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1.
Indian J Tuberc ; 69 Suppl 2: S264-S266, 2022.
Article in English | MEDLINE | ID: covidwho-2158998

ABSTRACT

Diabetes mellitus (DM) and tuberculosis (TB) are worldwide health burdens post-COVID-19. TB is the second-leading cause of death by a single infectious microbe. There is much evidence around the world about the responsibility of TB-DM co-morbidity. Both TB and DM prevalence is high in low- and middle-income countries. Especially the elderly with diabetes are more prone to TB infection due to compromised immune systems. Diabetic patients are three times as likely to develop tuberculosis as non-diabetic patients. DM interferes with the status of TB and leads to undesirable outcomes in the treatment of TB. This may later lead to the development of multidrug-resistant tuberculosis (MDR-TB). The coexistence of TB and DM leads to a high mortality rate and therefore becomes an enormous challenge for the medical field. This viewpoint includes the most current information about TB and DM, disease complications, treatment strategies, challenges to be faced in disease management and the importance of TB-DM bidirectional screening in older adults, which helps in early detection and better treatment programme.


Subject(s)
COVID-19 , Diabetes Mellitus , Tuberculosis, Multidrug-Resistant , Tuberculosis , Humans , Aged , COVID-19/complications , COVID-19/epidemiology , Tuberculosis/complications , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Diabetes Mellitus/epidemiology , Tuberculosis, Multidrug-Resistant/complications , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology , Comorbidity
2.
Front Cell Infect Microbiol ; 12: 943545, 2022.
Article in English | MEDLINE | ID: covidwho-2141706

ABSTRACT

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Disease Management , Humans , Mycobacterium tuberculosis/genetics , Sputum , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology
3.
J Pediatric Infect Dis Soc ; 11(Supplement_3): S67-S71, 2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2097390

ABSTRACT

The COVID-19 pandemic has set back the global tuberculosis (TB) response by several years. In 2020, access to TB prevention and care declined sharply, with TB notifications dropping by 18% compared to 2019. Declines were more pronounced in children, with a 24% drop in 0-14 year-olds and a 28% drop in 0-4 year-olds. As a result, in 2020 the number of deaths due to TB increased to 1.5 million across all ages, reversing a decade-long declining trend. Progress toward the UN High Level Meeting targets for 2022 is at risk, including the targets related to children for TB and drug-resistant TB treatments, and TB preventive therapy. Nonetheless, ending TB by 2030 as envisaged in the Sustainable Development Goals (SDGs) is still possible, but requires increased investments in accelerated case detection, subclinical TB, preventive therapy and an effective vaccine. Investing in TB could prepare the world better for fighting a future airborne pandemic.


Subject(s)
COVID-19 , Tuberculosis, Multidrug-Resistant , Tuberculosis , Child , Humans , Pandemics/prevention & control , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Tuberculosis/prevention & control , Tuberculosis, Multidrug-Resistant/drug therapy
5.
Braz J Biol ; 84: e258258, 2022.
Article in English | MEDLINE | ID: covidwho-2054598

ABSTRACT

According to studies carried out, approximately 10 million people developed tuberculosis in 2018. Of this total, 1.5 million people died from the disease. To study the behavior of the genome sequences of Mycobacterium tuberculosis (MTB), the bacterium responsible for the development of tuberculosis (TB), an analysis was performed using k-mers (DNA word frequency). The k values ranged from 1 to 10, because the analysis was performed on the full length of the sequences, where each sequence is composed of approximately 4 million base pairs, k values above 10, the analysis is interrupted, as consequence of the program's capacity. The aim of this work was to verify the formation of the phylogenetic tree in each k-mer analyzed. The results showed the formation of distinct groups in some k-mers analyzed, taking into account the threshold line. However, in all groups, the multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains remained together and separated from the other strains.


Subject(s)
Extensively Drug-Resistant Tuberculosis , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Cluster Analysis , Drug Resistance, Multiple, Bacterial/genetics , Extensively Drug-Resistant Tuberculosis/drug therapy , Extensively Drug-Resistant Tuberculosis/genetics , Extensively Drug-Resistant Tuberculosis/microbiology , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Phylogeny , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology
6.
Health Policy Plan ; 37(8): 979-989, 2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-2051393

ABSTRACT

Decentralized, person-centred models of care delivery for drug-resistant tuberculosis (DR-TB) continue to be under-resourced in high-burden TB countries. The implementation of such models-made increasingly urgent by the COVID-19 pandemic-are key to addressing gaps in DR-TB care. We abstracted data of rifampicin-resistant (RR)/multidrug-resistant tuberculosis (MDR-TB) patients initiated on treatment at 11 facilities between 2010 and 2017 in Sindh and Balochistan provinces of Pakistan. We analysed trends in treatment outcomes relating to programme expansion to peri-urban and rural areas and estimated driving distance from patient residence to treatment facility. Among the 5586 RR/MDR-TB patients in the analysis, overall treatment success decreased from 82% to 66% between 2010 and 2017, as the programme expanded. The adjusted risk ratio for unfavourable outcomes was 1.013 (95% confidence interval 1.005-1.021) for every 20 km of driving distance. Our analysis suggests that expanding DR-TB care to centralized hubs added to increased unfavourable outcomes for people accessing care in peri-urban and rural districts. We propose that as enrolments increase, expanding DR-TB services close to or within affected communities is essential.


