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You can’t treat pancreatitis without antibiotics by Dr Emma Goeman

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You can’t treat pancreatitis without antibiotics by Dr Emma Goeman

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You can’t treat pancreatitis without antibiotics by Dr Emma Goeman

  1. 1. The role of antibiotics in the management of pancreatitis. Dr Emma Goeman Advanced Trainee in Infectious Diseases (Paediatric) & Microbiology ICPMR, Westmead Hospital CICM ASM, May 2017 emma.goeman@health.nsw.gov.au
  2. 2. Introduction – Acute pancreatitis • Essentially an aseptic process of autolysis • >70-80% caused by gallstones & alcohol • Rare primary infectious causes • Secondary infection / infected pancreatic necrosis thought to be related to translocation & migration from the duodenum via pancreatic duct • Also haematogenous spread
  3. 3. Introduction • 5-10% overall case fatality • Up to 40% mortality from pancreatic necrosis • Mortality rates increase with superimposed infection • SIRS response indistinguishable • Antimicrobial prophylaxis de rigeur 2000s • Concerns about ABX: • Toxicity inc C difficile, microbial resistance (individual and hospital), fungal infection
  4. 4. Introduction • Normal WBC count, CRP, procalcitonin have high negative predictive values for infectious complications • Tissue sampling often needed to “rule in” true infection • Especially if: necrotising disease PLUS persistent organ failure and/or persistent systemic toxicity • Surgical debridement or drainage of infected necrotic material important in management
  5. 5. Other interventions of interest in reducing infective complications • Early enteral feeding • Probiotics • ?increased bowel ischaemia • Selective gut decontamination • Animal data supportive of full gut decontamination • Rectal colonisation > oropharyngeal colonisation predicts pancreatic microbiology • No statistically significant overall mortality reduction in human trials • 1 trial showed narrow mortality benefit when corrected for disease severity but SGD combined with systemic ABx Luiten 1998 Intensive Care Med. 1998 May;24(5):438-45. Sawa J Hepatobiliary Pancreat Surg. 2007;14(5):503-8. Epub 2007 Sep 28. Luiten Ann Surg. 1995 Jul;222(1):57-65.
  6. 6. Microbiology of infected pancreatic necrosis • Gut flora predominates: Enterobacteriaceae, enterococci, streptococci, staphylococci, anaerobes • Danish cohort 78 pts 2005-2011 (Schmidt 2014) underwent transmural drainage and necrosectomy • 45% enterococci • 42% Enterobacteriaceae • 22% fungi • Enterococci & fungi assoc with higher mortality • US data (1990s) • 35% E coli, 24% Klebsiella pneumoniae, 24% Enterococcus sp, 14% Staphylococci, 11% Pseudomonas • Suggested Gram negative predominance in biliary disease & Gram positive in ETOH-associated pancreatitis • Yeast: prevalence varies widely 12-37% Schmidt 2014 Pancreatology. 2014 Nov-Dec;14(6):444-9. doi: 10.1016/j.pan.2014.09.001. Lumsden 1990 Surg Gynecol Obstet. 1990 May;170(5):459-67. Mandell & Bennett Principles and Practice of Infectious Diseases
  7. 7. Antibiotic “prophylaxis” / pre-emptive treatment • Useful in early animal models but conflicting data in human studies • Consider antibiotic penetration • Improved by greater inflammation, reduced by necrosis • Poor: eg aminoglycosides, ampicillin, first gen cephalosporins • Variable (achieves MIC for some relevant organisms): eg cefotaxime, piperacillin • Good (achieves MIC for most relevant organisms): eg quinolones, imipenem, ceftazidime, cefepime, clindamycin, metronidazole, doxycycline, fluconazole Ho Arch Surg. 1997;132:187-192. Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition
