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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Connolly, Kristie L.Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States (author)

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

Article/chapterEnglish2019

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American Society for Microbiology,2019
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LIBRIS-ID:oai:DiVA.org:oru-71658
https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-71658URI
https://doi.org/10.1128/AAC.01644-18DOI

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Language:English
Summary in:English

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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
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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Mikrobiologi inom det medicinska området hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Microbiology in the medical area hsv//eng
antibiotic resistance
cefixime
ceftriaxone
clearance
gonorrhea
mouse model
pharmacokinetics

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Eakin, Ann E.Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States (author)
Gomez, CarolinaDepartment of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States (author)
Osborn, Blaire L.Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States (author)
Unemo, Magnus,1970-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 Microbiology(Swepub:oru)muo (author)
Jerse, Ann E.Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States (author)
Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United StatesDivision of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States (creator_code:org_t)

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In:Antimicrobial Agents and Chemotherapy: American Society for Microbiology63:30066-48041098-6596

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