Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China

• Published in: Annals of clinical microbiology and antimicrobials Vol. 23; no. 1; p. 40
• Main Authors: Zhao, Bing, Zheng, Huiwen, Timm, Juliano, Song, Zexuan, Pei, Shaojun, Xing, Ruida, Guo, Yajie, Ma, Ling, Li, Feina, Li, Qing, Li, Yan, Huang, Lin, Teng, Chong, Wang, Ni, Gupta, Aastha, Juneja, Sandeep, Huang, Fei, Zhao, Yanlin, Ou, Xichao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.05.2024; BMC
• Subjects: Antitubercular Agents - pharmacology; Breakpoint; Care and treatment; China - epidemiology; Drug resistance; Drug resistance in microorganisms; Epidemiology; Forecasts and trends; Genetic aspects; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - isolation & purification; Nitroimidazoles - pharmacology; Patient outcomes; Pretomanid; Prevalence; Resistance; Rifabutin; Tuberculosis; Tuberculosis, Multidrug-Resistant - epidemiology; Tuberculosis, Multidrug-Resistant - microbiology; Whole Genome Sequencing; China; Resistance; Breakpoint; Pretomanid; Mutation
• ISSN: 1476-0711; 1476-0711
• DOI: 10.1186/s12941-024-00697-0

Pretomanid is a key component of new regimens for the treatment of drug-resistant tuberculosis (TB) which are being rolled out globally. However, there is limited information on the prevalence of pre-existing resistance to the drug. To investigate pretomanid resistance rates in China and its underlying genetic basis, as well as to generate additional minimum inhibitory concentration (MIC) data for epidemiological cutoff (ECOFF)/breakpoint setting, we performed MIC determinations in the Mycobacterial Growth Indicator Tube™ (MGIT) system, followed by WGS analysis, on 475 Mycobacterium tuberculosis (MTB) isolated from Chinese TB patients between 2013 and 2020. We observed a pretomanid MIC distribution with a 99% ECOFF equal to 0.5 mg/L. Of the 15 isolates with MIC values > 0.5 mg/L, one (MIC = 1 mg/L) was identified as MTB lineage 1 (L1), a genotype previously reported to be intrinsically less susceptible to pretomanid, two were borderline resistant (MIC = 2-4 mg/L) and the remaining 12 isolates were highly resistant (MIC ≥ 16 mg/L) to the drug. Five resistant isolates did not harbor mutations in the known pretomanid resistant genes. Our results further support a breakpoint of 0.5 mg/L for a non-L1 MTB population, which is characteristic of China. Further, our data point to an unexpected high (14/475, 3%) pre-existing pretomanid resistance rate in the country, as well as to the existence of yet-to-be-discovered pretomanid resistance genes.