We have recently reported (D.L. Stevens, K.A. Maier, B.M. Laine, and J.E. 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. perfringens, 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 (micrograms/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.