  8. 8. Antibiotic “prophylaxis” / pre- emptive treatment • Early single-centre observational studies suggested reduction in rates of infected necrosis • Imipenem appeared to out-perform non-protocol Abx but confounders; microbiology not reported; longitudinal retrospective study design • Four RCTs promising but non-definitive due to issues with study design and sample size • (Luiten 1995, Pederzoll 1993, Salnio 1995, & Delcenserie 1996) • 3/4 reduced “sepsis” rates, 2/4 reduced pancreatic infection, no difference in need for surgery, 1/4 mortality reduction Ho Arch Surg. 1997;132:187-192. Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition
  9. 9. Antibiotic “prophylaxis” / pre-emptive treatment • Issues with more recent RCTs • Need for open label Abx prescribing in control patients • Small numbers of patients with pancreatic necrosis • High rates of CONS ?contamination • 2006 Cochrane review concluded decreased mortality but not infectious pancreatic necrosis Rokke Scand J Gastroenterol. 2007 Jun;42(6):771-6. Dellinger Ann Surg. 2007 May;245(5):674-83. Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition
  10. 10. Antibiotic “prophylaxis” / pre-emptive treatment • Rokke 2007 Norwegian RCT – underpowered, low recruitment • 73 pts randomised to early imipenem vs no Abx • No difference in mortality, LOS, surgery, need for ICU • Imipenem group had lower complication (12 versus 22 patients) (p=0.035) & infection rates • Dellinger 2007 US RCT • 100 pts with severe necrotising pancreatitis randomised to meropenem or placebo • No difference in pancreatic / peripancreatic infections, mortality (20 vs 18%, p=0.799), or need for surgical intervention. Rokke Scand J Gastroenterol. 2007 Jun;42(6):771-6. Dellinger Ann Surg. 2007 May;245(5):674-83. Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition
  11. 11. Antibiotic “prophylaxis” / pre-emptive treatment• Cochrane review 2010, 7 studies, 404 patients • All ABX: • Mortality: 8.4% vs 14.4% controls (NS) • Infected pancreatic necrosis: 19.7% vs 24.4% controls (NS) • Non pancreatic infection rates: 23.7 vs 36% (NS) • Overall infections: 37.5 vs 51.9% (NS) • Beta-lactams: • Mortality: 9.4% vs 15% (NS) • Infected pancreatic necrosis: 16.8% vs 24.2% (NS) • Non-pancreatic infections: 21 vs 32.5% (NS) • Overall infections: 34.4% vs 52.8% (NS) • Imipenem: • Mortality: 9% vs 13.4% • Pancreatic infection: RR 0.34 (95% CI 0.13-0.84) p= 0.02 • Overall infections: 25.6 vs 52.4 Cochrane Database Syst Rev. 2010 May 12;(5):CD002941. doi: 10.1002/14651858.CD002941.pub3.
  12. 12. • 78 trials, 7366 participants • Primary outcome: short term mortality • No evidence of difference with any interventions • 18 antibiotic trials included 2017
  13. 13. Short term mortality ACUTE PANCREATITIS (ALL) ANTIBIOTICS VS CONTROL
  14. 14. Serious adverse events (proportion) ACUTE PANCREATITIS (ALL) ANTIBIOTICS VS CONTROL
  15. 15. Serious adverse events (number)) ACUTE PANCREATITIS (ALL) ANTIBIOTICS VS CONTROL
  16. 16. ANTIBIOTICS VERSUS CONTROL COMPARISON ODDS RATIO CONFIDENCE INTERVAL ORGAN FAILURE 36/133 VS 38/125 0.78 [0.44, 1.38] INFECTED PANCREATIC NECROSIS 47/358 VS 54/356 0.82 [0.53, 1.25] SEPSIS 4/30 VS 8/30 0.42 [0.11, 1.60] TOTAL ADVERSE EVENTS (PROPORTION) 81/212 VS 109/217 0.51 [0.32, 0.80] TOTAL ADVERSE EVENTS (NUMBER) - 0.75 [0.58, 0.95] ACUTE PANCREATITIS (ALL)
  17. 17. ANTIBIOTICS VERSUS CONTROL COMPARISON ODDS RATIO CONFIDENCE INTERVAL SHORT TERM MORTALITY 41/351 VS 45/332 0.82 [0.52, 1.30] SERIOUS ADVERSE EVENTS (PROPORTION) 29/142 VS 31/139 0.84 [0.46, 1.54] SERIOUS ADVERSE EVENTS (NUMBER) - 0.79 [0.59, 1.06] ORGAN FAILURE 32/ 110 VS 33/101 0.78 [0.42, 1.45] INFECTED PANCREATIC NECROSIS 34/213 VS 37/213 0.85 [0.51, 1.42] SEPSIS 4/30 VS 8/30 0.42 [0.11, 1.60] ACUTE NECROTISING PANCREATITIS
