In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model [PublishAheadOfPrint]

Antimicrobial resistance among uropathogens has increased infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli such as Escherichia coli. This study monitored the in vivo efficacy of antofloxacin using bioluminescence imaging and determined pharmacokinetic/pharmacodynamic (PK/PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were performed after subcutaneous antofloxacin administration of 2.5, 10, 40 and 160 mg/kg. Following thigh infection, mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 hours. Efficacy was assessed by quantitative bacterial burdens in thigh homogenates and was compared with bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index AUC/MIC correlated well with efficacy (R²=0.92), and the dose-response relationship was relatively steep as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce a net bacterial stasis, 1-log₁₀ and 2-log₁₀ kill for each isolate were 38.7, 66.1 and 147.0 h, respectively. In vivo bioluminescence imaging showed a rapid decrease in bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with PK studies from humans will be useful in setting optimal dosing regimens for treatment of urinary tract infections due to E. coli.

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