AZITHROMYCIN PHARMACOKINETICS AND INTRACELLULAR CONCENTRATIONS IN LEGIONELLA PNEUMOPHILA-INFECTED AND UNINFECTED GUINEA-PIGS AND THEIR ALVEOLAR MACROPHAGES

Azithromycin pharmacokinetics in Legionella pneumophila-infected and uninfected guinea pigs were assessed by measuring the drug concentration in whole lungs or the drug content in bronchoalveolar lavage (BAL) fluid in separate experiments. Azithromycin concentrations were measured by using a bioassay. The mean azithromycin content in the BAL fluid of infected guinea pigs was higher than that in controls at 10 h (0.87 versus 0.39 mu g; P = 0.05), 24 h (1.10 versus 0.37 mu g; P = 0.003), and 48 h (1.21 versus 0.28 mu g; P = 0.05) after a single intraperitoneal injection of drug (15 mg/kg). The mean peak lung azithromycin concentration was higher in control animals than in infected animals (15.8 versus 13.4 mu g/ml). The mean lung azithromycin concentration in infected animals was significantly higher than that in controls 48 h after dosing (12.7 versus 10.4 mu g/g; P = 0.04). There were no significant differences between infected and uninfected animals in serum azithromycin levels. Complementary experiments assessed intracellular/extracellular concentration ratios of azithromycin and erythromycin in L. pneumophila-infected and control guinea pig alveolar macrophages. Azithromycin was highly concentrated in alveolar macrophages, and the intracellular/extracellular concentration ratios for infected cells were significantly higher (P < 0.0001) than those observed in controls after 4 h (127 versus 119), 24 h (481 versus 361), and 48 h (582 versus 520) of incubation. Erythromycin was also preferentially concentrated in infected cells (P < 0.0001). AZ intracellular concentrations were at least fivefold higher than those measured for erythromycin, and this differential increased with incubation time. Thus, azithromycin recovery from BAL fluid, and from guinea pig lungs at the 48-h time point, was higher in the presence of experimental Legionnaires' disease. This likely results from recruitment of phagocytes, including macrophages, that have an enhanced capacity to highly concentrate the drug.