Protection against staphylococcal pyrogenic exotoxin type C-enhanced endotoxin lethality with methylprednisolone and IgG

Although the exact pathogenesis of staphylococcal toxic-shock syndrome (TSS) has not been fully elucidated, it has become increasingly clear that TSS is a toxin-mediated disease. A primary role for S. aureus PE-C in the development of TSS is supported by the work of Schlievert et al. A striking property of this toxin is its ability to enhance host susceptibility to lethal endotoxin shock, and it has been hypothesized that PE-C in concert with low levels of endotoxin may trigger TSS in susceptible individuals. Currently, aggressive supportive measures are used in the treatment of hypotensive patients with TSS. The need for studies of the value of agents which modulate host responses, such as antiinflammatory drugs and immunoglobulins, has been suggested by several groups of investigators. In the present study, we tested the effect of large doses of methylprednisolone and ibuprofen and of pooled human IgG prepared for iv administration in the rabbit model of Schlievert. PE-C followed by endotoxin (at doses of < 0.05 LD₅₀ and < 0.002 LD₅₀, respectively, if given alone) killed 50%-100% of control rabbits. Methylprednisolone and IgG protected rabbits from lethality when given singly prior to PE-C or endotoxin. When given 50 min after endotoxin, neither agent alone appeared to affect survival. However, when methylprednisolone and immunoglobulin were both administered after endotoxin, mortality was decreased. The mechanisms responsible for the protective efects of these agents are presently unknown. Since antibodies to PE-C and endotoxin are found in normal human serum it is likely that our pooled immunoglobulin functioned as a means of passive immunization against one or both toxins. The action of methylprednisolone is probably complex, as has been shown in other models of endotoxin shock. Although inhibition of prostaglandin synthesis may be involved, the finding that ibuprofen was ineffective suggests that the cyclooxygenase pathway is not primarily involved in the events leading to lethality. Future studies of the mechanisms of action of these therapeutic agents and of their possible protective role in patients with TSS seem warranted.