Antibiotic Therapy for Prophylaxis of Infection in Severe Pancreatitis is Overrated. Jessica Yu, R2 10/26/09

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1 Antibiotic Therapy for Prophylaxis of Infection in Severe Pancreatitis is Overrated Jessica Yu, R2 10/26/09

2 Of 12 with pancreatitis 15% will get necrosis Of these, 40-70% progress to infection week 2-3

3 pathophysiology Insult to the pancreas induces abnormal colocalization of zymogen granules + lysozymes intracellular trypsin activation autodigestion SIRS/Sepsis, MOSF, Infection: E coli, Klebsiella, Enterobacter, Proteus, Pseudomonas, Bacteroides, Clostridium, Enterococci, Candida, gram positives

4 diagnosis Symptoms: Epigastric pain, nausea, vomiting Elevated enzymes: Amylase/lipase 3 x normal is 100% specific Severe: Ransons > 3, CRP > 150, APACHEII > 8, MOD score > 2 Necrosis: nonenhancement on CT scan Infection: pancreatic emphysema on imaging, FNA positive GS or culture treatment Resuscitation and supportive measures Nutrition TPN vs. EN. No PO FNA if OSF, no clinical improvement, or pancreatic emphysema on CT Antibiotics SIRS/Sepsis vs. Prophylaxis Necrosectomy surgical debridement of infected pancreas Postop debridement open packing, postoperative lavage, closure with drains alone

5 mortality acute pancreatitis: 5-10% infected pancreatic necrosis: up to 40%

6 Does routine antibiotic prophylaxis have a role in predictably reducing infection or mortality in SAP?

7 1974 Ranson s Criteria published 1975 Craig et al, Finch et al. antibiotic prophylaxis confers no benefit 1979 Kivisaari et al. role of CT scan in diagnosis Late 1980s pancreatic tissue concentration of bactericidal antibiotics carbapenems, FQ, flagyl 1993 Pederzoli et al. Imipenem vs. Control 1990s- present hundreds of publications regarding role of antibiotic prophylaxis, 12 RCTs (tx v. P), 2 Cochrane reviews in 3 years, multiple meta-analyses

8 Trial type N Antibiotic Infection Mortality Pederzoli et al RCT 75 IMI / placebo Sig 15% v. 49% NS Sainio et al RCT 60 Cefurox / placebo NS 30% v. 40% Sig 3% v 23% Luiten et al MC, RCT PO colistin, ampho, norflox and IV cefotax Sig NS Bassi et al Manes et al RCT 60 Peflox / IMI P= % v. 10% (P) 44% v. 20% (O) RCT 176 MERO / IMI NS 11% v. 14% (P) 22% v. 24% (O) NS 17% v. 10% NS Isenmann et al DB, MC, RCT 114 Cipro, Flagyl v. Placebo NS 12% v 9% NS 5% v. 7% Dellinger et al DB, MC, RCT 100 Mero / Placebo NS 18% vs. 12% NS 20% v 18%

9 Why antibiotic prophylaxis is overrated and tx on demand is the way to go

10 Dellinger et al. Ann Surg 2007 International, Multicenter, Double-blind, RCT Meropenem vs. Placebo in necrotizing pancreatitis N = 100 (50 meropenem, 50 placebo) 54yo, > 50% with > 30% necrosis, 80% ETOH or biliary Contrast CT or non-contrast CT + CRP > 120 or MOD > 2 Nutrition: 19% TPN, 42% enteral, 27% both Average treatment: 10d, stopped for infection requiring nonstudy abx, operation, death, or clinical improvement 42 day followup Everyone remained blinded to tx and results until study completion

11 Prophylaxis and Treatment on Demand are Equivalent Dellinger et al Meropenem Placebo P value % Pancreatic infection , NS Mortality rate , NS Mean # days to pancreatic infection % requiring intervention , NS % operations ctx Other infections (bacteremia, PNA, SSI, UTI) < 0.2, NS

