Apramycin efficacy in the treatment of carbapenem-resistantEnterobacteralesin murine blood stream infection models

Abstract

ABSTRACTBackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, its potential in the treatment of drug-resistant bloodstream infections (BSIs) has yet to be assessed.MethodsThe resistance gene annotations of 26 493 blood culture isolates were analyzed.In vitroprofiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for nineE. coliandK. pneumoniaeisolates.ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistantEnterobacteralesblood-culture isolates, in comparison to 46.4% of colistin and 2.1% of apramycin resistance. Apramycin activity against methylated ribosomes was > 100-fold higher than other aminoglycosides. Frequencies of resistance were < 10−9at 8 × MIC. Tentative epidemiological cutoffs (ECOFFs) were determined as 8 μg/mL forE. coliand 4 μg/mL forK. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log CFU reduction in the blood and peritoneum. Two doses of 80 mg/kg, resulting in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans, resulted in complete eradication of carbapenem- and aminoglycoside-resistant bacteremias.ConclusionEncouraging coverage and potent in-vivo efficacy against a selection of highly drug-resistantEnterobacteralesisolates in the mouse peritonitis model warrants further consideration of apramycin as a drug candidate for the treatment and prophylaxis of BSI.