Prophylaxis and treatment with antibiotics or probiotics in acute pancreatitis

(1) Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands (2) Department of Surgery, Tweesteden Hospital, Tilburg, The Netherlands (3) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands (4) Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

Entry Version: 

Version 1.0, August 12, 2016


Bouwense, Stefan A. van Baal, Mark C. van Santvoort, Hjalmar C. van Goor, Harry. Besselink, Marc G. (2016). Prophylaxis and treatment with antibiotics or probiotics in acute pancreatitis.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2016.19

1. Introduction

Acute pancreatitis is the most common gastrointestinal disease requiring acute hospitalization and its incidence is rising (23). Approximately 20% of patients develop necrotizing pancreatitis (4, 10). Necrotizing pancreatitis is defined by either pancreatic parenchymal necrosis and/or peripancreatic tissue necrosis (3, 4). These patients are at risk for (multiple) organ failure often due to a persisting systemic inflammatory response syndrome. If the (peri)pancreatic collections with necrosis remain sterile the majority of patients will recover with conservative measures without the need of an invasive intervention (10). Secondary infection of necrosis develops in 30% of patients with necrotizing pancreatitis which increases morbidity and mortality substantially (24, 35). Overall mortality of necrotizing pancreatitis (15% to 30%) is much higher as compared to mild pancreatitis (0% to 1%) (13, 18).

Secondary infection of the peripancreatic collections or pancreas necrosis is considered to be caused by bacterial translocation: the phenomenon that enteral bacteria cross the gastrointestinal mucosal barrier and invade the systemic compartment or by haematogenous spread from other sites in the body (9). Based on experimental and clinical studies it is believed that bacterial translocation is the results of a cascade of events depending on a disturbance of host-bacterial interactions on three levels: 1) the intestinal lumen; the presence of impaired small bowel motility and bacterial overgrowth, 2) the intestinal epithelium; structural mucosal barrier failure leading to increased gut permeability (15) and 3) the immune system; a dysregulation in the balance of the pro- and anti-inflammatory factors (2). Another possible pathway was found in an experimental study in rats suggesting that transmission by mesenteric lymphatics is also involved in the process of bacterial translocation (17).

Early in the disease course of necrotizing pancreatitis two treatment strategies have been suggested to prevent secondary infection of peripancreatic collections and pancreas necrosis:

  1. Prophylactic administration of antibiotics
  2. Therapeutic administration of probiotics.

These treatment strategies will be consecutively discussed.

2. Antibiotics

Multiple studies have studied the prophylactic use of systemic antibiotics in acute pancreatitis over the last decades (11, 37). The rationale for prophylactic treatment is to diminish potential hematogenous spread of pathogens after bacterial translocation has occurred.

In the last decades, 14 randomized controlled trials studied the effect of systemic antibiotic prophylaxis on prevention of infection of pancreatic necrosis (11, 37). In the 1990’s enthusiasm for antibiotic prophylaxis was expressed through a number of small case series and editorials (6, 8, 12, 26). As a result, many surgeons, such as in the United Kingdom, started using antibiotic prophylaxis.(25) Overall, the studies at that time were underpowered and generated variable results, but still the meta-analysis at that time suggested a reduction in morbidity and mortality. But there were also concerns about selection of multidrug resistant bacteria and opportunistic fungal infections (25).

A Cochrane review by Villatoro in 2006 suggested a survival benefit and a decrease in pancreatic sepsis associated with the prophylactic use of beta-lactam group antibiotics (36). However, due to two new double-blinded randomized clinical trials the conclusion on prophylactic antibiotics changed (7, 28). The Vilatoro group included those trials in their 2010 Cochrane review which included seven studies with in total 404 randomized patients. They found no statistically significant effect on the reduction of mortality (8.4% vs. 14.4%) and the presence of infected pancreatic necrosis (19.7% versus 24.4%). The rate of other infections (not related to necrosis) were also not significantly reduced by prophylactic antibiotics. A trend, but without statistically significant difference, was shown with beta-lactam antibiotics towards less mortality and infected pancreatic necrosis. Interestingly, this effect was stronger for imipenem which showed no reduction in mortality but a reduction in pancreatic infections (RR 0.34 95% CI 0.13 – 0.84) (37). Overall the quality of studies remained a major concern throughout the years regarding this subject; all studies were underpowered. It was concluded that there is no evidence for the prophylactic use of antibiotics in acute pancreatitis (37). This was confirmed by a second review, which also suggested that further research is needed to find sub-populations that may benefit from prophylactic antibiotics (11).

