Apramycin efficacy in the treatment of carbapenem-resistant<i>Enterobacterales</i>in murine blood stream infection models
ABSTRACT Background The 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.Methods The 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.Results Genotypic 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.Conclusion Encouraging 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 15. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Frimodt-Møller, Niels [VerfasserIn] |
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Volltext [kostenfrei] |
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| doi: |
10.1101/2023.12.10.570991 |
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| PPN (Katalog-ID): |
XBI041832914 |
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| 520 | |a ABSTRACT Background The 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.Methods The 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.Results Genotypic 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.Conclusion Encouraging 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. | ||
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| 700 | 1 | |a Hansen, Jon U. |4 aut | |
| 700 | 1 | |a Plattner, Michel |4 aut | |
| 700 | 1 | |a Huseby, Douglas L. |4 aut | |
| 700 | 1 | |a Almind, Stine Radmer |4 aut | |
| 700 | 1 | |a Haldimann, Klara |4 aut | |
| 700 | 1 | |a Gysin, Marina |4 aut | |
| 700 | 1 | |a Petersson, Anna |4 aut | |
| 700 | 1 | |a Ercan, Onur |4 aut | |
| 700 | 1 | |a Ganz, Lea |4 aut | |
| 700 | 1 | |a Hughes, Diarmaid |4 aut | |
| 700 | 1 | |a Lundberg, Carina Vingsbo |4 aut | |
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