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

Frimodt-Moller, N.; Hansen, J. U.; Plattner, M.; Huseby, D.; Almind, S. R.; Haldimann, K.; Gysin, M.; Petersson, A.; Ercan, O.; Ganz, L.; Hughes, D.; Lundberg, C. V.; Hobbie, S.

doi:10.1101/2023.12.10.570991

bioRxiv · 10.1101/2023.12.10.570991

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

Frimodt-Moller, N.·Hansen, J. U.·Plattner, M.·Huseby, D.·Almind, S. R.·Haldimann, K.·Gysin, M.·Petersson, A.·Ercan, O.·Ganz, L.·Hughes, D.·Lundberg, C. V.·Hobbie, S.

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Abstract

BackgroundThe 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 vitro profiling 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 nine E. coli and K. pneumoniae isolates. ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-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 < 10-9 at 8 x MIC. Tentative epidemiological cutoffs (ECOFFs) were determined as 8 g/mL for E. coli and 4 g/mL for K. 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-resistant Enterobacterales isolates in the mouse peritonitis model warrants further consideration of apramycin as a drug candidate for the treatment and prophylaxis of BSI.

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Frimodt-Moller, N., Hansen, J. U., Plattner, M., Huseby, D., Almind, S. R., Haldimann, K., Gysin, M., Petersson, A., Ercan, O., Ganz, L., Hughes, D., Lundberg, C. V., Hobbie, S.. 2023-12-10. Apramycin efficacy in the treatment of carbapenem-resistant Enterobacterales in murine blood stream infection models. https://doi.org/10.1101/2023.12.10.570991

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