Selective digestive tract decontamination (SDD) is used on many intensive care units, particularly in ventilated patients. The goal of decontamination of the upper respiratory and digestive tract attempts to reduce infections by decreasing the microorganisms’ colonization at these sites. Both selective decontamination of the oropharyngeal tract (SOD) and digestive tract (SDD) with nonabsorbable antibiotics have shown a modest decrease in mortality and reduced rates of bactaeremia (29). The only trial of SDD in patients with severe acute pancreatitis demonstrated a significant reduction of gram-negative bacterial colonization of the digestive tract, and a significant reduction of morbidity and mortality (14). Due to the moderate methodological quality (a non-blinded, underpowered study with lack of clear definitions) and the overall scarceness of evidence in severe acute pancreatitis, SDD is not considered standard practice in severe acute pancreatitis.


Current evidence does not support routine antibiotic prophylaxis or SDD in patients with severe acute pancreatitis (10). This, however, does not imply that antibiotic treatment (rather than prophylaxis) is ineffective and should not be started as soon as evidence for the superinfection of (peri) pancreatic necrosis emerges. In most cases infected (peri) pancreatic necrosis can be treated successfully with appropriate antibiosis which often eliminates the need for interventional approaches.

3. Probiotics

Probiotics are defined as: ‘Living micro-organisms which, when administered in adequate amounts, confer a health benefit on the host’ (1). Probiotics can be administered together with prebiotics (synbiotics), non-digestible fibers that, when added to probiotics, enhance their activity. Probiotics have been suggested to reduce bacterial translocation (in acute pancreatitis) through a beneficial effect on three levels of host-bacterial interactions; the intestinal lumen, the intestinal epithelium and the immune system.

Bacterial overgrowth of potential pathogens is prevented in the intestinal lumen by a direct antimicrobial effect and competitive growth (30). At the intestinal epithelium probiotics prevent bacterial adherence to the epithelial surface by competitive exclusion and inhibition of a pathogen-induced increase of epithelial permeability. They also regulate enterocyte gene expression involved in the maintenance of the mucosal barrier and thus may preserve epithelial function (15, 16). Also selected probiotic strains have been found capable of inhibiting local pro-inflammatory reactions in enterocytes after i.e. pathogenic bacterial adhesion or ischemia (16). Finally, in vitro probiotic strains have been shown to induce production of the anti-inflammatory cytokine interleukin-10. A similar effect is thought to have a regulatory effect on the mucosal and systemic immune system in humans (19).

In various experimental studies the prophylactic role of probiotics in acute pancreatitis has been examined. In rats with pancreatitis probiotics reduced overgrowth of potential pathogens in the duodenum resulting in reduced bacterial translocation to extra intestinal sites and a reduction in mortality (34).

In clinical studies the prophylactic use of probiotics was examined in several randomized controlled trials. In patients undergoing major abdominal surgery the administration of pre- and probiotics significantly reduced the incidence of postoperative infections, although there were some methodological issues in these studies (20, 27, 31).

Initially, two small randomized controlled trials, both from Hungary, studied probiotic prophylaxis in acute pancreatitis. The first trial showed in 45 patients with predicted mild and severe pancreatitis that probiotics reduce pancreatic sepsis and the need for surgical intervention (21). The second trial studied 62 patients with severe pancreatitis and concluded that nasojejunal feeding with synbiotics may prevent organ dysfunction in the late phase of severe acute pancreatitis (22). Because of the lack of stronger evidence, a larger randomized controlled multicenter trial was performed (PROPATRIA) where probiotics were compared with placebo in 298 patients with predicted severe pancreatitis. No probiotic effect was found in reducing infectious complications. There was, however a surprisingly higher rate of bowel ischemia (9 vs. 0) and mortality (16% vs. 6%) in the probiotics group (5). The mechanism explaining this adverse effect remains, unclear even after post hoc research in experimental animals (32, 33).


