INTRODUCTION:An effective rifampicin-resistant tuberculosis (RR-TB) treatment regimen should include prevention of resistance amplification. While bedaquiline (BDQ) has been recommended in all-oral RR-TB treatment regimen since 2019, resistance is rising at alarming rates. This may be due to BDQ's delayed bactericidal effect, which increases the risk of selecting for resistance to fluoroquinolones and/or BDQ in the first week of treatment when the bacterial load is highest. We aim to strengthen the first week of treatment with the injectable drug amikacin (AMK). To limit the ototoxicity risk while maximising the bactericidal effect, we will evaluate the safety of adding a 30 mg/kg AMK injection on the first and fourth day of treatment. METHODS AND ANALYSIS:We will conduct a single-arm clinical trial on 20 RR-TB patients nested within an operational study called ShoRRT (All oral Shorter Treatment Regimen for Drug resistant Tuberculosis). In addition to all-oral RR-TB treatment, patients will receive two doses of AMK. The primary safety endpoint is any grade 3-4 adverse event during the first 2 weeks of treatment related to the use of AMK. With a sample size of 20 patients, we will have at least 80% statistical power to support the alternative hypothesis, indicating that less than 14% of patients treated with AMK experience a grade 3-4 adverse event related to its use. Safety data obtained from this study will inform a larger multicountry study on using two high doses of AMK to prevent acquired resistance. ETHICS AND DISSEMINATION:Approval was obtained from the ethics committee of Rwanda, Rwanda Food and Drug Authority, Universitair Ziekenhuis, the Institute of Tropical Medicine ethics review board. All participants will provide informed consent. Study results will be disseminated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER:NCT05555303.

BackgroundNon-tuberculous mycobacteria (NTM) are environmental agents that can cause opportunistic pulmonary disease in humans and animals, often misdiagnosed as tuberculosis (TB). In this study, we describe the cases of NTM identified during the first national anti-TB drug resistance survey conducted in Mali and explore associated risk factors.MethodsSputum was collected from people presenting for pulmonary TB diagnosis from April to December 2019, regardless of age. Microscopy-positive patients were enrolled and tested using the Xpert MTB/RIF assay. A patient who tested negative for the Mycobacterium tuberculosis complex (MTBC) was tested for the presence of mycobacteria by amplification of the IS6110 and 16SrRNA (16S) genes through double quantitative real-time PCR, followed by nested PCR and Sanger sequencing of the IS6110-negative samples for NTM species identification.Results1,418 sputum smear-positive patients were enrolled, including 1,199 new cases, 211 previously treated cases, and 8 whose previous treatment history was unknown. Based on the results of Xpert MTB/RIF assay and in-house PCR methods, 1,331 (93.9%) patients were positive for MTBC, 48 (3.4%) for NTM, and no species identification was possible for 39 (2.7%). Advanced age of 65 and over with an OR 8.8 (95% CI 2.3-33.2 and p = 0.001) and previous TB treatment with an OR 3.4 (95% CI 1.2-9.6 and p = 0.016) were the risk factors statistically associated with NTM detection. M. avium complex (MAC) was the predominant NTM species, detected in 20 cases.ConclusionDetection of NTM in people presumed to have TB is an ongoing challenge, confounding correct TB diagnosis. Concomitant use of microscopy and GeneXpert testing among at-risk individuals could improve patient management.

BACKGROUND:STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks. METHODS:We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed. FINDINGS:Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (-9·7 percentage points difference [95% CI -18·7 to -1·8]; psuperiority=0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; psuperiority<0·0001) or the oral regimen (23·8% [16·9 to 31·1]; psuperiority=0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49). INTERPRETATION:Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated. FUNDING:US Agency for International Development and Janssen Research & Development.

