Download - 2011 - Systematic Review and Meta-Analysis of Antibiotic Prophylaxis in Severe AP

7/25/2019 2011 - Systematic Review and Meta-Analysis of Antibiotic Prophylaxis in Severe AP

1/11

Scandinavian Journal of Gastroenterology, 2011; 46: 261270

REVIEW ARTICLE

Systematic review and meta-analysis of antibiotic prophylaxis in severeacute pancreatitis

MATHIAS WITTAU1, BENJAMIN MAYER2, JAN SCHEELE1, DORIS HENNE-BRUNS1,

E. PATCHEN DELLINGER3 & RAINER ISENMANN4

1Department of General, Visceral and Transplantation Surgery, University Hospital, Ulm, Germany,

2Department of

Biometry, University of Ulm, Ulm, Germany, 3

Department of Surgery, Division of General Surgery, University of

Washington, Seattle, WA, USA, and 4

Department of Visceral Surgery, St. Anna Virngrundklinik, Ellwangen,

Germany

Abstract

Objective.The incidence of acute pancreatitis varies from 5 to 80 per 100,000 throughout the world. The most common

cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or

not prophylactic antibiotic administration could be a benecial approach. In order to provide evidence of the effect of

antibiotic prophylaxis in severe acute pancreatitis (SAP) we performed an updated systematic review and meta-analysis on

this topic.Methods.The review of randomized controlled trials was performed in accordance with the Preferred Reporting

Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We conducted a search of MEDLINE, EMBASE,

and the Cochrane Central Register of Controlled Trials. For assessment of the treatment effects we calculated the risk ratios

(RRs) for dichotomous data of included studies. Results.Fourteen trials were included with a total of 841 patients. The use

of antibiotic prophylaxis was not associated with a statistically signicant reduction in mortality (RR 0.74 [95% CI 0.50

1.07]), in the incidence of infected pancreatic necrosis (RR 0.78 [95% CI 0.601.02]), in the incidence of non-

pancreatic infections (RR 0.70 [95% CI 0.46

1.06]), and in surgical interventions (RR 0.93 [95% CI 0.72

1.20]).Conclusion. In summary, to date there is no evidence that supports the routine use of antibiotic prophylaxis in patients

with SAP.

Key Words: Acute pancreatitis, antibiotic prophylaxis, pancreatitis, prophylactic antibiotics

Introduction

The most common cause of death in patients suffering

from severe acute pancreatitis (SAP) is the infection of

pancreatic necrosis by enteric bacteria with mortality

rates of 30% (range 1462%) [1,2], spurring the

discussion of whether or not prophylactic antibioticadministration could be a benecial approach. Ran-

domized controlled clinical trials (RCTs) on this topic

published in the 1990s have shown lower rates of

infected pancreatic necrosis and reduced mortality

[3,4]. Contrary to this, statistically signicant positive

effects of this prophylaxis could not be conrmed by

three double blind randomized studies, published in

2004, 2007 and 2009 [1,5,6]. Several meta-

analyses on this issue were published since the late

1990s and intended to provide reliable evidence.

However, their results ranged from absolutely no

effect of antibiotic prophylaxis to positive effects

regarding mortality, the incidence of infected pancre-atic necrosis and the incidence of extrapancreatic

infections.

In order to provide reliable evidence of the effect of

antibiotic prophylaxis in SAP, we performed an

updated systematic review and a meta-analysis on

this topic.

Correspondence: Mathias Wittau, MD, Department of General, Visceral and Transplantation Surgery, University Hospital Ulm, Steinhoevelstr. 9, 89075 Ulm,

Germany. Tel: +49 73150053500. Fax: +49 73150053503. E-mail: [email protected]

(Received 13 July 2010; accepted 19 September 2010)

ISSN 0036-5521 print/ISSN 1502-7708 online 2011 Informa Healthcare

DOI: 10.3109/00365521.2010.531486


2/11

Methods

Data sources and study selection

A detailed protocol was developed prior to study

initiation. The review of RCTs was performed in

accordance with the Preferred Reporting Items for

Systematic Reviews and Meta-analysis (PRISMA)

statement [7]. We conducted a search of MEDLINE

(1966 to December 2009), MEDLINE in-process

and other non-indexed citations (December 2009),

EMBASE (1980 to December 2009), and the

Cochrane Central Register of Controlled Trials

(4th Quarter 2009) via PubMed and Ovid interfaces.

