In patients with acute alcohol-related pancreatitis, what is the safety and efficacy of prophylactic antibiotics vs placebo?

ReferenceStudy type
Evidence level
Number of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Dellinger EP, Tellado JM, Soto NE et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo- controlled study. Annals of Surgery. 2007; 245(5):674–683.RCT 1++

Multicentre, randomized, double- blind, powered, ITT
N=100Inclusion criteria: male or female patients’ ≥ 18 years of age with a confirmed diagnosis of necrotizing pancreatitis within 120 hours of the onset of symptoms. Patients with ≥ 30% necrosis of the pancreas confirmed by contrast-enhanced CT, if this was not possible then noncontrast scans with extensive or multiple peripancreatic fluid collections and pancreatic oedema (Balthazar grade E) and either CRP >120mg/l or a multiple organ dysfunction score >2.
Exclusion criteria: patients diagnosed with concurrent pancreatic or peripancreatic infection, patients who had received an investigational drug <30 days prior to enrolment, antimicrobial therapy for >48 hrs prior to randomization or who had an allergy to beta-lactam antimicrobial agents. Patients who received or were likely to require probenicid or who had progressing underlying disease, neutropenia, or cirrhosis (Child-Pugh class C) and pregnant or lactating females.

Patient characteristics: Meropenum group: male/female: 32/18; age: 18–64: 34 (68%); 65–74: 9 (18%); >75: 7 (14%); alcohol use: 29 (58%); alcohol aetiology: 18 (36%); % necrosis: <30%: 15 (30%); ≥30%: 26 (52%); Ranson score (mean/median): 4.5/4 (1–8)

Placebo group: male/female: 38/12; age: 18–64: 34 (68%); 65–74: 9(18%); >75: 7 (14%); Alcohol use: 33 (66%); Alcohol aetiology: 26 (52%); % necrosis: <30%: 10 (20%); ≥30%: 31 (62%); Ranson score (mean/median): 3.8/3.8 (0–8)
Meropenum 1g reconstituted in infusion fluid or dose administered over 15–30 minutes every 8 hrs. (recommended 14 days (ranged 7–21))

N=50
Placebo

N=50
At least 35 daysAstraZeneca Pharmaceuticals
Effect
Antibiotics vs placebo
Pancreatic infection
9/50 vs 6/50

Mortality
10/50 vs 9/50

Non-pancreatic infection
16/50 vs 24.50

Surgical intervention
13/50 vs 10/50

Length of stay
Not reported
Isenmann R, Runzi 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.RCT 1++

Multi-centre, double-blind, randomized
N=119 (5 drop outs)

N=114 included in ITT analysis
Inclusion criteria: patients with predicted severe attack of acute pancreatitis; defined as abdominal pain in combination with 3 fold elevation of serum amylase and/or lipase, serum CRP exceeding 150mg/L and/or presence of pancreatic necrosis on contrast-enhanced CT. Upper abdominal pain had to start within 72 hrs of inclusion.

Patient characteristics: Ciprofloxacin/metronidazole group: Male/female: 43/15; age: 47.9 (25.1–72.5); Alcohol aetiology: 32 (55%); Ranson 48h points: 2.5 (0–6)

Placebo group: Male/female: 44/12; age: 45.6 (21.9–78.4); alcohol aetiology: 34 (60%); Ranson 48h points: 2 (0–7)

Necrotizing subgroup: Ciprofloxacin/metronidazole group: Male/female: 31/10; Age: 46.4 (27.5–72.5); alcohol aetiology: 24 (59%); Ranson 48 h points: 3 (0–7)

Placebo: male/female: 25/10; age: 46.5 (21.9–78.4); alcohol aetiology: 20 (57%); Ranson 48 h points: 2 (0–7)
Ciprofloxacin 2 × 400 mg/day iv in combination with metronidazole 2 × 500mg/day iv

N= 58

(n=41 with necrotizing pancreatitis)
Placebo

N=56

(n=35 with necrotizing pancreatitis)
21 daysBayer Vital and Ratiopharm
Effect
Antibiotics vs placebo
Pancreatic infection
7/41 vs 5/35

Mortality
3/41 vs 4/35

Non-pancreatic infection
12/41 vs 12/34

Surgical intervention
7/30 vs 14/30

Length of stay
Not reported
Craig RM, Dordal E, Myles L. Letter: The use of ampicillin in acute pancreatitis. Annals of Internal Medicine. 1975; 83(6):831–832.RCT 1+N=39 (47 episodes)

Blinding unclear
Patients with acute pancreatitis. Diagnosed clinically and with elevated serum amylase

Patient population – Antibiotic: mean age 41 yrs, mean serum amylase 325 U/dl

Placebo: mean age 40 yrs, mean serum amylase 340 U/dl

Alcohol aetiology 43/46 episodes
Antibiotic

1 g every 6 hrs intravenously. When ng tube removed and clear fluids begun 2 × 500 mg every 6hrs to complete a seven day course