BACKGROUND:Non-tuberculous mycobacteria (NTM) are environmental agents that can cause opportunistic pulmonary disease in humans and animals, often misdiagnosed as tuberculosis (TB). In this study, we describe the cases of NTM identified during the first national anti-TB drug resistance survey conducted in Mali and explore associated risk factors. METHODS:Sputum was collected from people presenting for pulmonary TB diagnosis from April to December 2019, regardless of age. Microscopy-positive patients were enrolled and tested using the Xpert MTB/RIF assay. A patient who tested negative for the Mycobacterium tuberculosis complex (MTBC) was tested for the presence of mycobacteria by amplification of the IS6110 and 16SrRNA (16S) genes through double quantitative real-time PCR, followed by nested PCR and Sanger sequencing of the IS6110-negative samples for NTM species identification. RESULTS:1,418 sputum smear-positive patients were enrolled, including 1,199 new cases, 211 previously treated cases, and 8 whose previous treatment history was unknown. Based on the results of Xpert MTB/RIF assay and in-house PCR methods, 1,331 (93.9%) patients were positive for MTBC, 48 (3.4%) for NTM, and no species identification was possible for 39 (2.7%). Advanced age of 65 and over with an OR 8.8 (95% CI 2.3-33.2 and p = 0.001) and previous TB treatment with an OR 3.4 (95% CI 1.2-9.6 and p = 0.016) were the risk factors statistically associated with NTM detection. M. avium complex (MAC) was the predominant NTM species, detected in 20 cases. CONCLUSION:Detection of NTM in people presumed to have TB is an ongoing challenge, confounding correct TB diagnosis. Concomitant use of microscopy and GeneXpert testing among at-risk individuals could improve patient management.

OBJECTIVES:High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). DESIGN/METHODS:TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. RESULTS:Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% [95% confidence interval: 1.0,14.3]). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. CONCLUSION:We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.

The spread of multidrug-resistant tuberculosis (MDR-TB) is a growing problem in many countries worldwide. Resistance to one of the primary first-line drugs, rifampicin, is caused by mutations in the Mycobacterium tuberculosis rpoB gene. So-called borderline rpoB mutations confer low-level resistance, in contrast to more common rpoB mutations which confer high-level resistance. While some borderline mutations show lower fitness in vitro than common mutations, their in vivo fitness is currently unknown. We used a dataset of 394 whole genome sequenced MDR-TB isolates from Bangladesh, representing around 44 % of notified MDR-TB cases over 6 years, to look at differences in transmission clustering between isolates with borderline rpoB mutations and those with common rpoB mutations. We found a relatively low percentage of transmission clustering in the dataset (34.8 %) but no difference in clustering between different types of rpoB mutations. Compensatory mutations in rpoA, rpoB, and rpoC were associated with higher levels of transmission clustering as were lineages two, three, and four relative to lineage one. Young people as well as patients with high sputum smear positive TB were more likely to be in a transmission cluster. Our findings show that although borderline rpoB mutations have lower in vitro growth potential this does not translate into lower transmission potential or in vivo fitness. Proper detection of these mutations is crucial to ensure they do not go unnoticed and spread MDR-TB within communities.

AbstractThe spread of multidrug-resistant tuberculosis (MDR-TB) is a growing problem in many countries worldwide. Resistance to one of the primary first-line drugs, rifampicin, is caused by mutations in theMycobacterium tuberculosis rpoBgene. While some of these infrequent mutations show lower fitnessin vitrothan more common mutations, theirin vivofitness is currently unknown.We used a dataset of 394 whole genome sequenced MDR-TB isolates from Bangladesh, representing around 44% of notified MDR-TB cases over 6 years, to look at differences in transmission clustering between isolates with borderlinerpoBmutations and those with commonrpoBmutations. We found a relatively low percentage of transmission clustering in the dataset (34.8%) but no difference in clustering between different types ofrpoBmutations. Compensatory mutations inrpoA, rpoB, andrpoCwere associated with higher levels of transmission clustering as were lineages 2, 3, and 4 relative to lineage 1. Young people as well as patients with high sputum smear positive TB were more likely to be in a transmission cluster.Our findings show that although borderlinerpoBmutations have lowerin vitrogrowth potential this does not translate into lower transmission potential orin vivofitness. Proper detection of these mutations is crucial to ensure they do not go unnoticed and spread MDR-TB within communities.Data summaryWGS reads are available in the European Nucleotide Archive (PRJEB39569). In addition, WGS reads, as well as pDST and clinical data, are included in the ReSeqTB data platform and are accessible on registration athttps://platform.reseqtb.org/. Custom scripts for clustering are available athttps://github.com/conmeehan/pathophy.