The following medical subject heading terms

pancreatitis, antibiotics, and randomized con-

trolled trialand text terms were used with Boolean

operators NOT, AND and OR, as demon-

strated in Appendix A for MEDLINE. Reference listsfrom the trials selected by electronic searching and

conference abstracts from 2005 to 2009 (European

Pancreatic Club, American Pancreatic Association,

International Association of Pancreatology, United

European Gastroenterology Week, and Digestive Dis-

ease Week) were hand searched. Google Scholar was

used to search gray literature sources and Controlled-

trials.com/ClinicalTrials.gov for ongoing registered

clinical trials. Search was performed without language

restrictions non-English/non-German manuscripts

were translated.

Inclusion criteria

. Study design: RCTantibiotic prophylaxis versus

placebo or best supportive care.. Study population: patients with severe acute

pancreatitis. SAP was diagnosed with any of

the following: Ranson score, Acute Physiology

and Chronic Health Evaluation II score, Imrie

score, C-reactive protein levels >120 mg/L,

Balthazar CT grade E [8], Atlanta criteria [9]

or according to the Bangkok Working Party

Report 2002 [10].. Intervention: intravenous prophylactic antibiotic

administration.. Outcome data of mortality and incidence of

infected pancreatic necrosis available.

Data extraction

Data were independently extracted by two reviewers

(M. W. and J. S.). Each article was reviewed to

determine whether it met the predened inclusion

criteria. Reviewers extracted the following data from

each report using a standardized data collection

form: rst author, year of publication, number of

patients in the treatment and control arms, setting

(single-center/multicenter), blinding, name of antibi-

otic, dose and timing of antibiotic administration,

incidence of mortality, incidence of infected pancre-

atic necrosis, incidence of non-pancreatic infections,and need for surgery. Disagreements over values or

analyses were resolved by discussion and arbitration

of a third author (R. I.).

Assessment of internal validity

The internal validity of included RCTs was appraised

by one reviewer and checked by a second using

the criteria of the Cochrane Collaboration (sequence

generation, concealment of allocation, blinding,

incomplete outcome data, and selective outcome

reporting) [11,12].

Data synthesis and analysis

Analyses were performed using the Review Manager

software version 5.0 for Windows

(The Cochrane

Collaboration). For assessment of the treatment

effects, we calculated the risk ratios (RRs) for dichot-

omous data of included studies with their corre-

sponding 95% condence intervals (CIs). To

calculate an overall effect size, we combined the

single RRs with the xed effects MantelHaenszel

method, which assume homogeneity among the

studies [13]. In case of heterogeneity, the random

effects method according to DerSimonian and Laird

was used to calculate the overall effect [14]. The

decision for calculation with the xed or random

effects method was made by the I2 test. An I2 greater

than 50% indicates heterogeneity between the

included studies, and the random effects method

was used for calculation. p 0.05 was considered

statistically signicant. For qualitative evaluation of

publication bias we used funnel plots. The quanti-

tative assessment of the presence of publication bias

was performed with the Egger et al. [15] and

Begg et al. [16] tests. A sensitivity analysis wasconducted for class of antibiotic, risk of bias in the

trials, and blinding.

