Gas gangrene caused by Clostridium perfringens is associated with significant mortality and morbidity in spite of penicillin treatment. Although prompt surgical debridement has been established as the primary therapeutic objective, additional studies are needed for determination of the optimal antimicrobial therapy. In a mouse model of gas gangrene caused by Clostridium perfringens, clindamycin, metronidazole, rifampin, and tetracycline were all more efficacious than penicillin (P less than .05). Survival of penicillin-treated mice was not significantly better than that of untreated controls in spite of serum levels that ranged up to 77-1,800 micrograms/ml. Responses to metronidazole were highly dose dependent. For example, 60% of mice survived after 75 mg of metronidazole/kg, but only 10% survived after 19 mg/kg. In contrast, clindamycin was highly effective over a broad dosing range (8.6-86 mg/kg). The efficacy of all antibiotics was reduced if treatment was delayed or larger inocula of bacteria were used.

Mitten, J. Infect. Dis. 155:220-228, 1987) that clindamycin, rifampin, and tetracycline were more efficacious than penicillin in the treatment of fulminant gas gangrene in mice caused by Clostridium perfringens. We hypothesize that antibiotic efficacy correlated with bactericidal or toxin-suppressing properties of these agents. To investigate the possibility that penicillin is only bacteriostatic against C. perfingens, we performed macrobroth dilution MIC and MBC determinations using C. perfringens ATCC 13124. Mean MICs were equal to MBCs for the following antibiotics (micrograms per milliliter): clindamycin, 0.07; tetracycline, 0.05; rifampin, 0.03; metronidazole, 0.69; and penicillin, 0.27. The MIC/MBCs of chloramphenicol were 1.50/3.10 (,ug/ml). Because antibiotic efficacy did not correlate with bactericidal activity, we measured alpha-toxin activity and found complete suppression of alpha-toxin activity by tetracycline, metronidazole, rifampin, clindamycin, and chloramphenicol at concentrations equal to the MIC. In contrast, alpha-toxin activity persisted at concentrations of penicillin equal to and above the MIC. The dynamics of bacterial killing and kinetics of alpha-toxin production were next studied in log-phase cultures of C. perfringens with antibiotic concentrations 10 times the MIC. Clindamycin, metronidazole, and rifampin all caused rapid reductions in viability, turbidity, and alpha-toxin activity by 15 to 45 min. In contrast, penicillin demonstrated slower bacterial killing, increased turbidity (62.6% of control), and persistent alpha-toxin activity (80% of control values) for 2 h. Tetracycline and chloramphenicol were the least effective in reducing viability; however, the turbidity of cultures did not increase, and alpha-toxin activity was not detectable. Toxin suppression and rapid bacterial killing may in part explain the observed superior therapeutic efficacy of clindamycin, rifampin, and metronidazole compared with penicillin in the treatment of experimental gas gangrene.