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Three Part Question

In [patient with acute pancreatitis] does [prophylactic treatment with antibiotic] improve [the morbidity and mortality].

Clinical Scenario

A 45 years old man came to emergency department with sever epigastric pain and vomiting, he was tachycardic and hypotensive, immediate fluid resuscitation stabilized his hemodynamic status. Labs revealed high lipase and amylase suggesting acute pancreatitis; he was kept NPO on intravenous fluid and was treated with analgesics and anti-emetics. The case was referred to gastroenterologist for admission who on further discussion, was enquiring why antibiotic was not started in ED for a better outcomes?
This stimulated my thought, if starting prophylactic antibiotics in case of acute pancreatitis improve the outcome in term of morbidity and mortality.

Search Strategy

I searched the electronic data base of Pub Med, MEDLINE, EMBASE CINAHL, BIOSIS, and the Cochrane Central Register of Controlled Trials using the term “pancreatitis “[all fields],”antibacterial agents”, or “antimicrobial agents “ or “antibiotic“. Search was limited to English language, and human. There was no limitation of date.
Initial search produced many studies, but most of which was for diagnosed necrotizing pancreatitis, which had to be avoided since I wanted the topic to be confined to the emergency medicine setting, and the use of antibiotic in clinically proven pancreatitis in general rather than diagnosed necrotizing pancreatitis by radiological means.
This search yielded 86 research articles, most of which were irrelevant. I reviewed all citation abstracts, and only original published research articles that addressed the use of prophylactic antibiotics in acute pancreatitis were included. Five original research articles were identified that directly addressed the use of prophylactic antibiotics in acute pancreatitis.
Multiple meta-analysis and systemic review publications were included in the extended methodology. There were no limitations of gender, age or race.

Search Outcome

Altogether 86 papers were found of which 5 were directly relevant to the three part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ignatavicius et al 2012 Lithuania.	210 patients treated for SAP. . In Group 1 (n= 103), patients received prophylactic antibiotics (ciprofloxacin, metronidazole). In Group 2 (n= 107), patients were treated on demand.	Prospective non randomized cohort study. (1b)	The aim of this study was to compare the effects of antibiotics administered as prophylaxis and as treatment on demand. The primary endpoints were infectious complication rate, need for and timing of surgical interventions, incidence of nosocomial infections and mortality rate.	Ultrasound-guided fine needle aspiration [in 18 (16.8%) vs. 13 (12.6%) patients; P= 0.714], ultrasound-guided drainage [in 15 (14.0%) vs. six (5.8%) patients; P= 0.065] and open surgical necrosectomy [in 10 (9.3%) vs. five (4.9%) patients; P= 0.206] were performed more frequently and earlier [at 16.6 ± 7.8 days vs. 17.2 ± 6.7 days (P= 0.723); at 19.5 ± 9.4 days vs. 24.5 ± 14.2 days (P= 0.498), and at 22.6 ± 13.5 days vs. 26.7 ± 18.1 days (P= 0.826), respectively] in Group 2 compared with Group 1. There were no significant differences between groups in mortality and duration of stay in the surgical ward or intensive care unit.	Small number of patients. Not an emergency department setting.
Isenmann et al 2004 Germany	114 patients with acute pancreatitis were enrolled and 58 patients received antibiotics and 56 patient received placebo.	Retrospective cohort study double blinded. (2b)	The effect of prophylactic antibiotic treatment in patient with predicted severe acute pancreatitis	58 patients received antibiotics and 56 patients received placebo. 28% in the antibiotic group required open antibiotic treatment vs. 46% with placebo. 12% of the antibiotic group developed infected pancreatic necrosis compared with 9% of the placebo group (P = 0.585). Mortality was 5% in the antibiotic and 7% in the placebo 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.	Retrospective study. Very few patients with acute severe pancreatitis.
Manes et al 2006 Italy	215 patients with pancreatitis were randomized to either group A (N = 108), who started antibiotic therapy (meropenem 500 mg t.i.d.) at admission, or group B (N = 107), who received antibiotics after the demonstration of necrosis at computed tomography (CT). CT was performed in both groups after at least 48 hours of hospitalization. The clinical course of disease was compared in the two groups.	Randomized control study. (1b)	Antibiotic prophylaxis improves the outcome of acute pancreatitis.	30 patients in group A and 29 in B showed necrosis on CT. The two groups were similar in demographics and characteristics of disease. Antibiotic treatment was started after 4.56 +/- 1.2 days from hospitalization in group B and after 1.07 +/- 0.6 days in A. Pancreatic infection occurred in four patients in group A (13.3%) and in nine in B (31%) (p = 0.1). Extra-pancreatic infection occurred in 16.6% of patients in group A and in 44.8% in B (p < 0.05). Need for surgery and length of hospitalization were also higher in group B. Mortality rates were similar in the two groups, but, 3 of 4 patients with infected necrosis in group A and only 2 of 9 in group B died.	Small number of patients. Not an emergency department setting.
Luite et al, 1995 Netherland	102 patients with objective evidence of severe acute pancreatitis to were admitted. Patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination. Fifty patients were assigned to the selective decontamination group and 52 were assigned to the control group.	A randomized, controlled, multicenter trial. (1b)	whether selective decontamination reduces mortality in sever acute pancreatitis	There were 18 deaths in the control group (35%), compared with 11 deaths (22%) in the selective decontamination group. This difference was mainly caused by a reduction of late mortality (> 2 weeks) due to significant reduction of gram-negative pancreatic infection (p = 0.003). The average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < 0.05).	Small number of patients. The inclusion criteria was not clearly stated.
Nadim et al 2010 USA	502 patients from 8 studies. There were 253 patients with SAP who received prophylactic antibiotics, and 249 patients were randomized to the placebo arm	Systematic Review and Meta-analysis	The use of prophylactic systemic antibiotics to prevent infection and reduce mortality in severe acute pancreatitis sever acute pancreatitis (SAP).	There was no protective effect of antibiotic treatment with respect to mortality (RR, .76; 95% confidence interval [CI], .49 –1.16). With respect to morbidity, antibiotic prophylaxis did not protect against infected necrosis (RR, .79; 95% CI, .56–1.11) or surgical intervention (RR, .88; 95% CI, .65–1.20). There was, however, an apparent benefit in regards to non-pancreatic infections (RR, .60; 95% CI, .44 –.82), with a RR reduction of 40% (95% CI, 18%–56%), absolute risk reduction of 15% (95% CI, 6%–23%), and number needed to treat of 7 (95% CI, 4–17).	relatively small number of patients in each individual study, different outcome measurements, and the inclusion of low-quality studies.