There is currently no place for the treatment of acute pancreatitis patients with probiotics. Further research on probiotic prophylaxis in patients with organ failure has been returned to the experimental stage to study the possible mechanism of adverse events such as those observed in the PROPATRIA study.

4. Summary

Based on the current literature and in accordance with IAP/APA Acute Pancreatitis Guidelines(10):

  1. Intravenous antibiotic prophylaxis is not recommended for the prevention of infectious complications in acute pancreatitis. (GRADE 1B, strong agreement)
  2. Probiotic prophylaxis is not recommended for the prevention of infectious complications in acute pancreatitis. (GRADE 1B, strong agreement)

      3.  Intravenous antibiotics should be given  in case of suspected infection of     necrotising pancreatitis and further intervention considered.

5. References

  1. FAO/WHO (2001) Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria.Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria.
  2. Ammori BJ,Fitzgerald P,Hawkey P and McMahon MJ. The early increase in intestinal permeability and systemic endotoxin exposure in patients with severe acute pancreatitis is not associated with systemic bacterial translocation: molecular investigation of microbial DNA in the blood. Pancreas 26(1): 18-22,2003. PMID: 12499912.
  3. Bakker OJ,van Santvoort H,Besselink MG,Boermeester MA,van Eijck C,Dejong K, et al. Extrapancreatic necrosis without pancreatic parenchymal necrosis: a separate entity in necrotising pancreatitis? Gut 62(10): 1475-1480,2013. PMID: 22773550.
  4. Banks PA,Bollen TL,Dervenis C,Gooszen HG,Johnson CD,Sarr MG, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut 62(1): 102-111,2013. PMID: 23100216.
  5. Besselink MG,Van Santvoort HC,Buskens E,Boermeester MA,van GH,Timmerman HM, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 371(9613): 651-659,2008. PMID: 18279948.
  6. Bradley EL, III. Antibiotics in acute pancreatitis. Current status and future directions. Am.J.Surg. 158(5): 472-477,1989. PMID: 2683821.
  7. Dellinger EP,Tellado JM,Soto NE,Ashley SW,Barie PS,Dugernier T, et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled Study. Ann.Surg. 245(5): 674-683,2007. PMID: 17457158.
  8. Golub R,Siddiqi F and Pohl D. Role of antibiotics in acute pancreatitis: A meta-analysis. J Gastrointest.Surg. 2(6): 496-503,1998. PMID: 10457308.
  9. Guarner F and Malagelada JR. Gut flora in health and disease. Lancet 361(9356): 512-519,2003. PMID: 12583961.
  10. Guidelines WGIAAP. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13(4 Suppl 2): e1-15,2013. PMID: 24054878.
  11. Jiang K,Huang W,Yang XN and Xia Q. Present and future of prophylactic antibiotics for severe acute pancreatitis. World J Gastroenterol 18(3): 279-284,2012. PMID: 22294832.
  12. Johnson CD. Antibiotic prophylaxis in severe acute pancreatitis. Br J Surg 83(7): 883-884,1996. PMID: 8813769.
  13. Johnson CD and Abu-Hilal M. Persistent organ failure during the first week as a marker of fatal outcome in acute pancreatitis. Gut 53(9): 1340-1344,2004. PMID: 15306596.
  14. Luiten EJ,Hop WC,Lange JF and Bruining HA. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann.Surg. 222(1): 57-65,1995. PMID: 7618970.
  15. Lutgendorff F,Nijmeijer RM,Sandstrom PA,Trulsson LM,Magnusson KE,Timmerman HM, et al. Probiotics prevent intestinal barrier dysfunction in acute pancreatitis in rats via induction of ileal mucosal glutathione biosynthesis. PLoS One 4(2): e4512,2009. PMID: 19223985.
  16. Marco ML,Pavan S and Kleerebezem M. Towards understanding molecular modes of probiotic action. Curr Opin Biotechnol 17(2): 204-210,2006. PMID: 16510275.
  17. Mittal A,Phillips AR,Middleditch M,Ruggiero K,Loveday B,Delahunt B, et al. The proteome of mesenteric lymph during acute pancreatitis and implications for treatment. JOP 10(2): 130-142,2009. PMID: 19287105.
