 Oct 5;73(7):1194-1202. doi: 10.1093/cid/ciab359.
 
Grobbel HP(1)(2)(3), Merker M(2)(4), Köhler N(1)(2)(3), Andres S(5), Hoffmann H(6)(7), Heyckendorf J(1)(2)(3), Reimann M(1)(2)(3), Barilar I(4), Dreyer V(4), Hillemann D(5), Kalsdorf B(1)(2)(3), Kohl TA(4), Sanchez Carballo P(1)(2)(3), Schaub D(1)(2)(3), Todt K(6)(7), Utpatel C(4), Maurer FP(5)(8), Lange C(1)(2)(3)(9), Niemann S(2)(4)(5).
 
BACKGROUND: Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens.
METHODS: NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates.
RESULTS: In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST.
CONCLUSIONS: NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious 
Diseases Society of America. All rights reserved. For permissions, e-mail: 
journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciab359
PMCID: PMC8492214
PMID: 33900387
 
Exposure-safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis.
 
CPT Pharmacometrics Syst Pharmacol. 2021 Oct 9. doi:10.1002/psp4.12722. Online ahead of print.
 
Tanneau L(1), Svensson EM(1)(2), Rossenu S(3), Karlsson MO(1).
 
Bedaquiline (BDQ) has shown great value in the treatment of multidrug-resistant tuberculosis (MDR-TB) in recent years. However, exposure-safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels, in MDR-TB patients using the approved dose regimen. Data from 429 MDR-TB patients from two phase IIb studies were analyzed via non-linear mixed-effects modeling. Individual model-predicted concentrations and summary PK metrics were evaluated respectively in the QTcF interval and transaminase levels exposure-response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug-related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to critical QTcF interval increase. No exposure-safety relationship could be described with transaminase levels, despite previous reports of higher levels in BDQ-treated patients. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase levels elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.
 
This article is protected by copyright. All rights reserved.
 
DOI: 10.1002/psp4.12722
PMID: 34626526
 
Proposed linezolid dosing strategies to minimize adverse events for treatment of extensively drug-resistant tuberculosis.
 
Clin Infect Dis. 2021 Oct 4:ciab699. doi: 10.1093/cid/ciab699. Online ahead of print.
 
Imperial MZ(1), Nedelman JR(2), Conradie F(3), Savic RM(1).
 
BACKGROUND: We evaluated clinical trial data (Nix-TB, NCT02333799) to provide data-driven dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis.
METHODS: Based on 104 participants, a pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥grade 3 adverse events according to the Division of Microbiology and Infectious Disease Adult Toxicity table.
RESULTS: Predicted individual concentration-time profiles were a major predictor in all three toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median: 19% (90%CI: 17-22%) vs 5% (4-7%)) and severe anemia (15% (12-17%) vs 1% (0-2%)) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median: <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >10% decrease from pretreatment in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing dose from 1200 to 600 mg triggered by this marker may prevent 60% (90%CI: 45-72) of severe anemia.
CONCLUSIONS: Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm benefit-to-risk ratio.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious 
Diseases Society of America.
 
DOI: 10.1093/cid/ciab699
PMID: 34604901
 
Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study.
 
Lancet Infect Dis. 2021 Oct 7:S1473-3099(21)00452-7. doi: 10.1016/S1473-3099(21)00452-7. Online ahead of print.
 
Penn-Nicholson A(1), Georghiou SB(2), Ciobanu N(3), Kazi M(4), Bhalla M(5), David A(6), Conradie F(6), Ruhwald M(2), Crudu V(3), Rodrigues C(4), Myneedu VP(5), Scott L(6), Denkinger CM(7), Schumacher SG(2); Xpert XDR Trial Consortium.
 
BACKGROUND: The WHO End TB Strategy requires drug susceptibility testing and treatment of all people with tuberculosis, but second-line diagnostic testing with line-probe assays needs to be done in experienced laboratories with advanced infrastructure. Fewer than half of people with drug-resistant tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA, USA) to overcome these limitations.
METHODS: We did a prospective study involving individuals presenting with pulmonary tuberculosis symptoms and at least one risk factor for drug resistance in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin, and capreomycin in adults with positive results for Mycobacterium tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance was assessed against a composite reference standard of phenotypic drug-susceptibility testing and whole-genome sequencing. This study is registered with ClinicalTrials.gov, number NCT03728725.
FINDINGS: Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and the reference standard for any drug and were included in analysis. Sensitivity for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92-96) for isoniazid, 94% (222 of 235, 90-96%) for fluoroquinolones, 54% (178 of 328, 50-61) for ethionamide, 73% (60 of 82, 62-81) for amikacin, 86% (181 of 210, 81-91) for kanamycin, and 61% (53 of 87, 49-70) for capreomycin. Specificity was 98-100% for all drugs. Performance was equivalent to that of line-probe assays. The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex 
detection) was 2·96%.
INTERPRETATION: The Xpert MTB/XDR assay showed high diagnostic accuracy and met WHO's minimum target product profile criteria for a next-generation drug susceptibility test. The assay has the potential to diagnose drug-resistant tuberculosis rapidly and accurately and enable optimum treatment.
FUNDING: German Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.
 
Copyright © 2021 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/S1473-3099(21)00452-7
PMID: 34627496
 
Baseline assessment of pharmacovigilance activities in four sub-Saharan African countries: a perspective on tuberculosis.
 
BMC Health Serv Res. 2021 Oct 8;21(1):1062. doi: 10.1186/s12913-021-07043-6.
 
Tiemersma EW(1), Ali I(2), Alemu A(3), Avong YK(4)(5), Duga A(6)(7), Elagbaje C(8), Isah A(9), Kay A(10)(11), Mmbaga BT(12)(13), Mmari E(14), Mwamwitwa K(15), Nhlabatsi S(7), Sintayehu K(16), Arefayne A(16), Teferi M(17), Cobelens F(18), Härmark L(19).
 
BACKGROUND: New medicines have become available for the treatment of drug-resistant tuberculosis (DR-TB) and are introduced in sub-Saharan Africa (SSA) by the national TB programs (NTPs) through special access schemes. Pharmacovigilance is typically the task of national medicines regulatory agencies (NMRAs), but the active drug safety monitoring and management (aDSM) recommended for the new TB medicines and regimens was introduced through the NTPs. We assessed the strengths and challenges of pharmacovigilance systems in Eswatini, Ethiopia, Nigeria and Tanzania, focusing on their capacity to monitor safety of medicines registered and not registered by the NMRAs for the treatment of DR-TB.
METHODS: Assessment visits were conducted to all four countries by a 
multidisciplinary team. We used a pharmacovigilance indicator tool derived from existing tools, interviewed key stakeholders, and visited health facilities where DR-TB patients were treated with new medicines. Assessment results were verified with the local NMRAs and NTPs.
RESULTS: Most countries have enabling laws, regulations and guidelines for the conduct of pharmacovigilance by the NMRAs. The relative success of NTP-NMRA collaboration is much influenced by interpersonal relationships between staff. Division of roles and responsibilities is not always clear and leads to duplication and unfulfilled tasks (e.g. causality assessment). The introduction of aDSM has increased awareness among DR-TB healthcare providers.
CONCLUSION: aDSM has created awareness about the importance of pharmacovigilance among NTPs. In the future, a push for conducting pharmacovigilance through public health programs seems useful, but this needs to coincide with increased collaboration with between public health programs and NMRAs with clear formulation of roles and responsibilities.
 
© 2021. The Author(s).
 
DOI: 10.1186/s12913-021-07043-6
PMCID: PMC8499544
PMID: 34625085 [Indexed for MEDLINE]

 

From Our September 2021 Newsletter

Rifampicin mono-resistant tuberculosis is not the same as multidrug-resistant tuberculosis: a descriptive study from Khayelitsha, South Africa.

 
Antimicrob Agents Chemother. 2021 Aug 30:AAC0036421. doi:10.1128/AAC.00364-21. Online ahead of print.
 
Salaam-Dreyer Z(1), Streicher EM(2), Sirgel FA(2), Menardo F(3)(4), Borrell S(3)(4), Reinhard M(3)(4), Doetsch A(3)(4), Cudahy PGT(5), Mohr-Holland E(6), Daniels J(6), Dippenaar A(7), Nicol MP(8), Gagneux S(3)(4), Warren RM(2), Cox H(1)(9).
 
Rifampicin mono-resistant TB (RMR-TB, rifampicin resistance and isoniazid 
susceptibility) constitutes 38% of all rifampicin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rifampicin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rifampicin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV positive individuals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p<0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (p<0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 μg/ml (range 0.125-1 μg/ml). The majority (215/230, 93.5%) of RMR-TB isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.
 
DOI: 10.1128/AAC.00364-21
PMID: 34460307

Effect of Isoniazid Intake on Ethionamide Pharmacokinetics and Target Attainment in Multidrug-Resistant Tuberculosis Patients.
 
Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0027821. doi:10.1128/AAC.00278-21. Epub 2021 Jul 26.
 
Chirehwa MT(1), Court R(1), de Kock M(2), Wiesner L(1), de Vries N(3), Harding J(4), Gumbo T(5), Maartens G(1)(6), Warren R(2), Denti P(1), McIlleron H(1)(6).
 
Ethionamide is recommended as part of regimens to treat multidrug resistant and rifampicin-resistant tuberculosis. This study was conducted to (i) describe the distribution of ethionamide MICs, (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15 to 20 mg of drug/kg of body weight of ethionamide daily (in 500- or 750-mg doses) as part of a multidrug regimen. Pretreatment MICs of ethionamide for Mycobacterium tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured predose and at 2, 4, 6, 8, and 10 h postdose) were available for 84 patients. A one-compartment disposition model, including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid coadministration reduced ethionamide clearance by 31%, resulting in a 44% increase in AUC0-24. The median (range) MIC (n = 111) was 2.5 mg/liter (<0.3 to >40 mg/liter). Simulations showed increased daily doses of ethionamide (1,250 mg, 1,500 mg, and 1,750 mg for patients weighing ≤45 kg, 46 to 70 kg, and >70 kg, respectively) resulted in the probability of attaining an area under the concentration-time curve from 0 
to 24 h for the free, unbound fraction of a drug (fAUC0-24)/MIC ratio of ≥42 in more than 90% of patients only at the lowest MIC of 0.3 mg/liter. The WHO-recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.
 
