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Antimicrobial Agents and Chemotherapy, January 2006, p. 210-219, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.210-219.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia

Colleges of Pharmacy,¹ Medicine, University of Nebraska Medical Center, 600 South 42nd St., Omaha, Nebraska 68198,² Infectious Diseases Section, Veterans Affairs Medical Center,³ Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska 68105,⁴ Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska 68178⁵

Received 13 September 2004/ Returned for modification 13 November 2004/ Accepted 26 September 2005

This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.