In severe acute pancreatitis, sepsis mainly due to pancreatic or peripancreatic infection have emerged as the most serious complications and now accounts for more than 80% of deaths. Collective review of organisms associated with secondary pancreatic infection in patients with acute pancreatitis has revealed that most of them are intestinal flora. Several experimental studies including ours have revealed that acute pancreatitis promotes bacterial translocation (BT), which in turn leads to infection of the pancreas and septic complications. Prophylactic antibiotics given intravenously have been demonstrated to be beneficial in reducing the rate of pancreatic infection, but their survival benefit remains unclear. We have demonstrated that continuous regional arterial infusion (CRAI) of an antibiotic is more effective than intravenous administration in preventing pancreatic infection and improving survival, in a canine model of acute necrotizing pancreatitis. Our recent experimental study has revealed that CRAI of an antibiotic via the superior mesenteric artery (SMA) is effective in mitigating intestinal mucosal damage and preventing BT in acute pancreatitis, thereby improving survival. BT aggravates pancreatic necrosis and remote organ damage in acute pancreatitis, and SMA infusion of antibiotics is effective in preventing BT and is practical for clinical use.