In vitro interaction profiles of the new antitubercular drugs bedaquiline and delamanid with moxifloxacin against clinical Mycobacterium tuberculosis isolates

Objectives: The emergence of drug-resistant tuberculosis (TB) poses a serious challenge to existing anti-TB therapies. Hence, there is a direct need for identification of new drugs and effective combination regimens. Methods: In this study, minimum inhibitory concentrations (MICs) of the anti-TB drugs bedaquiline (BDQ), delamanid (DEL) and moxifloxacin (MFX) were evaluated using a resazurin microtiter assay (REMA) against five drug-resistant clinicalMycobacterium tuberculosis (MTB) isolates as well as the drug-susceptible reference strain H37Rv. In addition, their fractional inhibitory concentration indices (FICIs) were evaluated using a REMA-based calorimetric chequerboard assay to assess their interaction profiles against the MTB isolates. Results: The FICI indicated that BDQ acted synergistically with DEL against isoniazid (INH)-monoresistant, rifampicin (RIF)-monoresistant and extensively drug-resistant (XDR) clinical MTB isolates. In addition, the combination of DEL acted synergistically with MFX against INH-monoresistant, RIF-monoresistant and XDR clinical MTB isolates. Moreover, the combination of BDQ and MFX showed a synergistic effect against RIF-monoresistant and pre-XDR clinical MTB isolates. DEL at 0.125 x MIC (i.e. 0.015 mu g/mL) used in combination with BDQ at 0.25 x MIC (i.e. 0.015 mu g/mL) had a stronger bactericidal effect against the XDR-TB clinical isolate than DEL alone at 1 x MIC (i.e. 0.125 mu g/mL). Conclusion: Synergistic and additive effects between these two-drug combinations offer an attractive chemotherapeutic regimen against drug-resistant clinical MTB isolates. (C) 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.