Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis--a single-center randomized study. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. [Antibiotic use in necrotizing pancreatitis. Results of a controlled study]. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study. Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Early antibiotic treatment in acute necrotising pancreatitis.
Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein > 150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [> 30%] and C-reactive protein [> 30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5 (15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size. Antibiotic prophylaxis in necrotizing pancreatitis remains controversial. Until now, there have been no double-blind studies dealing with this topic.
                A total sample size of 200 patients was calculated to demonstrate with a power of 90% that antibiotic prophylaxis reduces the proportion of patients with infected pancreatic necrosis from 40% placebo (PLA) to 20% ciprofloxacin/metronidazole (CIP/MET). One hundred fourteen patients with acute pancreatitis in combination with a serum C-reactive protein exceeding 150 mg/L and/or necrosis on contrast-enhanced CT scan were enrolled and received either intravenous CIP (2 x 400 mg/day) + MET (2 x 500 mg/day) or PLA. Study medication was discontinued and switched to open antibiotic treatment when infectious complications, multiple organ failure sepsis, or systemic inflammatory response syndrome (SIRS) occurred. After half of the planned sample size was recruited, an adaptive interim analysis was performed, and recruitment was stopped.
                Fifty-eight patients received CIP/MET and 56 patients PLA. Twenty-eight percent in the CIP/MET group required open antibiotic treatment vs. 46% with PLA. Twelve percent of the CIP/MET group developed infected pancreatic necrosis compared with 9% of the PLA group (P = 0.585). Mortality was 5% in the CIP/MET and 7% in the PLA group. In 76 patients with pancreatic necrosis on contrast-enhanced CT scan, no differences in the rate of infected pancreatic necrosis, systemic complications, or mortality were observed.
                This study detected no benefit of antibiotic prophylaxis with respect to the risk of developing infected pancreatic necrosis. Recent evidence of pancreatic penetration of several antibiotics active against the usual flora found in pancreatic sepsis, at therapeutic minimal inhibitory concentration, prompted the authors to perform a randomized, multicenter, clinical trial on imipenem prophylaxis in acute pancreatitis. Seventy-four patients with computed tomographic (CT) scans demonstrating necrotizing pancreatitis within 72 hours of onset were randomly assigned to two groups receiving no antibiotic treatment or 0.5 gram of prophylactic imipenem administered intravenously every eight hours for two weeks. Pancreatic sepsis was always detected by means of cultures (percutaneous CT or ultrasound-guided needle aspiration and intraoperative samples). The incidence of pancreatic sepsis was much less in treated patients (12.2 versus 30.3 percent, p < 0.01). Therefore, the authors recommend prophylactic use of imipenem in patients with acute necrotizing pancreatitis. The clinical course and death rate in acute necrotizing pancreatitis (ANP) are largely determined by septic complications as part of bacterial invasion of the necrotic tissues. It remains unclear whether antibiotic prophylaxis reduces bacterial invasion of the necroses or septic complications. It was, therefore, the aim of this study to evaluate the effect of prophylactic administration of antibiotics to patients with ANP.
                In a prospective randomized study 13 patients with ANP and sterile necroses (quantified by contrast-enhanced computed tomography) were given twice daily 200 mg ofloxacin and twice daily 500 mg metronidazole intravenously. The results were compared to those in a control group of patients with ANP (n = 13) who had not initially received antibiotics. In both patient groups fine-needle biopsies of the necrotic areas were performed on days 1, 3, 5, 7 and 10. If there was evidence of infection, antibiotics were then also given to patients of the control group.
                The extent of the necroses was the same, 40%, in both groups. These necroses became infected in a median of 9.5 (treated group) and 10 days (untreated group). The clinical course, documented by the APACHE II score, showed significant improvement under antibiotic treatment (days 1-5-10: scores 15-13.0-9.5). In the (initially untreated) control group the clinical condition deteriorated significantly (days 1-5-10: score 11.5-15.0-16.0). The changes from days 1 to 5, 5 to 10 and 1 to 10 were highly significant (Wilcoxon test, P < 0.01). None of the patients in the antibiotic group died within the first 3 weeks, but 2 of the 13 in the control group died.