DOI: 10.1128/AAC.00278-21
PMID: 34310215
 
Lesion Penetration and Activity Limit the Utility of Second-Line Injectable Agents in Pulmonary Tuberculosis.
 
Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0050621. doi:10.1128/AAC.00506-21. Epub 2021 Jul 12.
 
Ernest JP(#)(1), Sarathy J(#)(2), Wang N(2), Kaya F(2), Zimmerman MD(2), Strydom N(1), Wang H(2), Xie M(2), Gengenbacher M(2)(3), Via LE(4)(5), Barry CE 3rd(4)(5), Carter CL(2), Savic RM(1), Dartois V(2)(3).
 
Amikacin and kanamycin are second-line injectables used in the treatment of multidrug-resistant tuberculosis (MDR-TB) based on the clinical utility of streptomycin, another aminoglycoside and first-line anti-TB drug. While streptomycin was tested as a single agent in the first controlled TB clinical trial, introduction of amikacin and kanamycin into MDR-TB regimens was not preceded by randomized controlled trials. A recent large retrospective meta-analysis revealed that compared with regimens without any injectable drug, amikacin provided modest benefits, and kanamycin was associated with worse outcomes. Although their long-term use can cause irreversible ototoxicity, they remain part of MDR-TB regimens because they have a role in preventing emergence of resistance to other drugs. To quantify the contribution of amikacin and kanamycin to second-line regimens, we applied two-dimensional matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging in large lung lesions, quantified drug exposure in lung and in lesions of rabbits with active TB, and measured the concentrations required to kill or inhibit growth of the resident bacterial populations. Using these metrics, we applied site-of-action pharmacokinetic and pharmacodynamic (PK-PD) concepts and simulated drug coverage in patients' lung lesions. The results provide a pharmacological explanation for the limited clinical utility of both agents and reveal better PK-PD lesion coverage for amikacin than kanamycin, consistent with retrospective data of contribution to treatment success. Together with recent mechanistic studies dissecting antibacterial activity from aminoglycoside ototoxicity, the limited but rapid penetration of streptomycin, amikacin, and kanamycin to the sites of TB disease supports the development of analogs with improved efficacy and tolerability.
 
DOI: 10.1128/AAC.00506-21
PMID: 34252307
 
GenTB: A user-friendly genome-based predictor for tuberculosis resistance powered by machine learning.
 
Genome Med. 2021 Aug 30;13(1):138. doi: 10.1186/s13073-021-00953-4.
 
Gröschel MI(1), Owens M(1), Freschi L(1), Vargas R Jr(1)(2), Marin MG(1)(2), Phelan J(3), Iqbal Z(4), Dixit A(1)(5), Farhat MR(6)(7).
 
BACKGROUND: Multidrug-resistant Mycobacterium tuberculosis (Mtb) is a 
significant global public health threat. Genotypic resistance prediction from Mtb DNA sequences offers an alternative to laboratory-based drug-susceptibility testing. User-friendly and accurate resistance prediction tools are needed to enable public health and clinical practitioners to rapidly diagnose resistance and inform treatment regimens.
RESULTS: We present Translational Genomics platform for Tuberculosis (GenTB), a free and open web-based application to predict antibiotic resistance from next-generation sequence data. The user can choose between two potential predictors, a Random Forest (RF) classifier and a Wide and Deep Neural Network (WDNN) to predict phenotypic resistance to 13 and 10 anti-tuberculosis drugs, respectively. We benchmark GenTB's predictive performance along with leading TB resistance prediction tools (Mykrobe and TB-Profiler) using a ground truth dataset of 20,408 isolates with laboratory-based drug susceptibility data. All four tools reliably predicted resistance to first-line tuberculosis drugs but had varying performance for second-line drugs. The mean sensitivities for GenTB-RF and GenTB-WDNN across the nine shared drugs were 77.6% (95% CI 
76.6-78.5%) and 75.4% (95% CI 74.5-76.4%), respectively, and marginally higher than the sensitivities of TB-Profiler at 74.4% (95% CI 73.4-75.3%) and Mykrobe at 71.9% (95% CI 70.9-72.9%). The higher sensitivities were at an expense of ≤ 1.5% lower specificity: Mykrobe 97.6% (95% CI 97.5-97.7%), TB-Profiler 96.9% (95% CI 96.7 to 97.0%), GenTB-WDNN 96.2% (95% CI 96.0 to 96.4%), and GenTB-RF 96.1% (95% CI 96.0 to 96.3%). Averaged across the four tools, genotypic resistance sensitivity was 11% and 9% lower for isoniazid and rifampicin respectively, on isolates sequenced at low depth (< 10× across 95% of the genome) emphasizingthe need to quality control input sequence data before prediction. We discuss differences between tools in reporting results to the user including variants underlying the resistance calls and any novel or indeterminate variants. 
CONCLUSIONS: GenTB is an easy-to-use online tool to 
rapidly and accurately predict resistance to anti-tuberculosis drugs.
GenTB can be accessed online at https://gentb.hms.harvard.edu , and the source code is available at https://github.com/farhat-lab/gentb-site .
 
© 2021. The Author(s).
 
DOI: 10.1186/s13073-021-00953-4
PMCID: PMC8407037
PMID: 34461978

 

From Our August 2021 Newsletter

Impact of the revised definition of extensively drug-resistant tuberculosis.
 
Eur Respir J. 2021 Aug 19;58(2):2100641. doi: 10.1183/13993003.00641-2021. Print 2021 Aug.
 
Veziris N(1), Bonnet I(2), Morel F(2), Guglielmetti L(2), Maitre T(3), Fournier Le Ray L(3), Sougakoff W(2), Robert J(2), Aubry A(2); CNR MyRMA; Members of the CNR-MyRMA (French National Reference Center for Mycobacteria.
 
Collaborators: Cambau E, Mougari F, Ok V.
 
Recently, the World Health Organization (WHO) has released a revised definition of extensively drug resistant (XDR) tuberculosis (TB) that should be used for clinical and surveillance purposes starting from 1 January, 2021 [1, 2]. The previous definition of XDR-TB was TB that is resistant to any fluoroquinolone (levofloxacin and/or moxifloxacin) and to at least one of three second-line injectable drugs (SLIs: capreomycin, kanamycin and amikacin), in addition to multidrug resistance. The revised definition is: TB caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional group A drug. WHO group A drugs currently include fluoroquinolones (levofloxacin or moxifloxacin), linezolid and bedaquiline. In addition, pre-XDR-TB is now a WHO-endorsed definition, identified as MDR/RR-TB with any fluoroquinolone resistance. Although the previous definition of XDR-TB has proved to be predictive of poor treatment outcome [3], the 2020 update appears in line with recent changes of treatment regimens given, i.e. less frequent use of SLI in favour of the potent oral drugs, bedaquiline and linezolid. Moreover, a large meta-analysis failed to show an association between mortality reduction and SLI use, whereas this association was shown for bedaquiline and linezolid [4]. In this study, we aimed to measure retrospectively the impact of the revised definition on the epidemiology of XDR-TB in France.
 
DOI: 10.1183/13993003.00641-2021
PMID: 33926973
 
Adjunctive surgery versus medical treatment among patients with cavitary multidrug-resistant tuberculosis.
 

Eur J Cardiothorac Surg. 2021 Jul 23:ezab337. doi: 10.1093/ejcts/ezab337. Online ahead of print.
 
Vashakidze SA(1)(2), Gogishvili SG(1), Nikolaishvili KG(1), Avaliani ZR(1), Chandrakumaran A(3), Gogishvili GS(1), Magee M(4), Blumberg HM(5), Kempker RR(5).
 
OBJECTIVES: Surgical resection is recommended as adjunctive treatment for multidrug-resistant (MDR) tuberculosis (TB) in certain scenarios; however, data are limited. We sought to evaluate the impact of surgery by comparing TB outcomes among patients with cavitary disease who received medical versus combined medical and surgical treatment.
METHODS: A cohort of all patients with cavitary MDR or extensively drug-resistant (XDR) TB treated in Tbilisi, Georgia, between 2008 and 2012. Patients meeting indications for surgery underwent adjunctive resection in addition to medical treatment. We compared TB outcomes (proportions achieving cure/complete) among patients who received adjunctive surgery to those who received medical treatment alone using an adjusted robust Poisson regression.
RESULTS: Among 408 patients, 299 received medical treatment alone and 109 combined medical and surgical treatment. Patients in the non-surgical group were older and had higher rates of tobacco and alcohol use and bilateral disease compared to the surgical group. Patients in the surgical group had higher rates of XDR disease (28% vs 15%). Favourable outcomes were higher among the surgical versus non-surgical group cohort (76% vs 41%). After adjusting for multiple factors, the association between adjunctive resection and favourable outcome remained (adjusted risk ratio 1.6, 95% confidence interval 1.3-2.0); the relationship was also observed in secondary models that excluded patients with bilateral disease (contraindication for surgery) and patients receiving 
<6 months of treatment. Major postoperative complications occurred among 8 patients (7%) with no postoperative mortality.
CONCLUSIONS: Adjunctive surgery is safe and may improve the effectiveness of treatment among select patients with cavitary MDR- and XDR-TB.
 
© The Author(s) 2021. Published by Oxford University Press on behalf of the 
European Association for Cardio-Thoracic Surgery. All rights reserved.
 
DOI: 10.1093/ejcts/ezab337
PMID: 34297819
 
 
A Semi-Mechanistic Model of the Bactericidal Activity of High-Dose Isoniazid Against Multi Drug-Resistant Tuberculosis: Results from a Randomized Clinical Trial.
 
Am J Respir Crit Care Med. 2021 Aug 17. doi: 10.1164/rccm.202103-0534OC. Online ahead of print.
 
