Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

Migliori, Giovanni Battista

doi:10.1183/09031936.00199814

Cited by 21 publications

(17 citation statements)

References 22 publications

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“…Recently, this novel efflux mechanism of resistance has been identified to be responsible for low-level resistance to bedaquiline and clofazimine [48,64,65]. Unfortunately, to date, an adequate protocol to test bedaquiline susceptibility has not been developed and agreed upon [34,35].…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…Although more is now known about the efficacy and tolerability of linezolid [18][19][20][21][22][23][24][25] and interest has been recently raised by the possibility of using other re-proposed compounds (carbapenems [26][27][28], sulphonamides [29,30], and mefloquine [31], among others), the new anti-TB drugs delamanid [32] and bedaquiline are particularly promising [33][34][35].…”

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confidence: 99%

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Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence

et al. 2016

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@ERSpublications Systematic review of the available scientific evidence on the role of bedaquiline in new effective M/XDR-TB regimens http://ow.ly/V68ZFThe importance of adequately managing multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) cases for TB control and elimination are underlined in the new World Health Organization (WHO) "End TB Strategy" [1, 2] as part of pillar one (integrated, patient-centred care and prevention; element 2: treatment of all people with TB including drug-resistant TB, and patient support) and in the recently published "Framework towards TB elimination in low incidence countries" in its priority action 5 (optimise the prevention and care of drug-resistant TB) and the related background documents [3][4][5]. Furthermore, both in the End TB Strategy ( pillar 3: intensified research and innovation) and in the Framework towards TB elimination in low incidence countries ( priority action 7: invest in research and new tools) the need for new anti-TB drugs is strongly emphasised [1,3,6]. The reasons why new anti-TB drugs are needed are rather obvious if you look closely at the dimensions of the MDR-TB epidemic and the treatment successes achieved so far.Out of the 480 000 MDR-TB cases estimated by WHO to have occurred in 2014, only 123 000 (one quarter) have been diagnosed and notified [1]. Overall, 3.3% of new and 20% of retreatment cases harbour MDR-TB resistant strains of Mycobacterium tuberculosis, of whom 9.7% are proven to be XDR-TB [1]. The country with the highest prevalence of MDR-TB cases is Belarus (34% in new and 69% in retreatment cases), where 29% of the cases are reported to be XDR-TB [1,7].Treatment of MDR-TB and XDR-TB has proven, so far, to be long, expensive and difficult-to-manage, and unfortunately, its outcomes are suboptimal in most cohorts [8,9]. Although XDR-TB cases actually represent a relatively small proportion of all MDR-TB cases (9%), their treatment and management are significantly more challenging both for clinicians and national programmes [1]. Globally, treatment success of MDR-TB cases in the 2012 cohort was 50% (16% died, 16% were lost to follow-up, 10% failed, and 8% had no outcome information). Among the cases with a resistance pattern beyond XDR-TB the proportion of treatment success is unfortunately as low as 20%, with 49% failure and death [8,10].The design of an effective regimen to treat MDR-and XDR-TB is based on the stepwise use of second-line TB drugs whose choice needs to be guided by drug susceptibility testing (DST) [11][12][13]. Unfortunately, at the programmatic level neither the drugs needed nor the specific DST to test them are always available

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Section: Safety and Tolerabilitymentioning

confidence: 99%

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Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence

et al. 2016

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“…Breakpoints for bedaquiline are still provisional (10,11) and patients are started on treatment without susceptibility tests. We adopted 0.25 mg·L −1 as susceptibility breakpoint in 7H10 and 7H11(12, 13), which is above the MIC that inhibits 90% of the isolates or strains (0.12 mg·L −1 ).…”

Section: Manuscriptmentioning

confidence: 99%

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Ghodousi

Rizvi²,

Baloch

et al. 2019

Preprint

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20We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential 21 culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were 22 tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs 23 associated with cross-resistance to clofazimine and appearance of specific mutations was documented in 24 six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs. 25 26 27 93 strains collected from two patients reported as "failure" at the end of treatment (patient-4 MIC 0.25 94 mg·L −1 , eight fold higher than baseline and patient-5 MIC 0.125 mg·L −1 , four fold higher than baseline) 95 would have been categorised as susceptible. This finding indicates that monitoring MICs during treatment 96 could be a better predictor for failure than single testing at critical concentration. The genetic basis of 97 4 resistance to bedaquiline is still the subject of much uncertainty. WGS analysis in different studies showed 98 that bedaquiline-clofazimine cross resistance arises through mutations in Rv0678 (6,7,8) and pepQ (9). In 99 this study, we show that the increase of MIC to bedaquiline and clofazimine could be explained by 100 mutations emerging during therapy in Rv0678. As reported in table 1 we observed four different mutations 101 and three of these were previously reported as associated 102 to bedaquiline resistance in MTB clinical strains (8). We show that the same mutations are associated to 103 Clofazimine resistance. As a result, regimens that contain both drugs might have to be reconsidered when 104 these mutations are identified, to reduce the risk of failure for the patients and transmission of such strains 105 in the community. Altogether, these data show that resistance to bedaquiline emerges during treatment 106 and emphasize the importance of using MIC and whenever possible molecular based surveillance in 107 national programmes implementing bedaquiline for the treatment of MDR/XDR-TB to monitor the 108 emergence of resistance. Moreover, a classification of mutations associated to bedaquiline and clofazimine 109 resistance is crucial to lead future development of tools for fast detection of resistance. Introducing drugs 110 without proper diagnostics to monitor drug resistance may lead to amplification of hardly treatable cases. 111 112 Ethics approval 113 Ethical clearance was approved by the Institutional review board for HIV, TB and Malaria programme, 114 Pakistan.

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“…We read with interest the correspondence by Prasanta Raghab Mohapatra commenting on our editorial [1], which was aimed at discussing the absence of adequate drug susceptibility protocol for the new drug bedaquiline.…”

Section: From the Authorsmentioning

confidence: 99%

“…SALFINGER and MIGLIORI [1] discussed some important issues of bedaquiline, the most promising drug for treating multidrug-resistant (MDR) tuberculosis (TB) in the early twenty-first century. I am afraid of some issues that could be detrimental to the future of TB control.…”

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Bedaquiline: finding the pores on the pot

Mohapatra

2015

Eur Respir J

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Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

Cited by 21 publications

References 22 publications

Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence

Bedaquiline and multidrug-resistant tuberculosis: a systematic and critical analysis of the evidence

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Bedaquiline: finding the pores on the pot

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