Stevens D L, Maier K A, Mitten J E
Antimicrob Agents Chemother. 1987 Feb;31(2):213-8. doi: 10.1128/AAC.31.2.213.
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.
我们最近报道过（D.L. 史蒂文斯、K.A. 迈尔、B.M. 莱恩和J.E. 米滕，《传染病杂志》155:220 - 228，1987年），在治疗由产气荚膜梭菌引起的小鼠暴发性气性坏疽方面，克林霉素、利福平及四环素比青霉素更有效。我们推测抗生素的疗效与这些药物的杀菌或毒素抑制特性相关。为研究青霉素对产气荚膜梭菌仅具有抑菌作用的可能性，我们使用产气荚膜梭菌ATCC 13124进行了常量肉汤稀释法测定最低抑菌浓度（MIC）和最低杀菌浓度（MBC）。以下抗生素的平均MIC等于MBC（微克/毫升）：克林霉素，0.07；四环素，0.05；利福平，0.03；甲硝唑，0.69；青霉素，0.27。氯霉素的MIC/MBC为1.50/3.10（微克/毫升）。由于抗生素疗效与杀菌活性不相关，我们检测了α毒素活性，发现在等于MIC的浓度下，四环素、甲硝唑、利福平、克林霉素及氯霉素可完全抑制α毒素活性。相比之下，在等于及高于MIC的青霉素浓度下，α毒素活性持续存在。接下来，我们在抗生素浓度为MIC的10倍的产气荚膜梭菌对数期培养物中研究了细菌杀灭动力学及α毒素产生动力学。克林霉素、甲硝唑及利福平在15至45分钟内均使活力、浊度及α毒素活性迅速降低。相比之下，青霉素杀菌较慢，浊度增加（为对照的62.6%），且α毒素活性在2小时内持续存在（为对照值的80%）。四环素和氯霉素在降低活力方面效果最差；然而，培养物的浊度未增加，且未检测到α毒素活性。毒素抑制及快速细菌杀灭可能部分解释了在治疗实验性气性坏疽中观察到的克林霉素、利福平及甲硝唑相比青霉素具有更好治疗效果的原因。