Gausi K(1), Ignatius EH(2), Sun X(3), Kim S(4), Moran L(5), Wiesner L(1), von Groote-Bidlingmaier F(6), Hafner R(7), Donahue K(8), Vanker N(6), Rosenkranz SL(3)(8), Swindells S(9), Diacon AH(6), Nuermberger EL(10), Dooley KE(10), Denti P(11); A5312 Study Team.
 
RATIONALE: There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown.
OBJECTIVE: Characterizing the association between isoniazid pharmacokinetics (standard or high-dose) and early bactericidal activity against M. tuberculosis (drug-sensitive and inhA-mutated) and N acetyltransferase 2 status.
METHODS: ACTG A5312/INHindsight is 7-day early bactericidal activity study with isoniazid at normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary TB received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (CFU) on solid culture and time-to-positivity (TTP) in liquid culture were jointly analyzed using nonlinear mixed-effects modeling.
RESULTS: Fifty-nine adults were included in this analysis. Decline in sputum CFU was described by a one-compartment model, while an exponential bacterial growth model was used to interpret TTP data. The model found bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship. The model predicted lower potency but similar maximum-kill of isoniazid against inhA-mutated isolates compared to drug-sensitive. Based on simulations from the PK/PD model, to achieve a drop in bacterial load comparable to 5mg/kg against drug-sensitive TB, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg.
CONCLUSIONS: Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates while mitigating toxicity risks associated with higher doses. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.
 
DOI: 10.1164/rccm.202103-0534OC
PMID: 34403326
 
The effect of isoniazid intake on ethionamide pharmacokinetics and target attainment in multidrug-resistant tuberculosis patients.
 
Antimicrob Agents Chemother. 2021 Jul 26:AAC0027821. doi: 10.1128/AAC.00278-21. Online ahead of print.
 
Chirehwa MT(1), Court R(1), de Kock M(2), Wiesner L(1), de Vries N(3), Harding J(4), Gumbo T(5), Maartens G(1)(6), Warren R(2), Denti P(1), McIlleron H(1)(6).
 
Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. The study was conducted to (i) describe the distribution of ethionamide minimum inhibitory concentrations (MICs), (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target AUC0-24/MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15-20 mg/kg of ethionamide daily (in 500 or 750 mg doses), as part of a multidrug regimen. Pretreatment MICs of ethionamide for M. tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured pre-dose and at 2, 4, 6, 8 and 10 hours post-dose) were available for 84 patients. A one-compartment disposition model including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid co-administration reduced ethionamide clearance by 31% resulting in a 44% increase in AUC0-24. The median (range) MIC (n=111) was 2.5 mg/L (<0.3 to >40 mg/L). Simulations showed increased daily doses of ethionamide (1 250 mg, 1 500 mg, and 1 750 mg for patients weighing ≤45 kg, 46-70 kg, and >70 kg, respectively) resulted in the probability of attaining a fAUC0-24/MIC ratio ≥ 42 in more than 90% of patients, only at the lowest MIC of 0.3 mg/L. The WHO recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.
 
DOI: 10.1128/AAC.00278-21
PMID: 34310215

 

From Our July 2021 Newsletter

Acceptability, feasibility, and likelihood of stakeholders implementing the novel BPaL regimen to treat extensively drug-resistant tuberculosis patients.
 
BMC Public Health. 2021 Jul 16;21(1):1404. doi: 10.1186/s12889-021-11427-y.
 
van de Berg SEJ(#)(1), Pelzer PT(#)(2), van der Land AJ(1), Abdrakhmanova E(3), Ozi AM(4), Arias M(1), Cook-Scalise S(5), Dravniece G(1)(6), Gebhard A(1), Juneja S(5), Handayani R(7), Kappel D(5), Kimerling M(1), Koppelaar I(1), Malhotra S(5), Myrzaliev B(8), Nsa B(9), Sugiharto J(10), Engel N(11), Mulder C(#)(1)(12), van den Hof S(#)(1)(13).
 
BACKGROUND: BPaL, a 6 month oral regimen composed of bedaquiline, pretomanid, 
and linezolid for treating extensively drug-resistant tuberculosis (XDR-TB) is a potential alternative for at least 20 months of individualized treatment regimens (ITR). The ITR has low tolerability, treatment adherence, and success rates, and hence to limit patient burden, loss to follow-up and the emergence of resistance it is essential to implement new DR-TB regimens. The objective of this study was to assess the acceptability, feasibility, and likelihood of implementing BPaL in Indonesia, Kyrgyzstan, and Nigeria.
METHODS: We conducted a concurrent mixed-methods study among a cross-section of health care workers, programmatic and laboratory stakeholders between May 2018 and May 2019. We conducted semi-structured interviews and focus group discussions to assess perceptions on acceptability and feasibility of implementing BPaL. We determined the proportions of a recoded 3-point Likert scale (acceptable; neutral; unacceptable), as well as the overall likelihood of implementing BPaL (likely; neutral; unlikely) that participants graded per regimen, pre-defined aspect and country. We analysed the qualitative results using a deductive framework analysis.
RESULTS: In total 188 stakeholders participated in this study: 63 from Kyrgyzstan, 51 from Indonesia, and 74 from Nigeria The majority were health care workers (110). Overall, 88% (146/166) of the stakeholders would likely implement BPaL once available. Overall acceptability for BPaL was high, especially patient friendliness was often rated as acceptable (93%, 124/133). In contrast, patient friendliness of the ITR was rated as acceptable by 45%. Stakeholders appreciated that BPaL would reduce workload and financial burden on the health care system. However, several stakeholders expressed concerns regarding BPaL safety (monitoring), long-term efficacy, and national regulatory requirements regarding introduction of the regimen. Stakeholders stressed the importance of addressing current health systems constraints as well, especially in treatment and safety monitoring systems.
CONCLUSIONS: Acceptability and feasibility of the BPaL regimen is high among TB stakeholders in Indonesia, Kyrgyzstan, and Nigeria. The majority is willing to start using BPaL as the standard of care for eligible patients despite country-specific health system constraints.
 
© 2021. The Author(s).
 
DOI: 10.1186/s12889-021-11427-y
PMCID: PMC8284025
PMID: 34271884
 
Concordance of Drug-resistance Profiles Between Persons With Drug-resistant Tuberculosis and Their Household Contacts: A Systematic Review and Meta-analysis.
 
Clin Infect Dis. 2021 Jul 15;73(2):250-263. doi: 10.1093/cid/ciaa613.
 
Chiang SS(1)(2), Brooks MB(3), Jenkins HE(4), Rubenstein D(1), Seddon JA(5)(6), van de Water BJ(3), Lindeborg MM(3), Becerra MC(3)(7), Yuen CM(3)(7).
 
BACKGROUND: Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts.
METHODS: We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.
RESULTS: We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7-67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3-90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases.
CONCLUSIONS: Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious 
Diseases Society of America. All rights reserved. For permissions, e-mail: 
journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciaa613
PMID: 32448887
 
Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review.
 
J Infect. 2021 Jul;83(1):27-36. doi: 10.1016/j.jinf.2021.05.010. Epub 2021 May 17.
 
Dillard LK(1), Martinez RX(2), Perez LL(2), Fullerton AM(3), Chadha S(2), McMahon CM(3).
 
Objectives estimate the prevalence of ototoxic hearing loss in drug-resistant tuberculosis (DR-TB) patients treated with aminoglycoside antibiotics via a systematic review and meta-analysis. Estimate the annual preventable cases of hearing loss in DR-TB patients and leverage findings to discuss primary, secondary and tertiary prevention. Methods studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in DR-TB patients were included. We performed a random effects meta-analysis to determine pooled prevalence of ototoxic hearing loss overall and by medication type. Preventable hearing loss cases were estimated using World Health Organization (WHO) data on DR-TB treatment and prevalence determined by the meta-analysis. Results eighteen studies from 10 countries were included. Pooled prevalence of ototoxic hearing loss and the corresponding 95% confidence interval (CI) was 40.62% CI [32.77- 66.61%] for all drugs (kanamycin: 49.65% CI [32.77- 66.61%], amikacin: 38.93% CI [26.44-53.07%], capreomycin: 10.21% CI [4.33-22.21%]). Non-use of aminoglycosides may result in prevention of approximately 50,000 hearing loss cases annually. Conclusions aminoglycoside use results in high prevalence of ototoxic hearing loss. Widespread prevention of hearing loss can be achieved by following updated WHO guidelines for DR-TB treatment. When hearing loss cannot be avoided, secondary and tertiary prevention should be prioritized.
 
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.jinf.2021.05.010
PMID: 34015383
 
Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis.
 
Nat Med. 2021 Jul;27(7):1171-1177. doi: 10.1038/s41591-021-01358-x. Epub 2021 May 24.
 
Gygli SM(#)(1)(2), Loiseau C(#)(1)(2), Jugheli L(1)(2)(3), Adamia N(3), Trauner A(1)(2), Reinhard M(1)(2), Ross A(1)(2), Borrell S(1)(2), Aspindzelashvili R(3), Maghradze N(1)(2)(3), Reither K(1)(2), Beisel C(4), Tukvadze N(1)(2)(3), Avaliani Z(3), Gagneux S(5)(6).
 
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual deaths due to antimicrobial resistance1. Drug resistance-conferring mutations frequently cause fitness costs in bacteria2-5. Experimental work indicates that these drug resistance-related fitness costs might be mitigated by compensatory mutations6-10. However, the clinical relevance of compensatory evolution remains poorly understood. Here we show that, in the country of Georgia, during a 6-year nationwide study, 63% of MDR-TB was due to patient-to-patient transmission. Compensatory mutations and patient incarceration were independently associated with transmission. Furthermore, compensatory mutations were overrepresented among isolates from incarcerated individuals that also frequently spilled over into the non-incarcerated population. As a result, up to 31% of MDR-TB in Georgia was directly or indirectly linked to prisons. We conclude that prisons fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of fitness-compensated strains with high transmission potential.
 
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
 
DOI: 10.1038/s41591-021-01358-x
PMID: 34031604
 
Treatment and pregnancy outcomes of pregnant women exposed to second-line anti-tuberculosis drugs in South Africa.
 