Results

The process of identifying relevant trials is shown

in Figure 1. A total of 1633 literature records were

retrieved by initial search. After removing duplicates

and articles not related to pancreatitis or antibiotic

prophylaxis or humans, 24 articles were assessed for

262 M. Wittau et al.


3/11

eligibility. Ten articles were judged not eligible: three

early trials including different severities of disease and

ampicillin prophylaxis [1719], one trial on antibiotic

timing [20], and ve trials comparing two or more

different antibiotic drugs or different dosing duration

[2125]. One record was a report of a subgroup

analysis of patients with proven necrosis of two ran-

domized trails [26]. The data of this report were not

included in the analysis. Finally, 14 trials were

included in the qualitative and quantitative analysis

[1,36,27,2835].

Study characteristics

Of the 14 included RCTs (Table I), nine were single-

center and ve mulitcenter trials. Eight trials use a

carbapenem-based prophylaxis, four studies a

quinolone-based prophylaxis imidazole, one trial

used a combination of ceftazidime, amikacin and

imidazole, and one trial used cefuroxime for prophy-

laxis. The 14 RCTs comprised a total of 841 patients

with SAP. Of these, 420 patients were randomized to

the prophylaxis group and 421 to the control group.

Data regarding mortality, incidence of infection of

pancreatic necrosis and non-pancreatic infections and

surgical intervention are summarized in Table I. No

important baseline differences between the treatment

groups were identied.

Study validity

The internal validity of the trials was heterogeneous

(Table II). Three trials were judged having low risk of

bias and 11 trials having high risk of bias. Three

Records identified through databasesearching:

EMBASE (n= 1039)Medline + Medline in process (n= 430)Cochrane Central Register of ControlledTrials (n = 159)

Additional records identifiedthrough other sources

(n = 5)

Records after duplicates removed(n = 1426)

Records screened(n = 1426)

Records excluded(n = 1402)

Articles assessed foreligibility(n = 24)

Studies included inqualitative synthesis

(n = 14)

Studies included inquantitative synthesis

(meta-analysis)(n = 14)

Articles excluded:Antibiotics vs. antibiotics (n = 5)Antibiotic timing (n = 1)RCT with unclear/different severity(n = 3)Subgroup analysis of 2 RCTs (n = 1)

Figure 1. Flow diagram: meta-analysis of RCTs in patients with severe acute pancreatitis.

Evidence of antibiotic prophylaxis in severe acute pancreatitis 263


4/11

TableI.Characteristicsofincludedstudies.

Study

YearB

linded

Antibiotic

type

n

Mortality,

n

Infectednecrosis,

n

Surgery,

n

Non-pancreatic

infections

,n

Setting

Pederzolietal.

[3]

1993N

umber

Imipenem

41

3

5

12

6

single-center

None

33

4

10

11

16

Sainioetal.

[4]

1995N

umber

Cefuroxime

30

1

9

7

NR

single-center

None

30

7

12

14

NR

Delcenserieetal.

[29]

1996N

umber

Ceftazidime+Amikacin

+Metronidazole

11

1

0

0

0

single-center

None

12

3

3

3

4

Schwarzetal.

[30]

1997N

umber

Ooxacin+Metronidazole

13

0

8

NR

4

single-center

None

13

2

7

NR

6

Nordbacketal.

[31]

2001N

umber

Imipenem(primary)

25

2

1

2

NR

single-center

Imipenem(secondary)

33

5

6

5

NR

Spicaketal.

[32]

2002N

umber

Ciprooxacin+Metronidazole

33

5

1

6

NR

multicenter

Ciprooxacin+Metronidazole(ondemand)

30

3

0

7

NR

Spicaketal.

[33]

2003N

umber

Meropenem

20

4

3

4

NR

multicenter

Meropenem(ondemand

)

21

5

6

5

NR

Isenmannetal.

[1]

2004D

ouble-b

linded

Ciprooxacin+Metronidazole

58

3

7

10

13

multicenter

None

56

4

5

6

13

Rkkeetal.

[27]

2007N

umber

Imipenem

36

3

3#

3

3

multicenter

None

37

4

6#

3

12

Dellingeretal.