N=23 (episodes)

NG suction and i.v fluids until asymptomatic for 48 hrs
Placebo

N=23 (episodes)
Length of hospitalisationLeukocytosis Pain or tenerness
Serum amylase
Fever
Bristol lab.
Syracuse, New York
Effect
Antibiotic
(mean no. of days with findings*)
Placebo
(mean no. of days with findings*)
P value
Leukocytosis (absolute counter greater than 10 000)1.82.30.2
Subjects with 8 or more days findings33
Pain or tenderness3.03.00.5
Subjects with 8 or more days findings12
Elevated serum amylase6.05.00.3
Subjects with 8 or more days findings109
Fever3.03.00.6
Subjects with 8 or more days findings10
Death (no.)00ns
Complications (no.)00ns
Finch WT, Sawyers JL, Schenker S. A prospective study to determine the efficacy of antibiotics in acute pancreatitis. Annals of Surgery. 1976; 183(6):667–671.Double blind Randomised by card 1+N=58Patients with acute pancreatitis. Diagnosed clinically and confirmed by serum amylase value greater than 160 Somogyi units per 100 ml

Exclusion criteria included: Blunt abdominal trauma, previous history compatible with cholelithiasis or choledocholithiasis, medications: steroids, thorazine, thiazole diuretics, parathyroid disease, peptic ulcer, non- pancreas related fever

Patient population – antibiotics: mean age 35 yrs, male:female 19:12, 14/71 black and 17/31 white, febrile on admission 15/31 (48%), average serum amylase 770 Somogyi units, average white blood count 10.4 1000/cc. Aetiology alcohol 22/31

Oral cholecystogram: normal study 8/19, non- visualisation on first dose 1/19, non-visualisation on double dose 6/19, normal on double dose 3/19, stones 1/19

Upper GI series: normal 15/19, C-loop deformity 3/19, retrogastric mass- pseudocyst 1/19

No antibiotics: mean age 37 yrs, male:female 15:12, 17/27 black and 10/27 white, febrile on admission 15/31 (44%), average serum amylase 780 Somogyi units, average white blood count 10.6 1000/cc. Alcohol aetiology 16/27

Oral cholecystogram: normal study 12/20, non- visualisation on first dose 1/20, non-visualisation on double dose 2/20, normal on double dose 3/20, stones 2/20

Upper GI series: normal 13/16, C-loop deformity 3/16, retrogastric mass- pseudocyst 0/16
Antibiotics

N=31

Ampicillin 500 mg every 6 hrs 19/31 1 g every 6 hrs 11/31

(or Keflin 1 g every 6 hrs for 7 days if penicillin sensitivity, 1/31)

Nothing by mouth, NG suction until return of intestinal peristalsis and return of serum amylase to normal, intravenous fluids: maintenance 1500 cc 5% Dextrose with ¼ normal saline per square metre per 24 hr

Replacement: gastric output to be replaced cc per cc with 5% Dextrose with ½ normal saline with supplemental KCL included. Anticholinergics: atropine 0.4 mg i.m every 6 hrs, Meperidine for pain, Librium 25 to 50 mg i.m four times daily, thiamine 100 mg i.m once on admission, no aspirin, Tylenol or other antipyrectics
No antibiotics

N=27
24 mth study periodLength of hospitalisation, serum amylase, afebrile by day, recurrent pancreatitis, complicationsNone reported
Antibiotic N=31No antibiotic N=27P value
Total days hospitalised, mean (range)10.4 (3 to 8)11.3 (3 to 29)ns
Normal Serum Amylase by day (range)5.0 (2 to 11)4.5 (2 to 13)ns
Afebrile by day (range)7.2 (3 to 14)5.7 (1 to 11)ns
Recurrent pancreatitis6 (19.4%)2 (7.4%)P<0.05
Complications
Alcoholic gastritis11ns
Delirium tremens34ns
Pseudocyst10ns
Deaths10ns
Howes R, Zuidema GD, Cameron JL. Evaluation of prophylactic antibiotics in acute pancreatitis. Journal of Surgical Research. 1975; 18(2):197–200.RCT 1+
Odd/even number allocation
N=95Patients with a clinical diagnosis of acute pancreatitis with a serum amylase of 160 Caraway units per 100 ml or greaterAmpicillin
N=44

1 g every 6 hrs for 5 days

Iv and then orally when patient eating

History of penicillin allergy or if one developed then lincomycin 600 mg i.v every 8 hr and then 500 mg orally every 6 hrs for 5 days
N=4

In addition

i.v fluids, nasogastric suction, Demerol administration and intramuscular atropine
No antibiotics

