PATHOGENS

CLINICAL

  • Increased incidence in HIV+ pts[21][27], esp. with older "d-drugs," (ddI[28] and d4T), previous pancreatitis, or CD4 < 200.
  • Less commonly associated with other medications: 3TC (children), ribavirin, IV/aerosolized pentamidine, TMP-SMX, dapsone, INH, rifampin, corticosteroids, erythromycin, valproic acid.
  • Other causes: gallstones (most common cause in general population), alcohol, hypertriglyceridemia (fasting TG >1000 may be assoc. with LPV/r and other PIs), post-ERCP, HIV (acute HIV infection), OIs (CMV, toxoplasmosis, MAC, TB, PCP, cryptosporidiosis), SARS-coronavirus-2[2].
  • Hx: Acute, constant, upper abdominal pain that may radiate to back; nausea +/- vomiting. Presentation varies from no symptoms to shock/coma.
  • PE: Fever, tachycardia, epigastric tenderness. Hemorrhagic discoloration of flanks (Grey-Turner’s sign) or periumbilical area (Cullen’s sign) in ~1% cases.

DIAGNOSIS

  • Elevated lipase (>3x normal) more specific than elevated amylase. Mildly increased lipase also common with asymptomatic HIV[25], renal failure, bowel disease, DKA, macrolipasemia, medications. Lipase remains elevated longer than amylase.
  • Increased amylase nonspecific. Common in asymptomatic HIV infection[25][26] and other conditions: renal insufficiency, intestinal or fallopian tube disease, macroamylasemia, acidosis, various medications. Usually >3x normal in pancreatitis, but may be normal.
  • Contrast-enhanced CT useful to R/O other Dx and to stage severity of pancreatitis. Not indicated for mild disease unless Dx uncertain. For typical presentation, wait 2-3 days after admission when necrosis is best identified by lack of enhancement [6].
  • MRI more sensitive for mild pancreatitis and more specific for categorizing fluid collections as necrosis, abscess, hemorrhage or pseudocyst; but less clinical correlation available with MRI [6].
  • Overall, gallstones are most common cause of pancreatitis. U/S usually obtained initially to look for gallstones and biliary tract dilatation. Consider MRCP or endoscopic U/S if needed to further evaluate the biliary tract. Urgent ERCP (< 24h) indicated if cholangitis suspected (elevated bilirubin and fever). Fluid should be obtained for stain and culture.
  • If infected necrosis suspected, CT- or U/S-guided FNA will reveal pathogen in ~80% of aspirates.

TREATMENT

Initial therapy

  • Stop potentially causative medications.
  • Administer IV fluids. Rates of 200-500 ml/hr often needed in first 12-24 hrs. (Third-spacing common. Vigorous fluid replacement needed initially to avoid hemoconcentration.)
  • Control pain. (Often requires narcotics.)

Antibiotics

  • Infection probably due to translocation of gut flora. Infection rate proportional to extent of necrosis.
  • Infection uncommon in first 2 wks of illness.
  • Well-designed trials have shown no benefit of prophylactic ABx, even for severe pancreatitis[15][14][20][18][1]. Prophylactic ABx may cause superinfection with resistant bacteria and Candida[22][23].
  • Infected necrosis usually presents in 2nd or 3rd wk. Both sterile and infected necrosis cause abd pain, fever, leukocytosis. CT- or U/S-guided aspiration can help guide Tx.
  • GI flora (aerobes and anaerobes) often present in infected necrosis. ABx with good penetration: piperacillin/tazobactam, carbapenems (imipenem, meropenem, ertapenem, doripenem), fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), cefepime, metronidazole, clindamycin, fluconazole.
  • Since infections are often hospital-acquired, consider broad empiric coverage of infected necrosis with piperacillin/tazobactam or a carbapenem alone or a combination of cefepime + metronidazole.[13]
  • Quinolone-resistant E. coli are common; therefore, quinolones should not be used unless culture results are available showing susceptibility[13].
  • Because of increasing resistance the following ABx are not recommended for empiric Tx: ampicillin-sulbactam, cefoxitin, cefotetan[7].
  • Due to increasing resistance, especially of B. fragilis, and increased risk of C. difficile infection, clindamycin is considered inferior to metronidazole for anaerobic coverage[7].
  • If culture results available, tailor Abx accordingly.
  • If OI suspected or Dx’d, see appropriate module for management
  • If extensive resistance is identified, the following may be considered: ceftolozane-tazobactam + metronidazole (especially for resistant pseudomonas); ceftazidime-avibactam + metronidazole (especially for producers of ESBLs, AmpC beta-lactamases, KPC (not MBL)[7].
  • Based on Cx data and the stability of the pt, consider step-down to the following PO/NG/NJ ABx regimens: amoxicillin-clavulanic acid, moxifloxacin, ciprofloxacin + metronidazole, a cephalosporin + metronidazole, trimethoprim-sulfamethoxazole + metronidazole.
  • Length of ABx Tx for complicated intraabdominal infections is generally 4 days after source-control obtained[9]. For infected pancreatic necrosis, drainage is often delayed to allow collections to wall-off; therefore, source-control is often delayed.

