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

Azithromycin pharmacokinetics in Legionella pneumophila-infected and u ninfected guinea pigs were assessed by measuring the drug concentratio n in whole lungs or the drug content in bronchoalveolar lavage (BAL) f luid in separate experiments. Azithromycin concentrations were measure d 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 intraperito neal injection of drug (15 mg/kg). The mean peak lung azithromycin con centration was higher in control animals than in infected animals (15. 8 versus 13.4 mu g/ml). The mean lung azithromycin concentration in in fected animals was significantly higher than that in controls 48 h aft er dosing (12.7 versus 10.4 mu g/g; P = 0.04). There were no significa nt differences between infected and uninfected animals in serum azithr omycin levels. Complementary experiments assessed intracellular/extrac ellular concentration ratios of azithromycin and erythromycin in L. pn eumophila-infected and control guinea pig alveolar macrophages. Azithr omycin was highly concentrated in alveolar macrophages, and the intrac ellular/extracellular concentration ratios for infected cells were sig nificantly 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 in fected cells (P < 0.0001). AZ intracellular concentrations were at lea st fivefold higher than those measured for erythromycin, and this diff erential increased with incubation time. Thus, azithromycin recovery f rom BAL fluid, and from guinea pig lungs at the 48-h time point, was h igher in the presence of experimental Legionnaires' disease. This like ly results from recruitment of phagocytes, including macrophages, that have an enhanced capacity to highly concentrate the drug.