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Apramycin efficacy ...
Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
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- Frimodt-Møller, Niels (author)
- Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.
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- Hansen, Jon U. (author)
- Statens Serum Inst, DK-2300 Copenhagen, Denmark.
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- Plattner, Michel (author)
- Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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- Huseby, Douglas L. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Radmer Almind, Stine (author)
- Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.
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- Haldimann, Klara (author)
- Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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- Gysin, Marina (author)
- Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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- Petersson, Anna (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Ercan, Onur (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Ganz, Lea (author)
- Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Vingsbo Lundberg, Carina (author)
- Statens Serum Inst, DK-2300 Copenhagen, Denmark.
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- Hobbie, Sven N. (author)
- Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.;Univ Hosp Basel, Div Clin Bacteriol, Basel, Switzerland.
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Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark Statens Serum Inst, DK-2300 Copenhagen, Denmark. (creator_code:org_t)
- Elsevier, 2024
- 2024
- English.
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In: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 64:1
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Abstract
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- BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed.MethodsThe resistance gene annotations of 40 888 blood-culture isolates were analysed. 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 a total of nine Escherichia coli and Klebsiella pneumoniae isolates.ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia.ConclusionEncouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Keyword
- Bacteraemia
- Bloodstream infections
- Peritonitis
- Antimicrobial resistance
- Aminoglycoside antibiotics
Publication and Content Type
- ref (subject category)
- art (subject category)
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Frimodt-Møller, ...
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Hansen, Jon U.
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Plattner, Michel
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Huseby, Douglas ...
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Radmer Almind, S ...
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Haldimann, Klara
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Gysin, Marina
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Petersson, Anna
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Ercan, Onur
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Ganz, Lea
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Hughes, Diarmaid ...
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Vingsbo Lundberg ...
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Hobbie, Sven N.
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- MEDICAL AND HEALTH SCIENCES
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and Infectious Medic ...
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Uppsala University