Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment

Polsfuss, Silke; Hofmann-Thiel, Sabine; Merker, Matthias; Krieger, David; Niemann, Stefan; Rüssmann, Holger; Schönfeld, Nicolas; Hoffmann, Harald; Kranzer, Katharina

doi:10.1093/cid/ciz074

Cited by 60 publications

(53 citation statements)

References 7 publications

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“…A regimen containing fewer than four effective drugs carries the risk of losing the value of new potent drugs due to resistance acquisition, e.g. by mutations in rv0678 as recently reported [66]. It should also be noted that the majority of isolates in our cohort were sampled prior to the availability of BDQ and DLM.…”

Section: Discussionmentioning

confidence: 81%

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

Klopper

Heupink

Hill-Cawthorne

et al. 2020

BMC Med

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Background: Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations. Methods: We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants. Results: Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role. Conclusion:The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naïve patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile.

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Section: Discussionmentioning

confidence: 81%

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

Klopper

Heupink

Hill-Cawthorne

et al. 2020

BMC Med

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“…Eight publications presented longitudinal studies where BDQ or DLM resistance was developed after (in vivo or in vitro) drug exposure [5,6,[25][26][27][28][29][30]. Some of these longitudinal studies evaluated two to eight isolates from the same patient.…”

Section: Description Of Collected Articlesmentioning

confidence: 99%

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

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Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM.

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“…For identification of RAVs, we used a curated list of resistance-conferring mutations adapted from published sources (43,44) as listed in Supplementary Methods 3. We supplemented these mutations lists with more recent published data for new and repurposed drugs (45)(46)(47)(48). For mutations in the bedaquiline/clofazimine resistance-associated gene Rv0678 and delamanid resistance-associated genes fbiA/B/C, fgd1 and ddn, where a wide array of different mutations leading to loss of function occur, we took a more sensitive approach and manually evaluated all non-synonymous SNPs and indels for potential to cause resistance.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment

Cited by 60 publications

References 7 publications

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

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