BMC Pregnancy Childbirth. 2021 Jun 28;21(1):453. doi: 10.1186/s12884-021-03956-6.
 
Mokhele I(1), Jinga N(2), Berhanu R(2)(3), Dlamini T(4), Long L(2)(3), Evans D(2).
 
BACKGROUND: Multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) in pregnant women is a cause for concern globally; few data have described the safety of second-line anti-TB medications during pregnancy. We aim to describe TB treatment and pregnancy outcomes among pregnant women receiving second-line anti-tuberculosis treatment for MDR/RR-TB in Johannesburg, South Africa.
METHODS: We conducted a retrospective record review of pregnant women (≥ 18 years) who received treatment for MDR/RR-TB between 01/2010-08/2016 at three outpatient treatment sites in Johannesburg, South Africa. Demographic, treatment and pregnancy outcome data were collected from available medical records. Preterm birth (< 37 weeks), and miscarriage were categorized as adverse pregnancy outcomes.
RESULTS: Out of 720 women of child-bearing age who received MDR/RR-TB treatment at the three study sites, 35 (4.4%) pregnancies were identified. Overall, 68.7% (24/35) were HIV infected, 83.3% (20/24) were on antiretroviral therapy (ART). Most women, 88.6% (31/35), were pregnant at the time of MDR/RR-TB diagnosis and four women became pregnant during treatment. Pregnancy outcomes were available for 20/35 (57.1%) women, which included 15 live births (11 occurred prior to 37 weeks), 1 neonatal death, 1 miscarriage and 3 pregnancy terminations. Overall, 13/20 (65.0%) women with known pregnancy outcomes had an adverse pregnancy outcome. Of the 28 women with known TB treatment outcomes 17 (60.7%) completed treatment successfully (4 were cured and 13 completed treatment), 3 (10.7%) died and 8 (28.6%) were lost-to follow-up.
CONCLUSIONS: Pregnant women with MDR/RR-TB suffer from high rates of adverse pregnancy outcomes and about 60% achieve a successful TB treatment outcome. These vulnerable patients require close monitoring and coordinated obstetric, HIV and TB care.
 
DOI: 10.1186/s12884-021-03956-6
PMCID: PMC8240388
PMID: 34182944
 
Analysis of the side effect of QTc interval prolongation in the bedaquiline regimen in drug resistant tuberculosis patients.
 
J Basic Clin Physiol Pharmacol. 2021 Jun 25;32(4):421-427. doi: 10.1515/jbcpp-2020-0415.
 
Ardhianto D(1), Suharjono(1), Soedarsono(2), Fatmawati U(3).
 
OBJECTIVES: Indonesia is one of the top 20 countries with the highest prevalence of drug resistant tuberculosis (DR-TB) worldwide with a percentage of new cases of 2.4% and retreatment of 13%. Bedaquiline (BDQ) is one of the drugs that used in the individual long regimen treating DR-TB. BDQ is also combined with levofloxacin (LFX) and/or clofazimine (CFZ) that can cause QTc interval prolongation. The aim was to study the differences in the use of BDQ regimens to the lengthening of the QTc interval and to study risk factors (diabetes, hypokalemia, sex, BMI, and age) in BDQ regimen.
METHODS: This study was an observational retrospective study with a total sampling method, which was conducted at Dr. Soetomo General Hospital Surabaya. Samples from this study were patients diagnosed with DR-TB at Dr. Soetomo General Hospital Surabaya in the period of January 2015-December 2019 who used BDQ regimen and met the inclusion criteria. The ECG data were analyzed from the mean of each group (BDQ regimen and risk factors), also analyzed using statistical analysis.
RESULTS: Data obtained from total sample in this study were 73 patients. The most widely used different regimens in this study were the combination of BDQ + LFX by 36 patients (49.3%), BDQ + LFX + CFZ by 16 patients (21.9%), BDQ by 11 patients (15.1%) and BDQ + CFZ 10 patients (13.7%). Out of 73 patients, 52 patients (71.2%) experienced lengthening of the QT interval and grade 1 of QTc interval prolongation occurred in most patients and also the onset was mostly one month after using BDQ regimen. The side effects of QTc interval prolongation from groups of combination and risk factors were no difference in each month (p>0.05).
CONCLUSIONS: This study can be concluded that there were no differences in the QTc prolongation between the groups of BDQ regimen (BDQ, BDQ + LFX, BDQ + CFZ and BDQ + LFX + CFZ) and the groups of risk factors.
 
© 2021 Walter de Gruyter GmbH, Berlin/Boston.
 
DOI: 10.1515/jbcpp-2020-0415
PMID: 34214323
 
Cardiac safety of multidrug-resistant tuberculosis treatment: moving towards 
individualised monitoring.

 
Lancet Infect Dis. 2021 Jul;21(7):894-895. doi: 10.1016/S1473-3099(20)30836-7. Epub 2021 Feb 12.
 
Hewison C(1), Guglielmetti L(2).

We are not alone in welcoming the study by Kelly E Dooley and colleagues that sheds light on the QT prolonging effects of the combination of bedaquiline and delamanid, two key drugs for the treatment of multidrug-resistant or rifampicin-resistant tuberculosis. Clinicians treating multidrug-resistant or rifampicin resistant tuberculosis worldwide only recently started losing sleep over the fear of QT interval prolongation, a well-known adverse event of many drugs. A heart rate-corrected QT interval (QTc) of 500 ms or more increases the risk of potentially fatal ventricular arrhythmias, including torsade de pointes. Despite the frequent, long-term use of QT interval-prolonging drugs, including moxifloxacin, which is used as a positive control in thorough QT studies, ECG monitoring became routine during multidrug or rifampicin-resistant tuberculosis treatment only after the first phase 2 trials showed QT prolongation during treatment with bedaquiline and delamanid. These concerns initially led WHO to formulate conservative recommendations regarding their use in combination. Many of these fears have since been dispelled by increasing evidence. 
In particular, WHO guidelines, based on a review of data done in 2019 including the results of the study by Dooley and colleagues, showed no additional safety concerns related to this combination. 

DOI: 10.1016/S1473-3099(20)30836-7
PMID: 33587896 [Indexed for MEDLINE]

 

From Our June 2021 Newsletter

Evidence-based Definition for Extensively Drug-resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2021 Jun 9. doi: 10.1164/rccm.202009-3527OC. Online ahead of print.
 
Roelens M(1), Battista Migliori G(2), Rozanova L(1), Estill J(1)(3), Campbell JR(4), Cegielski JP(5), Tiberi S(6)(7), Palmero D(8), Fox GJ(9), Guglielmetti L(10)(11), Sotgiu G(12), Brust JCM(13), Bang D(14)(15), Lange C(16)(17)(18), Menzies D(19), Keiser O(1), Raviglione M(20)(21).
 
RATIONALE: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was defined as resistance to rifampicin and isoniazid (multidrug-resistant tuberculosis, MDR-TB), any fluoroquinolone (FQ) and any second-line injectable drug (SLID). In 2019 the World Health Organization issued new recommendations for managing patients with drug-resistant tuberculosis, substantially limiting the role of SLID in MDR-TB treatment and thus putting that XDR-TB definition into question.
OBJECTIVE: To propose an up-to-date definition for XDR-TB.
METHODS: We used a large dataset to assess treatment outcomes for MDR-TB patients exposed to any type of longer regimen. We included patients with bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We did logistic regression to estimate adjusted odds ratios (aORs) for unfavourable treatment outcome (failure, relapse, death, loss-to-follow-up) by resistance pattern (FQ, SLID) and Group A drug use (moxifloxacin/levofloxacin, linezolid, bedaquiline).
MEASUREMENTS AND MAIN RESULTS: We included 11,666 patients with MDR-TB; 4653 (39.9%) had an unfavourable treatment outcome. Resistance to FQs increased the odds of an unfavourable treatment outcome (aOR 1.91; 95% confidence interval [95%CI] 1.63-2.23). Administration of bedaquiline and/or linezolid improved treatment outcomes regardless of resistance to FQ and/or SLID. Among XDR-TB 
patients, compared to persons receiving no Group A drug, aORs for unfavourable outcome were 0.37 (95%CI 0.20-0.69) with linezolid only, 0.40 (95%CI 0.21-0.77) with bedaquiline only, and 0.21 (95%CI 0.12-0.38) with both.
CONCLUSIONS: Our study supports a new definition of XDR-TB as MDR plus additional resistance to FQ plus bedaquiline and/or linezolid, and helps assess the adequacy of this definition for surveillance and treatment choice.
 
DOI: 10.1164/rccm.202009-3527OC
PMID: 34107231

Impact of bedaquiline on treatment outcomes of multidrug-resistant tuberculosis in a high-burden country.
 
Eur Respir J. 2021 Jun 10;57(6):2002544. doi: 10.1183/13993003.02544-2020. Print 2021 Jun.
 
Chesov D(1)(2)(3), Heyckendorf J(2)(3)(4), Alexandru S(5), Donica A(5), Chesov E(6)(2), Reimann M(2)(3), Crudu V(5), Botnaru V(6), Lange C(2)(3)(4).
 
BACKGROUND: Evaluation of novel anti-tuberculosis (TB) drugs for the treatment of multidrug-resistant (MDR)-TB continues to be of high interest on the TB research agenda. We assessed treatment outcomes in patients with pulmonary MDR-TB who received bedaquiline-containing treatment regimens in the Republic of Moldova, a high-burden MDR-TB country.
METHOD: We systematically analysed the SIMETB national electronic TB database and performed a retrospective propensity score-matched comparison of treatment outcomes in a cohort of patients with MDR-TB who started treatment during 2016-2018 with a bedaquiline-containing regimen (bedaquiline cohort) and a cohort of patients treated without bedaquiline (non-bedaquiline cohort).
RESULTS: Following propensity score matching, 114 patients were assigned to each cohort of MDR-TB patients. Patients in the bedaquiline cohort had a higher 6-month sputum culture conversion rate than those in the non-bedaquiline cohort (66.7% versus 40.3%; p<0.001). Patients under bedaquiline-containing regimens had a higher cure rate assessed by both World Health Organization (WHO) and TBnet definitions (55.3% versus 24.6%; p=0.001 and 43.5% versus 19.6%; p=0.004, respectively), as well as a lower mortality rate (8.8% versus 20.2%; p<0.001 and 10.9% versus 25.2%; p=0.01, respectively). In patients who previously failed on MDR-TB treatment, >40% of patients achieved a cure with a bedaquiline-containing regimen.
CONCLUSIONS: Bedaquiline-based MDR-TB treatment regimens result in better disease resolution when compared with bedaquiline-sparing MDR-TB treatment regimens under programmatic conditions in a country with a high burden of MDR-TB.
 