                Antibiotic prophylaxis neither prevented nor delayed bacterial infection of the necrotic pancreas. But it significantly improved the clinical course if started before the onset of infection of the pancreatic necroses. In patients with severe, necrotizing pancreatitis, it is common to administer early, broad-spectrum antibiotics, often a carbapenem, in the hope of reducing the incidence of pancreatic and peripancreatic infections, although the benefits of doing so have not been proved.
                A multicenter, prospective, double-blind, placebo-controlled randomized study set in 32 centers within North America and Europe. Participants: One hundred patients with clinically severe, confirmed necrotizing pancreatitis: 50 received meropenem and 50 received placebo. Interventions: Meropenem (1 g intravenously every 8 hours) or placebo within 5 days of the onset of symptoms for 7 to 21 days. Main Outcome Measures: Primary endpoint: development of pancreatic or peripancreatic infection within 42 days following randomization. Other endpoints: time between onset of pancreatitis and the development of pancreatic or peripancreatic infection; all-cause mortality; requirement for surgical intervention; development of nonpancreatic infections within 42 days following randomization.
                Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group (P = 0.401). Overall mortality rate was 20% (10 of 50) in the meropenem group and 18% (9 of 50) in the placebo group (P = 0.799). Surgical intervention was required in 26% (13 of 50) and 20% (10 of 50) of the meropenem and placebo groups, respectively (P = 0.476).
                This study demonstrated no statistically significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention, and did not support early prophylactic antimicrobial use in patients with severe acute necrotizing pancreatitis. We investigated the effect of early jejunal feeding on septic complications and mortality rate in patients with acute pancreatitis in a two-phase, prospective, controlled study.
                In the first, randomized phase of the study, conventional parenteral nutrition was compared with early (within 24-72 h after the onset of symptoms) enteral nutrition. Of 89 patients admitted with acute pancreatitis, 48 patients were randomized into a parenteral group (Rindex 10, Infusamin S, Intralipid 10%; 30 kcal/kg) and 41 patients into an enteral group (jejunal tube feeding; Survimed OPD; 30 kcal/kg).
                The rate of septic complications (infected pancreatic necrosis, abscess) was lower in the enteral group (P = 0.08, chi(2) test). In the second phase of the study, early jejunal feeding was combined with prophylactic imipenem (Tienam, 500 mg intravenously twice each day) when necrosis of the pancreas was detected by abdominal computed tomography. When the outcomes of 92 patients in the third group were compared with those of patients in the parenteral group, the rate of septic complications decreased significantly (P = 0.03). Multiple organ failure (P = 0.14) and mortality (P = 0.13) tended to decrease.
                We believe that the combination of early enteral nutrition and selective, adequate antibiotic prophylaxis may prevent multiple organ failure in patients with acute pancreatitis. Despite improvements in surgical treatment and intensive care, mortality from severe acute pancreatitis remains high. We have carried out a randomised study of 60 consecutive patients with alcohol-induced necrotising pancreatitis to find out whether early antibiotic treatment can improve outcome. 30 patients were assigned cefuroxime (4.5 g/day intravenously) from admission. In the second group, no antibiotic treatment was given until clinical or microbiologically verified infection or after a secondary rise in C-reactive protein. The inclusion criteria were C-reactive protein concentration above 120 mg/L within 48 h of admission and low enhancement (< 30 Hounsfield units) on contrast-enhanced computed tomography. There were more infectious complications in the non-antibiotic than in the antibiotic group (mean per patient 1.8 vs 1.0, p = 0.01). The most common cause of sepsis was Staphylococcus epidermidis; positive cultures were obtained from pancreatic necrosis or the central venous line in 14 of 18 patients with suspected but blood-culture-negative sepsis. Mortality was higher in the non-antibiotic group (seven vs one in the antibiotic group; p = 0.03). Four of the eight patients who died had cultures from pancreatic necrosis positive for Staph epidermidis. We conclude that cefuroxime given early in necrotising pancreatitis is beneficial and may reduce mortality, probably by decreasing the frequency of sepsis.
No benefit of antibiotics in preventing infection of pancreatic necrosis or mortality was found, except for when imipenem (a beta-lactam) was considered on its own, where a significantly decrease in pancreatic infection was found. None of the studies included in this review were adequately powered. Further better designed studies are needed if the use of antibiotic prophylaxis is to be recommended.