Evaluation of survival and pharmacodynamic relationships for five fluoroquinolones in a neutropenic murine model of pneumococcal lung infection
Abstract
STUDY OBJECTIVE: To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection.
DESIGN: Animal experiment.
SETTING: University-affiliated research center.
ANIMALS: Neutropenic and control mice weighing 24-29 g.
INTERVENTION: After induction of neutropenia, renal failure, and infection with Streptococcus pneumoniae, the mice received one of five fluoroquinolones twice/day for 72 hours beginning 12 hours after infection. Dosages were selected to approximate 0.1 x AUC0-24 (area under the concentration-time curve from 0-24 hours) and AUC0-24 achieved in humans. Control mice received normal saline. Survival was assessed at regular intervals for up to 10 days. At least 10 mice were included in each cohort (range 10-34).
MEASUREMENTS AND MAIN RESULTS: Ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, and moxifloxacin were studied at subtherapeutic and therapeutic dosages against three quinolone-susceptible isolates of S. pneumoniae that lacked mutations in parC, parE, and gyrA. Pharmacokinetic profile of each agent and dosing regimen was determined. A composite survival curve for all fluoroquinolones and isolates was constructed. Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model. Survival…
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