Copyright ©ERS 2021.
 
DOI: 10.1183/13993003.02544-2020
PMID: 33334942


World Health Organization recommendations on the treatment of drug-resistant tuberculosis, 2020 update.
 
Eur Respir J. 2021 Jun 4;57(6):2003300. doi: 10.1183/13993003.03300-2020. Print 2021 Jun.
 
Mirzayev F(1), Viney K(1), Linh NN(1), Gonzalez-Angulo L(1), Gegia M(1), Jaramillo E(1), Zignol M(1), Kasaeva T(1).
 
Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major challenge for patients, healthcare workers and healthcare services. In November 2019, the World Health Organization (WHO) convened an independent international expert panel to review new evidence on the treatment of multidrug- (MDR) and rifampicin-resistant (RR) TB, using the Grading of Recommendations Assessment, Development and Evaluation approach.Updated WHO guidelines emerging from this review, published in June 2020, recommend a 
shorter treatment regimen for patients with MDR/RR-TB not resistant to fluoroquinolones (of 9-11 months), with the inclusion of bedaquiline instead of an injectable agent, making the regimen all oral. For patients with MDR-TB and additional fluoroquinolone resistance, a regimen composed of bedaquiline, pretomanid and linezolid may be used under operational research conditions (6-9 months). Depending on the drug-resistance profile, extent of TB disease or disease severity, a longer (18-20 months) all-oral, individualised treatment regimen may be used. In addition, the review of new data in 2019 allowed the WHO to conclude that there are no major safety concerns on the use of bedaquiline for >6 months' duration, the use of delamanid and bedaquiline together and the use of bedaquiline during pregnancy, although formal recommendations were not made on these topics.The 2020 revision has highlighted the ongoing need for high-quality evidence and has reiterated the need for clinical trials and other research studies to contribute to the development of evidence-based policy.
 
Copyright ©The authors 2021.
 
DOI: 10.1183/13993003.03300-2020
PMCID: PMC8176349
PMID: 33243847


Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.
 
Int J Tuberc Lung Dis. 2021 Jun 1;25(6):453-460. doi: 10.5588/ijtld.21.0035.
 
Oelofse S(1), Esmail A(1), Diacon AH(2), Conradie F(3), Olayanju O(1), Ngubane N(4), Howell P(3), Everitt D(5), Crook AM(6), Mendel CM(5), Wills GH(6), Olugbosi M(7), Del Parigi A(5), Sun E(5), Calatroni A(8), Spigelman M(5), Dheda K(9).
 
BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).
METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.
RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.
CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.
 
DOI: 10.5588/ijtld.21.0035
PMCID: PMC8171246
PMID: 34049607

 
Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis.
 
Nat Med. 2021 May 24. doi: 10.1038/s41591-021-01358-x. Online ahead of print.
 
Gygli SM(#)(1)(2), Loiseau C(#)(1)(2), Jugheli L(1)(2)(3), Adamia N(3), Trauner A(1)(2), Reinhard M(1)(2), Ross A(1)(2), Borrell S(1)(2), Aspindzelashvili R(3), Maghradze N(1)(2)(3), Reither K(1)(2), Beisel C(4), Tukvadze N(1)(2)(3), Avaliani Z(3), Gagneux S(5)(6).
 
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual deaths due to antimicrobial resistance1. Drug resistance-conferring mutations frequently cause fitness costs in bacteria2-5. Experimental work indicates that these drug resistance-related fitness costs might be mitigated by compensatory mutations6-10. However, the clinical relevance of compensatory evolution remains poorly understood. Here we show that, in the country of Georgia, during a 6-year nationwide study, 63% of MDR-TB was due to patient-to-patient transmission. Compensatory mutations and patient incarceration were independently associated with transmission. Furthermore, compensatory mutations were overrepresented among isolates from incarcerated individuals that also frequently spilled over into the non-incarcerated population. As a result, up to 31% of MDR-TB in Georgia was directly or indirectly linked to prisons. We conclude that prisons fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of fitness-compensated strains with high transmission potential.
 
DOI: 10.1038/s41591-021-01358-x
PMID: 34031604

All-oral longer regimens are effective for the management of multidrug resistant tuberculosis in high burden settings.
 
Eur Respir J. 2021 Jun 17:2004345. doi: 10.1183/13993003.04345-2020. Online ahead of print.
 
Khan PY(1)(2)(3), Franke MF(4)(5)(3), Hewison C(6), Seung KJ(4)(7), Huerga H(8), Atwood S(7), Ahmed S(9), Khan M(10), Sultana T(11), Manzur-Ul-Alam M(11), Vo LNQ(12)(13), Lecca L(14), Yae K(15), Kozhabekov S(16), Tamirat M(17), Gelin A(18), Vilbrun SC(19), Kikvidze M(20), Faqirzai J(21), Kadyrov A(22), Skrahina A(23), Mesic A(24), Avagyan N(6), Bastard M(8), Rich ML(4)(7), Khan U(12)(3), Mitnick CD(4)(5)(3).
 
BACKGROUND: Recent World Health Organisation guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline- and/or delamanid as part of their multidrug regimen.
METHODS: Patients with a positive baseline culture were included. Six-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.
RESULTS: Culture conversion was observed in 83.8% (526/628) of patients receiving an all-oral regimen and 85.5% (425/497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95%CI: 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.
CONCLUSIONS: Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.
 
Copyright ©The authors 2021. For reproduction rights and permissions contact 
permissions@ersnet.org.
 
DOI: 10.1183/13993003.04345-2020
PMID: 34140298

From Our May 2021 Newsletter

 

Multidrug-resistant tuberculosis imported into low-incidence countries-a GeoSentinel analysis, 2008-2020.

J Travel Med. 2021 May 12:taab069. doi: 10.1093/jtm/taab069. Online ahead of 
print.
 
Eimer J(1), Patimeteeporn C(2), Jensenius M(3), Gkrania-Klotsas E(4), Duvignaud 
A(5), Barnett ED(6), Hochberg NS(7), Chen LH(8), Trigo-Esteban E(9), Gertler 
M(10), Greenaway C(11), Grobusch MP(12)(13), Angelo KM(2), Hamer DH(7)(14), 
Caumes E(15)(16), Asgeirsson H(1)(17).
 
BACKGROUND: Early detection of imported multidrug-resistant tuberculosis (MDR-TB) is crucial, but knowledge gaps remain about migration- and travel-associated MDR-TB epidemiology. The aim was to describe epidemiologic characteristics among international travelers and migrants with MDR-TB. METHODS: Clinician-determined and microbiologically confirmed MDR-TB diagnoses deemed to be related to travel or migration were extracted from GeoSentinel, a global surveillance network of travel and tropical medicine clinics, from January 2008 through December 2020. MDR-TB was defined as resistance to both isoniazid and rifampicin. Additional resistance to either a fluoroquinolone or a second-line injectable drug was categorized as pre-extensively drug-resistant (pre-XDR) TB, and as extensively drug-resistant (XDR) TB when resistance was detected for both. Sub-analyses were performed based on degree of resistance and country of origin.
RESULTS: Of 201 patients, 136 had MDR-TB (67.7%), 25 had XDR-TB (12.4%), 23 had pre-XDR TB (11.4%), and 17 had unspecified MDR- or XDR-TB (8.5%); 196 (97.5%) were immigrants, of which 92 (45.8%) originated from the former Soviet Union. The median interval from arrival to presentation was 154 days (interquartile range [IQR]: 10-751 days); 34.3% of patients presented within 1 month after immigration, 30.9% between 1 and 12 months, and 34.9% after ≥1 year. Pre-XDR- and XDR-TB patients from the former Soviet Union other than Georgia presented earlier than those with MDR-TB (26 days [IQR: 8-522] vs. 369 days [IQR: 84-827]) while patients from Georgia presented very early, irrespectively of the level of resistance (8 days [IQR: 2-18] vs. 2 days [IQR: 1-17]). 
CONCLUSIONS: MDR-TB is uncommon in traditional travellers. Purposeful medical migration may partly explain differences in time to presentation among different groups. Public health resources are needed to better understand factors contributing to cross-border MDR-TB spread and to develop strategies to optimize care of TB-infected patients in their home countries before migration.
 
© International Society of Travel Medicine 2021. Published by Oxford University 
Press. All rights reserved. For Permissions, please e-mail: 
journals.permissions@oup.com.
 
DOI: 10.1093/jtm/taab069
PMID: 33987682


Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.
 
Clin Microbiol Infect. 2021 Apr 23:S1198-743X(21)00169-5. doi: 
10.1016/j.cmi.2021.04.001. Online ahead of print.
 
Hu Y(1), Zheng X(1), Davies Forsman L(2), Ning Z(3), Chen C(4), Gao Y(1), Zhang 
Z(3), Lu W(4), Werngren J(5), Bruchfeld J(2), Hoffner S(6), Xu B(7).
 
OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the 
recommended 2-year MDR-TB treatment. 
METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. 
RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance. CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.
 
Copyright © 2021 European Society of Clinical Microbiology and Infectious 
Diseases. Published by Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/j.cmi.2021.04.001
PMID: 33895338


Tuberculosis, COVID-19 and hospital admission: Consensus on pros and cons based on a review of the evidence.
 
Pulmonology. 2021 May-Jun;27(3):248-256. doi: 10.1016/j.pulmoe.2020.12.016. Epub 
2021 Jan 28.
 
