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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:
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, 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 , and the source code is available at .
© 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, 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:
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]