Nutritional support

  • Mild pancreatitis: Start a low-fat soft or solid diet as soon as pt can tolerate it [16]. Initial low-fat diet is associated with shorter hospital stays than initial clear-liquid diet.
  • Severe pancreatitis: Offer low-fat oral feeding when symptoms improve, usually by 72 hrs after admission. Only begin enteral nutrition (nasogastric or nasoduodenal) if oral feeding not tolerated by day 5[10][11].
  • For those receiving enteral nutrition, NG feeding is comparable to NJ feeding. [19]
  • Give parenteral nutrition only if adequate enteral feeding not tolerated.

FOLLOW UP

Stage severity

  • Obtain contrast-enhanced CT unless pancreatitis is mild. Necrosis best detected 2-3 days after admission. Necrosis >30% predicts higher mortality.
  • Factors associated with more severe disease: age ≥60 yrs, BMI >30, severe coexisting conditions, and long-term, heavy alcohol use.
  • Mortality highest in those with persistent multi-organ failure and infected necrosis.
  • Early deaths (first 2 wks) primarily due to multisystem organ failure. Late deaths (>2 wks) mainly due to pancreatic or extra-pancreatic infection.

Diagnose and treat complications

  • Gallstone pancreatitis
    • U/S is recommended for initial evaluation of the biliary tract and gallbladder.
    • Urgent ERCP (< 24 h) indicated for cholangitis. (Suspect cholangitis in pts with fever, abdominal pain, and jaundice.)[4][17]
    • For pts without cholangitis but with continued cholestasis, image with MRCP or U/S to look for obstruction and determine need for ERCP.
    • Cholecystectomy should be performed before discharge in mild cases. For cases with fluid collections, cholecystectomy may be delayed until collections have resolved or become walled-off[29].
  • Pancreatic and peripancreatic fluid collections (May develop in first 4 wks.)
    • Edematous (non-necrotic) collections
      • Imaging shows homogenous fluid
      • Usually resolve spontaneously over time
      • If they persist >4 wks, may form walled-off pseudocyst
      • No drainage needed for walled-off sterile collections unless they cause symptoms. Symptoms may results from: (1) obstruction of the gastric outlet, intestines, or biliary tract; (2) persistent pain or unwellness; or (3) a disconnected duct[29].
    • Necrotic collections
      • Imaging shows fluid and necrotic debris
      • If they persist >4 wks, become walled-off necrosis
      • May become infected.
  • Uninfected collections.
    • Manage conservatively unless symptomatic
  • Infected collections
    • Suspect infection if a pt deteriorates, esp after 2 weeks. Image. Gas is seen in ~50% of infected collections.
    • For infected collections a step-up approach is recommended [5].
      • Empiric ABx (see above) for unstable pts.
      • FNA for bacterial and fungal stain and culture. (Positive culture obtained in ~80% of cases.)[3]
      • ABx tailored according to culture results when available
      • Endoscopic transmural drainage or percutaneous drainage as needed[24]. (If pt is stable, drainage may be delayed several wks to allow the collection to wall-off[8].)
      • Minimally invasive debridement only if required.
      • Open necrosectomy should only be performed if above approach fails[12].

OTHER INFORMATION

  • Monitor triglycerides in pts taking PIs.

