Activity and local delivery of azithromycin in a mouse model of Haemophilus influenzae lung infection

Abstract

We compared the activities of azithromycin and erythromycin against Haemophilus influenzae in a mouse model of nonparenchymatous lower respiratory tract infection. In vitro and in vivo efficacy data for both drugs were analyzed relative to their pharmacokinetics in lungs and in vivo uptake by phagocytes. Aged C57BL/6 mice (mean age, 15.1 +/- 1.9 months) were infected intratracheally with 10(8) CFU of H. influenzae serotype b. Oral drug administration was initiated 4 h after infection by various dosage regimens. In terms of bacterial killing in the lung, azithromycin was much more active than erythromycin (P less than 0.01). Its in vivo activity was also more durable after a single administration relative to the durability of three doses of erythromycin given at 6-h intervals. The MIC of azithromycin was eightfold lower than that of erythromycin, and better penetration and a longer half-life in lung tissue were achieved after a single oral administration. Phagocytes delivered increased amounts of both drugs to the infected lungs, particularly at the site of infection (bronchoalveolar airspaces), and detectable levels of azithromycin were maintained locally for long periods. The fact that the efficacy of azithromycin coincided with the arrival of large numbers of polymorphonuclear leukocytes within the airspaces suggests that active extracellular concentrations were provided by the release of azithromycin from these cells. This further supports the potential value of once-daily azithromycin regimens for the treatment of lower respiratory tract infections in humans, provided that inhibitory concentrations against common pathogens such as H. influenzae are maintained for adequate periods of time.