[5]

2007D

ouble-

blinded

Meropenem

50

10

9

13

16

multicenter

None

50

9

6

10

24

Barredaetal.

[34]

2009N

umber

Imipenem

24

0

3

4

7

single-center

None

34

0

2

2

5

Garcia-Barrasaetal.

[6]

2009D

ouble-

blinded

Ciprooxacin

22

4

8

11

6

single-center

None

19

2

8

8

8

Xueetal.

[35]

2009N

umber

Imipenem

29

3

8

9

NR

single-center

None

27

4

10

9

NR

Yangetal.

[28]

2009N

umber

Imipenem

28

2

6

4

13

single-center

None

26

3

8

5

9

#Dataprovidedbyauthorafterpersonalcommunication(O.

Rkke).



5/11

studies were double-blinded whereas 11 trials were

unblinded.

Evaluation of publication bias

We found no clear evidence of publication bias

(Figure 2). Only the funnel plot of the outcome

parameter mortality did not show absolute symme-

try, suggesting a possibility of publication bias.

The Begg et al. [16] test indicated the pre-

sence of publication bias (p = 0.023) while the Egger

et al. [15] test did not show a publication

bias regarding the outcome parameter mortality

(p = 0.11).

Mortality

There were 841 patients involved in 14 trials

(Figure 3). Ninety-six patients died, 41/420 (9.7%)

in the prophylactic antibiotic group and 55/421 (13%)

in the control group. In the trial of Barreda et al. [34]

no patient died. Therefore, in this trial the RR was not

estimable. The use of antibiotic prophylaxis was not

associated with a statistically signicant reduction in

Table II. Assessment of internal validity.

Study/Author YearAdequate sequencegeneration

Concealedallocation Blinding

Addressing incompleteoutcome data

Free from selectiveoutcome reporting

Pederzoli et al. [3] 1993 Yes Unclear No Yes Yes

Sainio et al. [4] 1995 Unclear Yes No Yes Yes

Delcenserie et al. [29] 1996 Yes Unclear No Unclear Yes

Schwarz et al. [30] 1997 Unclear Unclear No Yes Yes

Nordback et al. [31] 2001 Unclear Unclear No Yes Yes

Spicak et al. [32] 2002 No Unclear No Unclear Yes

Spicak et al. [33] 2003 Unclear Unclear No Unclear Yes

Isenmann et al. [1] 2004 Yes Yes Yes Yes Yes

Rkke et al. [27] 2007 Yes Unclear No Yes Yes

Dellinger et al. [5] 2007 Yes Yes Yes Yes Yes

Barreda et al. [34] 2009 Unclear Unclear No Yes Yes

Garcia-Barrasa et al. [6] 2009 Yes# Yes# Yes Yes Yes

Xue et al. [35] 2009 Yes Unclear No Yes Yes

Yang et al. [28] 2009 Yes Unclear No Yes Yes

#Details provided by author after personal communication (J. Busquets).

0.22

1.5

1

0.5

0SE (log[RR])

0.5 1 2 5

RR

Figure 2. Funnel plot: infected necrosis.



6/11

mortality (xed effect model, pooled RR 0.74 [95%

CI 0.501.07]). There was no heterogeneity between

the trials (p = 0.84; I2 = 0%).

Infected necrosis

Data of the incidence of infected necrosis were avail-

able in all trials (Figure 4). Of 841 patients, 160 devel-

oped infected pancreatic necrosis, 71/420 (17%) in

the prophylactic antibiotic group and 89/421 (21%) in

the control group. The use of antibiotic prophylaxis

was not associated with a statistically signicant

reduction in the incidence of infected pancreatic

necrosis (xed effect model, pooled RR 0.78 [95%

CI 0.601.02]). There was no heterogeneity between

the trials (p = 0.58; I2 = 0%).

Non-pancreatic infection

Nine trials reported data of the incidence of non-

pancreatic infections (Figure 5) [1,3,5,6,2730,34].

