Azithromycin achieves high concentrations in phagocytic cells and in fibroblasts. The newer macrolides also have this property but the intracellular penetration of azithromycin in relation to extracellular concentration is particularly notable. As a weak base, azithromycin is thought to concentrate in lysosomes of phagocytes and fibroblasts but many in vitro factors such as pH and temperature also affect the uptake process. Uptake of azithromycin by polymorphonuclear leucocytes results in an intracellular/extracellular concentration ratio of approximately 40 after one hour of incubation. Intraphagocytic antimicrobial activity has been demonstrated but is rather less than might be anticipated from the intracellular concentrations that are reached. Importantly, the high antibiotic levels found intracellularly do not appear to disrupt normal phagocyte function. Although azithromycin levels in the blood are low soon after administration, tissue concentrations are high and sustained. It appears that fibroblasts serve as a reservoir of drug in tissue, allowing activity against organisms and possibly transferring antibiotic to phagocytic cells for activity against intracellular pathogens and delivery to infection sites.

Enterococcus faecium clinical isolates A902 and BM4538, which were resistant to relatively high levels of vancomycin (128 and 64 g/ml, respectively) and to low levels of teicoplanin (4 g/ml), and Enterococcus faecalis clinical isolates BM4539 and BM4540, which were resistant to moderate levels of vancomycin (16 g/ml) and susceptible to teicoplanin (0.25 g/ml), were studied. Prior to the late 1980s, Enterococcus faecium and Enterococcus faecalis were considered uniformly susceptible to vancomycin, which was often the only antibiotic effective against multiresistant strains. Therefore, reports of vancomycin resistance in enterococci from Europe in 1988 (32, 48) and subsequently from the United States raised considerable concern (19). Since then, vancomycin-resistant enterococci have become increasingly prevalent.Glycopeptide resistance in enterococci results from the production of modified peptidoglycan precursors ending in D-Ala-D-Lac (VanA, VanB, and VanD) or D-Ala-D-Ser (VanC, VanE, and VanG), to which glycopeptides exhibit low binding affinities, and from the elimination of the high-affinity D-Ala-D-Ala-ending precursors synthesized by the host Ddl ligase (10,20,22,44). Acquired resistance to glycopeptides in the three D-Ala-D-Lac types, VanA, VanB, and VanD, can be classified depending on the levels of resistance to vancomycin and susceptibility or resistance to teicoplanin (10,22). VanA-type strains display high-level inducible resistance to both vancomycin and teicoplanin, whereas VanB-type strains have various levels of inducible resistance to vancomycin only, since teicoplanin is not an inducer (10). VanD-type strains are characterized by constitutive resistance to moderate levels of both glycopeptides (22)

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The interaction of azithromycin with normal human serum was examined in relation to serum protein binding, MIC, and kinetics of killing of bacteria. While the binding of azithromycin to serum proteins is low (8.5% at a concentration of 0.01 mM in 95% serum), the presence of 40% serum during the MIC test decreased MICs by 26-fold for serum-resistant Escherichia coli and 15-fold for Staphylococcus aureus. Erythromycin had a similar but lesser effect, while roxithromycin was less active against S. aureus in the presence of serum. The rate of killing of E. coli and S. aureus by azithromycin was increased in the presence of serum. The enhancement of antibiotic activity by serum was pH independent, and heat inactivation and preabsorption with homologous bacteria failed to inhibit enhancement by serum. The macromolecular incorporation of [3H]thymidine by E. coli continuously exposed to 2 ,ug of azithromycin per ml (0.25x the MIC) and 40% serum was decreased by 80% at pH 7.8 and by 48% at pH 7.2, while azithromycin alone failed to inhibit incorporation. Inhibition of nucleic acid biosynthesis at pH 7.2 in the presence of serum was also detected with sub-MICs of erythromycin, norfloxacin, and gentamicin but not roxithromycin. A diffusible serum factor was shown to interact with azithromycin to inhibit the growth of E. coli in an agar diffusion assay to detect antibiotic-serum synergy.