Background Outcomes of retreatment for rifampicin-resistant tuberculosis (RR-TB) are rarely reported. We report 'definitive outcomes' after a cascade approach to RR-TB treatment. After a bacteriologically adverse outcome for the 9-months fluoroquinolone-based Short Treatment Regimen (STR), patients were retreated with a bedaquiline-based regimen (BDQ-regimen). Methods A Retrospective cohort study of RR-TB patients treated with the STR during 2012-2019 and retreated with a BDQ-regimen in case of failure or relapse was conducted. Definitive relapse-free cure took into account BDQ-regimen outcomes. Results Of 367 patients treated with the STR, 20 (5.4%) experienced failure or relapse. Out of these 20 patients, 14 started a BDQ-regimen, of whom none experienced failure or relapse. Definitive end of treatment outcomes of STR after revising with third-line BDQ-regimen outcomes, 84.7% (311/367) were cured relapse-free, 10.6% (39/367) died during treatment and 3.0% (11/367) were lost to follow-up during treatment with either the STR or BDQ-regimen. Six patients (1.6%; 6/367) with STR failure/relapse died before starting a BDQ-regimen. No patient had definitive treatment failure or relapse and remained without treatment. Conclusions If fluoroquinolone resistance is excluded or rare, it is beneficial to use fluoroquinolone as the core drug for a first RR-TB treatment regimen and to safeguard bedaquiline for those in need of retreatment.

OBJECTIVE:To investigate the performance of GeneXpert MTB/RIF Ultra to accurately detect rifampicin resistance for less common rpoB mutations that potentially confer phenotypic resistance, we tested 28 such Mycobacterium tuberculosis cultures with Xpert Ultra.RESULTS:They represented 22 different (combinations of) rpoB mutations. Of 28 isolates tested, one was reported by Xpert Ultra as "No rifampicin resistance detected", 8 yielded a "Rifampicin indeterminate" result, and 19 were identified as rifampicin resistant. Overall, our results corroborate previous observations on the "Indeterminate" results for mutations at codon 432, while we add Lys446Gln as additional "Indeterminate" result and Pro439Leu as a false rifampicin-susceptible result. Furthermore, we document other uncommon point mutations and indels across the rpoB gene that are mostly correctly identified as rifampicin resistant by Xpert ultra (V3). Taken together, "Indeterminate" results in Xpert Ultra may indicate underlying rpoB mutations within the rifampicin-resistance determining region and thus increase the post-test probability of rifampicin resistance, albeit to an unknown extent.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

Background The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. Methods We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Findings Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11.0% (95% CI 2.9-19.0), adjusted for HIV status and randomisation protocol (p<0.0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0.0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22.2%, 95% CI 13.1-31.2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Interpretation Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.

Background: Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed. Objectives: To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis. Data Sources: Pubmed, clinicaltrials.gov. and Cochrane library. Study eligibility criteria: Quantitative studies presenting original data on clinical efficacy or safety of pretomanid. Participants: Patients with tuberculosis. Interventions: Treatment with pretomanid or pretomanid-containing regimens in minimum one study group. Methods: Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated. Results: Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1-2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2-8) patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanidmoxifloxacin-pyrazinamide treatment, 91% (95% CI 59-100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83-95) on pretomanid-bedaquiline -linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported. Conclusions: Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role. Tinne Gils, Clin Microbiol Infect 2022;28:31 (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Previous studies showed that a fluoroquinolone-based short treatment regimen is effective for the treatment of tuberculosis (TB) resistant to the most important first-line TB drug, rifampicin. How to replace the fluoroquinolone in case of resistance to fluroquinolone, the most potent second-line drug, is unknown. Our findings show that replacing a fluoroquinolone by bedaquiline in the same short treatment regimen resulted in an early and sustained treatment response. When linezolid was used to the strengthen the fluoroquinolone-based regimen during the first treatment months the same early effect was not shown. Our findings suggest that bedaquiline, but probably not linezolid, can act as the treatment’s core drug and can assure relapse-free cure. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflicts of interest: B.C. de Jong reports grant funding from USAID for the STREAM trial on Bedaquiline for MDR-TB; and membership of a Panacea scientific advisort board, both within the 36 months prior to manuscript submission. All other authors declare no conflicts of interest.

