PANCREAS NEWS
Which Antibiotic and What Dosage Must Be Used to Prevent Infection of Necrotic Pancreatic Tissue?
JOP expert comment
(R Pezzilli: pezzilli@orsola-malpighi.med.unibo.it)
The mortality rate of severe acute pancreatitis still ranges between 10 and 20%, and infected pancreatic necrosis is the leading cause of death. For this reason the prevention of infection of necrotic tissue remains an important objective in pancreatic research. Since the first study of the efficacy of imipenem in preventing the infection of pancreatic tissue in acute pancreatitis [Pederzoli P, et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993; 176:480-3. (AN: 93242503; PMID: 8480272)], several other studies have been published [Sainio V, et al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet 1995; 346:663-7. (AN: 95387770; PMID: 7658819)] - [Delcenserie R, et al. Prophylactic antibiotics in treatment of severe acute alcoholic pancreatitis. Pancreas 1996; 13:198-201. (AN: 96426926; PMID: 8829189)] - [Schwarz M, et al. Antibiotic use in necrotizing pancreatitis. Results of a controlled study. Dtsch Med Wochenschr 97; 122:356-61. (AN: 97259146; PMID: 9118789)].
A meta-analysis [Golub R, et al. Role of antibiotics in acute pancreatitis: A meta-analysis. J Gastrointest Surg 1998; 2:496-503. (AN: 99390105; PMID: 10457308). Full text] which considered only the randomized, controlled trials on this issue concluded that prophylactic antibiotic therapy of patients with necrotizing pancreatitis is able to reduce the infection rate and the mortality rate if the antibiotics used have proven pancreatic tissue penetration and have antimicrobical activity against the bacteria frequently found in pancreatic infection.
We have seen numerous replications of the initial study confirming the efficacy of imipenem as the antibiotic of choice in the prophylaxis of infection of necrotic pancreatic tissue; the last one has recently been published [Maravi-Poma E, et al. Early antibiotic treatment (prophylaxis) of septic complications in severe acute necrotizing pancreatitis: a prospective, randomized, multicenter study comparing two regimens with imipenem-cilastatin. Intensive Care Med 2003, Oct 10 [Epub ahead of print]. (PMID: 14551680). Full text]. This study answers two important questions: i) what is the optimal dosage of impinem in the prevention of infection of the necrotic pancreatic tissue?, and ii) what is the risk of fungal superinfection using this antibiotic regimen?. In this study, two imipenem regimens for the prevention of septic complications in patients with severe acute necrotizing pancreatitis (ANP) were compared in 92 patients. Five-hundreds mg of imipenem/cilastatin was administered four times daily starting at the time of the diagnosis of acute necrotizing pancreatitis within the first 96 hours from the onset of symptoms. Patients were randomized to receive antibiotic prophylaxis either for 14 days (Group 1) or for at least 14 days and for as long as major systemic complications of the disease persisted (Group 2). The antibiotic was maintained in Group 2 for about 20 days. The incidence of infected pancreatic necrosis, pancreatic abscess, and extrapancreatic infections was 11%, 17%, and 28% in Group 1 and 17%, 13%, and 35% in Group 2; these differences were not statistically significant. Pancreatic or extrapancreatic infection by Candida albicans occurred in 7% and 22% of patients, respectively. The total mortality rate was 18.5% and mortality secondary to septic complications was 10.9%, without differences between the groups. In patients with persisting systemic complications at day 14, mortality was almost always secondary to septic complications and decreased from 25% (Group 1) to 8.8% (Group 2) by maintaining antibiotic prophylaxis. Compared to a 14-day imipenem prophylaxis, a longer antibiotic administration in patients with ANP is not associated with a reduction in the incidence of septic complications of the disease. However, prolonged imipenem administration in patients with persisting systemic complications tends to reduce mortality in acute necrotizing pancreatitis as compared to a 14-day regimen. This study adds important information until poor examined: more cases of Candida infection appeared as the cause of extrapancreatic infection, and mortality among patients with fungal infections was greater than that among patients with non-fungal infections (25% vs 14.5%).
An open question is: since 1993, the year in which the initial study on the efficacy of imipenem was published, is this the only antibiotic which can be used prophylactically? An adequate spectrum of action linked to an effective pancreatic tissue concentration represents a goal for the utilization of an antibiotic in the prevention of infection of necrotic tissue during the course of acute pancreatitis. Other antibiotics tested in the past, such as pefloxacin, failed to demonstrate efficacy when compared to imipenem [Bassi C, et al. Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 1998; 115:1513-7. (AN: 99055593; PMID: 9834279). Full text].
Recently, Manes and coworker reported the results of a randomized, controlled trial in which meropenem was compared with imipenem [Manes G, et al. Prophylaxis with meropenem of septic complications in acute pancreatitis: a randomized, controlled trial versus imipenem. Pancreas 2003; 27:E79-83. (AN: 22938252; PMID: 14576501). Full text]. Meropenem is part of the same family as imipenem but has some advantages with respect to imipenem; it has considerable stability in the presence of renal dehydropeptidase-I and has enhanced activity against gram-negative bacteria, including Pseudomonas aeruginosa. In this study, 176 patients with necrotizing pancreatitis were prospectively randomized for prophylactic treatment with 0.5 g meropenem t.i.d. intravenously or 0.5 g imipenem q.i.d. intravenously. The occurrence of infection of pancreatic necrosis, the rate of extrapancreatic infections, systemic and local complications, need for surgery, mortality rate, and length of hospitalization were recorded for each group. When a septic complication of pancreatic necrosis was suspected, fine needle aspiration with cultures of the sample was performed. Surgery was performed in cases of verified infected necrosis. No difference was observed between patients treated with meropenem and those treated with imipenem in terms of incidence of pancreatic infection (11.4% versus 13.6%) and extrapancreatic infections (21.6% versus 23.9%), and their clinical outcome. Thus, meropenem is as effective as imipenem in preventing septic complications of patients with severe acute pancreatitis and if the results are confirmed, it may become a valid alternative to imipenem, having major advantages.
As for imipenem, we await further study addressed specifically to the optimal doses of this antibiotic, and most importantly, we await studies which answer the following questions: what are the resistant strains selected by meropenem, and which are the nosocomial infections and fungal superinfection resulting from this new treatment?
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