In Vivo Efficacy of Trovafloxacin against Bacteroides fragilis in Mixed Infection with either Escherichia coli or a Vancomycin-Resistant Strain of Enterococcus faecium in an Established-Abscess Murine Model

Abstract

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis-vancomycin-resistant Enterococcus faecium (VREF)-ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of 99m Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log 10 reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C max was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. coli combination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

Effect of Recombinant Murine Granulocyte Colony-Stimulating Factor with or without Fluoroquinolone Therapy on Mixed-Infection Abscesses in Mice

“…This occurred despite the fact that the MICs of moxifloxacin against both bacterial strains were higher, lower daily doses of moxifloxacin were administered, and the AUC 0-24 h for moxifloxacin in mice is lower (21,23). Consequently, our results suggest that, in this animal model at least, moxifloxacin is more potent than trovafloxacin.…”

“…Moxifloxacin was even more effective than trovafloxacin in reducing the counts of both bacterial strains (P Ͻ 0.05; Table 1) although, in contrast, it did not significantly reduce the weight of abscesses 8 days after inoculation (Table 1). Unlike trovafloxacin (23), moxifloxacin demonstrated no visible toxic effects with the doses administered. Cytokine concentrations of TNF-␣, IL-10, and IL-6 of all groups were around the detection limit (data not shown).…”

“…Subgroups receiving antibiotic therapy were treated for 5 days (day 3 to day 7 after inoculation) with single daily doses of trovafloxacin at 150 mg/kg subcutaneously or twice-daily doses of moxifloxacin at 48 mg/kg subcutaneously given at 12-hour intervals (total daily dose, 96 mg/kg). The trovafloxacin dosing regimen was previously shown to result in a significant reduction in abscess weight and bacterial counts in this model (23). The moxifloxacin doses were the maximum that could be injected subcutaneously in mice and, for comparison, were given twice daily due to the shorter half-life of this fluoroquinolone in mice compared to trovafloxacin (21,23).…”

“…The trovafloxacin dosing regimen was previously shown to result in a significant reduction in abscess weight and bacterial counts in this model (23). The moxifloxacin doses were the maximum that could be injected subcutaneously in mice and, for comparison, were given twice daily due to the shorter half-life of this fluoroquinolone in mice compared to trovafloxacin (21,23). Control mice received injections of pyrogen-free saline.…”

“…In our laboratory, we have employed a subcutaneous mouse model to study the treatment of small mixed-infection abscesses (22,23). The aim of the present study was to investigate whether immunomodulation of host defenses with recombinant murine G-CSF (rmG-CSF) would improve the efficacy of trovafloxacin or moxifloxacin treatment of established abscesses in our mouse model.…”