Estimation of country-specific tuberculosis resistance antibiograms using pathogen genomics and machine learning.

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.

Molecular characterization of drug-resistant Mycobacterium tuberculosis among Filipino patients derived from the national tuberculosis prevalence survey Philippines 2016.

Tuberculosis, caused by Mycobacterium tuberculosis, remains a high burden disease and leading cause of mortality in the Philippines. Understanding the genetic diversity of M. tuberculosis strains in the population, including those that are multi-drug resistant (MDR), will aid in formulating strategies for effective TB control and prevention. By whole genome sequencing of M. tuberculosis isolates (n = 100) from patients of the Philippine 2016 National Tuberculosis Prevalence Survey, we sought to provide a baseline assessment of the genotypic and phylogenetic characteristics of the isolates. The majority (96/100) of the isolates were EAI2-Manila strain-type (lineage 1), with one Lineage 2 (Beijing), one Lineage 3 (CAS1), and two Lineage 4 (LAM9) strains. The EAI2-Manila clade was not significantly associated with patient's phenotypic and in silico drug resistance profile. Five (5/6) MDR-TB isolates predicted by in silico profiling were concordant with phenotypic drug resistance profile. Twenty-one mutations were identified in nine drug resistance-related genes, all of which have been reported in previous studies. Overall, the results from this study contribute to the growing data on the molecular characteristics of Philippine M. tuberculosis isolates, which can help in developing tools for rapid diagnosis of TB in the country, and thereby reducing the high burden of disease.