Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models

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Fältnamn	Indikatorer	Metadata
000		04990naa a2200517 4500
001		oai:DiVA.org:uu-534273
003		SwePub
008		240703s2024 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5342732 URI
024	7	a https://doi.org/10.1016/j.ijantimicag.2024.1071812 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Frimodt-Møller, Nielsu Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.4 aut
245	1 0	a Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
264	1	b Elsevier,c 2024
338		a electronic2 rdacarrier
500		a Niels Frimodt-Møller, Diarmaid Hughes, Carina Vingsbo Lundberg and Sven N. Hobbie share senior authorship
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Infektionsmedicin0 (SwePub)302092 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Infectious Medicine0 (SwePub)302092 hsv//eng
653		a Bacteraemia
653		a Bloodstream infections
653		a Peritonitis
653		a Antimicrobial resistance
653		a Aminoglycoside antibiotics
700	1	a Hansen, Jon U.u Statens Serum Inst, DK-2300 Copenhagen, Denmark.4 aut
700	1	a Plattner, Michelu Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.4 aut
700	1	a Huseby, Douglas L.u Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut0 (Swepub:uu)douhu661
700	1	a Radmer Almind, Stineu Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.4 aut
700	1	a Haldimann, Klarau Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.4 aut
700	1	a Gysin, Marinau Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.4 aut
700	1	a Petersson, Annau Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
700	1	a Ercan, Onuru Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
700	1	a Ganz, Leau Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.4 aut
700	1	a Hughes, Diarmaid,d 1956-u Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut0 (Swepub:uu)diarhugh
700	1	a Vingsbo Lundberg, Carinau Statens Serum Inst, DK-2300 Copenhagen, Denmark.4 aut
700	1	a Hobbie, Sven N.u Univ Zurich, Inst Med Microbiol, CH-8006 Zurich, Switzerland.;Univ Hosp Basel, Div Clin Bacteriol, Basel, Switzerland.4 aut
710	2	a Rigshospitalet, Dept Clin Microbiol, DK-2100 Copenhagen, Denmark.b Statens Serum Inst, DK-2300 Copenhagen, Denmark.4 org
773	0	t International Journal of Antimicrobial Agentsd : Elsevierg 64:1q 64:1x 0924-8579x 1872-7913
856	4	u https://doi.org/10.1016/j.ijantimicag.2024.107181y Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1881535/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-534273
856	4 8	u https://doi.org/10.1016/j.ijantimicag.2024.107181

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Av författaren/redakt...: Frimodt-Møller, ...; Hansen, Jon U.; Plattner, Michel; Huseby, Douglas ...; Radmer Almind, S ...; Haldimann, Klara; visa fler...; Gysin, Marina; Petersson, Anna; Ercan, Onur; Ganz, Lea; Hughes, Diarmaid ...; Vingsbo Lundberg ...; Hobbie, Sven N.; visa färre...

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