CORRELATION OF INCREASED AZITHROMYCIN CONCENTRATIONS WITH PHAGOCYTE INFILTRATION INTO SITES OF LOCALIZED INFECTION

Azithromycin reaches high concentrations in phagocytic and other host cells, suggesting that they may transport this agent to specific sites of infection. Models of localized infection (Haemophilus influenzae m iddle ear infection in gerbils, Streptococcus pyogenes implanted conta minated paper disc and Streptococcus pneumoniae pneumonia in mice) tha t induced severe inflammatory response after challenge were used to ex plore this hypothesis. Animals were given a single 100 or 50 mg/kg po dose of azithromycin at various times from 2 to 120 h following introd uction of a pathogen or sterile medium. When azithromycin was given du ring a period of little or no inflammation, there was marginal differe nce between concentrations found in infected or non-infected sites (bu lla, disc, lung). However, when the compound was given during a period of inflammation, considerably higher drug concentrations were found i n infected sites than in non-infected sites at 5-24 h after dosing (0. 38-0.44 mg/c compared with 0.07-0.14 mg/L of bulla wash; 1.01-1.75 mu g compared with less than or equal to 0.01-0.03 mu g at the disc site; 1.72-5.28 mg/kg compared with 0.7-1.53 mg/kg of lung). When the obser vation periods were extended to include 48, 56 or 96 h after dosing, t he ratio of azithromycin infection site concentration: serum concentra tion steadily increased with time in all model systems (middle ear, im planted disc and pneumonia), reflecting the maintenance of concentrati ons at the sites of infection, while serum concentrations declined. Bi oassay of cell pellets and supernatants, obtained from pooled bulla wa shes of gerbils treated with azithromycin during a period of inflammat ion, revealed that cellular components accounted for about 75% of the azithromycin detected. These data show that increased azithromycin con centrations occur at sites of localized infection. This correlates wit h the presence of inflammation and is associated with the cellular com ponents of the inflammatory response. Therefore, phagocytes may be imp ortant vehicles for delivering azithromycin to and sustaining azithrom ycin concentrations at sites of infection.