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

Abstract

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×MIC (i.e. 0.015μg/mL) used in combination with BDQ at 0.25×MIC (i.e. 0.015μg/mL) had a stronger bactericidal effect against the XDR-TB clinical isolate than DEL alone at 1×MIC (i.e. 0.125μg/mL).

CONCLUSION:

Synergistic and additive effects between these two-drug combinations offer an attractive chemotherapeutic regimen against drug-resistant clinical MTB isolates.

• Authors: Yuvaraj Chandramohan, Venkatesan Padmanaban, Ramalingam Bethunaickan, Srikanth Tripathy, Soumya Swaminathan, Uma Devi Ranganathan
• Journal: Journal of global antimicrobial resistance (J Glob Antimicrob Resist) Vol. 19 Pg. 348-353 (12 2019) ISSN: 2213-7173 [Electronic] Netherlands
• PMID: 31226332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antitubercular Agents
• Diarylquinolines
• Nitroimidazoles
• OPC-67683
• Oxazines
• Oxazoles
• Xanthenes
• resazurin
• bedaquiline
• Moxifloxacin

Topics

• Antitubercular Agents (pharmacology)
• Diarylquinolines (pharmacology)
• Drug Resistance, Multiple, Bacterial
• Drug Synergism
• Extensively Drug-Resistant Tuberculosis (microbiology)
• Humans
• Microbial Sensitivity Tests
• Moxifloxacin (pharmacology)
• Mycobacterium tuberculosis (drug effects)
• Nitroimidazoles (pharmacology)
• Oxazines
• Oxazoles (pharmacology)
• Tuberculosis, Multidrug-Resistant (microbiology)
• Xanthenes