Rifabutin Acts in Synergy and Is Bactericidal with Frontline Mycobacterium abscessus Antibiotics Clarithromycin and Tigecycline, Suggesting a Potent Treatment Combination.

Mark Pryjma,Ján Burian,Charles J Thompson

doi:10.1128/aac.00283-18

Mark Pryjma, Ján Burian + Show 1 more

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https://doi.org/10.1128/aac.00283-18

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Abstract

ABSTRACTMycobacterium abscessus is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections. Because these bacteria are intrinsically multidrug resistant, treatment options are limited and have questionable efficacy. The current treatment regimen relies on a combination of antibiotics, including clarithromycin paired with amikacin and either imipenem or cefoxitin. Tigecycline may be added when triple therapy is ineffective. We initially screened a library containing the majority of clinically available antibiotics for anti-M. abscessus activity. The screen identified rifabutin, which was then investigated for its interactions with M. abscessus antibiotics used in drug regimens. Combination of rifabutin with either clarithromycin or tigecycline generated synergistic anti-M. abscessus activity, dropping the rifabutin MIC below concentrations found in the lung. Importantly, these combinations generated bactericidal activity. The triple combination of clarithromycin, tigecycline, and rifabutin was also synergistic, and clinically relevant concentrations had a sterilizing effect on M. abscessus cultures. We suggest that combinations including rifabutin should be further investigated for treatment of M. abscessus pulmonary infections.

Highlights

Mycobacterium abscessus is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections
Our results show that the combination of RFB, CLR, and TGC was synergistic with an fractional inhibitory concentration index (FICI) of 0.375; MIC values in triple combinations were lower than MIC values of any combination of two antibiotics (Table 4). 3D checkerboard aac.asm.org 4
In a screen for antibiotics active against M. abscessus, we identified RFB and showed that it was synergistic with CLR and TGC in both growth and time-kill analyses

Summary

Introduction

Mycobacterium abscessus is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections Because these bacteria are intrinsically multidrug resistant, treatment options are limited and have questionable efficacy. Combination of rifabutin with either clarithromycin or tigecycline generated synergistic anti-M. abscessus activity, dropping the rifabutin MIC below concentrations found in the lung. Tigecycline (TGC) is sometimes used as a supplement to the triple antibiotic therapy when these antibiotics are ineffective The efficacies of these antibiotics, especially in combinations, are limited by induction of resistance genes by CLR. Treatment of pulmonary M. abscessus infections is further complicated by the pharmacodynamic properties of TGC, IPM, FOX, and AMK, all of which have limited penetration into the lung [8]. Since the current protocol for M. abscessus therapy employs combinations of CLR, AMK, FOX, IPM, and TGC, we investigated their interactions with RFB

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