  18. Mofidi R,Duff MD,Wigmore SJ,Madhavan KK,Garden OJ and Parks RW. Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br.J.Surg. 93(6): 738-744,2006. PMID: 16671062.
  19. Niers LE,Timmerman HM,Rijkers GT,van Bleek GM,van Uden NO,Knol EF, et al. Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines. Clin Exp Allergy 35(11): 1481-1489,2005. PMID: 16297146.
  20. Nomura T,Tsuchiya Y,Nashimoto A,Yabusaki H,Takii Y,Nakagawa S, et al. Probiotics reduce infectious complications after pancreaticoduodenectomy. Hepatogastroenterology. 54(75): 661-663,2007. PMID: 17591036.
  21. Olah A,Belagyi T,Issekutz A,Gamal ME and Bengmark S. Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br.J.Surg. 89(9): 1103-1107,2002. PMID: 12190674.
  22. Olah A,Belagyi T,Poto L,Romics L, Jr. and Bengmark S. Synbiotic control of inflammation and infection in severe acute pancreatitis: a prospective, randomized, double blind study. Hepatogastroenterology. 54(74): 590-594,2007. PMID: 17523328.
  23. Peery AF,Dellon ES,Lund J,Crockett SD,McGowan CE,Bulsiewicz WJ, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 143(5): 1179-1187 e1171-1173,2012. PMID: 22885331.
  24. Petrov MS,Shanbhag S,Chakraborty M,Phillips AR and Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology 139(3): 813-820,2010. PMID: 20540942.
  25. Powell JJ,Campbell E,Johnson CD and Siriwardena AK. Survey of antibiotic prophylaxis in acute pancreatitis in the UK and Ireland. Br.J.Surg. 86(3): 320-322,1999. PMID: 10201771.
  26. Powell JJ,Miles R and Siriwardena AK. Antibiotic prophylaxis in the initial management of severe acute pancreatitis. Br.J.Surg. 85(5): 582-587,1998. PMID: 9635800.
  27. Rayes N,Seehofer D,Hansen S,Boucsein K,Muller AR,Serke S, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 74(1): 123-127,2002. PMID: 12134110.
  28. Rokke O,Harbitz TB,Liljedal J,Pettersen T,Fetvedt T,Heen LO, et al. Early treatment of severe pancreatitis with imipenem: a prospective randomized clinical trial. Scand J Gastroenterol 42(6): 771-776,2007. PMID: 17506001.
  29. Roquilly A,Marret E,Abraham E and Asehnoune K. Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-analysis. Clin Infect Dis 60(1): 64-75,2015. PMID: 25252684.
  30. Servin AL. Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol Rev 28(4): 405-440,2004. PMID: 15374659.
  31. Sugawara G,Nagino M,Nishio H,Ebata T,Takagi K,Asahara T, et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann.Surg. 244(5): 706-714,2006. PMID: 17060763.
  32. van Baal MC,Kohout P,Besselink MG,van Santvoort HC,Benes Z,Zazula R, et al. Probiotic treatment with Probioflora in patients with predicted severe acute pancreatitis without organ failure. Pancreatology 12(5): 458-462,2012. PMID: 23127536.
  33. van Baal MC,van Rens MJ,Geven CB,van de Pol FM,van den Brink IW,Hannink G, et al. Association between probiotics and enteral nutrition in an experimental acute pancreatitis model in rats. Pancreatology 14(6): 470-477,2014. PMID: 25458667.
  34. van Minnen LP,Timmerman HM,Lutgendorff F,Verheem A,Harmsen W,Konstantinov SR, et al. Modification of intestinal flora with multispecies probiotics reduces bacterial translocation and improves clinical course in a rat model of acute pancreatitis. Surgery 141(4): 470-480,2007. PMID: 17383524.
  35. van Santvoort HC,Bakker OJ,Bollen TL,Besselink MG,Ahmed Ali U,Schrijver AM, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology 141(4): 1254-1263,2011. PMID: 21741922.
  36. Villatoro E,Bassi C and Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev(4): CD002941,2006. PMID: 17054156.
  37. Villatoro E,Mulla M and Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev(5): CD002941,2010. PMID: 20464721.