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Apramycin efficacy ...
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Frimodt-Møller, NielsRigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.
(author)
Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
- Article/chapterEnglish2024
Publisher, publication year, extent ...
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Elsevier,2024
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-534273
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-534273URI
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https://doi.org/10.1016/j.ijantimicag.2024.107181DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Niels Frimodt-Møller, Diarmaid Hughes, Carina Vingsbo Lundberg and Sven N. Hobbie share senior authorship
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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.
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Hansen, Jon U.Statens Serum Inst, DK-2300 Copenhagen, Denmark.
(author)
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Plattner, MichelUniv Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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Huseby, Douglas L.Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi(Swepub:uu)douhu661
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Radmer Almind, StineRigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.
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Haldimann, KlaraUniv Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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Gysin, MarinaUniv Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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Petersson, AnnaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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Ercan, OnurUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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Ganz, LeaUniv Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.
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Hughes, Diarmaid,1956-Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi(Swepub:uu)diarhugh
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Vingsbo Lundberg, CarinaStatens Serum Inst, DK-2300 Copenhagen, Denmark.
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Hobbie, Sven N.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)
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In:International Journal of Antimicrobial Agents: Elsevier64:10924-85791872-7913
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Gysin, Marina
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