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

Ismail, Nazir; Omar, Shaheed Vally; Moultrie, Harry; Bhyat, Z.; Conradie, Francesca; Enwerem, Martin; Ferreira, Héverson Batista; Hughes, Jennifer; Joseph, Lavania; Kock, Yulene; Letsaolo, Vancy; Maartens, Gary; Meintjes, Graeme; Ngcamu, Dumisani; Okozi, Nana; Padanilam, Xavier; Reuter, Anja; Romero, R; Schaaf, Simon; Riele, Julian Te; Variava, Ebrahim; Meulen, Minty van der; Ismail, Farzana; Ndjeka, Norbert

doi:10.1016/s1473-3099(21)00470-9

Cited by 63 publications

(46 citation statements)

References 25 publications

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Section: Resultsmentioning

confidence: 99%

“…Loss-of-function mutations in rv0678 are a common mechanism of resistance to the new antitubercular drug bedaquiline as well as the antileprotic/antitubercular drug clofazimine (38,40,41). There are several reports of rv0678 mutations arising at a high frequency in Mtb clinical isolates (41)(42)(43)(44)(45). Further, some rv0678 mutations pre-date the introduction of bedaquiline to TB treatment regimens and may have arisen in response to other selective pressures, such as clofazimine treatment of leprosy infections (43).…”

Section: Crispr Interference-based Chemical-genetic Profiling Identif...mentioning

confidence: 99%

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Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in M. tuberculosis

Poulton

Azadian

DeJesus

et al. 2022

Preprint

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Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB. One promising drug target in Mtb is the arabinogalactan biosynthetic enzyme DprE1, and there have been over a dozen unique chemical scaffolds identified which inhibit the activity of this protein. Among the most promising lead compounds are the benzothiazinones BTZ043 and PBTZ169, both of which are currently in or have completed phase IIa clinical trials. Due to the potential clinical utility of these drugs, we sought to identify potential synergistic interactions and new mechanisms of resistance using a genome-scale CRISPRi chemical-genetic screen with PBTZ169. We found that knockdown of rv0678, the negative regulator of the mmpS5/L5 drug efflux pump, confers resistance to PBTZ169. Mutations in rv0678 are the most common form of resistance to bedaquiline and there is already abundant evidence of these mutations emerging in bedaquiline-treated patients. We confirmed that rv0678 mutations from clinical isolates confer low level cross-resistance to BTZ043 and PBTZ169. While it is yet unclear whether rv0678 mutations would render benzothiazinones ineffective in treating TB, these results highlight the importance of monitoring for clinically-prevalent rv0678 mutations during ongoing BTZ043 and PBTZ169 clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Crispr Interference-based Chemical-genetic Profiling Identif...mentioning

confidence: 99%

Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in M. tuberculosis

Poulton

Azadian

DeJesus

et al. 2022

Preprint

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“…20-22 This is particularly important since resistance to Group A drugs in particular is associated with worse MDR/RR-TB treatment outcomes. 23,24…”

Section: Discussionmentioning

confidence: 99%

Cost and availability of drugs and treatment regimens and availability of drug resistance testing for tuberculosis in Europe

Günther

Guglielmetti

Leu

et al. 2022

Preprint

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Background: Access to comprehensive diagnostics and novel anti-tuberculosis medicines is crucial to improve tuberculosis control at times of emerging Mycobacterium tuberculosis drug resistance. Methods: We investigated access to genotypic and phenotypic M tuberculosis drug susceptibility testing (DST), availability of anti-tuberculosis drugs and calculated cost of drugs and treatment regimens at major tuberculosis treatment centers in countries of the World Health Organization (WHO) European region. Results are stratified by middle and high- income countries. Results: Overall, 43 treatment centers in 43 countries participated in the study. Phenotypic DST was available for WHO group A drugs levofloxacin/moxifloxacin, bedaquiline and linezolid, in 75%/82%, 48%, and 72% of countries, respectively. Overall, 84% and 56% of countries had access to bedaquiline and delamanid, while only 14% had access to rifapentine. Median cost (in Euros) of regimens for drug-susceptible tuberculosis, multidrug-resistant tuberculosis (shorter regimen, including bedaquiline for six months) and pre-extensively drug-resistant tuberculosis (including delamanid) were 44, 764 and 7 094 in middle income countries (n=12), and 280, 29 765, 207 035 in high income countries (n=29). Conclusion: Tuberculosis control in Europe is limited by widespread lack of DST capacity to new and re-purposed drugs, lack of access to essential medications and high treatment cost for drug-resistant tuberculosis.

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“…Without this, shifting to new (core) drugs can’t bring lasting progress. 44 Before a background regimen has been identified that limits ADR to a minimum in the average NTP, new TB core drugs should not become the standard of care for TB that is still susceptible to an older core drug. The ‘ancient’ vision of TB control, with emphasis on ADR prevention, is still highly relevant considering the high rates of ADR to bedaquiline in settings where it has been used for a sufficient time on a sufficiently large scale, despite background regimens respecting current recommendations which strongly emphasize using these newer drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The ‘ancient’ vision of TB control, with emphasis on ADR prevention, is still highly relevant considering the high rates of ADR to bedaquiline in settings where it has been used for a sufficient time on a sufficiently large scale, despite background regimens respecting current recommendations which strongly emphasize using these newer drugs. 44 , 45 …”

Section: Discussionmentioning

confidence: 99%

Acquired rifampicin resistance during first TB treatment: magnitude, relative importance, risk factors and keys to control in low-income settings

Deun¹,

Bola

Lebeke

et al. 2022

JAC-Antimicrobial Resistance

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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.

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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

Cited by 63 publications

References 25 publications

Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in M. tuberculosis

Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in M. tuberculosis

Cost and availability of drugs and treatment regimens and availability of drug resistance testing for tuberculosis in Europe

Acquired rifampicin resistance during first TB treatment: magnitude, relative importance, risk factors and keys to control in low-income settings

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