The distributions of radiolabelled free cefoxitin (FC) and liposome-encapsulated cefoxitin (LC) were compared in an animal model of intra-abdominal sepsis. Intraperitoneally administered LC was initially retained in the peritoneal cavity with subsequent preferential drug targeting to the liver (14% injected LC) and spleen (6% injected LC) by 3 h post-injection. Differing patterns of liposomal drug and lipid retention indicated that drug release from the liposome complex occurred within the peritoneum, liver and spleen. Intraperitoneal FC was rapidly taken up into the systemic circulation, with peak recovery in the blood (9% injected FC) and liver (5% injected FC) at 1 h post-injection. FC was also rapidly eliminated; 7% of the injected drug was recovered in the kidney 1 h post-injection. A negligible amount of FC was recovered in the spleen and very little FC or LC was found in the lungs of treated animals. Unlike FC, LC was found to provide a sustained bactericidal drug level (> 40 micrograms mL-1) in the peritoneal fluid for up to 5 h post-injection. LC also achieved significantly higher drug levels, compared with FC, within the liver at 3 and 5 h post-injection. Since severe intra-abdominal sepsis is often characterized by the presence of intraphagocytic bacteria in hepatic and splenic reticuloendothelial systems, the enhanced delivery of liposome-encapsulated anti-microbial agents, such as cefoxitin, to the liver and spleen may provide a more effective treatment for the septic condition.

Liposomal encapsulation of antimicrobial agents has been used to improve drug delivery, particularly against intracellular pathogens. The effect of unilamellar liposomes on macrophage activation in response to Escherichia coli lipopolysaccharide was examined. Liposomes caused a dose-and time-dependent inhibition of tumor necrosis factor release by lipopolysaccharide-treated cells. The accumulation of tumor necrosis factor mRNA transcripts was unaffected, suggesting a posttranscriptional mechanism for this effect. However, induction of macrophage procoagulant activity was unaffected by liposomes, indicating a selective rather than a global inhibition. These data suggest that liposomes used for drug delivery may modulate the host response to infection.Standard therapy for the management of secondary bacterial peritonitis includes fluid resuscitation to restore normal hemodynamics, surgical intervention to deal with the underlying pathological process and to reduce the bacterial inoculum, and the use of antimicrobial agents to treat local and systemic infections. Despite modem therapeutic approaches, clinical failures occur, some of which are attributed to antibiotic failure. The reasons for the lack of efficacy of various antimicrobial regimens include bacterial resistance, inadequate antibiotic levels, the failure of antibiotics to penetrate into sites of residual infection, and the reduced levels of antibiotic activity within the abnormal microenvironment of infection. Various novel approaches have been used to overcome some of these deficiencies. Liposome-encapsulated antibiotics have been shown to have improved penetration into phagocytic cells and have been advocated for use against intracellular microbes (1,22). Indeed, this carrier system augmented the efficacy of various antimicrobial agents against a wide range of microorganisms that survive within macrophages (1, 6, 9, 25). Our laboratory -has previously reported that the use of cefoxitin encapsulated within unilamellar liposomes (95% dipalmitoylphosphatidylcholine, 5% phosphatidylserine) significantly reduced the mortality rate compared with that with the use of free cefoxitin in an intra-abdominal infection model in the rat (5). Improved survival correlated with a reduction in residual bacterial numbers in the peritoneal cavity and the liver, suggesting that the beneficial effect of liposome-encapsulated cefoxitin was mediated via the improved microbicidal activity.Experimental intra-abdominal infection has been shown to initiate the release of numerous cytokines by cells of the monocyte/macrophage lineage (11). Among these, tumor necrosis factor (TNF) appears to play a central role in the host response to infection, including the lethality associated with endotoxemia (3,13,17,26,27 595-9486. ment with anti-TNF antibodies prevents the hemodynamic and pathological alterations as well as the lethal effects of endotoxin administration. On the basis of the importance of TNF in the development of the host response to intra-abdominal infection, we hypoth...