Comment(s)

Infectious complications are the leading cause of death in patients with severe acute pancreatitis. Currently, there is controversy concerning the therapeutic possibilities to reduce the incidence of bacterial infection in this disease. Numerous studies are available which apparently support the prophylactic use of antibiotics in patients with acute severe pancreatitis. The results, however, are contradicting and interpretation is difficult as these studies have used various antibiotic drugs with different application schemes and heterogeneous study end points. The role of systemic antibiotics in the management of acute pancreatitis remains controversial. The development of complications such as infected pancreatic necrosis, abscesses, and infected pseudocysts, herald the development of a deteriorating disease process that is associated with considerable morbidity and mortality. The use of appropriate antibiotics in the setting of SAP would appear to be a logical choice in the management of this condition. However, most of the RCTs conducted thus far have failed to show the benefit of antibiotics.

Clinical Bottom Line

Prophylactic antibiotics are not effective in reducing the incidence of (peri)-pancreatic infection in patients with severe disease. The only rational indication for antibiotics is documented infection. The spectrum of prophylactic antibiotics should include both aerobic and anaerobic gram-negative and gram-positive microorganisms. Also, fungal infections are often present in these patients, and antifungal coverage or even prophylaxis should be considered, especially if multiple risk factors for invasive candidacies are present. The present studies do not support the use of prophylactic antibiotics to reduce the frequency of surgical intervention, infected necrosis, or mortality in patients with severe acute pancreatitis. They may, however, be beneficial in protecting against the development of non-pancreatic infections; further better designed studies are needed if the use of antibiotic prophylactics is to be recommended.

References

1. Ignatavicius P, Vitkauskiene A, Pundzius J, et al. (2012). Effects of prophylactic antibiotics in acute pancreatitis. Hepato-Pancreato-Biliary journal (HPB) 2012 2012;14(6):396-402.
2. Isenmann R, Runzi M, Kron M, et al. (2004). Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004 2006;101(6):1348-1353.
3. Manes G, Uomo I, Menchise A, et al. (2006). Timing of Antibiotic Prophylaxis in Acute Pancreatitis: A Controlled Randomized Study with Meropenem. American Journal of Gastroenterology 2006 2006;101(6):1348-1353.
4. Luiten EJ, Hop WC, Lange JF, et al. (1995). Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Annals of Surgery Journal 1995 1995; 222(1): 57–65.
5. Nadim SJ, Suhal SM, Spencer RI, et al. (2009). Antibiotic prophylaxis is not protective in severe acute pancreatitis: a systematic review and meta-analysis. The American Journal of Surgery 2009 2009; 197, 806-813.