Bacteroides fragilis-induced intra-abdominal abscess in an experimental model treated with telithromycin (HMR 3647).

BACKGROUND: Telithromycin (HMR 3647), a novel ketolide, is known to have activity against Bacteroides fragilis in vitro. METHODS: We tested this ketolide in an animal model of intra-abdominal abscess produced by intraperitoneal injection of B. fragilis with sterile feces and BaSO(4) mixture. Telithromycin was tested at two doses, 1. 25 and 2.0 mg/dose twice daily, and compared with clindamycin, cefotetan or metronidazole, all given at 2.0 mg/dose twice daily for 10 days. Absence of bacteria at the infected site was considered a cure and a positive culture considered a failure. RESULTS: The cure rate was 18% (5/28) on saline therapy, 74% (20/27) on telithromycin and 82% (23/28) on clindamycin, whereas it was 61% (17/28) on metronidazole and 59% (16/27) on cefotetan therapy. A high tissue antibiotic concentration (3-5 times the MIC) of telithromycin was found and this is presumably related to its superior efficacy. Delayed therapy initiated 7 days after infection instead of immediate therapy cured only 32% of the animals treated. The lower dose of telithromycin (1.25 mg/dose twice daily) was as effective as the higher dose (2 mg/dose twice daily). CONCLUSIONS: We found that telithromycin is as effective as clindamycin and more effective than metronidazole and cefotetan in this experimental model. These results suggest that telithromycin may be tested in future for the treatment of B. fragilis infections in humans.

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

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.

Difloxacin reverses multidrug resistance in HL-60/AR cells that overexpress the multidrug resistance-related protein (MRP) gene.

In this study, we have examined the in vitro chemosensitizing activity of difloxacin, a quinolone antimicrobial agent, in the multidrug-resistant human myeloid leukemia HL-60/AR cell line. HL-60/AR cells were found to overexpress multidrug resistance-associated protein (MRP) mRNA as compared to HL-60 cells. Difloxacin, in a concentration-dependent manner, increased the sensitivity of HL-60/AR cells to daunorubicin, adriamycin, and vincristine, and partially corrected the altered drug transport. In addition, difloxacin corrected subcellular distribution of adriamycin by inducing redistribution of the drug from the perinuclear region to the nucleus in HL-60/AR cells. The chemosensitizing effect of difloxacin was observed at clinically achievable concentrations. We conclude that difloxacin is an effective chemosensitizer of MRP-associated multidrug-resistant tumor cells and is a potential candidate for clinical use to reverse multidrug resistance.

Difloxacin reverses multidrug-resistance in p388 adr cells via a mechanism independent of p-glycoprotein and without correcting drug transport or subcellular drug distribution.

In this study, we have examined in vitro chemosensitizing activity of difloxacin, a quinolone antimicrobial agent, in multidrug resistant murine leukemia P388/ADR cell line that overexpresses P-glycoprotein and exhibits decreased accumulation of anthracyclines and vincristine. Difloxacin, in a concentration-dependent manner, increased the sensitivity of P388/ADR cells to daunorubicin, adriamycin and vincristine without correcting the altered drug accumulation and subcellular distribution of daunorubicin. Furthermore, difloxacin had no significant effect on intracellular accumulation of rhodamine 123 dye, a substrate for P-glycoprotein. In addition, difloxacin increased the sensitivity of drug sensitive parental P388 cells to vincristine. Taken together these data suggest that difloxacin reverses MDR by a mechanism independent of P-glycoprotein. The chemosensitizing effect of difloxacin was observed at clinically achievable plasma concentrations. These data suggest that difloxacin is an effective chemosensitizer of multidrug resistant tumor cells and is a potential candidate for clinical use to reverse MDR.