Abstract
BACKGROUND: Mycobacteroides abscessus are rapidly growing non-tuberculous mycobacteria that cause chronic lung and soft tissue infections. Treatment options are often severely limited due to intrinsic resistance to most antimicrobials. Amikacin has historically been a mainstay of combination treatment regimens. However, irreversible hearing loss and vestibular toxicity have led to a search for alternative agents. Apramycin is a novel aminoglycoside currently in phase I clinical trials that may offer lower potential for ototoxic and renal toxic side effects. OBJECTIVES: The goal of this study was to compare apramycin's in vitro activity with amikacin and other aminoglycosides against a large collection of M. abscessus clinical isolates, both alone and in combination with clofazimine or linezolid. We also tested the activity of apramycin against a more limited collection of other species of rapidly growing mycobacteria. METHODS: Analysis was performed using reference broth microdilution minimal inhibitory concentration testing, inkjet printer-assisted checkerboard assays, and time-kill assays. RESULTS: Against M. abscessus, the MIC(50/90) for apramycin (2 μg/mL) was 8-fold lower than for amikacin (16 μg/mL). Plazomicin was inactive, and organisms were rarely susceptible to tobramycin. Synergy was not detected by checkerboard assay. In time-kill studies, clofazimine modestly potentiated activity of apramycin and. to a lesser extent, amikacin. Apramycin and amikacin showed delayed bacterial killing that either achieved or approached a bactericidal threshold. Apramycin was similarly potent against other rapidly growing mycobacteria tested. CONCLUSIONS: Apramycin exhibits more potent in vitro activity against a diverse set of M. abscessus and other rapidly growing mycobacteria than approved aminoglycosides.