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.https://bit.ly/3i43wb6

BACKGROUND:Rifampicin-resistant tuberculosis (RR-TB) treatment requires combination treatment, which frequently causes serious adverse events and globally results in not much more than 60% treatment success. In Niger, a high cure rate was obtained with a RR-TB treatment strategy based on a second-line injectable drug (SLID)-containing Short Treatment Regimen (STR), with linezolid replacing the SLID in patients with ototoxicity. Given the availability of novel anti-tuberculosis drugs, WHO recommends all-oral RR-TB treatment. Considering the high level of success with the Niger treatment strategy, it would only be justified to replace it in case robust evidence shows that the WHO all-oral bedaquiline/linezolid (BDQ/LZD)-containing STR (experimental arm) performs better than the Niger RR-TB treatment strategy, (control arm) in terms of safety, effectiveness and adherence. METHODS:A pragmatic randomised clinical trial (RCT) using stratified block randomisation, conducted between April 2021 and March 2024, prospectively enrols participants diagnosed with RR-TB in one of the four RR-TB units of the nation. Depending of the month in which patients are diagnosed with RR-TB, patients with FQ-susceptible RR-TB are enrolled in either the experimental arm or control arm. DISCUSSION:To increase the feasibility of conducting a RCT, embedded in routine activities of all Niger's RR-TB Units, we used a creative trial design. We randomised by monthly blocks, whereby the regimen used changes every month, using the month of RR-TB diagnosis as stratifying variable. This approach was deemed feasible for Niger's national tuberculosis programme, as it simplifies the work of the clinicians running the RR-TB units. Our creative design may serve as an example for other national programs. Findings will inform national and international RR-TB treatment guidelines, and will also strengthen the evidence-base on how to develop robust RR-TB treatment regimens. TRIAL REGISTRATION:Pan African Clinical Trial Register PACTR202203645724919 . Registered on 15 March 2022.

Background The incidence of acquired rifampicin resistance (RIF-ADR; RR) during first-line treatment varies. Objectives Compare clinically significant RIF-ADR versus primary and reinfection RR, between regimens (daily versus no rifampicin in the continuation phase; daily versus intermittent rifampicin in the continuation phase) and between rural Bangladesh and Kinshasa, Democratic Republic of Congo. Methods From patients with treatment failure, relapse, or lost to follow-up, both the outcome and baseline sputum sample were prospectively collected for rpoB sequencing to determine whether RR was present in both samples (primary RR) or only at outcome (RIF-ADR or reinfection RR). Results The most frequent cause of RR at outcome was primary RR (62.9%; 190/302). RIF-ADR was more frequent with the use of rifampicin throughout versus only in the intensive phase (difference: 3.1%; 95% CI: 0.2-6.0). The RIF-ADR rate was higher with intermittent versus daily rifampicin in the continuation phase (difference: 3.9%; 95% CI: 0.4-7.5). RIF-ADR after rifampicin-throughout treatment was higher when resistance to isoniazid was also found compared with isoniazid-susceptible TB. The estimated RIF-ADR rate was 0.5 per 1000 with daily rifampicin during the entire treatment. Reinfection RR was more frequent in Kinshasa than in Bangladesh (difference: 51.0%; 95% CI: 34.9-67.2). Conclusions RR is less frequently created when rifampicin is used only during the intensive phase. Under control programme conditions, the RIF-ADR rate for the WHO 6 month rifampicin daily regimen was as low as in affluent settings. For RR-TB control, first-line regimens should be sturdy with optimal rifampicin protection. RIF-ADR prevention is most needed where isoniazid-polyresistance is high, (re)infection control where crowding is extreme.