A total of 563 patients were included in the analysis.

Study or Subgroup

Barreda et al 09

Delcenserie et al 96

Dellinger et al 07

Garcia-Barrasa 09

Isenmann et al 04Nordback et al 01

Pederzoli et al 93

Rokke et al 07

Sainio et al 95

Schwarz et al 97

Spicak et al 02

Spicak et al 03

Xue et al 09

Yang et al 09

Total (95% Cl)

Total events

Heterogeneity: Chiz= 7.25, df = 12 (p= 0.84); Iz= 0%

Test for overall effect: Z = 1.59 (p= 0.11)

420 421 100.0% 0.74 [0.50, 1.07]

41 55

0

1

10

4

32

3

3

1

0

5

4

3

2

24

11

50

22

5825

41

36

30

13

33

20

29

28

0

3

9

2

45

4

4

7

2

3

5

4

3

34

12

50

19

5633

33

37

30

13

30

21

27

26

Not estimable

0.36 [0.04, 3.00]

1.11 [0.49, 2.50]

1.73 [0.35, 8.41]

0.72 [0.17, 3.09]0.53 [0.11, 2.50]

0.60 [0.15, 2.51]

077 [0.19, 3.20]

0.14 [0.02, 1.09]

0.20 [0.01,3.80]

1.52 [0.40, 5.81]

0.84 [0.26, 2.69]

0.70 [0.17, 2.84]

0.62 [ 0.11, 3.41]

5.2%

16.2%

3.9%

7.3%7.8%

8.0%

7.1%

12.6%

4.5%

5.7%

8.8%

7.5%

5.6%

Prophylaxis Control

Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl

Risk Ratio Risk Ratio

0.2 0.5Favours Experimental Favours Control1 2 5

Figure 3. Forest plot of relative risk; [95% condence intervals]: mortality.

Study or Subgroup

Barreda et al 09Delcenserie et al 96Dellinger et al 07Garcia-Barrasa 09Isenmann et al 04Nordback et al 01Pederzoli et al 93Rokke et al 07

Sainio et al 95Schwarz et al 97Spicak et al 02Spicak et al 03Xue et al 09Yang et al 09

Total (95% Cl)

Total events



420 421 100.0% 0.78 [0.60, 1.02]

71 89

30987153

981386

2411502258254136

301333202928

236856

106

12706

108

3412501956333337

301330212726

2.13 [0.38, 11.76]0.15 [0.01, 2.70]1.50 [0.58, 3.90]0.86 [0.40, 1.85]1.35 [0.46, 4.01]0.22 [0.03, 1.71]0.40 [0.15, 1.06]0.51 [0.14, 1.90]

0.75 [0.37, 1.51]1.14 [0.59, 2.22]

2.74 [0.12, 64.69]0.53 [0.15, 1.82]0.74 [0.35, 1.61]0.70 [0.28, 1.74]

1.8%3.7%6.6%9.4%5.6%5.7%

12.2%6.5%

13.2%7.7%0.6%6.4%

11.4%9.1%

Prophylaxis Control



0.2 0.5

Favours Experimental Favours Control

1 2 5

Figure 4. Forest plot of relative risk; [95% condence intervals]: infected pancreatic necrosis.



7/11

One hundred sixty-ve patients developed non-

pancreatic infections, 68/283 (24%) in the prophy-

lactic antibiotic group and 97/280 (35%) in the

control group. The use of antibiotic prophylaxis

was not associated with a statistically signicant

reduction in the incidence of non-pancreatic infec-

tions (random effect model, pooled RR 0.70 [95% CI

0.461.06]). There was a statistically signicant het-

erogeneity between the trials (p = 0.03; I2 = 53%).

Surgical intervention

Data of the number of surgical interventions were

available in 13 trials (Figure 6) [1,36,2729,3135].

A total of 815 patients were included in the analysis.

One hundred seventy-three patients underwent sur-

gery, 85/407 (21%) in the prophylactic antibiotic

group and 88/408 (21.5%) in the control group.

