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

Abstract

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 pairand 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.

Plasma Protein Binding and Volume of Distribution: Determination, Prediction and Use in Early Drug Discovery

“…This correlated well with large clinical studies on voriconazole, where free drug AUC was considered rather than total drug AUC [4]. Similar work on the fluoroquinolone antibiotics has shown free AUC/MIC ratio to be a successful predictor of efficacy in a rat model of pneumococcal pneumonia, and in the case of moxifloxacin, the free AUC/MIC was similar to that reported in human [5]. In clinical studies of the bcr-abl/c-kit inhibitor, imatinib, in patients with advanced gastrointestinal stromal tumors, hematotoxicity was assessed as percent absolute neutrophil count and percent platelets.…”

Animal Models ofStreptococcus pneumoniaeDisease

“…In both cases, rats showed increased susceptibility to pneumococcal pneumonia. These models have been used by the same research group in studies on phagocytosis and antibiotic efficacy (84,184,199). A sophisticated surgical method based on the delivery of bacteria into the apical lobe bronchi of adult rats was described in the early 1990s (79).…”

Fact versus Fiction: a Review of the Evidence behind Alcohol and Antibiotic Interactions

“…Efficacy. Levofloxacin, moxifloxacin, and trovafloxacin had improved efficacy in alcohol-fed rats compared to alcohol-free rats (24). All antibiotics were equally effective at improving survival and had improved efficacy in alcohol-fed rats.…”

“…PK/PD. The effects of alcohol on levofloxacin, moxifloxacin, and trovafloxacin were studied in a rat pneumonia model (24). The mean serum C max and AUC were higher in the ethanol-fed group for all FQs, with a statistically significant difference in the moxifloxacin group.…”