Cross-resistance among rifamycins in mycobacterium tuberculosis clinical isolates

Abstract

Introduction: Rifamycins (RFMs) are a group of antimycobacterial drugs that belong to the large family of ansamycin. RFMs inhibit Mycobacterial growth by blocking the RNA polymerase subunit B (rpoB). High level cross-resistance among RFMs in Mycobacterium tuberculosis (M. tuberculosis) clinical isolates is commonly inferred. However, previous studies reported that the minimum inhibitory concentrations (MICs) of rifabutin (RFB) among rifampicin (RIF)-resistant M. tuberculosis carrying rpoB mutations varies depending on the mutation position. Objective: -To determine the proportion of cross-resistance among rifamycins and to assess the use of the GenoType MTBDRplus Version 2.0 assay in predicting differential susceptibility to rifamycins in M. tuberculosis isolates. Method: -A total of 300 unique baseline isolates which were collected between June 2015-April 2016 for routine laboratory based surveillance of RIF drug resistance in selected districts of South Africa were included. Drug susceptibility testing (DST) for RIF (1.0 μg/ml), RFB (0.5 μg/ml) and rifapentine (RFP) (0.5 μg/ml) was performed by the MGIT 960 system using World Health Organisation (WHO) recommended critical concentration (c.c). The MycoTB plate was used to determine MICs for RIF and RFB. To determine rpoB mutations, all the isolates were tested by Genotype MTBDRplus version 2.0 assay method and undefined isolates were sent for Sanger sequencing. Results: -The proportion of cross resistance among RFMs were: across all three (216/300;72%), between RIF and RFB (217/300;72%) and RIF and RFP (292/300;98%). The S531L mutation was the mostly associated with cross resistance to all RFMs (144/153;94%), while the D516V mutation was associated with differential susceptibility to RFB (50/52;96%). Conclusion: -The results show high levels of cross resistance across all rifamycins, however 28% of MDR/XDR-TB cases could potentially benefit from RFB as a substitute drug to the failing RIF. These findings provided additional evidence of the strong association of specific rpoB mutations with the development of RFMs cross and differential susceptibility. The use of LPA and rpoB mutations specifically S531L and D516V can be beneficial in rapidly differentiating phenotypic differential susceptibility to RFB according to this study.