Reduction by Cefodizime of the Pulmonary Inflammatory Response Induced by Heat-Killed Streptococcus pneumoniae in Mice

Abstract

It has recently become apparent that overwhelming inflammatory reactions 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 investigate the influence of CEF on the pulmonary inflammatory response induced by Streptococcus pneumoniae, we infected mice with repeated intranasal inoculations of 107 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 polymorphonuclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recruitment was not primarily mediated by leukotriene B4 in this model. The 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-α) and interleukin-6 (IL-6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-α, but it did not interfere with IL-1α secretion in the lungs of infected mice. The fractional and selective downregulation of inflammatory cells and cytokines by CEF suggests cell-specific and intracellular specific mechanisms of interaction of the drug. The immunomodulatory properties of CEF may help restrain excessive inflammatory reactions, thus contributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.

Comparison of Pulmonary Inflammatory and Antioxidant Responses to Intranasal Live and Heat-Killed Streptococcus pneumoniae in Mice

“…The development of the inflammatory response reflected the growth of the live bacteria in the lung tissue. The early peaks in pulmonary TNFα, IL-1, IL-6, CXCL1, and CXCL2 were associated with concomitant increases in serum CXCL1, CXCL2, and IL-6, which correspond well to the findings reported earlier by Bergeron and colleagues [8,9]. TNFα and IL-1β are both important contributors to the neutrophil response to bacteria, including that to S. pneumoniae [10].…”

“…In order to mimic the innate immune stimulating aspects of pneumonia, independent of virulent bacteria, Bergeron's group studied, in a separate series of experiments, the effects of repeated administration of heat-killed S. pneumoniae [8,9]. In these studies, BAL and lung tissue samples were taken after 4, 12, and 24 h to investigate anti-inflammatory effects of antibacterial compounds.…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or “Immuno-Fairy Tales”?

“…Experimental models using immunocompromised animals confirmed the better efficacy of cefodizime than of other cephalosporins. Interestingly, in a model of pulmonary inflammatory responses induced by heat-killed Streptococcus pneumoniae, cefodizime abrogated TNF-␣ and IL-6 release into the bronchoalveolar lavage fluid and downregulated the strong PMN recruitment otherwise observed (29). In addition, a recent paper reported that cefodizime modulated the pulmonary response to heat-killed Klebsiella pneumoniae by stimulating the early immune response and further reducing late recruitment of neutrophils and IL-1 levels (28).…”

Ceftiofur Regulates LPS-Induced Production of Cytokines and Improves LPS-Induced Survival Rate in Mice

“…Beyond their antibacterial activity, these compounds are reported to exert anti-inflammatory and immunomodulatory activity in vitro and in vivo [2][3][4]. It has been reported previously that antimicrobials can affect several steps in the inflammatory process, such as migration of neutrophils, modulation of oxidative burst and production of cytokines [5][6][7].…”