N=47
Length of hospitalisationDeaths, length of hospitalisation, amylase elevation, fever, septic complicationsNone reported
Effect
AntibioticNo antibioticP value
Deaths00ns
Hospitalisation (days)912ns
Amylase elevation (days)22ns
Fever (days)33ns
Septic complications (No. of patients)56ns
Pederzoli P, Bassi C, Vesentini S et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surgery, Gynecology & Obstetrics. 1993; 176(5):480–483.RCT 1+

Randomized multicentre
N=74Inclusion criteria: no previous pancreatic disaease, admission within 48hrs of onset, no clinical evidence of sepsis, no previous antibiotic therapy, availability of contrast CT within 72 hrs of onset and presence of detectable pancreatic necrosis (graded on degree of enhancement- >30%=mildly necrotic; <30 but more than 50%=moderately necrotic; <50% extensively necrotic)

Patient characteristics: Control group: Age (mean): 50; Male/female: 20/13; Alcohol aetiology: 11; Mean Ranson score: 3.6; Necrosis: mild: 20; moderate: 11; severe:2

Treatment group: Age (mean): 54; Male/female: 24/17; Alcohol aetiology: 13; Mean Ranson score: 3.7; Necrosis: mild: 15, moderate: 12; severe 14
Imipenem 0.5 g iv every 8 hrs + standard therapy (see control)- for 14 days

N=41
Control group: standard therapy: NG suction, H2 blockers, antiprotease drugs TPN and analgesics.

N=33
14 days (until discharge)Not reported
Effect
Antibiotics vs placebo
Pancreatic infection
5/41 vs 10/23
Mortality
3/41 vs 4/33
Non-pancreatic infection
6/41 vs 16/33
Surgical intervention
12/41 vs 11/33
Length of stay
Not reported
Sainio V, Kemppainen E, Puolakkainen P et al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet. 1995; 346(8976):663–667. Ref ID: 2564RCT 1+
Numbered envelopes
N=60Patients with severe necrotising alcohol- induced pancreatitis

Inclusion criteria: CRP above 120 mg/L within 48 hrs of admission and low contrast enhancement of the pancreas
Efuroxime 3 doses of 1.5 p i.v

N=30

Continued until clinical recovery and fall to normal CRP concentrations
Control

N=

No antibiotics were given before infection verified or CRP of more than 20% in the acute phase
Mortality
Pancreatic infection
Non-pancreatic infection
Surgical intervention
Length of stay
Until clinical recovery
Antibiotics vs placebo
Pancreatic infection
9/30 vs 12.30

Mortality
1/30 vs 7/30
Non-pancreatic infection
Not reported

Surgical intervention
7/30 vs 14/30

Length of stay
Mean 33.2 (SD22.1) vs 43.8 (43.1)
Schwarz M, Isenmann R, Meyer H et al. Antibiotic use in necrotizing pancreatitis. Results of a controlled study ( English Abstract). Deutsche Medizinische Wochenschrift. 1997; 122(12):356–361. Ref ID: 2565RCT 1+N=26Patients with sever acute pancreatitis and sterile necrosisOxfloxacin 200 mg bd i.v and metronidazole 500 mg bd iv for ten dayControlMortality
Pancreatic infection
Non- pancreatic infection
Surgical infection
10 daysNot reported
Effect
Antibiotics vs placebo
Pancreatic infection
8/13 vs 7/13
Mortality
0/13 vs 2/13
Non-pancreatic infection
4/13 vs 6/13
Surgical infection
Not reported
Length of stay
Not reported
Nordback I, Sand J, Saaristo R et al. Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis--a single-center randomized study. Journal of Gastrointestinal Surgery. 2001; 5(2):113–118. Ref ID: 2566RCT 1−
No details of allocation concealment, randomisation, blinding >50% patients excluded post- randomisation
N=92 (randomised)

N=32 included
Patients with acute pancreatitis based on clinical criteria, raised serum amylase and CT verified pancreatitits.

The diagnosis of necrotising pancreatitis was based on CRP > 150 mg/L during first 48 hrs after admission and necrotic areas in the pancreas on the CT

Patient population: Imipenem male:female 23:2, mean age 47 yrs, alcohol aetiology 20/25, C- reactive protein mean 211, pancreatic necrosis on CT < 30% 8/25
Control: male:female 28:5, mean age 46 yrs, alchol aetiology 25/33, CRP mean 214, pancreatic necrosis on CT < 30% 13/33

There were no significant differences reported at baseline
Imipenem 1.0 g plus cilastatin i.v three times a dayControlMortality
Pancreatic infection
Non- pancreatic infection
Surgical infection
5 days or moreNot reported
Antibiotics vs placebo
Pancreatic infection
1/25 vs 6/33
Mortality
2/25 vs 5/33
Non-pancreatic infection
4/25 vs 1/33
Surgical intervention
2/25 vs 5/33
Length of stay

From: Evidence Tables

Cover of Alcohol Use Disorders
Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet].
NICE Clinical Guidelines, No. 100.
National Clinical Guideline Centre (UK).
Copyright © 2010, National Clinical Guidelines Centre.

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