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From our December 2023 Newsletter

1. Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and 
therapeutic challenges of an "orphan disease"

Eur J Pediatr. 2023 Nov;182(11):5167-5179. doi: 10.1007/s00431-023-05167-x. Epub 2023 Sep 14.
Schäfer HL(1), Barker M(2), Follmann P(3), Günther A(2), Hörning A(4), Kaiser-Labusch P(5), Kerzel S(6), Maier C(7), Roth S(6), Schmidt C(8), Schütz K(9), Stehling F(10), Struffert M(7), Timmesfeld N(11), Vöhringer P(12), Brinkmann F(7)(13).
Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss).

CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects.

TRIAL REGISTRATION: Deutsches Register Klinischer Studien (, DRKS00023817, 2020-09-08.

WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease).•Choice of treatment regimen and monitoring of side effects.

WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.
© 2023. The Author(s).
DOI: 10.1007/s00431-023-05167-x
PMCID: PMC10640426
PMID: 37707590 [Indexed for MEDLINE]

2. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.
Lancet Microbe. 2023 Nov 3:S2666-5247(23)00172-6. doi: 10.1016/S2666-5247(23)00172-6. Online ahead of print.
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
3. Tuberculosis Variant with Rifampin Resistance Undetectable by Xpert MTB/RIF, Botswana.
Emerg Infect Dis. 2023 Nov;29(11):2403-2406. doi: 10.3201/eid2911.230987.
Modongo C, Barilar I, Wang Q, Molefi T, Makhondo T, Niemann S, Shin SS.
GeneXpert MTB/RIF, a tool widely used for diagnosing tuberculosis, has limitations for detecting rifampin resistance in certain variants. We report transmission of a pre-extensively drug-resistant variant in Botswana that went undetected by GeneXpert. The public health impact of misdiagnosis emphasizes the need for comprehensive molecular testing to identify resistance and guide treatment.
DOI: 10.3201/eid2911.230987
PMCID: PMC10617350
PMID: 37877680 [Indexed for MEDLINE]

4. Community-based directly observed therapy is effective and results in better treatment outcomes for patients with multi-drug resistant tuberculosis in Uganda.
BMC Health Serv Res. 2023 Nov 13;23(1):1248. doi: 10.1186/s12913-023-10120-7.
Makabayi-Mugabe R(1)(2), Musaazi J(3), Zawedde-Muyanja S(3)(4), Kizito E(3), Fatta K(5), Namwanje-Kaweesi H(4), Turyahabwe S(6), Nkolo A(4).
BACKGROUND: Health facility-based directly observed therapy (HF DOT) is the main strategy for the management of patients with drug-resistant tuberculosis (DR TB) in Uganda, however, this still yields sub-optimal treatment outcomes. We set out to assess the effectiveness of community-based directly observed therapy (CB DOT) for the treatment of DR TB in Uganda.

METHODS: Using a previously developed patient-centered model for CB DOT, we assigned community health workers (CHWs) as primary caregivers to patients diagnosed with DR TB. CHWs administered daily DOT to patients in their homes. Once a month, patients received travel vouchers to attend clinic visits for treatment monitoring. We assessed the effectiveness of this model using a quasi-experimental pre and post-study. From December 2020 to March 2022, we enrolled adult DR-TB patients on the CB DOT model. We collected retrospective data from patients who had received care using the HF DOT model during the year before the study started. The adjusted effect of CB DOT versus HF DOT on DR TB treatment success was estimated usingmodified Poisson regression model with robust cluster variance estimator.

RESULTS: We analyzed data from 264 DR TB patients (152 HF DOT, 112 CB DOT). The majority were males (67.8%) with a median age of 36 years (IQR 29 to 44 years). Baseline characteristics were similar across the comparison groups, except for educational level, regimen type, and organizational unit with age being borderline. The treatment success rate in the CB DOT group was 12% higher than that in the HF DOT (adjusted prevalence ratio (aPR)= 1.12 [95%CI 1.01, 1.24], P-value=0.03). Males were less likely to achieve treatment success compared to their female counterparts (aPR=0.87 [95% CI 0.78, 0.98], P-value=0.02). A total of 126 (47.7%) of 264 patients reported at least one adverse event. The HF DOT group had a higher proportion of patients with at least one adverse event compared to the CB DOT group (90/152 [59.2%] versus 36/112 [32.1], P-value<0.01). The model was acceptable among patients (93.6%) and health workers (94.1%).

CONCLUSIONS: CB DOT for DR-TB care is effective and results in better treatment outcomes than HF DOT. The cost-effectiveness of this model of care should be further evaluated.
© 2023. The Author(s).
DOI: 10.1186/s12913-023-10120-7
PMCID: PMC10644403
PMID: 37957610 [Indexed for MEDLINE]

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: 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
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:
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 
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:

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. 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:
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 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 number, NCT02589782.).

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


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