Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: a breakpoint artefact?

Objectives: It has long been assumed that some rifampicin-resistant Mycobacterium tuberculosis strains are susceptible to, and thus treatable with, rifabutin. However, clinical breakpoints for susceptibility testing of rifabutin as well as the evidence for a clinical effect of rifabutin in rifampicin-resistant strains remains poorly defined. The objective of this study was to re-evaluate the breakpoint for rifabutin in relation to its MIC wild-type distribution and the presence of mutations in rpoB. Methods: The MIC in 7H10 Middlebrook medium was determined for clinical isolates of M. tuberculosis (n95), where a majority were multidrug resistant. Additionally, all strains were screened for rpoBmutations by sequen-cing and the GenoType MTBDRplus assay. Results: Rifampicin resistance was confirmed by genotypical and/or phenotypical tests in 73 isolates (76.8%). Nineteen isolates, defined as rifampicin resistant and rifabutin susceptible according to the present breakpoint, exhibited significantly higher MICs of rifabutin (0.064–0.5 mg/L) than rifabutin-susceptible isolates without any detectable mutations in rpoB (P,0.001). These 19 isolates were clearly resistant to rifampicin (MIC 2–256 mg/L) and all but one had mutations in rpoB, with 9 (47.4%) specifically in Asp516Val. Conclusions:Our results indicate that rifampicin-resistant but rifabutin-susceptible isolates according to the presen