12 Cochrane Review 2006, Antibiotic therapy vs. Placebo Reverse their previous 2003 conclusion that prophylaxis improves mortality and decrease pancreatic infection. Mortality benefit only. 5 studies N=294 (150 therapy, 144 control) Imipenem, Cefuroxime Ofloxacin/Flagyl, Ciprofloxacin/Flagyl RESULTS Pancreatic infection: 20% v. 27%, ns No difference in number of operations Fungal infection: 4% v. 4.99%, ns Mortality: 6% v. 15.3% Beta lactam and mortality: 6.3% v. 16.7% Beta lactam and infected necrosis: 15.6% v. 29% POINTS 1 double blind, placebo-controlled RCT with cipro/flagyl, Dellinger et al not included Mortality only reaches significance with Sainio study

13 Sainio et al, Gastroenterology 1995 Single Center, RCT ( ) Cefuroxime 4.5g/day vs. Control (tx on demand) until clinical recovery N=60 (30 cefurox, 30 control) All ETOH CRP > 140, CT confirmed necrosis Nutrition: not mentioned RESULTS Pancreatic infection: 30% v. 40%, ns Blood ctx + sepsis: 13% vs. 27% Mortality: 3% (1 death) vs. 23% (7 death), p =.028 POINTS Fraught with catheter related infections: Staph epidermidis in pancreas or cath tip in 14 of 18 patients with sepsis Early deaths: 2 of 7 deaths in control group were on days 2 and 4 unlikely secondary to infected pancreatic necrosis Difference in operative management?

14 Given that prophylaxis and treatment on demand are equivalent regarding pancreatic infection and mortality which one will you choose?

15 Consequences of antibiotic use Adverse effects of antibiotics Leukopenia, thrombocytopenia, anemia, diarrhea, myoglobinuria, renal failure Resistance Ciprofloxacin resistance in 18 of 23 (78%) isolates v. 6 of 28 (21%), Isenmann 2004 comparing cipro/flagyl vs. placebo Imipenem resistance in 42-46% of isolates, Maravi-Poma 2003 comparing 14d vs. longer tx Resistance in 52% infected panc necrosis tx with antibiotics, AB-R infections associated with longer ICU stay 53d vs. 31d (p = 0.02), De Waele 2004 In VAP/Bacteremia associated with LOS, Cost, Mortality Ultimately affects flora of all hospitalized patients

16 Critical care improvements Decreased pancreatic infection since 1980s. Pederzoli control group had 50%, Sainio 40%, compared to < 20% in more recent studies. TPN in 100% 19% Cost Imipenem 500mg tid - $120/day, $1700 for 2wks Meropenem 1g tid - $228/day, $3200 for 2wks

17 Consider each patient individually, but in general The benefit of prophylaxis is not reproducible in DB, PC, RCTs The only 2 DB, PC, RCTs support the equivalence of treatment on demand and prophylaxis If prophylaxis versus on demand use are equivalent then consider Adverse effects of antibiotics, Increased risk of antibiotic resistance Cost Cochrane Review and Dr. Bassi are back tracking

18 References Balthazar EJ. Complications of acute pancreatitis: clinical and CT evaluation. Rad Clin N Am. 2002;40:1211 Bassi C et al. Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology. 1998;115: Bradley EL, A clinically based classification system for acute pancreatitis. Summary of the ISAP, Atlanta, Arch Surg 1993;128(5): Cameron JL, ed. Current Surgical Therapy, 9th ed Dellinger EP et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: randomized, double-blind, placebo-controlled study. Ann Surg. 2007;245(5): Dervenis C et al. Diagnosis, objective assessment of severity, and management of acute pancreatitis. Santorini. Int J Pancreatol. 1999;25(3): Howard TJ and Temple MB. Prophylactic antibiotics alter the bacteriology of infected necrosis in severe acute pancreatitis. J Am Coll Surg. 2002;195(6): Isenman R et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: placebo-controlled double blind trial. Gastroent. 2004;126: Manes G et al. Prophylaxis with meropenem of septic complications in acute pancreatitis: randomized controlled trial versus imipenem. Pancreas. 2003;27(4):e79-83 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-cilastin. Int Care Med. 2003;29: 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 Schwartz s Principles of Surgery, 8th ed Sharma et al. Prophylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis: meta-analysis. 2001;22:28-31 Sainio V et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet 1995;346:663-7 Vege SS et al. Outcomes of intraabdominal fungal vs. bacterial infections in severe acute pancreatitis. Am J Gastroenterol. 2009;104(8) Villatoro E et al. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev CD Waele JJD et al. Emergence of antibiotic resistance in infected pancreatic necrosis. Arch Surg 2004;139:

19 Dellinger 2007