  18. 18. ANTIBIOTICS VERSUS CONTROL COMPARISON ODDS RATIO CONFIDENCE INTERVAL SHORT TERM MORTALITY 46/272 vs 54/270 0.82 [0.53, 1.27] SERIOUS ADVERSE EVENTS (PROPORTION) 19/83 vs 26/81 0.56 [0.27, 1.18] SERIOUS ADVERSE EVENTS (NUMBER) - 0.81 [0.52, 1.25] ORGAN FAILURE 20/69 vs 20/68 0.89 [0.40, 1.99] INFECTED PANCREATIC NECROSIS 24/172 vs 30/169 0.73 [0.41, 1.33] SEVERE ACUTE PANCREATITIS
  19. 19. Additional data – what about timing Manes Am J Gastroenterol. 2006 Jun;101(6):1348-53. • Early (day 1) versus late (day 4) meropenem • Pancreatic infection 13.3% vs 31% (NS) • Extra-pancreatic infection 16.6% vs 44.8% (p<0.05) • No mortality benefit
  20. 20. Australian antimicrobial resistance data 2015 (AGAR) – Gram negatives • 7,330 isolates analysed – Enterobacteriaceae, Pseudomonas aeruginosa & Acinetobacter species • Enterobacteriaceae 89.6% • Overall 75% community onset, 25% hospital onset • Hospital onset > community onset: Enterobacter cloacae, Serratia marcescens • Mortality: • 10.6% community-onset • 18.6% hospital-onset • Average length of stay 7d • Principal clinical manifestation (known for 5083 episodes): • Urinary tract infection 43% • Biliary tract infection 16% • Intra-abdominal infection other than biliary tract 10% AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report
  21. 21. Australian antimicrobial resistance data 2015 (AGAR) AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report E. coli K. pneumoniae P. aeruginosa Mortality by antibiotic use – hospital onset sepsis
  22. 22. Australian antimicrobial resistance data 2015 (AGAR) AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report E. cloacae K. oxytoca P. mirabilis Mortality by antibiotic use – hospital onset sepsis
  23. 23. Australian antimicrobial resistance data 2015 (AGAR) – Gram negatives %I/R Ampicillin Amox-clav Pip-tazo E coli 57% 22% 6% K pneumoniae N/A 9% 6% E cloacae complex N/A N/A 20% P. aeruginosa N/A N/A 13% AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report
  24. 24. Australian antimicrobial resistance data 2015 (AGAR) – Gram negatives %I/R Cephazolin Ceftriaxone Meropenem Gentamicin Ciprofloxacin E coli 22% 11 0 8 16 K pneumoniae 11% 6 0.3 5 9 E cloacae complex 97% 26 3 7 7 P. aeruginosa N/A N/A 8 3 9 AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report
  25. 25. Australian antimicrobial resistance data 2015 (AGAR) • Extended spectrum beta-lactamase (ESBL) production: • E. coli 11.5% (majority ST131) • Klebsiella pneumoniae 7.7% • Carbapenemase production (eg. metallo beta lactamase/ MBL) • 0.30% among Enterobacteriaceae & Pseudomonas aeruginosa • Most commonly blaIMP-4 • Plasmid mediated quinolone resistance • E coli 15.8% • Klebsiella pneumoniae 9.1% • Enterobacter cloacae 7.4% AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report
  26. 26. Australian antimicrobial resistance data 2015 (AGAR) - Enterococcus • 1014 isolates / episodes • 50:50 community to hospital onset • Hospital E faecium > E faecalis (72 vs 28%) • Community E faecalis > E faecium (65 vs 35%) • 30 day all cause mortality 20% (E faecium 26%, E faecalis 16%) • VRE faecium mortality 29% vs vancomycin susceptible E faecium 23% (NS) • VRE prevalence • 0.9% E faecalis • 50% E faecium AGAR GROUP, June 2016, Australian Enterococcal Sepsis Outcome Program (AESOP) 2015 Final Report
  27. 27. Clinical bottom line / Conclusions • No significant mortality / adverse event benefit from pre-emptive / prophylactic antibiotics for acute pancreatitis, including severe / necrotic disease • Trends to benefit • Data heterogeneous and variable quality • Predicting infected necrosis is challenging • Circumstantially better data for carbapenems than BLBLIs • Stack up risk factors • Know your local microbial epidemiology • Pursue peripheral and tissue diagnostics • Treat established infected pancreatic necrosis and extrapancreatic infection • Apply the “if it was your mother” test?? • Primum non nocere

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