Subject(s)
COVID-19 , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/therapeutic use , Humans , Pakistan , Pandemics , Politics , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology
7.
PLoS Biol ; 20(8): e3001721, 2022 08.
Article in English | MEDLINE | ID: covidwho-2039215

ABSTRACT

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


Subject(s)
Extensively Drug-Resistant Tuberculosis , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Extensively Drug-Resistant Tuberculosis/drug therapy , Extensively Drug-Resistant Tuberculosis/microbiology , Humans , Microbial Sensitivity Tests , Mutation , Mycobacterium tuberculosis/genetics , Phenotype , Rifampin , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/genetics , Tuberculosis, Multidrug-Resistant/microbiology
9.
Microbiol Spectr ; 10(5): e0125222, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2029475

ABSTRACT

Tuberculosis (TB) remains one of the most important infectious diseases globally. Establishing a resistance profile from the initial TB diagnosis is a priority. Rapid molecular tests evaluate only the most common genetic variants responsible for resistance to certain drugs, and Whole Genome Sequencing (WGS) needs culture prior to next-generation sequencing (NGS), limiting their clinical value. Targeted sequencing (TS) from clinical samples avoids these drawbacks, providing a signature of genetic markers that can be associated with drug resistance and phylogeny. In this study, a proof-of-concept protocol was developed for detecting genomic variants associated with drug resistance and for the phylogenetic classification of Mycobacterium Tuberculosis (Mtb) in sputum samples. Initially, a set of Mtb reference strains from the WHO were sequenced (WGS and TS). The results from the protocol agreed >95% with WHO reported data and phenotypic drug susceptibility testing (pDST). Lineage genetics results were 100% concordant with those derived from WGS. After that, the TS protocol was applied to sputum samples from TB patients to detect resistance to first- and second-line drugs and derive phylogeny. The accuracy was >90% for all evaluated drugs, except Eto/Pto (77.8%), and 100% were phylogenetically classified. The results indicate that the described protocol, which affords the complete drug resistance profile and phylogeny of Mtb from sputum, could be useful in the clinical area, advancing toward more personalized and more effective treatments in the near future. IMPORTANCE The COVID-19 pandemic negatively affected the progress in accessing essential Tuberculosis (TB) services and reducing the burden of TB disease, resulting in a decreased detection of new cases and increased deaths. Generating molecular diagnostic tests with faster results without losing reliability is considered a priority. Specifically, developing an antimicrobial resistance profile from the initial stages of TB diagnosis is essential to ensure appropriate treatment. Currently available rapid molecular tests evaluate only the most common genetic variants responsible for resistance to certain drugs, limiting their clinical value. In this work, targeted sequencing on sputum samples from TB patients was used to identify Mycobacterium tuberculosis mutations in genes associated with drug resistance and to derive a phylogeny of the infecting strain. This protocol constitutes a proof-of-concept toward the goal of helping clinicians select a timely and appropriate treatment by providing them with actionable information beyond current molecular approaches.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis , Humans , Sputum , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Phylogeny , Microbial Sensitivity Tests , Reproducibility of Results , Genetic Markers , Pandemics , Tuberculosis/microbiology , Drug Resistance , Tuberculosis, Multidrug-Resistant/drug therapy
10.
Front Cell Infect Microbiol ; 12: 958240, 2022.
Article in English | MEDLINE | ID: covidwho-2022659

ABSTRACT

Suboptimal efficacy of the current antibiotic regimens and frequent emergence of antibiotic-resistant Mycobacterium tuberculosis (Mtb), an etiological agent of tuberculosis (TB), render TB the world's deadliest infectious disease before the COVID-19 outbreak. Our outdated TB treatment method is designed to eradicate actively replicating populations of Mtb. Unfortunately, accumulating evidence suggests that a small population of Mtb can survive antimycobacterial pressure of antibiotics by entering a "persister" state (slowly replicating or non-replicating and lacking a stably heritable antibiotic resistance, termed drug tolerance). The formation of drug-tolerant Mtb persisters is associated with TB treatment failure and is thought to be an adaptive strategy for eventual development of permanent genetic mutation-mediated drug resistance. Thus, the molecular mechanisms behind persister formation and drug tolerance acquisition are a source of new antibiotic targets to eradicate both Mtb persisters and drug-resistant Mtb. As Mtb persisters are genetically identical to antibiotic susceptible populations, metabolomics has emerged as a vital biochemical tool to differentiate these populations by determining phenotypic shifts and metabolic reprogramming. Metabolomics, which provides detailed insights into the molecular basis of drug tolerance and resistance in Mtb, has unique advantages over other techniques by its ability to identify specific metabolic differences between the two genetically identical populations. This review summarizes the recent advances in our understanding of the metabolic adaptations used by Mtb persisters to achieve intrinsic drug tolerance and facilitate the emergence of drug resistance. These findings present metabolomics as a powerful tool to identify previously unexplored antibiotic targets and improved combinations of drug regimens against drug-resistant TB infection.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis, Lymph Node , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Carbon , Drug Resistance , Drug Tolerance , Humans , Tuberculosis, Multidrug-Resistant/drug therapy
12.
Front Immunol ; 13: 870768, 2022.
Article in English | MEDLINE | ID: covidwho-1957155

ABSTRACT

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , COVID-19/diagnosis , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology
14.
Trials ; 23(1): 484, 2022 Jun 13.
Article in English | MEDLINE | ID: covidwho-1885333

ABSTRACT

BACKGROUND: Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. METHODS: TB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DISCUSSION: TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment. TRIAL REGISTRATION: Clinicaltrials.gov NCT02589782. Registered on 28 October 2015.


