PREVIOUS LITERATURE IN DR-TB

From Our March 2022 Newsletter

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

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

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

From Our February 2022 Newsletter

 

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

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

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

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

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

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

From Our December 2021 Newsletter

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

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

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

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

© 2021 Ausi et al.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2021. Published by Elsevier Ltd.

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

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

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

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

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

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

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

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

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

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

Sağıroğlu P(1), Atalay MA(1).

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

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

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

DOI: 10.1080/14737159.2021.1997594 PMID: 34689662

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

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

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

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

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

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

DOI: 10.1002/psp4.12722 PMID: 34626526

 

From Our November 2021 Newsletter

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

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

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

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

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

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

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

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

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


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

 

From Our October 2021 Newsletter

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

 

From Our September 2021 Newsletter

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

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

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

 

From Our August 2021 Newsletter

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

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

 

From Our July 2021 Newsletter

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

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

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

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

 

From Our June 2021 Newsletter

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

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


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


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

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

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

From Our May 2021 Newsletter

 

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

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


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


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

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

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


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

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

From Our April 2021 Newsletter

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

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

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

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

From Our March 2021 Newsletter

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

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

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


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



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

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

From Our February 2021 Newsletter

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

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

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

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

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

Copyright © 2021 Elsevier Ltd. All rights reserved.

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


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


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


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


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

From Our January 2021 Newsletter

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

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

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

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

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

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

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

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

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