Basis for recommendation

  1. Dellinger EP, Tellado JM, Soto NE, et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study. Ann Surg. 2007;245(5):674-83.  [PMID:17457158]

    Comment: This is the second randomized, double-blind, placebo-controlled trial of prophylactic antibiotics for severe acute pancreatitis. In this trial 50 patients received meropenem, and 50 received placebo. As in previous blinded, placebo-controlled study, there was no difference in rate of infection or death.

References

  1. Wang K, Luo J, Tan F, et al. Acute Pancreatitis as the Initial Manifestation in 2 Cases of COVID-19 in Wuhan, China. Open Forum Infect Dis. 2020;7(9):ofaa324.  [PMID:32959016]
  2. Wolbrink DRJ, Kolwijck E, Ten Oever J, et al. Management of infected pancreatic necrosis in the intensive care unit: a narrative review. Clin Microbiol Infect. 2020;26(1):18-25.  [PMID:31238118]

    Comment: In the management of pancreatic necrosis, the authors stress the importance of reevaluating the indication for antimicrobial treatment and invasive source control. Invasive diagnostics via fine-needle aspiration (FNA), preferably prior to the start of broad-spectrum antimicrobial therapy, is advocated. Antimicrobial stewardship principles include paying attention to altered pharmacokinetics in the critically ill, de-escalating broad-spectrum therapy once cultures become available, and withdrawing antibiotics once source control has been established. These are important to prevent the development of antimicrobial resistance, especially in patients who may require repeated courses of antibiotics during the prolonged course of their illness

  3. Boxhoorn L, Voermans RP, Bouwense SA, et al. Acute pancreatitis. Lancet. 2020;396(10252):726-734.  [PMID:32891214]

    Comment: This update on the overall management of acute pancreatitis includes a discussion of the timing of drainage of infected necrosis and suggests that waiting for the infection to wall-off may lead to ABx overuse and poorer outcomes. A randomized trial is underway to help answer this question: Postponed or immediate drainage of infected necrotizing pancreatitis (POINTER trial)

  4. Baron TH, DiMaio CJ, Wang AY, et al. American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis. Gastroenterology. 2020;158(1):67-75.e1.  [PMID:31479658]

    Comment: A clinical practice update from the AGA recommends a step-up approach to management of infected pancreatic necrosis. This approach includes percutaneous drainage or endoscopic transmural drainage using either plastic stents and irrigation or self-expanding metal stents/lumen-apposing metal stents alone, followed by direct endoscopic necrosectomy, and then surgical debridement if needed. Approaches should be based on the available clinical expertise.

  5. Expert Panel on Gastrointestinal Imaging, Porter KK, Zaheer A, et al. ACR Appropriateness Criteria® Acute Pancreatitis. J Am Coll Radiol. 2019;16(11S):S316-S330.  [PMID:31685100]
  6. Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect (Larchmt). 2017;18(1):1-76.  [PMID:28085573]

    Comment: These recommendations by the Surgical Infection Society are an update to the SIS/IDSA guidelines in the Solomkin reference, 2010. They caution against the use of ampicillin-sulbactam, cefoxitin, cefotetan, and fluoroquinolones for empiric Tx due to increasing levels of resistance. They mention the use of ceftolozane-tazobactam + metronidazole or ceftazidime-avibactam + metronidazole only when resistant pseudomonas or KPC-producing GNRs respectively are present and not covered by other ABx.

  7. Forsmark CE, Vege SS, Wilcox CM. Acute Pancreatitis. N Engl J Med. 2016;375(20):1972-1981.  [PMID:27959604]

    Comment: This overview includes recommendations for a step-up approach for treating infected necrosis. The authors recommend starting ABx and, if the pt is stable, delaying drainage for several weeks until the necrosis is walled off.

  8. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996-2005.  [PMID:25992746]

    Comment: In this trial (the STOP-IT trial) investigators randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 days. The primary outcome, a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days, was reached in 22% of patients in both groups. For pts with complicated intraabdominal infections, this trial supports stopping ABx 4 days after source control is obtained.

