Background New antibiotics for gonorrhea are needed due to the emergence of resistance to extended-spectrum cephalosporins in Neisseria gonorrhoeae (Ng). We recently established the 17β-estradiol mouse model of gonococcal lower genital tract infection for testing antibiotics that utilize free time above MIC as the pharmacokinetic (PK) driver to predict efficacy. We further established the mouse model for antibiotic testing by defining the in vivo efficacy of ciprofloxacin (CIP), an antibiotic that uses the free area under the curve over MIC (fAUC/MIC).
Methods Lower genital tract infection with Ng strain FA1090 was established in female mice using published methods for two days, after which increasing oral doses of CIP (or controls) were administered (n = 10–20 mice/group) and infection was quantified for 8 days. Plasma drug levels from uninfected mice were measured after administration of similar doses of CIP, and PK parameters (modeled using WinNonlin software) were correlated with observed efficacy.
Results Single oral doses ranging from 5 to 60 mg/kg CIP showed significant activity against strain FA1090, with the highest doses (15, 30, and 60 mg/kg) clearing 100% of infections within 8 days; these correspond to predicted fAUC/MICs of 66–264. The 60 mg/kg dose cleared infection in all mice within 48 h, which we defined previously as the endpoint in the model that best correlates with in vivo exposures required for successful CRO/CFX treatment regimens.
Conclusion The gonorrhea mouse model shows a dose-dependent response for CIP against a CIPS strain with a dose of 60 mg/kg required to clear infection in 48 hrs. PK modeling suggests that achieving exposures necessary for effective treatment of CIPR strains (mic ≥1 µg/ml) would be challenging. These data that establish PK/PD correlations for CIP - with a fAUC/MIC driver- further strengthens the usefulness of this mouse model to test novel antimicrobial compounds against gonorrhea.
Disclosure No significant relationships.
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