Discordance in genotypic and phenotypic drug susceptibility results: time to reconsider critical concentration of rifampicin

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide, killing millions every year. The emergence of multidrug-resistant and extensively drug-resistant TB forms poses a challenge to the TB control programs. In the past few decades, several molecular tests for rapid detection and drug resistance determination have been developed. But these can miss the genetic mutations that confer low-level resistance to rifampicin (RIF), a critical constituent for treating drug-susceptible TB. On the other hand, for the phenotypic methods, a cutoff value is fixed, known as critical concentration (CC). The current WHO-endorsed CC for rifampicin is 1.0 μg/mL in liquid culture for confirmation of drug resistance; because of that in this system too, low-level RIF resistance may not be correctly identified. Therefore, it is important that either the CC for phenotypic methods is lowered or the specific mutations are included in the molecular tests. This study provides important insights in that direction.