The use of antibiotic prophylaxis was not associated

with a statistically signicant reduction in surgical

interventions (xed effect model, pooled RR 0.93

[95% CI 0.721.20]). There was no heterogeneity

between the trials (p = 0.67; I2 = 0%).

Sensitivity analysis

In order to determine whether class of antibiotic, risk

of bias in the trials, or blinding had a signicant effect

Study or Subgroup

Barreda et al 09


Dellinger et al 07

Garcia-Barrasa 09

Isenmann et al 04

Nordback et al 01

Pederzoli et al 93

Rokke et al 07

Sainio et al 95

Spicak et al 02

Spicak et al 03

Xue et al 09

Yang et al 09

Total (95% Cl)

Total events



407 408 100.0% 0.93 [0.72, 1.20]

85 88

4

0

13

11

10

2

12

3

7

6

4

9

4

24

11

50

22

58

25

41

36

30

33

20

29

28

2

3

10

8

6

5

11

3

14

7

5

9

5

34

12

50

19

56

33

33

37

30

30

21

27

26

2.83 [0.56, 14.24]

0.15 [0.01, 2.70]

1.30 [0.63, 2.68]

1.19 [0.61, 2.33]

1.61 [0.63, 4.13]

0.53 [0.11, 2.50]

0.88 [0.45, 1.73]

1.03 [0.22, 4.76]

0.50 [0.24, 1.06]

0.78 [0.29, 2.06]

0.84 [0.26, 2.69]

0.93 [0.44, 1.99]

0.74 [0.22, 2.47]

1.8%

3.7%

11.1%

9.6%

6.8%

4.8%

13.6%

3.3%

15.6%

8.2%

5.4%

10.4%

5.8%

Prophylaxis Control



0.2 0.5


1 2 5

Figure 6. Forest plot of relative risk; [95% condence intervals]: surgical intervention.

Study or Subgroup

Barreda et al 09


Dellinger et al 07

Garcia-Barrasa 09

Isenmann et al 04Pederzoli et al 93

Rokke et al 07

Schwarz et al 97

Yang et al 09

Total (95% Cl)

Total events

Heterogeneity: Tauz= 0.20; Chiz= 17.12, df = 8 (p= 0.03); Iz= 53%


283 280 100.0% 0.70 [0.46, 1.06]

68 97

7

0

16

6

136

3

4

13

24

11

50

22

5841

36

13

28

5

4

24

8

1316

12

6

9

34

12

50

19

5633

37

13

26

1.98 [0.71, 5.51]

0.12 [0.01, 2.01]

0.67 [0.41, 1.10]

0.65 [0.27, 1.53]

0.97 [0.49, 1.90]0.30 [0.13, 0.68]

0.26 [0.08, 0.84]

0.67 [0.24, 1.82]

1.34 [0.69, 2.60]

9.7%

2.0%

17.3%

11.6%

14.4%12.2%

8.2%

9.9%

14.6%

Prophylaxis Control

Events Total Events Total Weight M-H, Random, 95% Cl M-H, Random, 95% Cl


0.2 0.5


1 2 5

Figure 5. Forest plot of relative risk; [95% condence intervals]: non-pancreatic infections.



8/11

on strength and direction of results, we performed a

sensitivity analysis.

Carbapenem-based prophylaxis

Eight trials used carbapenem-based prophylaxis

[3,5,27,28,31,3335]. This prophylaxis was not asso-

ciated with a statistically signi

cant reduction in mor-tality (RR 0.80 [95% CI 0.501.27]), the incidence of

infected pancreatic necrosis (RR 0.69 [95% CI 0.48

1.01]), the incidence of non-pancreatic infections

(random RR 0.69 [95% CI 0.351.36]), and in sur-

gical interventions (RR 1.00 [95% CI 0.711.40]).

