REDUCTION BY CEFODIZIME OF THE PULMONARY INFLAMMATORY RESPONSE INDUCED BY HEAT-KILLED STREPTOCOCCUS-PNEUMONIAE IN MICE

It has recently become apparent that overwhelming inflammatory reactio ns contribute to the high mortality rate associated with pneumococcal infection in immunocompetent hosts. Cefodizime (CEF) is an antibiotic that seems to be endowed with immunomodulating properties. To investig ate the influence of CEF on the pulmonary inflammatory response induce d by Streptococcus pneumoniae, we infected mice with repeated intranas al inoculations of 10(7) CFU of heat-killed fluorescein isothiocyanate -labeled bacteria, which are insensitive to the killing properties of the drug. CEF downregulated but did not abolish the strong polymorphon uclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recru itment was not primarily mediated by leukotriene B-4 in this model. Th e drug did not interfere with intrinsic mechanisms of phagocytosis by PMNs and alveolar macrophages. CEF totally abrogated the pneumococcus- induced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL- 6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-alpha; but i t did not interfere with IL-1 alpha secretion in the lungs of infected mice, The fractional and selective downregulation of inflammatory cel ls and cytokines by CEF suggests cell-specific and intracellular speci fic mechanisms of interaction of the drug. The immunomodulatory proper ties of CEF may help restrain excessive inflammatory reactions, thus c ontributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.