Nazir Ahmed Ismail and colleagues1Ismail NA Omar SV Moultrie H et al.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; (published online Nov 12.)https://doi.org/10.1016/S1473-3099(21)00470-9Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar have published their groundbreaking research on the epidemiological and genetic aspects of bedaquiline resistance and the clinical outcomes in patients with rifampicin-resistant tuberculosis. Ismail and colleagues concluded that bedaquiline resistance was associated with poorer treatment outcomes. The authors also identified the Rv0678 mutation as related to bedaquiline resistance and linked with possible bedaquiline and clofazimine cross-resistance.1Ismail NA Omar SV Moultrie H et al.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; (published online Nov 12.)https://doi.org/10.1016/S1473-3099(21)00470-9Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar The WHO classification of drugs used to treat multidrug-resistant and rifampicin-resistant tuberculosis lists bedaquiline as a group A drug and clofazimine as a group B drug. Additionally, WHO has recently redefined extensively drug-resistant tuberculosis as tuberculosis caused by a Mycobacterium tuberculosis strain that fulfils the definition of multidrug-resistant or rifampicin-resistant tuberculosis (ie, strains that are resistant to both rifampicin and isoniazid or rifampicin alone) and that is also resistant to any fluoroquinolone and at least one additional group A drug.2Viney K Linh NN Gegia M et al.New definitions of pre-extensively and extensively drug-resistant tuberculosis: update from the World Health Organization.Eur Respir J. 2021; 57: 1-5Crossref Scopus (12) Google Scholar Thus, bedaquiline resistance or clofazimine resistance (increasing the risk of bedaquiline resistance through cross-resistance) places patients with tuberculosis at a higher risk of developing extensively drug-resistant tuberculosis. As per the current WHO recommendations, bedaquiline and clofazimine are essential components of all the shorter and longer regimens for treating multidrug-resistant and rifampicin-resistant tuberculosis.3WHOWHO consolidated guidelines on tuberculosis, module 4: treatment—drug-resistant tuberculosis treatment.https://apps.who.int/iris/rest/bitstreams/1280998/retrieveDate: 2020Date accessed: December 31, 2021Google Scholar The novel and shorter bedaquiline, pretomanid, and linezolid regimen has been shown to have more favourable treatment outcomes in patients with drug-resistant tuberculosis in the Nix-TB and ZeNix trials than the second-line injectable-based shorter regimen for treating multidrug-resistant and rifampicin-resistant tuberculosis that was previously recommended by WHO.4Mishra G Nix-TB and ZeNix trials: paving the way for shorter regimens for drug-resistant tuberculosis.Asian Pac J Trop Med. 2021; 14: 431-432Crossref Scopus (1) Google Scholar However, the speed with which national programmes, including the Indian national tuberculosis elimination programme, are implementing bedaquiline-based or clofazimine-based regimens is not reflected in the pace of capacity building for rapid diagnostic tools for detecting drug resistance. This capacity building process is important since none of the regimens has a 100% success rate in treating patients with drug-resistant tuberculosis, and some patients are expected to have unfavourable treatment outcomes due to factors such as extensive disease, adverse drug reactions, and loss to follow-up. With the increased exposure of these medications to patients in all prescribed multidrug-resistant and rifampicin-resistant tuberculosis treatment regimens, resistance might increase in the population. In the absence of the availability of rapid tools to diagnose resistance to important second-line drugs, such resistance would be catastrophic, especially for the programmatic management of drug-resistant tuberculosis that is difficult to treat. For drug sensitivity testing, WHO currently recommends the traditional and time-consuming culture-based phenotypic bedaquiline drug sensitivity testing, which is not commonly available in the field. The development of rapid molecular diagnostic methods that can detect resistance to at least all medicines from group A (ie, levofloxacin, moxifloxacin, bedaquiline, and linezolid) is urgently needed. At the start of treatment, the availability of whole-genome sequencing for all patients with confirmed tuberculosis would be ideal. The Rv0678 mutation seems to be an appealing target for developing rapid diagnostic tools for bedaquiline resistance. National tuberculosis programmes across the globe need to develop and scale-up facilities for rapid diagnostic techniques for detecting drug resistance to important second-line anti-tuberculosis drugs, including bedaquiline, in a similar manner in which they are accepting the WHO-recommended bedaquiline-based treatment regimens for multidrug-resistant tuberculosis. We declare no competing interests. Implications of bedaquiline-resistant tuberculosisNazir Ahmed Ismail and colleagues show a 3·8% baseline resistance to bedaquiline in patients with rifampicin-resistant tuberculosis and 2·3% prevalence of acquired resistance to bedaquiline during treatment with the currently recommended all-oral treatment regimen.1 Treatment included all three WHO group A drugs (ie, a fluoroquinolone, bedaquiline, and linezolid).2 These findings underpin the importance of evaluating treatment regimens in routine care in settings with the necessary capacity to document all relevant bacteriological outcomes, including acquired resistance to key drugs. Full-Text PDF 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 studyBedaquiline 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. Full-Text PDF

