The concentrations of azithromycin in whole blood, plasma, erythrocytes and polymorphonuclear leucocytes (PMNLs) were measured in 6 healthy volunteers following the last administration of a three-day regimen of 500 mg once daily. Marked enrichment of azithromycin was observed in PMNLs; the drug concentration amounted to 119 +/- 31 (SD) mg/l 6 hours after the administration. Twelve days thereafter 42 +/- 10 mg/l azithromycin was still measured in the PMNLs, although the drug was no longer demonstrable in plasma (< 0.02 mg/l). The elimination of azithromycin from the PMNLs (half-life 210 +/- 69 hours) was clearly slower than the elimination from plasma (half-life 93 +/- 70 hours). The maximal concentrations of azithromycin in plasma (0.64 +/- 0.27 mg/l) and erythrocytes (0.17 +/- 0.06 mg/l) were much lower and occurred earlier (tmax = 3 hours) than those observed in the PMNLs. The enrichment factor for azithromycin in PMNLs relative to plasma came to 177 +/- 92 at 3 hours or 1814 +/- 706 at 120 hours after the last administration. In a parallel in vitro study, the effect of accumulation of azithromycin in PMNLs on the intracellular survival of ingested staphylococci was investigated. At subinhibitory extracellular concentrations of azithromycin as low as 0.03 mg/l (MIC = 1 mg/l), a significant reduction in bacterial viability was observed, thus demonstrating antibacterial activity of the intracellularly enriched antibiotic.