Emerging bedaquiline-resistant tuberculosis

Tuberculosis is the leading cause of death attributed to a single infectious pathogen worldwide. Despite the availability of anti-tuberculosis therapies for more than half a century, the number of people affected by tuberculosis reached a historical peak in 2021.1WHOGlobal tuberculosis report 2022. World Health Organization, Geneva2022Google Scholar In the absence of a vaccine that is substantially more effective than the Mycobacterium bovis bacilli Calmette Guérin vaccine, the elimination of tuberculosis is highly unlikely anytime soon. Over the past decade, a substantial increase in the number of individuals identified with multidrug-resistant or rifampicin-resistant tuberculosis has been observed.1WHOGlobal tuberculosis report 2022. World Health Organization, Geneva2022Google Scholar Although a large part of this increase is attributed to improvements in the availability of molecular diagnostics for rifampicin resistance, overall antimicrobial resistance to Mycobacterium tuberculosis is increasing. Approximately 15% of all deaths globally that are related to antimicrobial resistant M tuberculosis are attributed to tuberculosis.2Antimicrobial Resistance CollaboratorsGlobal burden of bacterial antimicrobial resistance in 2019: a systematic analysis.Lancet. 2022; 399: 629-655Summary Full Text Full Text PDF PubMed Scopus (3101) Google Scholar The current standard anti-tuberculosis treatment regimen with rifampicin, isoniazid, pyrazinamide, and ethambutol has been in use since the 1970s. New drugs such as clofazimine, moxifloxacin, meropenem, and linezolid became available in the 1990s; and, although not designed for tuberculosis treatment, they were found to have anti-tuberculosis activity. Only since 2014, two novel drugs became available for the treatment of tuberculosis: bedaquiline and delamanid. In 2020, a third novel anti-tuberculosis drug, pretomanid, became available. Unfortunately, the phase 3 trial evaluating delamanid did not report superiority of this drug compared with a placebo in achieving treatment success,3von Groote-Bidlingmaier F Patientia R Sanchez E et al.Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.Lancet Respir Med. 2019; 7: 249-259Summary Full Text Full Text PDF PubMed Scopus (121) Google Scholar and too little information is available on pretomanid's contribution to effective anti-tuberculosis treatment regimen. By contrast, bedaquiline showed cure rates and survival benefits in the treatment of drug-resistant tuberculosis compared with no other anti-tuberculosis compounds before. Retrospective registry data from South Africa demonstrated that inclusion of bedaquiline in treatments for patients with multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis was associated with a substantial reduction in all-cause mortality compared with standard regimens.4Schnippel K Ndjeka N Maartens G et al.Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.Lancet Respir Med. 2018; 6: 699-706Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar Results of clinical trials (NiX-TB, ZeNiX-TB, TB-Practecal, and STREAM-Stage2) have shown that approximately 90% of patients affected by multidrug-resistant or rifampicin-resistant tuberculosis and extensively-drug-resistant tuberculosis achieve treatment success on bedaquiline-based regimens when administered over 6 months only. This observation led to a substantial revision of the WHO guidelines for the management of patients with drug-resistant tuberculosis in 2022.5WHOWHO consolidated guidelines on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update. World Health Organization, Geneva2022Google Scholar Fortunately, among all second-line anti-tuberculosis medicines, bedaquiline has the lowest risk for adverse events.6Lan Z Ahmad N Baghaei P et al.Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.Lancet Respir Med. 2020; 8: 383-394Summary Full Text Full Text PDF PubMed Scopus (121) Google Scholar Moreover, successful treatment outcomes did not differ in patients with pan drug-susceptible tuberculosis who received isoniazid, pyrazinamide, and linezolid plus bedaquiline for 8 weeks only, compared with patients who received standard treatment regimen with rifampicin and isoniazid over 6 months and including pyrazinamide and ethambutol during the first 2 months of therapy.7Paton NI Cousins C Suresh C et al.Treatment strategy for rifampin-susceptible tuberculosis.N Engl J Med. 2023; 388: 873-887Crossref PubMed Scopus (19) Google Scholar Concerns about resistance have existed since the early development of bedaquiline as an anti-tuberculosis medicine. Two mechanisms are important for acquired bedaquiline resistance: mutations in atpE, which encodes the bedaquiline target, associated with high-level drug resistance; and mutations in Rv0678, which derepress the transcription of the MmpL5-MmpS5 efflux transporter, associated with low-level drug resistance. As clofazimine resistance is also associated with mutations in Rv0678 through the same mechanism, previous exposure to clofazimine might lead to bedaquiline resistance without previous bedaquiline exposure.8Xu J Li D Shi J et al.Bedquiline Resistance mutations: correlations with drug exposures and impact on the proteome in M tuberculosis.Antimicrob Agents Chemother. 2023; 67e0153222Crossref Scopus (0) Google Scholar Studies from Pakistan9Ghodousi A Rizvi AH Baloch AQ et al.Acquisition of cross-resistance to bedaquiline and clofazimine following treatment for tuberculosis in Pakistan.Antimicrob Agents Chemother. 2019; 63: e00915-e00919Crossref PubMed Scopus (40) Google Scholar and Moldova10Chesov E Chesov D Maurer FP et al.Emergence of bedaquiline resistance in a high tuberculosis burden country.Eur Respir J. 2022; 592100621Crossref PubMed Scopus (14) Google Scholar showed that six (20%) of 30 and four (15%) of 26 strains of M tuberculosis acquired bedaquiline resistance under therapy, respectively. In The Lancet Microbe, Brigitta Derendinger and colleagues' study11Derendinger B Dippenaar A de Vos M et al.Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study.Lancet Microbe. 2023; (published online Nov 3.)https://doi.org/10.1016/S2666-5247(23)00172-6Google Scholar from South Africa found that 18 (47%) of 38 M tuberculosis strains had acquired bedaquiline resistance during treatment. Baseline fluoroquinolone resistance, previous exposure to clofazimine, and an insufficient number of effective medicines in a treatment regimen were identified as risk factors for acquired bedaquiline resistance, confirming previous findings.9Ghodousi A Rizvi AH Baloch AQ et al.Acquisition of cross-resistance to bedaquiline and clofazimine following treatment for tuberculosis in Pakistan.Antimicrob Agents Chemother. 2019; 63: e00915-e00919Crossref PubMed Scopus (40) Google Scholar, 10Chesov E Chesov D Maurer FP et al.Emergence of bedaquiline resistance in a high tuberculosis burden country.Eur Respir J. 2022; 592100621Crossref PubMed Scopus (14) Google Scholar Until recently, bedaquiline was under the closed patent of a pharmaceutical company. Global advocacy efforts have been made to grant licenses that enable the Global Drug Facility to tender, procure, and distribute generic versions of bedaquiline, improving access to this drug. The recent international rollout of the bedaquiline, pretomanid, and linezolid (moxifloxacin) regimen has occurred in many places where patients are affected by drug-resistant tuberculosis in the absence of adequate drug-susceptibility testing capacity. These unfortunate circumstances can lead to the risk of programmatically selecting drug-resistant strains of M tuberculosis. Molecular tools can now predict the presence of drug-resistance associated mutations and guide clinicians to design effective treatment regimens.12Grobbel HP Merker M Kohler N et al.Design of multidrug-resistant tuberculosis treatment regimens based on DNA sequencing.Clin Infect Dis. 2021; 73: 1194-1202Crossref PubMed Scopus (15) Google Scholar Provision of novel treatments must go hand-in-hand with access to precise diagnostics; otherwise, the positive effects of bedaquiline-based therapies on treatment outcomes cannot be sustained. CL is supported by the German Center for Infection Research (TTU 02.709); has received speaker's honoraria from Insmed, Gilead, and Janssen; and is a member of the Data Safety Board of trials from Medicines sans Frontiers, outside of the scope of this work. AMM was a member of the Data Safety Board of trials from Janssen. AV declares no competing interests. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort studyBedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed. 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