Abstract
Mycobacterium abscessus is a difficult respiratory pathogen to treat, when compared to other nontuberculus mycobacteria (NTM), due to its drug resistance. In this study, we aimed to find a new clarithromycin partner that potentiated strong, positive, synergy against M. abscessus among current anti-M. abscessus drugs, including omadacycline, amikacin, rifabutin, bedaquiline, and cefoxitine. First, we determined the minimum inhibitory concentrations required of all the drugs tested for M. abscessus subsp. abscessus CIP104536T treatment using a resazurin microplate assay. Next, the best synergistic partner for clarithromycin against M. abscessus was determined using an in vitro checkerboard combination assay. Among the drug combinations evaluated, omadacycline showed the best synergistic effect with clarithromycin, with a fractional inhibitory concentration index of 0.4. This positive effect was also observed against M. abscessus clinical isolates and anti-M. abscessus drug resistant strains. Lastly, this combination was further validated using a M. abscessus infected zebrafish model. In this model, the clarithromycin-omadacyline regimen was found to inhibit the dissemination of M. abscessus, and it significantly extended the lifespan of the M. abscessus infected zebrafish. In summation, the synergy between two anti-M. abscessus compounds, clarithromycin and omadacycline, provides an attractive foundation for a new M. abscessus treatment regimen.
Highlights
Mycobacterium abscessus is a deadly, drug-resistant, nontuberculous mycobacteria (NTM), that has been increasing in prevalence worldwide (Pan et al, 2017)
These results were consistent with the survival curves and the CFU determination (Figures 3B,C). These results indicate that the combination of CLA and OMD significantly inhibited Mab growth in the ZF bodies and, extended the lifespan of the infected ZF. Some antibiotics, such as AMK, CFX, and IMP, show effectiveness against Mab, only CLA shows persuasive evidence of clinical efficacy for the treatment of pulmonary disease caused by Mab (Nie et al, 2014)
Based on the meta-analysis performed by Diel et al, the clinical treatment success rate of Mab pulmonary disease is generally 41%
Summary
Mycobacterium abscessus (hereafter referred as Mab) is a deadly, drug-resistant, nontuberculous mycobacteria (NTM), that has been increasing in prevalence worldwide (Pan et al, 2017). In 2017, the British Thoracic Society (BTS) guidelines recommended a revised antibiotic therapy comprised of intravenous amikacin (AMK), tigecycline (TGC), and imipenem (IMP) administered with a macrolide, for the initial treatment phase. For the continuation phase, nebulized AMK and a macrolide were used in combination with one to three of the following oral antibiotics: linezolid, clofazimine (CFZ), minocycline cotrimoxazole, and moxifloxacin (Haworth et al, 2017). Recent American Thoracic Society (ATS) guidelines recommended a revised antibiotic therapy for Mab treatment. The initial treatment phase comprises parental drugs (AMK, IMP or cefoxitin, TGC) and oral drugs (Azithromycin; AZT or CLA, CFZ, Linezolid). Oral drugs such as AZT or CLA, CFZ, linezolid, and inhaled AMK were combined.
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