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Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model
Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
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2019 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 3, article id e01644-18Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Microbiology , 2019. Vol. 63, no 3, article id e01644-18
Keywords [en]
antibiotic resistance, cefixime, ceftriaxone, clearance, gonorrhea, mouse model, pharmacokinetics
National Category
Pharmaceutical Sciences Microbiology in the medical area
Identifiers
URN: urn:nbn:se:oru:diva-71658DOI: 10.1128/AAC.01644-18ISI: 000459683500006PubMedID: 30642924Scopus ID: 2-s2.0-85062283684OAI: oai:DiVA.org:oru-71658DiVA, id: diva2:1281378
Note

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

Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-06-18Bibliographically approved

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Unemo, Magnus

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