Allix-Béguec C, et al. - This study was undertaken to determine if DNA sequencing can be used to precisely predict profiles of susceptibility to first-line antituberculosis drugs (isoniazid, rifampin, ethambutol, and pyrazinamide). Findings suggested an association of genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs with phenotypic susceptibility to these drugs.

Methods

• For this investigation, researchers obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents.
• After that, they identified mutations associated with drug resistance and drug susceptibility across nine genes as well as predicted individual phenotypes unless mutations of unknown association were also present for each isolate.
• Complete susceptibility profiles were predicted to identify how whole-genome sequencing might direct first-line drug therapy.
• These profiles were predicted to be susceptible to all 4 drugs (ie, pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs.
• Finally, they simulated the way in which the negative predictive value changed with the prevalence of drug resistance.

Results

• Ten thousand, two hundred nine isolates were analyzed in this investiagtion.
• It was observed that the largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794).
• Findings revealed that resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity.
• It was noted that out of 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted.
• Three thousand, nine hundred fifty-two (97.9%) were correctly predicted among the 4037 phenotypic profiles that were predicted to be pansusceptible.