Activities of Garenoxacin against Quinolone-Resistant Streptococcus pneumoniae Strains In Vitro and in a Mouse Pneumonia Model

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Abstract
Garenoxacin is a novel des-F(6) quinolone with enhanced in vitro activities against both gram-positive and gram-negative bacteria. We compared the activity of garenoxacin with that of trovafloxacin (TVA) against Streptococcus pneumoniae , together with their efficacies and their capacities to select for resistant mutants, in a mouse model of acute pneumonia. In vitro, garenoxacin was more potent than TVA against wild-type S. pneumoniae and against a mutant with a single mutation ( parC ), a mutant with double mutations ( gyrA and parC ), and a mutant with triple mutations ( gyrA , parC , and parE ). Swiss mice were infected with 10 5 CFU of virulent, encapsulated S. pneumoniae strain P-4241 or its derived isogenic parC , gyrA , gyrA parC , and efflux mutants and 10 7 CFU of poorly virulent clinical strains carrying a parE mutation or gyrA , parC , and parE mutations. The drugs were administered six times, every 12 h, beginning at either 3 or 18 h postinfection. The pulmonary pharmacokinetic parameters in mice infected with strain P-4241 and treated with garenoxacin or TVA (25 mg/kg of body weight) were as follows: maximum concentration of drug in serum ( C max ; 17.3 and 21.2 μg/ml, respectively), C max /MIC ratio (288 and 170, respectively), area under the concentration-time curve (AUC; 48.5 and 250 μg · h/ml, respectively), and AUC/MIC ratio (808 and 2,000, respectively). Garenoxacin at 25 and 50 mg/kg was highly effective (survival rates, 85 to 100%) against the wild-type strain and mutants harboring a single mutation. TVA was as effective as garenoxacin against these strains. TVA at 200 mg/kg and garenoxacin at 50 mg/kg were ineffective against the mutant with the parC and gyrA double mutations and the mutant with the gyrA , parC , and parE triple mutations. The efficacy of garenoxacin was reduced only when strains bore several mutations for quinolone resistance.

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