Subject(s)
Antitubercular Agents/therapeutic use , Diarylquinolines/therapeutic use , Linezolid/therapeutic use , Rifampin/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Adolescent , Adult , Antibiotics, Antitubercular/pharmacology , Antibiotics, Antitubercular/therapeutic use , Antitubercular Agents/pharmacology , Diarylquinolines/pharmacology , Humans , Linezolid/pharmacology , Pandemics , Rifampin/pharmacology , Treatment Outcome , Tuberculosis, Multidrug-Resistant/diagnosis , Young Adult
15.
17.
BMC Public Health ; 22(1): 976, 2022 05 14.
Article in English | MEDLINE | ID: covidwho-1865290

ABSTRACT

BACKGROUND: Loss to follow-up (LTFU) from tuberculosis (TB) treatment and care is a major public health problem as patients can be infectious and also may develop a multi-drug resistant TB (MDR-TB). The study aimed to assess whether LTFU differs by the distance TB patients travelled to receive care from the nearest health facility. METHODS: A total of 402 patient cards of TB patients who received care were reviewed from March 1-30, 2020. The Kaplan-Meir curve with the Log-rank test was used to compare differences in LTFU by the distance travelled to reach to the nearest health facility for TB care. The Cox proportional hazard regression model was used to identify predictors. All statistical tests are declared significant at a p-value< 0.05. RESULTS: A total of 37 patients were LTFU with the incidence rate of 11.26 per 1000 person-months of observations (PMOs) (95% CI: 8.15-15.53). The incidence rate ratio was 12.19 (95% CI: 5.01-35.73) among the groups compared (those who travelled 10 km or more versus those who travelled less than 10 km). Age ≥ 45 years (aHR = 7.71, 95% CI: 1.72, 34.50), educational status (primary schooling, aHR = 3.54, 95% CI: 1.49, 8.40; secondary schooling, aHR = 2.75, 95% CI: 1.08, 7.03), lack of family support (aHR = 2.80, 95% CI: 1.27, 6.19), nutritional support (aHR = 3.40, 95% CI:1.68, 6.89), ≥ 10 km distance to travel to a health facility (aHR = 6.06, 95% CI: 2.33, 15.81) had significantly predicted LTFU from TB treatment and care. CONCLUSIONS: LTFU from adult TB care and treatment was 12 times higher among those who travelled ≥10 km to reach a health facility compared to those who travelled less. To retain adult TB patients in care and ensure appropriate treatment, health professionals and other stakeholders should give due attention to the factors that drive LTFU. We suggest identifying concerns of older patients at admission and those who travel long distance and establish social support platforms that could help people to complete TB treatment.


Subject(s)
HIV Infections , Tuberculosis, Multidrug-Resistant , Tuberculosis , Adult , Ethiopia/epidemiology , Follow-Up Studies , HIV Infections/epidemiology , Humans , Lost to Follow-Up , Middle Aged , Proportional Hazards Models , Retrospective Studies , Risk Factors , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Tuberculosis, Multidrug-Resistant/drug therapy
19.
CPT Pharmacometrics Syst Pharmacol ; 11(5): 628-639, 2022 05.
Article in English | MEDLINE | ID: covidwho-1858907

ABSTRACT

Bedaquiline (BDQ) is recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) for the majority of patients. Given its long terminal half-life and safety concerns, such as QTc-prolongation, re-introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation-based study, we investigated different loading dose strategies for BDQ re-introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re-introduction, including no loading dose, 1- and 2-week loading doses (200 mg and 400 mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR-TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc-prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6 weeks) require a 2-week loading dose of 200 mg once daily in the typical patient. If treatment was interrupted for longer than 8 weeks, a 2-week loading dose (400 mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re-introduction providing guidance to clinicians for safe and efficacious BDQ dosing.


Subject(s)
Long QT Syndrome , Tuberculosis, Multidrug-Resistant , Antitubercular Agents , Diarylquinolines/pharmacokinetics , Humans , Tuberculosis, Multidrug-Resistant/drug therapy
20.
Lancet Infect Dis ; 22(4): 496-506, 2022 04.
Article in English | MEDLINE | ID: covidwho-1839428

ABSTRACT

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.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Clofazimine/therapeutic use , Cross-Sectional Studies , Diarylquinolines/therapeutic use , Humans , Longitudinal Studies , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Rifampin/pharmacology , Rifampin/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology
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