  9. Bakker OJ, van Brunschot S, van Santvoort HC, et al. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med. 2014;371(21):1983-93.  [PMID:25409371]

    Comment: In this trial 208 pts with acute pancreatitis at risk for complications were randomized to early NJ feeding started within 24 hr of randomization or on-demand oral feeding for up to 4 days. There was no difference in the primary endpoint of major infection or death (30% in the early NJ group vs. 27% in the on-demand oral-feeding group). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding. This trial supports offering oral feeding to pts with acute pancreatitis and only starting tube feedings after 4-5 days if the patient is unable to eat at that time.

  10. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108(9):1400-15; 1416.  [PMID:23896955]
  11. Mouli VP, Sreenivas V, Garg PK. Efficacy of conservative treatment, without necrosectomy, for infected pancreatic necrosis: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):333-340.e2.  [PMID:23063972]
  12. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133-64.  [PMID:20034345]

    Comment: These guidelines from the Surgical Infection Society and the Infectious Diseases Society of America recommend empiric coverage for healthcare-associated complicated intra-abdominal infections with one of the following regimens: piperacillin-tazobactam, a carbapenem, cefepime plus metronidazole, or ceftazidime plus metronidazole. Since most infections of pancreatic necrosis occur several weeks after hospitalization, most are considered to be healthcare-associated. MRSA coverage is only recommended if the pt is colonized with MRSA or has increased risks for MRSA infection. Empiric regimens should be tailored as soon as results are obtained from blood cultures or FNA.

  13. Hart PA, Bechtold ML, Marshall JB, et al. Prophylactic antibiotics in necrotizing pancreatitis: a meta-analysis. South Med J. 2008;101(11):1126-31.  [PMID:19088522]

    Comment: A meta-analysis of 7 trials (including 6 of the trials in the Bai meta-analysis) and 429 pts showed no significant difference in the rate of infected necrosis or mortality when pts given prophylactic antibiotics were compared with controls.
    Rating: Important

  14. Bai Y, Gao J, Zou DW, et al. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2008;103(1):104-10.  [PMID:17925000]

    Comment: This meta-analysis of 7 trials involving 467 pts showed no significant difference in rates of infected pancreatic necrosis or mortality among patients who received prophylactic antibiotics vs. controls who did not.

  15. Eckerwall GE, Tingstedt BB, Bergenzaun PE, et al. Immediate oral feeding in patients with mild acute pancreatitis is safe and may accelerate recovery--a randomized clinical study. Clin Nutr. 2007;26(6):758-63.  [PMID:17719703]
  16. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med. 2006;354(20):2142-50.  [PMID:16707751]

    Comment: ERCP with endoscopic sphincterotomy performed by an experienced endoscopist recommended for gallstone pancreatitis with bile-duct obstruction.

  17. Mazaki T, Ishii Y, Takayama T. Meta-analysis of prophylactic antibiotic use in acute necrotizing pancreatitis. Br J Surg. 2006;93(6):674-84.  [PMID:16703633]

    Comment: This meta-analysis, which includes 2 trials published after Golub's 1999 meta-analysis (below), shows no benefit from prophylactic ABx in preventing infected necrosis or death in acute necrotizing pancreatitis.

  18. Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol. 2005;100(2):432-9.  [PMID:15667504]

    Comment: 50 subjects with severe acute pancreatitis randomized to early NG or NJ feeding. No difference in pain pattern, analgesic requirement, or clinical manifestations. 25% died: 5 of 27 fed by NG and 7 of 23 fed by NJ tube.

  19. Isenmann R, Rünzi M, Kron M, et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology. 2004;126(4):997-1004.  [PMID:15057739]

    Comment: Only placebo-controlled, double-blind trial. Pts with necrosis on CT scan or CRP >15 mg/dL randomized to receive ciprofloxacin and metronidazole (N=58) or placebo (N=56). No difference in rate of infected necrosis or mortality.

  20. Gan I, May G, Raboud J, et al. Pancreatitis in HIV infection: predictors of severity. Am J Gastroenterol. 2003;98(6):1278-83.  [PMID:12818269]

    Comment: Retrospective study of 73 HIV+ pts with acute pancreatitis. Mortality and complication rates similar to those of HIV-negative pts, but higher cut-off scores recommended to predict severity in HIV+ pts. APACHE II (>14 points most accurate, >12 more sensitive) was better than Ranson (>4) or Glasgow (>4) for predicting a severe course.

