Mechanism of penicillin failure — Several studies in experimental infection suggest that penicillin fails when large numbers of organisms are present [38,39]. In a mouse model of myositis due to S. pyogenes, penicillin was ineffective when treatment was delayed for two hours after initiation of infection [39]. Survival of erythromycin-treated mice was greater than that of both penicillin-treated mice and untreated controls if treatment was initiated within two hours. Mice receiving clindamycin, however, had survival rates of 100 percent, 100 percent, 80 percent, and 70 percent when treatment was delayed 0, 2, 6, and 16.5 hours, respectively [39,40].

Eagle suggested that penicillin failed in this type of infection because of the "physiologic state of the organism" [38]. This phenomenon has recently been attributed to the inoculum effect in vitro and in vivo [41,42]. Penicillin and other beta-lactam antibiotics are most effective against rapidly growing bacteria. As a result, they would be expected to have the greatest efficacy when organisms are growing rapidly in the early stages of infection or in mild infections. On the other hand, the efficacy of beta lactams may decrease when bacterial growth slows as higher concentrations of GAS accumulate. S. pyogenes achieves concentrations in deep-seated infection which are sufficiently high to reduce the effectiveness of beta lactam antibiotics [38].

There is now a better understanding of the mechanism by which penicillin becomes less effective when high concentrations of GAS are present or when they are making the transition from the logarithmic to the stationary phase of growth. Since penicillin mediates its antibacterial action against GAS by intimately interacting with penicillin-binding proteins (PBP), we compared the PBP patterns of Group A streptococci at different stages of growth. Binding of radiolabeled penicillin by all PBPs was decreased in stationary cells relative to cells in the logarithmic phase of growth; furthermore, PBPs 1 and 4 were undetectable at 36 hours [41]. Thus, the loss of certain PBPs during stationary-phase growth in vitro may be responsible for the inoculum effect observed in vivo and may account for the failure of penicillin in both experimental and human cases of severe streptococcal infection.

Clindamycin — The shortcomings of penicillin in treating GAS infections has prompted a search for alternative antibiotic therapies. Clindamycin has several potential advantages in treating GAS infections.

• The efficacy of clindamycin is not affected by inoculum size or stage of growth [41,43]
• Clindamycin suppresses the synthesis of bacterial toxins [44,45]
• Clindamycin facilitates phagocytosis of S. pyogenes by inhibiting synthesis of the antiphagocytic M-protein [45]
• Clindamycin suppresses synthesis of penicillin-binding proteins which, in addition to being targets for penicillin, are involved in cell wall synthesis and degradation [43]
• Clindamycin has a longer postantibiotic effect than beta-lactams such as penicillin
• Clindamycin causes suppression of tumor necrosis factor [46]
• A retrospective analysis demonstrated that clindamycin use was associated with better outcomes than beta-lactam antibiotics in patients with strep TSS [47]

Recommended antibiotic therapy — Definitive studies which establish the most effective antibiotic regimen in treating strep TSS are not available. We recommend therapy with clindamycin (900 mg intravenously every eight hours). An alternative used by others is combined therapy in which penicillin G (4 million units intravenously every four hours in patients with normal renal function) is given with clindamycin. However, the only reason to add penicillin to clindamycin is to cover the patient in the rare event that the organism is resistant to clindamycin; this occurs in fewer than 0.1 percent of isolates in the United States.