Migliori GB(1), Visca D(2), van den Boom M(3), Tiberi S(4), Silva DR(5), Centis 

R(6), D'Ambrosio L(7), Thomas T(8), Pontali E(9), Saderi L(10), Schaaf HS(11), 

Sotgiu G(10); contributing members of the Global Tuberculosis Network.
 
The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World Health Organization documents, based on Global Tuberculosis Network (GTN) expert opinion. The core published documents and guidelines on the topic have been reviewed. The proportion of new TB cases admitted to hospital ranges between 50% and 100% while for multidrug-resistant (MDR) TB patients it ranges between 85 and 100% globally. For TB patients with COVID-19 the proportion of cases admitted is 58%, probably reflecting different scenarios related to the diagnosis of COVID-19 before, after or at the same time of the active TB episode. The hospital length of stay for drug-susceptible TB ranges from 20 to 60 days in most of countries, ranging from a mean of 10 days (USA) to around 90 days in the Russian Federation. Hospitalization is longer for MDR-TB (50-180 days). The most frequently stated reasons for recommending hospital admission include: severe TB, infection control concerns, co-morbidities and drug adverse events which cannot be managed at out-patient level. The review also provides suggestions on hospital requirements for safe admissions as well as patient discharge criteria, while underlining the relevance of patient-centred care through community/home-based care.
 
Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier 
España, S.L.U. All rights reserved.
 
DOI: 10.1016/j.pulmoe.2020.12.016
PMCID: PMC7843149
PMID: 33547028 [Indexed for MEDLINE]


Diagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralised high throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance.

Clin Microbiol Infect. 2021 Apr 29:S1198-743X(21)00209-3. doi: 
10.1016/j.cmi.2021.04.022. Online ahead of print.
 
Dippenaar A(1), Derendinger B(1), Dolby T(2), Beylis N(3), van Helden PD(1), 
Theron G(1), Warren RM(1), de Vos M(4).
 
OBJECTIVES: To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods.
METHODS: Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies.
RESULTS: FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared to FluoroType MTBDR VER 2.0 [manual DNA extraction: 91.6% (294/321) vs. 89.8% (291/324) (p=0.4); automated DNA extraction: 92.1% (305/331) vs 87.7% (291/332) (p=0.05)]. FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance.
CONCLUSIONS: The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralised molecular drug susceptibility testing model.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.cmi.2021.04.022
PMID: 33933566
 
Rapid Tuberculosis Diagnostics Including Molecular First- and Second-Line Resistance Testing Based on a Novel Microfluidic DNA Extraction Cartridge.
 
J Mol Diagn. 2021 May;23(5):643-650. doi: 10.1016/j.jmoldx.2021.02.004. Epub 
2021 Feb 23.
 
Beutler M(1), Homann AR(2), Mihalic M(3), Plesnik S(3), Niebling L(2), Eckart 
M(4), Allerheiligen V(4), Czurratis D(5), Maharjan B(6), Shrestha B(6), Parpieva 
N(7), Turaev L(7), Sayfutdinov Z(7), Hofmann-Thiel S(8), Grasse W(9), 
Metzger-Boddien C(9), Paust N(2), Hoffmann H(10).
 
Xpert MTB/RIF testing has improved tuberculosis (TB) diagnostics and rifampicin (Rif) resistance testing worldwide. However, it has weaknesses, such as its restriction to Rif resistance testing and the inability to use extracted DNA for further testing. Herein, a holistic diagnostic workflow, including TB detection 
and resistance testing toward Rif, isoniazid, and important second-line drugs (SLDs), based on a novel microfluidic DNA extraction cartridge (TB-Disk), is presented. DNA from 73 precharacterized sputum samples was extracted with TB-Disk, including 45 clinical and bacteriologically confirmed TB samples, nine TB-negative samples, and 19 sputum samples spiked with twofold dilutions of TB bacteria. The extracted DNA was subjected to further testing with FluoroType MTB (FT-MTB), GenoType MTBDRplus (GT-plus), and GenoType MTBDRsl. A total of 100% (20/20) and 72% (18/25) of smear-positive and smear-negative TB samples were identified as Mycobacterium tuberculosis complex positive. A total of 79% (33/42) of subsequently GT-plus tested samples yielded a valid result. Eight samples were identified as multidrug-resistant TB by GT-plus and further tested for resistance toward SLDs using GenoType MTBDRsl, yielding 75% (6/8) valid results. FT-MTB with cartridge-based DNA extraction (Disk-DNA) and DNA extracted with FluoroLyse yielded similar analytical sensitivities. FT-MTB with Disk-DNA was 100% specific. TB-Disk in combination with FT-MTB enables sensitive TB detection. The Disk-DNA can be further  used for screening resistance toward first-line drugs and SLDs.
 
Copyright © 2021 Association for Molecular Pathology and American Society for 
Investigative Pathology. Published by Elsevier Inc. All rights reserved.
 
DOI: 10.1016/j.jmoldx.2021.02.004
PMID: 33636391

From Our April 2021 Newsletter

 Dynamic needs and challenges of people with drug-resistant tuberculosis and HIV  in South Africa: a qualitative study.
 
Lancet Glob Health. 2021 Apr;9(4):e479-e488. doi: 10.1016/S2214-109X(20)30548-9.
 
Daftary A(1), Mondal S(2), Zelnick J(3), Friedland G(4), Seepamore B(5), Boodhram R(6), Amico KR(7), Padayatchi N(6), O'Donnell MR(8).
 
BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.
METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.
FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.
INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens.
FUNDING: US National Institutes of Health.
TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S2214-109X(20)30548-9
PMCID: PMC8009302
PMID: 33740409 [Indexed for MEDLINE]

Outcomes of multidrug-resistant tuberculosis treated with bedaquiline or delamanid.
 
Clin Infect Dis. 2021 Apr 10:ciab304. doi: 10.1093/cid/ciab304. Online ahead of print.
 
Hwang H(1), Kang H(2), Kwon YS(3), Jeon D(4), Shim TS(5), Yim JJ(1).
 
BACKGROUND: Since September 1, 2016, bedaquiline and delamanid have been administered for treatment of patients with multidrug-resistant/rifampicin-resistant tuberculosis after the official approval in South Korea. This study aimed to assess and compare the final treatment outcomes of patients who received bedaquiline with those of patients who received delamanid.
METHODS: This is a nationwide cohort study of patients with multidrug-resistant/rifampicin-resistant tuberculosis in whom bedaquiline or delamanid was administered from September 1, 2016, to February 28, 2018, after receiving the official approval in South Korea. Patients were classified into the bedaquiline and delamanid group according to the first used drug. We evaluated and compared the final treatment outcomes between the groups.
RESULTS: During the study period, 284 patients with multidrug-resistant/rifampicin-resistant tuberculosis were approved to use bedaquiline or delamanid and 260 were included in the final analysis; 119 (45.8%) and 141 patients (54.2%) were classified into bedaquiline and delamanid groups, respectively. Among them, 30 patients (11.5%) exhibited additional resistance to second-line injectable drugs, 94 patients (36.2%) had additional resistance to fluoroquinolones, and 37 patients (14.2%) had resistance to both drugs. The overall treatment success rate was 79.2%. Initiation of bedaquiline rather than delamanid was not associated with treatment success (adjusted odds ratio = 0.671, 95% confidence interval = 0.350-1.285).Frequencies of adverse events were not significantly different between the two groups.
CONCLUSIONS: Initial choice of bedaquiline or delamanid did not make any significant difference in the final treatment outcome or the frequencies of adverse events among patients with multidrug-resistant/rifampicin-resistant tuberculosis.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciab304
PMID: 33837767

 Patients' perceptions regarding multidrug-resistant tuberculosis and barriers to seeking care in a priority city in Brazil during COVID-19 pandemic: A  qualitative study.
 
PLoS One. 2021 Apr 9;16(4):e0249822. doi: 10.1371/journal.pone.0249822. eCollection 2021.
 
Santos FLD(1), Souza LLL(1), Bruce ATI(1), Crispim JA(1), Arroyo LH(1), Ramos ACV(1), Berra TZ(1), Alves YM(1), Scholze AR(1), Costa FBPD(1), Martoreli Júnior JF(1), Moncaio ACS(2), Pinto IC(1), Arcêncio RA(1).
 
This study aimed to analyze the discourses of patients who were diagnosed with multidrug-resistant tuberculosis, the perception of why they acquired this health condition and barriers to seeking care in a priority city in Brazil during the COVID-19 pandemic. This was an exploratory qualitative study, which used the theoretical-methodological framework of the Discourse Analysis of French matrix, guided by the Consolidated Criteria for Reporting Qualitative Research. The study was conducted in Ribeirão Preto, São Paulo, Brazil. Seven participants were interviewed who were undergoing treatment at the time of the interview. The analysis of the participants' discourses allowed the emergence of four discursive blocks (1) impact of the social determinants in the development of multidrug-resistant tuberculosis, (2) barriers to seeking care and difficulties accessing health services, (3) perceptions of the side effects and their impact on multidrug-resistant tuberculosis treatment, and (4) tuberculosis and COVID-19: a necessary dialogue. Through discursive formations, these revealed the determinants of multidrug-resistant tuberculosis. Considering the complexity involved in the dynamics of multidrug-resistant tuberculosis, advancing in terms of equity in health, that is, in reducing unjust differences, is a challenge for public policies, especially at the current moment in Brazil, which is of accentuated economic, political and social crisis. The importance of psychosocial stressors and the lack of social support should also be highlighted as intermediary determinants of health. The study has also shown the situation of COVID-19, which consists of an important barrier for patients seeking care. Many patients reported fear, insecurity and worry with regard to returning to medical appointments, which might contribute to the worsening of tuberculosis in the scenario under study.
 
DOI: 10.1371/journal.pone.0249822
PMCID: PMC8034748
PMID: 33836024 [Indexed for MEDLINE]

 Culture conversion at six months in patients receiving bedaquiline- and  delamanid-containing regimens for the treatment of multidrug-resistant  tuberculosis.
 
Int J Infect Dis. 2021 Apr 3:S1201-9712(21)00293-9. doi: 10.1016/j.ijid.2021.03.075. Online ahead of print.
 
