Pharmacodynamic assessment of apramycin against Mycobacterium abscessus in a hollow fibre infection model

Abstract

Background: Mycobacterium abscessus is an important cause of pulmonary infections, particularly among people with cystic fibrosis. Current treatment options for M. abscessus are suboptimal. Apramycin is a promising alternative aminoglycoside for M. abscessus, in part due to its ability to avoid intrinsic aminoglycoside-modifying enzymes in this pathogen.

Objectives: Define the pharmacodynamic activity of apramycin doses against M. abscessus.

Methods: Apramycin and amikacin pharmacodynamics were assessed against two amikacin-susceptible M. abscessus subsp. abscessus isolates (ATCC 19977 and NR-44261) using a 14-day hollow fibre infection model (HFIM). Viable bacterial counts were determined during exposure to amikacin (15-20 mg/kg q24h) and 3 fractionated doses of apramycin (15 mg/kg q12h, 30 mg/kg q24h, 60 mg/kg q48h) using pharmacokinetic profiles predicted in epithelial lining fluid.

Results: Against ATCC 19977, apramycin activity exceeded that of amikacin, with maximum bacterial reductions between 1.51 and 2.18 log10 cfu/mL for the different doses. Apramycin 15 mg/kg q12h displayed slightly better killing compared with the other apramycin dosing regimens between 96 and 144h before regrowth occurred. NR-44261 was not inhibited by amikacin and the activity of apramycin against this isolate was similar between the three doses (∼0.5 log10 cfu/mL reductions). After 14 days of exposure to apramycin monotherapy, ATCC 19977 and NR-44261 became apramycin resistant with MICs of >32 mg/L.

Conclusions: Apramycin exhibited greater pharmacodynamic activity than amikacin against amikacin-susceptible M. abscessus isolates and may be a promising therapy for this pathogen. However, antibiotic combination strategies to minimize apramycin resistance from emerging may be necessary.