In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli

Abstract

The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.

Immunomodulatory Activities of Fluoroquinolones

“…This lack of correlation between survival and elimination of bacterial burden suggests that trovafloxacin, too, exerts an effect on cytokines in this infection model. In rats injected with heat-killed B. fragilis and E. coli, trovafloxacin partially reduced the serum concentrations of TNF-α [62]. These data suggest that trovafloxacin modulates the production and/or secretion of TNF-α , thus, contributing to its in vivo efficacy against mixed infections in rats.…”

“…The decrease in mortality rate and elimination of infection was dose proportional. In general, TNF-α levels were low in all trovafloxacin-treated animals [62,63]. The protective effect of trovafloxacin could probably be due to its antibacterial efficacy, as trovafloxacin exerts a significant in vitro activity against both anaerobes as well as Enterobacteriaceae [64].…”

Intra‐Abdominal Anaerobic Infections: Bacteriology and Therapeutic Potential of Newer Antimicrobial Carbapenem, Fluoroquinolone, and Desfluoroquinolone Therapeutic Agents

“…Onderdonk [38], using a mixed cecal inoculum, and Thadepalli et al [39], using a combination of B. fragilis and E. coli, found comparable efficacy of trovafloxacin with that of clindamycin and gentamicin in the therapy of an experimental intra-abdominal abscess model. Stearne et al [40] compared the efficacy of trovafloxacin in a murine subcutaneous model of mixed infection with B. fragilis and E. coli or B. fragilis and vancomycin-resistant Enterococcus faecium (VREF).…”

Fluoroquinolones and Anaerobes

“…In similar experiments, Stearne et al [8] found that trovafloxacin was able to decrease abscess weight as well as the bacterial counts of B. fragilis (MIC, 0.25 mg/mL) after treatment for 5 days. In experimental intraabdominal abscesses caused by B. fragilis (MIC, 0.24 mg/mL) and E. coli, trovafloxacin as a single agent was observed to produce survival rates that were comparable to those resulting from treatment with clindamycin plus gentamicin [7]. Onderdonk [87] also studied the effectiveness of trovafloxacin in a rat model of intra-abdominal sepsis.…”

“…Ciprofloxacin lacked in vitro potency against many important anaerobic bacteria, but several newer quinolones looked promising [2][3][4][5][6]. Trovafloxacin was the first fluoroquinolone to receive approval from the US Food and Drug Administration for the treatment of anaerobic bacteria, such as Bacteroides fragilis, Peptostreptococcus species, and Prevotella species isolated from patients with intra-abdominal and pelvic infections [7,8]. Levofloxacin and sparfloxacin are not as potent as trovafloxacin in vitro but possess good activity against selective anaerobic bacteria [9,10].…”