Enhanced Activity of Apramycin and Apramycin-Based Combinations Against Mycobacteroides abscessus

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.

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.

Analysis was performed using reference broth microdilution minimal inhibitory concentration testing, inkjet printer-assisted checkerboard assays, and time-kill assays.

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.

Apramycin exhibits more potent in vitro activity against a diverse set of M. abscessus and other rapidly growing mycobacteria than approved aminoglycosides.