Maretbayeva SM(1), Rakisheva AS(2), Adenov MM(3), Yeraliyeva LT(3), Algozhin YZ(1), Stambekova AT(1), Berikova EA(3), Yedilbayev A(4), Rich ML(5), Seung KJ(5), Issayeva AM(6).
 
Rifampicin-resistant/multidrug-resistant (RR/MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis (TB) are serious public health problem in Kazakhstan. In 2012 and 2013, stringent regulatory authorities approved the first new TB drugs in fifty years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. The endTB Observational Study is a multi-country study that enrolled patients receiving a bedaquiline- or delamanid-containing regimen for RR/MDR-TB between 01 April 2015 and 30 September 2018. In Kazakhstan, 675 patients participated in the study; all had at least 6-months or longer of follow-up after the start of treatment. The present analysis focuses on endTB Observational Study patients living in Kazakhstan who had a positive baseline sputum culture (220 patients) and initiated a bedaquiline- or delamanid-containing regimen between February 1, 2016 and March 31, 2018. Of them, 195 (89%) of patients experienced culture conversion within six months.
 
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.ijid.2021.03.075
PMID: 33823277

From Our March 2021 Newsletter

Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis.
 
J Antimicrob Chemother. 2021 Mar 12;76(4):1019-1024. doi: 10.1093/jac/dkaa550.
 
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
 
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
 
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkaa550
PMCID: PMC7953320
PMID: 33378452

Dynamic needs and challenges of people with drug-resistant tuberculosis and HIV  in South Africa: a qualitative study.
 
Lancet Glob Health. 2021 Apr;9(4):e479-e488. doi: 10.1016/S2214-109X(20)30548-9.
 
Daftary A(1), Mondal S(2), Zelnick J(3), Friedland G(4), Seepamore B(5), Boodhram R(6), Amico KR(7), Padayatchi N(6), O'Donnell MR(8).
 
BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.
METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.
FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.
INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens. FUNDING: US National Institutes of Health. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S2214-109X(20)30548-9
PMID: 33740409

Neuropsychiatric toxicity and cycloserine concentrations during treatment for  multidrug-resistant tuberculosis.
 
Int J Infect Dis. 2021 Mar 5:S1201-9712(21)00206-X. doi: 10.1016/j.ijid.2021.03.001. Online ahead of print.
 
Court R(1), Centner CM(2), Chirehwa M(3), Wiesner L(4), Denti P(5), de Vries N(6), Harding J(7), Gumbo T(8), Maartens G(9), McIlleron H(10).
 
BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). There are limited prospective clinical data on the incidence and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine.
METHOD: We prospectively evaluated neuropsychiatric toxicity using validated screening tools in patients with multi-drug resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma.
RESULTS: We recruited 144 participants: 78 men; median age 35.2 years; 91 (63%) HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance (aHR:0.34, p:0.03) and high-dose pyridoxine (200 mg vs. 150 mg daily).
CONCLUSION: We observed a high incidence of early neuropsychiatric toxicity in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.
 
Copyright © 2021. Published by Elsevier Ltd.
 
DOI: 10.1016/j.ijid.2021.03.001
PMID: 33684562


Drug susceptibility patterns of Mycobacterium tuberculosis from adults with  multidrug-resistant tuberculosis and implications for a household contact  preventive therapy trial.
 
BMC Infect Dis. 2021 Feb 24;21(1):205. doi: 10.1186/s12879-021-05884-4.
 
Demers AM(1), Kim S(2), McCallum S(3), Eisenach K(4), Hughes M(3), Naini L(5), Mendoza-Ticona A(6), Pradhan N(7), Narunsky K(8), Poongulali S(9), Badal-Faesen S(10), Upton C(11), Smith E(12), Shah NS(13), Churchyard G(14)(15), Gupta A(7)(16), Hesseling A(1), Swindells S(17); ACTG A5300/IMPAACT I2003 PHOENIx Feasibility study team.
 
BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).
METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.
RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.
CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
 
DOI: 10.1186/s12879-021-05884-4
PMCID: PMC7903693
PMID: 33627075 [Indexed for MEDLINE]



Targeted next generation sequencing directly from sputum for comprehensive  genetic information on drug resistant Mycobacterium tuberculosis.
 
Tuberculosis (Edinb). 2021 Mar;127:102051. doi: 10.1016/j.tube.2021.102051. Epub 2021 Jan 8.
 
Kambli P(1), Ajbani K(2), Kazi M(3), Sadani M(4), Naik S(5), Shetty A(6), Tornheim JA(7), Singh H(8), Rodrigues C(9).
 
BACKGROUND: Timely drug resistance detection is essential to global tuberculosis management. Unfortunately, rapid molecular tests assess resistance to only a few drugs, with culture required for comprehensive susceptibility test results.
METHODS: We evaluated targeted next generation sequencing (tNGS) for tuberculosis on 40 uncultured sputum samples. Resistance profiles from tNGS were compared with profiles from Xpert MTB/RIF, line probe assay (LPA), pyrosequencing (PSQ), and phenotypic testing. Concordance, sensitivity, specificity, and overall test agreement were compared across assays.
RESULTS: tNGS provided results for 39 of 40 samples (97.5%) with faster turnaround than phenotypic testing (median 3 vs. 21 days, p = 0.0068). Most samples were isoniazid and rifampin resistant (N = 31, 79.5%), 21 (53.8%) were fluoroquinolone resistant, and 3 (7.7%) were also resistant to Kanamycin. Half were of the Beijing lineage (N = 20, 51.3%). tNGS from uncultured sputum identified all resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectable drugs that was identified by other methods. Agreement between tNGS and existing assays was excellent for isoniazid, rifampin, and SLDs, very good for levofloxacin, and good for moxifloxacin.
CONCLUSION: tNGS can rapidly identify tuberculosis, lineage, and drug resistance with faster turnaround than phenotypic testing. tNGS is a potential alternative to phenotypic testing in high-burden settings.
 
Copyright © 2021 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/j.tube.2021.102051
PMID: 33450448

 Effectiveness of Preventive Therapy for Persons Exposed at Home to  Drug-Resistant Tuberculosis, Karachi, Pakistan.
 
Emerg Infect Dis. 2021 Mar;27(3):805-812. doi: 10.3201/eid2703.203916.
 
Malik AA, Gandhi NR, Lash TL, Cranmer LM, Omer SB, Ahmed JF, Siddiqui S, Amanullah F, Khan AJ, Keshavjee S, Hussain H, Becerra MC.
 
In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.
 
Fluoroquinolone-based preventive therapy reduced risk for tuberculosis disease by 65%.
 
DOI: 10.3201/eid2703.203916
PMCID: PMC7920671
PMID: 33624580

From Our February 2021 Newsletter

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Lancet Infect Dis. 2021 Feb 12:S1473-3099(20)30770-2. doi: 10.1016/S1473-3099(20)30770-2. Online ahead of print.

Dooley KE(1), Rosenkranz SL(2), Conradie F(3), Moran L(4), Hafner R(5), von Groote-Bidlingmaier F(6), Lama JR(7), Shenje J(8), De Los Rios J(7), Comins K(6), Morganroth J(9), Diacon AH(10), Cramer YS(2), Donahue K(11), Maartens G(12); AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team.

Collaborators: Alli O, Gottesman J, Guevara M, Hikuam C, Hovind L, Karlsson M, McClaren J, McIlleron H, Murtaugh W, Rolls B, Shahkolahi A, Stone L, Tegha G, Tenai J, Upton C, Wimbish C.

BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.
METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.
FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.
INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.
FUNDING: Division of AIDS, National Institutes of Health.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30770-2
PMID: 33587897


Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment.
 
Expert Rev Respir Med. 2021 Feb;15(2):221-237. doi: 10.1080/17476348.2021.1828069. Epub 2020 Oct 10.
 
Seddon JA(1)(2), Johnson S(1)(2), Palmer M(1), van der Zalm MM(1), Lopez-Varela E(1)(3), Hughes J(1), Schaaf HS(1).
 
INTRODUCTION: An estimated 30,000 children develop multidrug-resistant (MDR) tuberculosis (TB) each year, with only a small proportion diagnosed and treated. This field has historically been neglected due to the perception that children with MDR-TB are challenging to diagnose and treat. Diagnostic and therapeutic developments in adults have improved pediatric management, yet further pediatric-specific research and wider implementation of evidence-based practices are required.
AREAS COVERED: This review combines the most recent data with expert opinion to highlight best practice in the evaluation, diagnosis, treatment, and support of children and adolescents with MDR-TB disease. A literature search of PubMed was carried out on topics related to MDR-TB in children. This review provides practical advice on MDR-TB prevention and gives updates on new regimens and novel treatments. The review also addresses host-directed therapy, comorbid conditions, special populations, psychosocial support, and post-TB morbidity, as well as identifying outstanding research questions.
EXPERT OPINION: Increased availability of molecular diagnostics has the potential to aid with the diagnosis of MDR-TB in children. Shorter MDR-TB disease treatment regimens have made therapy safer and shorter and further developments with novel agents and repurposed drugs should lead to additional improvements. The evidence base for MDR-TB preventive therapy is increasing.
 
DOI: 10.1080/17476348.2021.1828069
PMID: 32965141


Systematic Review of Mutations Associated with Isoniazid Resistance Points to  Continuing Evolution and Subsequent Evasion of Molecular Detection, and  Potential for Emergence of Multidrug Resistance in Clinical Strains of  Mycobacterium tuberculosis.
 
Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02091-20. doi:
10.1128/AAC.02091-20. Print 2021 Feb 17.
 
Valafar SJ(1).
 
Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, and fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INHr] and 3,502 INH susceptible [INHs]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of katG (katG315; n = 4,271), locus -15 of inhA (inhA-15; n = 787), and locus -8 of inhA (inhA-8; 106). However, the diagnostic value of inhA-8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INHr isolates lacking the first two mutations. I catalogued 45 new loci (29 katG, nine inhA, and seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates, no mechanism of resistance was detected, making them likely to escape molecular detection, and in the case of INH monoresistance, likely to convert to multidrug-resistant TB (MDR-TB). Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.
 