Abstract Background Drug-resistant tuberculosis (DR-TB) is considered to be a public health threat and is difficult to cure, requiring a lengthy treatment with potent, potentially toxic drugs. The novel antimicrobial agent bedaquiline has shown promising results for patients with DR-TB, improving the rate of culture conversion and reducing TB-related mortality. However, increasing numbers of cases with acquired bedaquiline resistance (ABR) have been reported in recent years. Methods This systematic review aimed to assess the frequency of ABR and characteristics of patients acquiring it. Studies showing data on sequential bedaquiline drug-susceptibility testing in patients treated with a bedaquiline-containing regimen were included. The databases CENTRAL, PubMed and Embase were manually searched, and 866 unique records identified, eventually leading to the inclusion of 13 studies. Phenotypic ABR was assessed based on predefined MIC thresholds and genotypic ABR based on the emergence of resistance-associated variants. Results The median (IQR) frequency of phenotypic ABR was 2.2% (1.1%–4.6%) and 4.4% (1.8%–5.8%) for genotypic ABR. Among the studies reporting individual data of patients with ABR, the median number of likely effective drugs in a treatment regimen was five, in accordance with WHO recommendations. In regard to the utilization of important companion drugs with high and early bactericidal activity, linezolid was included in the regimen of most ABR patients, whereas the usage of other group A (fluoroquinolones) and former group B drugs (second-line injectable drugs) was rare. Conclusions Our findings suggest a relevant frequency of ABR, urging for a better protection against it. Therefore, treatment regimens should include drugs with high resistance-preventing capacity through high and early bactericidal activity.

The short treatment regimen (STR) achieves a >80% cure in rifampicin-resistant tuberculosis (RR-TB) patients. However, ototoxicity induced by the injectable is a concern. This is the first study to evaluate the replacement of injectables by linezolid in patients with audiometry abnormalities at baseline or during the treatment. We conducted a retrospective cohort study of all RR-TB patients started on the STR between 2016 and June, 2019, in Niger. Patients underwent audiometry every 2 months in 2016 and every month since 2017. Of 195 patients, 16.9% (33 out of 195) received linezolid from the start (n=17), or switched from injectables to linezolid during treatment (n=16), based on audiometry abnormalities. In 2016, two patients developed severe ototoxicity despite switching to linezolid. Since 2017, no patient developed severe hearing loss or complete deafness. Severe haematological toxicity was observed in 18.1% (six out of 33) of patients on linezolid, none of which was life threatening. The use of linezolid was associated with severe but manageable adverse events (hazard ratio 8.9, 95% CI 2.5–31.5; p=0.001). A total of 90.9% (30 out of 33) of patients on a linezolid-containing STR were cured, and none experienced treatment failure. Three died, but not due to adverse events. Baseline and monthly audiometry monitoring and using linezolid after detection of hearing abnormalities appears effective to prevent severe ototoxicity, while keeping high treatment success and manageable adverse events.

We report 2 cases for whom Xpert MTB/RIF falsely signaled rifampicin-resistant tuberculosis, based on unusually low cycle threshold and 3 of 5 probes missing. Other mycobacterial tests were negative. Further optimization of the Xpert MTB/RIF algorithm is warranted.