Azithromycin, a novel azalide antibiotic, concentrated in human and mouse polymorphonuclear leukocytes (PMNs), murine peritoneal macrophages, and mouse and rat alveolar macrophages, attaining intracellular concentrations up to 226 times the external concentration in vitro. In murine peritoneal macrophages, azithromycin achieved concentration gradients (internal to external) up to 26 times higher than erythromycin. The cellular uptake of azithromycin was dependent on temperature, viability, and pH and was decreased by 2,4-dinitrophenol. Azithromycin did not decrease phagocyte-mediated bactericidal activity or affect PMN or macrophage oxidative burst activity (H202 release or Nitro Blue Tetrazolium reduction, respectively). Azithromycin remained in cells for several hours, even after extracellular drug was removed. However, its release was significantly enhanced by phagocytosis of Staphylococcus aureus (82 versus 23% by 1.5 h). In vivo, 0.05 ,ig of azithromycin was found in peritoneal fluids of mice 20 h after oral treatment with a dose of 50 mg/kg. Following caseinate-induced PMN infiltration, there was a sixfold increase in peritoneal cavity azithromycin to 0.32 ,ug, most of which was intracellular. Therefore, the uptake, transport, and later release of azithromycin by these cells demonstrate that phagocytes may deliver active drug to sites of infection.

Human Recombinant IL-1 was investigated for its ability to increase non-specific resistance to Staphylococcus aureus in neutropenic mice. Mice, rendered neutropenic with cyclophosphamide and then administered IL-1 intraperitoneally, demonstrated enhanced resistance to subsequent challenge with S. aureus as measured by increased survival and bacterial clearance. No protective effects were observed with heat inactivated IL-1. Efficacy was observed only when both IL-1 and the subsequent bacterial challenge were administered into the same site. Despite the observed protective effects, animals treated with IL-1 did not have increased numbers of blood leukocytes or peritoneal phagocytes prior to infection or at the times coincident with bacterial clearance. Based upon these observations, enhanced activity of resident macrophages may be responsible for the protective effects observed in IL-1 treated mice.

Intravenous injection of bacterial endotoxin into mice at any time during ongoing infection with Listeria monocytogenes resulted in a markedly increased multiplication of this organism in the liver and spleen. Experiments designed to investigate the basis of this infection-enhancing effect revealed that endotoxin was also capable of inhibiting the expression of adoptive T-cell-mediated anti-Listeria immunity if given to normal recipient mice up to 48 h before they were infused with protective T-cells. On the other hand, endotoxin had only a marginal effect on the expression of adoptive immunity if given to donor mice before their spleen cells were harvested for adoptive transfer. Taken together, these results indicate that endotoxin probably interferes with the antibacterial function of macrophages rather than with mediator lymphocytes. The additional finding that the infection-enhancing action of endotoxin could be greatly reduced by making mice "tolerant" to endotoxin suggests that the acquisition of tolerance to this effect of endotoxin may be an important adaptive mechanism in acquired resistance to infection with gram-negative bacteria.

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Enhanced systemic antibacterial resistance was acquired by ACF1 (H-2ad) and B6D2F1 (H-2bd) mice bearing allogenetic BP-3 (H-2b) and SA-1 (H-2a) footpad tumors, respectively. This effect was dose dependent, in that the implantation of greater numbers of tumor cells produced larger tumors and higher levels of nonspecific resistance. Although the rejection of the tumor was T-cell dependent, the generation of nonspecific resistance was not. Thus, T-cell-deficient mice bearing progressively growing tumor allografts generated significant levels of antibacterial resistance. Two mechanisms were found to be involved in the generation of nonspecific resistance: (i) an acquired radioresistant mechanism responsible for initially destroying a large proportion of injected bacteria and (ii) an acquired radiosensitive mechanism responsible for destroying a significant number of bacteria after 24 h.