Copyright © 2021 American Society for Microbiology.
 
DOI: 10.1128/AAC.02091-20
PMID: 33361298


4. Evaluating Integrated Care for People Living With HIV and Multidrug-Resistant  Tuberculosis in South Africa: A Case-Based Approach Using the Chronic Care Model.
 
J Assoc Nurses AIDS Care. 2021 Feb 15. doi: 10.1097/JNC.0000000000000242. Online ahead of print.
 
Geiger K(1), Bergman A, Farley JE.
 
In South Africa, tuberculosis (TB) and multidrug-resistant TB (MDR-TB) frequently occur in people living with HIV. World Health Organization guidelines recommend the integration of MDR-TB and HIV care but, in practice, fully integrated care is difficult to achieve. In this article, we use five elements of the Chronic Care Model as a framework for evaluating a case of integrated. MDR-TB/HIV care and to highlight opportunities for nurses to improve care delivery and patient outcomes. We apply the Chronic Care Model framework to a concrete example by examining the case of a 33-year-old man who developed MDR-TB treatment failure while concurrently taking a powerful new MDR-TB antiretroviral therapy regimen for his HIV.
 
Copyright © 2021 Association of Nurses in AIDS Care.
 
DOI: 10.1097/JNC.0000000000000242
PMID: 33595985


5. Should treatment of low-level rifampicin mono-resistant tuberculosis be different?
 
J Clin Tuberc Other Mycobact Dis. 2021 Jan 29;23:100222. doi:
10.1016/j.jctube.2021.100222. eCollection 2021 May.
 
Gopie FA(1)(2), Commiesie E(3), Baldi S(4), Kamst M(5), Kaur D(6), de Lange WCM(7), Pinas PS(4), Stijnberg D(3), Wongsokarijo M(4), Zijlmans CWR(2), de Zwaan R(5), van Soolingen D(5), Vreden SGS(1), de Vries G(8).
 
BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation.
METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates.
FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%.
INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment. regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB.
FUNDING: None.
 
© 2021 The Authors. Published by Elsevier Ltd.
 
DOI: 10.1016/j.jctube.2021.100222
PMCID: PMC7869001
PMID: 33598570

From Our January 2021 Newsletter

 Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with
multidrug-resistant tuberculosis.

 
J Antimicrob Chemother. 2020 Dec 30:dkaa550. doi: 10.1093/jac/dkaa550. Online ahead of print.
 
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
 
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
 
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkaa550
PMID: 33378452

HIV infection and multidrug resistant tuberculosis: a systematic review and
meta-analysis.

 
BMC Infect Dis. 2021 Jan 11;21(1):51. doi: 10.1186/s12879-020-05749-2.
 
Sultana ZZ(1), Hoque FU(2), Beyene J(3), Akhlak-Ul-Islam M(4), Khan MHR(5), Ahmed S(6), Hawlader DH(7), Hossain A(8)(9)(10).
 
Erratum in BMC Infect Dis. 2021 Jan 20;21(1):86.
 
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global efforts to combat tuberculosis. Inconsistent findings on the association between HIV infection and MDR-TB were present in many studies. We aimed to review existing data on the relationship
between HIV infection and MDR-TB systematically to assess the contribution of HIV on MDR-TB worldwide. We also investigated the patterns of MDR-TB by age, country-wise income, study designs, and global regions.
METHODS: We utilized PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for meta-analysis that were published between January 12,010, and July 30, 2020. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV and MDR-TB with a 95%
confidence interval. We investigated the potential publication-bias by checking funnel plot asymmetry and using the Egger's test. Moreover, we assessed the heterogeneity using the I2 statistic. Sensitivity analysis was performed based on sample size and adjustment factors. The protocol was registered with PROSPERO-CRD42019132752.
RESULTS: We identified 1603 studies through a database search, and after subsequent eliminations we selected 54 studies including 430,534 TB patients. The pooled odds of MDR-TB was 1.42 times higher in HIV-positive patients than HIV-negative patients (OR=1.42,CI=1.17-1.71, I2=75.8%). Subgroup analysis revealed that the estimated pooled odds for South-East Asian countries was 1.86, which is the highest in WHO regions (OR=1.86,CI=1.30-2.67, I2=0.00%), followed by Europe and Africa. The effect estimate was found to be higher for primary MDR-TB (OR=2.76,CI=1.70-4.46, I2=0.00%). There was also a trend towards increased odds of MDR-TB for HIV patients older than 40 years (OR=1.56,CI=1.17-2.06). The association was found to be significant in high-burden TB countries (OR=1.75, CI=1.39-2.19) and in high-income countries
(OR=1.55, CI=1.06-2.27).
CONCLUSION: Such findings indicate that HIV infection raises the risk of MDR-TB, and after contrasting it with the results of the earlier pooled study, it appeared to be an upward risk trend. Moreover, we found that the risk is the highest in the South-East Asian region. A balanced allocation of resources is needed to halt both primary and secondary MDR-TB, particularly in HIV infected people with 40 years of age and older.
 
DOI: 10.1186/s12879-020-05749-2
PMCID: PMC7802168
PMID: 33430786 [Indexed for MEDLINE]

"Take the treatment and be brave": Care experiences of pregnant women with
rifampicin-resistant tuberculosis.

 
PLoS One. 2020 Dec 21;15(12):e0242604. doi: 10.1371/journal.pone.0242604.
eCollection 2020.
 
Loveday M(1)(2), Hlangu S(1), Furin J(3).
 
BACKGROUND: There are few data on the on the care experiences of pregnant women with rifampicin-resistant TB.
OBJECTIVE: To describe the treatment journeys of pregnant women with RR-TB-including how their care experiences shape their identities-and identify areas in which tailored interventions are needed.
METHODS: In this qualitative study in-depth interviews were conducted among a convenience sample from a population of pregnant women receiving treatment for RR-TB. This paper follows COREQ guidelines. A thematic network analysis using an inductive approach was performed to analyze the interview transcripts and notes. The analysis was iterative and a coding system developed which focused on the
care experiences of the women and how these experiences affected their perceptions of themselves, their children, and the health care system in which treatment was received.
RESULTS: Seventeen women were interviewed. The women described multiple challenges in their treatment journeys which required them to demonstrate sustained resilience (i.e. to "be brave"). Care experiences required them to negotiate seemingly contradictory identities as both new mothers-"givers of
life"-and RR-TB patients facing a complicated and potentially deadly disease. In terms of their "pregnancy identity" and "RR-TB patient identity" that emerged as part of their care experiences, four key themes were identified that appeared to have elements that were contradictory to one another (contradictory areas).
These included: 1) the experience of physical symptoms or changes; 2) the experience of the "mothering" and "patient" roles; 3) the experience of the care they received for their pregnancy and their RR-TB; and 4) the experience of community engagement. There were also three areas that overlapped with both
roles and during which identity was negotiated/reinforced and they included: 1) faith; 2) socioeconomic issues; and 3) long-term concerns over the child's health. At times, the health care system exacerbated these challenges as the women were not given the support they needed by health care providers who were
ill-informed or angry and treated the women in a discriminatory fashion. Left to
negotiate this confusing time period, the women turned to faith, their own mothers, and the fathers of their unborn children.
CONCLUSION: The care experiences of the women who participated in this study highlight several gaps in the current health care system that must be better addressed in both TB and perinatal services in order to improve the therapeutic journeys for pregnant women with RR-TB and their children. Suggestions for
optimizing care include the provision of integrated services, including specialized counseling as well as training for health care providers; engagement of peer support networks; provision of socioeconomic support; long-term medical care/follow-up for children born to women who were treated for RR-TB; and inclusion of faith-based services in the provision of care.
 
DOI: 10.1371/journal.pone.0242604
PMCID: PMC7751874
PMID: 33347448 [Indexed for MEDLINE]

Lesion Heterogeneity Coincides With Long-Term Heteroresistance in MDR-TB.
 
J Infect Dis. 2021 Jan 12:jiab011. doi: 10.1093/infdis/jiab011. Online ahead of
print.
 
Chen Y(1)(2), Ji L(2), Liu Q(1)(3), Li J(2), Hong C(2), Jiang Q(1)(2), Gan M(4), Takiff HE(5)(6)(7), Yu W(2), Tan W(2), Gao Q(1)(2).
 
Tuberculosis (TB) heteroresistance, in which only a fraction of the bacteria in a TB patient contains drug-resistant mutations, has been a rising concern. However, its origins and prevalence remain elusive. Here, whole-genome sequencing was performed on 83 serial isolates from 31 MDR-TB patients and heteroresistance was detected in isolates from 21 (67.74%) patients. Heteroresistance persisted in the host for long periods, spanning months to years, and was associated with having multiple tubercular lesions. Our findings indicate that heteroresistance is common and persistent in MDR-TB patients and
may affect the success of their treatment regimens.
 
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/infdis/jiab011
PMID: 33433601

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A
Prospective Multicountry Study.

 
Am J Respir Crit Care Med. 2021 Jan 1;203(1):111-119. doi: 10.1164/rccm.202001-0135OC.
 
Franke MF(1)(2), Khan P(3), Hewison C(4), Khan U(3), Huerga H(5), Seung KJ(2)(6), Rich ML(2)(6), Zarli K(7), Samieva N(8), Oyewusi L(9), Nair P(10), Mudassar M(3), Melikyan N(5), Lenggogeni P(11), Lecca L(12), Kumsa A(13), Khan M(14), Islam S(15), Hussein K(16), Docteur W(17), Chumburidze N(18), Berikova
E(19), Atshemyan H(20), Atwood S(6), Alam M(15), Ahmed S(3), Bastard M(5), Mitnick CD(1)(2)(6).
 
Comment in Am J Respir Crit Care Med. 2021 Jan 1;203(1):11-13.
 
Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry
cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for
nonconversion.
Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture
conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with
conversion.
Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.
 
DOI: 10.1164/rccm.202001-0135OC
PMCID: PMC7781121
PMID: 32706644

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