  21. De Waele JJ, Vogelaers D, Blot S, et al. Fungal infections in patients with severe acute pancreatitis and the use of prophylactic therapy. Clin Infect Dis. 2003;37(2):208-13.  [PMID:12856213]

    Comment: In spite of ABx prophylaxis, given to the majority of 106 pts with severe necrotizing pancreatitis, 46 (43%) developed infected necrosis, and 1/3 of these infections were caused by Candida. Early fluconazole treatment tended to reduce rate of fungal infection (16% vs. 58%, p=.13) but not death (28% vs. 32%). This non-randomized study points out the risk of fungal infection in pts receiving prophylactic antibiotics.

  22. Gloor B, Müller CA, Worni M, et al. Pancreatic infection in severe pancreatitis: the role of fungus and multiresistant organisms. Arch Surg. 2001;136(5):592-6.  [PMID:11343553]

    Comment: Among 103 pts with severe necrotizing pancreatitis given prophylactic antibiotics, 33 (32%) developed infected necrosis: 7 had resistant bacteria and 8 fungi. Mortality was higher in those with resistant bacterial infections. This study emphasizes the risk of superinfection with prophylactic antibiotics.

  23. Baril NB, Ralls PW, Wren SM, et al. Does an infected peripancreatic fluid collection or abscess mandate operation? Ann Surg. 2000;231(3):361-7.  [PMID:10714629]

    Comment: 42 of 82 pts with CT-guided aspiration had positive Cx: 6 of 25 treated initially with percutaneous catheter drainage required subsequent surgery; 5 of 11 with primary surgical drainage required additional surgery; 6 were treated with antibiotics alone. Mortality in these 3 groups - 8%, 9%, and 33%. Percutaneous catheter drainage is appropriate initial management for some pts with infected pancreatic fluid.

  24. Argiris A, Mathur-Wagh U, Wilets I, et al. Abnormalities of serum amylase and lipase in HIV-positive patients. Am J Gastroenterol. 1999;94(5):1248-52.  [PMID:10235202]

    Comment: At first visit 31 of 86 (36%) ambulatory, HIV+ pts had elevated amylase or lipase. Over 8 months, 52 (60%) had at least one elevation: 26-amylase, 8-lipase, 18-both. 12 had an increase >2x ULN. Risk factors for elevated enzymes included HBV or HCV infection and previous intravenous TMP-SMX.

  25. Foo Y, Konecny P. Hyperamylasaemia in asymptomatic HIV patients. Ann Clin Biochem. 1997;34 ( Pt 3):259-62.  [PMID:9158822]

    Comment: 39 of 163 (24%) asymptomatic, HIV+ out-pts had elevated amylase levels: 17-salivary, 11-pancreatic, 6-salivary and pancreatic, 5-macroamylase. (Non-pancreatic causes may be detected by amylase fractionation or calculation of the amylase-to-creatinine renal clearance ratio.)

  26. Cappell MS, Marks M. Acute pancreatitis in HIV-seropositive patients: a case control study of 44 patients. Am J Med. 1995;98(3):243-8.  [PMID:7872340]

    Comment: Retrospective study comparing 44 HIV+ and 44 HIV-negative pts with acute pancreatitis. HIV+ pts had more medication-associated pancreatitis and more severe courses. APACHE II (score >9) was better predictor of severe disease than the Ranson scale, which does not include leukopenia or chronic illness.

  27. Martínez E, Milinkovic A, de Lazzari E, et al. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet. 2004;364(9428):65-7.  [PMID:15234858]

    Comment: 10-fold greater risk of pancreatitis with coadministration of TDF and ddI. If TDF and ddI are given together, dose of ddI should be reduced.

  28. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13(4 Suppl 2):e1-15.  [PMID:24054878]

    Comment: These guidelines from the International Association of Pancreatology and the American Pancreatic Association list 38 specific recommendations according to literature reviews. For patients with infected necrotizing pancreatitis, invasive intervention (percutaneous catheter drainage, endoscopic transluminal drainage/ necrosectomy, minimally invasive or open necrosectomy) should be delayed where possible until at least 4 weeks after initial presentation to allow the collection to become ‘walled-off’. (See Boxhoorn above for consideration of immediate drainage once infection is diagnosed.)

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Last updated: December 6, 2020