CEFDINIR (CL-983), A NEW ORAL AMINO-2-THIAZOLYL CEPHALOSPORIN, INHIBITS HUMAN NEUTROPHIL MYELOPEROXIDASE IN THE EXTRACELLULAR MEDIUM BUT NOT THE PHAGOLYSOSOME

Cefdinir, a new oral 2-amino-5-thiazolyl cephalosporin, inhibited the luminol-amplified chemiluminescence (LACL) response of human neutrophi ls stimulated by PMA but not opsonized zymosan, in a concentration-dep endent but not time-dependent manner. The LACL response to opsonized z ymosan in cytochalasin B-treated neutrophils was, however, inhibited b y cefdinir. Various cephalosporins, regardless of the presence of a 2- amino-5-thiazolyl moiety, did not significantly alter the neutrophil L ACL response triggered by PMA and zymosan. The LACL response induced b y the calcium ionophore A23187 and FMLP was also impaired by cefdinir, and this impairment was increased in cytochalasin B-treated neutrophi ls. Superoxide anion generation by neutrophils, measured in terms of l ucigenin-amplified chemiluminescence and cytochrome c reduction, was n ot altered. Spontaneous and FMLP-induced neutrophil degranulation, ass essed by lysozyme and p-glucuronidase release, were not modified by ce finir. Furthermore, cefdinir inhibited LACL generation in cell-free sy stems consisting of H2O2, Nal, and either horseradish peroxidase or a myeloperoxidase-containing neutrophil extract. Orthodianisidine oxidat ion in these two acellular systems was inhibited by cefdinir. Cefdinir did not alter neutrophil bacterial killing at concentrations that inh ibited myeloperoxidase-containing neutrophil extract-dependent reactio ns induced by soluble stimuli. Taken together, these data strongly sug gest that cefdinir directly inhibits the activity of myeloperoxidase-c ontaining neutrophil extract released into the extracellular medium du ring neutrophil stimulation by soluble mediators, but has no effect on that released into the phagolysosome during phagocytosis. This unusua l property of a member of the p-lactam family could be of interest in modulating the exaggerated inflammatory process often associated with infectious diseases.