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 immunosuppression of the cellular arm of the host defence system would greatly reduce the delivery of azithromycin to sites of infection and hence impair efficacy. Therefore, we evaluated the pharmacokinetics and pharmacodynamics of azithromycin in a Staphylococcus aureus intramuscular infection model in normal and immunosuppressed mice, employing therapeutic and prophylactic regimens. Immunosuppression was induced by daily doses of cyclophosphamide that culminated in leucopenia with an underlying granulocytopenic condition, with circulating peripheral granulocytes numbering from < or = 0.1-0.3 x 10(9)/L. Azithromycin tissue levels were not reduced in infection loci in granulocytopenic mice but moderate increases in Cmax and AUC values were observed, relative to similar tissues from normal mice. The tissue half-life of azithromycin in infected tissues in a therapeutic mode (75 h) was three-fold longer than in a prophylactic mode (25 h); this correlated with the degree of inflammation (therapy was withheld until inflammation was evident; i.e., prophylaxis reduced inflammation). Histological examination of infected tissues from normal and leucopenic mice was indistinguishable despite a 70%-85% reduction in circulating granulocytes. Compared with untreated infected controls, bactericidal activity was noted following prophylaxis with azithromycin and bacteraemia was suppressed in mice receiving azithromycin therapeutically. In summary, these data indicate that azithromycin delivery and efficacy in a moderately immunosuppressed animal model are unimpaired.
Girard
D
D
Central Research Division, Pfizer Inc, Groton, CT 06340, USA.
Regan
P A
PA
Milisen
W B
WB
Retsema
J A
JA
Swindell
A C
AC
D000380:Agranulocytosis / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D017963:Azithromycin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016470:Bacteremia / Q000382:microbiology; D015169:Colony Count, Microbial; D003520:Cyclophosphamide / Q000494:pharmacology; D006207:Half-Life; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007958:Leukocyte Count; D007970:Leukopenia / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000276:immunology
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D017963:Azithromycin; D003520:Cyclophosphamide