529 Polymyxin B Reduces Total Parenteral Nutrition-Associated Hepatic Steatosis by Its Antibacterial Activity and by Blocking Deleterious Effects of Lipopolysaccharide* ITZHAK PAPPO, MD*; HERVE BERCOVIER, DVM†; ELLIOT M. BERRY, MD‡; YOSEF HAVIV, BSc*; RUTH GALLILY, MSC, PHD§; AND HERBERT R. FREUND, MD* From the *Departments of Surgery, †Medicine, ‡Clinical Microbiology, and §Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel Correspondence: Herbert R. Freund, MD, Department of Surgery, Hadassah University Hospital Mount Scopus, P.O.B. 24035, Jerusalem 91240 Israel. * This work was presented at the 11th Annual Meeting of the Surgical Infection Society, April 8-10, 1991, Fort Lauderdale, Florida. ABSTRACT. Overgrowth of Gram-negative bacteria as a re- sult of total parenteral nutrition (TPN) and bowel rest could be responsible for the release of a variety of hepatotoxic substances such as endotoxin or tumor necrosis factor (TNF) and the ensuing TPN-associated liver function derangements. Polymyxin B is an effective antimicrobial agent as well as a blocking agent for endotoxin (lipopolysaccharide) activity and TNF production. In the present study we compared the oral and intravenous effects of polymyxin in rats receiving TPN in an attempt to define these two possible mechanisms of action of polymyxin on TPN-associated hepatic steatosis. Both oral, as well as intravenous polymyxin B, significantly reduced total hepatic fat and triglyceride accumulation in TPN rats, more so in the intravenous group exhibiting close to control levels. Both polymyxin-treated groups exhibited signif- icantly lower Gram-negative bacterial counts in the cecum, with the oral group exhibiting a lower count than the IV group. The spontaneous production of TNF by peritoneal macro- phages was markedly increased in rats receiving TPN and very close to being undetected in both groups receiving TPN and polymyxin. We believe polymyxin B protects the liver during TPN by both its antimicrobial effect which prevents overgrowth of gut Gram-negative bacteria and the subsequent translocation of endotoxin, and by its specific antilipopolysaccharide activity which, in the present study, completely abolished hepatic stea- tosis and TNF production during TPN. (Journal of Parenteral and Enteral Nutrition 16 :529-532, 1992) Hepatic complications are common in both infants and adults receiving total parenteral nutrition (TPN), and who have no underlying liver diseased Several etiol- ogies and mechanisms have been proposed, and almost all macro- and microcomponents of the nutrient solution have been implicated as the cause of TPN-associated hepatic dysfunction.’ Bacterial overgrowth as a result of bowel rest also has been suggested as a possible mechanism for liver function derangements. Clinical and experimental studies with TPN and metronidazole resulted in reduced liver func- tion derangements and a significant decrease in hepatic lipid accumulation in both patients’ and rats.’ In subsequent experiments we found that although the total number of bacteria (mainly strict anaerobes) re- mained similar in TPN and control rats, bowel rest and TPN resulted in a significant increase in the number of Gram-negative bacteria in the cecum of TPN rats.4 This overgrowth of Gram-negative bacteria, as well as bacte- rial translocation and deranged gut immune function,5-7 could be responsible for the excessive release and transit through the gut wall of a variety of hepatotoxic sub- stances such as bacterial cell wall polymers,’ platelet activating factor, endotoxin, or tumor necrosis factor (TNF).’ This hypothesis gained credence in a recent study where rats receiving TPN and various regimens of bowel decontamination, including polymyxin B, exhib- ited reduced bacterial counts in the cecum, reduced TNF production by peritoneal macrophages, representing splanchnic reticuloendothelial cell function, and lower total hepatic fat and triglyceride levels.&dquo; Polymyxin B is an effective antimicrobial agent and a blocking agent for endotoxin activity and in consequence of TNF production. Both of these effects could explain the protection afforded by polymyxin B against the pos- tulated lipopolysaccharide-induced hepatic toxicity and steatosis. In the present study, we compared oral and intrave- nous administration of polymyxin B in rats receiving TPN to evaluate the beneficial effects and mechanisms of action of intravenous polymyxin B on TPN-associated hepatic steatosis. MATERIALS AND METHODS Forty-six male Sabra rats weighing 300 ± 30 g under- went jugular vein cannulation with a 22-gauge silicone tubing while under anesthesia with Ketamine (25 mg/ kg) and Droperidol (0.5 mg/kg). The catheters were placed in a spring-coil apparatus and attached to a swivel mechanism. No harness was used. Placement of catheters was performed under strictly sterile conditions. After surgery, the animals were placed in metabolic cages,