Effect of ethanol on fluoroquinolone efficacy in a rat model of pneumococcal pneumonia.
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.
Olsen
Keith M
KM
College of Pharmacy, University of Nebraska Medical Center, Omaha 68198, USA.
Gentry-Nielsen
Martha
M
Yue
Mei
M
Snitily
Mary U
MU
Preheim
Laurel C
LC
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000382:microbiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007958:Leukocyte Count; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013296:Streptococcus pneumoniae
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000431:Ethanol