INFLUENCE OF IMMUNOSUPPRESSION ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF AZITHROMYCIN IN INFECTED-MOUSE TISSUES

Azithromycin has been shown to preferentially distribute to infection loci. Due to the potential contribution of phagocytes as transporters of drug to these sites, there has been some concern that immunosuppres sion of the cellular arm of the host defence system would greatly redu ce the delivery of azithromycin to sites of infection and hence impair efficacy. Therefore, we evaluated the pharmacokinetics and pharmacody namics of azithromycin in a Staphylococcus aureus intramuscular infect ion model in normal and immunosuppressed mice, employing therapeutic a nd prophylactic regimens. Immunosuppression was induced by daily doses of cyclophosphamide that culminated in leucopenia with an underlying granulocytopenic condition, with circulating peripheral granulocytes n umbering from less than or equal to 0.1-0.3 x 10(9)/L. Azithromycin ti ssue levels were not reduced in infection loci in granulocytopenic mic e but moderate increases in C-max and AUC values were observed, relati ve to similar tissues from normal mice. The tissue half-life of azithr omycin in infected tissues in a therapeutic mode (75 h) was three-fold longer than in a prophylactic mode (25 h); this correlated with the d egree of inflammation (therapy was withheld until inflammation was evi dent; i.e., prophylaxis reduced inflammation). Histological examinatio n of infected tissues from normal and leucopenic mice was indistinguis hable despite a 70%-85% reduction in circulating granulocytes. Compare d with untreated infected controls, bactericidal activity was noted fo llowing prophylaxis with azithromycin and bacteraemia was suppressed i n mice receiving azithromycin therapeutically. In summary, these data indicate that azithromycin delivery and efficacy in a moderately immun osuppressed animal model are unimpaired.