Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model

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Fältnamn	Indikatorer	Metadata
000		04965naa a2200457 4500
001		oai:DiVA.org:oru-71658
003		SwePub
008		190122s2019 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-716582 URI
024	7	a https://doi.org/10.1128/AAC.01644-182 DOI
040		a (SwePub)oru
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Connolly, Kristie L.u Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States4 aut
245	1 0	a Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model
264	1	b American Society for Microbiology,c 2019
338		a print2 rdacarrier
500		a Funding Agencies:National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health AAI14024 Uniformed Services University of the Health Sciences (USUHS) AAI14024 NIAID's suite of preclinical services HHSN2722011000221
520		a There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESCS strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, fTMIC) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against the ESCR strain H041. However, fractionation (TIDq8h) of a 120 mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤ 50% of mice with therapeutic times estimated from single-dose PK data, of 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESCS strain requiring doses that yielded an fTMIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCR strain and were useful in designing effective dosing regimens.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Mikrobiologi inom det medicinska området0 (SwePub)301092 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Microbiology in the medical area0 (SwePub)301092 hsv//eng
653		a antibiotic resistance
653		a cefixime
653		a ceftriaxone
653		a clearance
653		a gonorrhea
653		a mouse model
653		a pharmacokinetics
700	1	a Eakin, Ann E.u Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States4 aut
700	1	a Gomez, Carolinau Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States4 aut
700	1	a Osborn, Blaire L.u Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States4 aut
700	1	a Unemo, Magnus,d 1970-u Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology4 aut0 (Swepub:oru)muo
700	1	a Jerse, Ann E.u Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States4 aut
710	2	a Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United Statesb Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States4 org
773	0	t Antimicrobial Agents and Chemotherapyd : American Society for Microbiologyg 63:3q 63:3x 0066-4804x 1098-6596
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-71658
856	4 8	u https://doi.org/10.1128/AAC.01644-18

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Av författaren/redakt...: Connolly, Kristi ...; Eakin, Ann E.; Gomez, Carolina; Osborn, Blaire L ...; Unemo, Magnus, 1 ...; Jerse, Ann E.

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