Risk of bias in the trials and blinding

Three trials were of low risk of bias and double-

blinded [1,5,6]. There was not statistically signicant

reduction in mortality (RR 1.09 [95% CI 0.582.08]),

the incidence of infected pancreatic necrosis (RR 1.18[95% CI 0.702.01]) (Figure 7), the incidence of

non-pancreatic infections (RR 0.75 [95% CI 0.52

1.08]), and in surgical interventions (RR 1.34 [95%

CI 0.862.09]).

Discussion

Antibiotic prophylaxis in SAP is a controversial issue

since nearly two decades. Several randomized trials

focused on this topic with contrary results ranging

from a positive effect on mortality, incidence of

infected necrosis and non-pancreatic infection to

absolute no effect on these outcome parameters. In

order to clarify this important issue we performed an

updated meta-analysis including all 2009 published

RCTs. In patients with SAP antibiotic prophylaxis is

not associated with a statistically signicant decrease

in mortality, the incidence of infected pancreatic

necrosis, the incidence of non-pancreatic infection,or the need for surgery. Further, the sensitivity anal-

yses could not nd any statistically signicant effect

on the direction of results regarding carbapenem-

based antibiotic prophylaxis (six trials with imipenem

and two trials with meropenem), risk of bias in the

trials, or blinding. These ndings are consistent with

those of Jafri et al. [36] for type of antibiotics and

higher-quality studies but, however, in contrast to

those of Villatoro et al. [37] for the parameter infected

pancreatic necrosis with imipenem prophylaxis.

Villatoro et al. found a statistically signicant decrease

of infected pancreatic necrosis with imipenem in an

analysis of three trails whereas in our analysis with

carbapenem prophylaxis no statistically signicant

decrease could be seen, nevertheless with borderline

signicance. Although this meta-analysis indicate a

borderline signicance for the outcome parameter

infected pancreatic necrosis with a pooled RR of 0.78

[95% CI 0.601.02], the likelihood that there was

statistically signicance for the important outcomes

of mortality or surgery was not even borderline

close to signicance, especially in higher-quality

double-blinded trials. Thus, the real effect for the

Study or Subgroup

Barreda et al 09


Dellinger et al 07

Garcia-Barrasa 09

Isenmann et al 04Nordback et al 01

Pederzoli et al 93

Rokke et al 07

Sainio et al 95

Schwarz et al 97

Spicak et al 02

Spicak et al 03

Xue et al 09

Yang et al 09

Total (95% Cl)

Total events



130 125 100.0% 1.18 [0.70, 2.01]

24 19

3

0

9

8

71

5

3

9

8

1

3

8

6

24

11

50

22

5825

41

36

30

13

33

20

29

28

2

3

6

8

56

10

6

12

7

0

6

10

8

34

12

50

19

5633

33

37

30

13

30

21

27

26

2.13 [0.38, 11.76]

0.15 [0.01, 2.70]

1.50 [0.58, 3.90]

0.86 [0.40, 1.85]

1.35 [0.46, 4.01]0.22 [0.03, 1.71]

0.40 [0.15, 1.06]

0.51 [0.14, 1.90]

0.75 [0.37, 1.51]

1.14 [0.59, 2.22]

2.74 [0.12, 64.69]

0.53 [0.15, 1.82]

0.74 [0.35, 1.61]

0.70 [0.28, 1.74]

0.0%

0.0%

30.5%

43.6%

25.9%0.0%

0.0%

0.0%

0.0%

0.0%

0.0%

0.0%

0.0%

0.0%

Prophylaxis Control



0.2 0.5Favours Experimental Favours Control1 2 5

Figure 7. Forest plot of relative risk; [95% condence intervals]: infected pancreatic necrosis trials with low risk of bias.



9/11

patient, dying or needing an operation, never comes

close to signicance.

Further, the relationship between methodological

quality of the trials and the outcome, as described by

de Vries et al. [38] could be conrmed by our sen-

sitivity analysis, i.e. the higher quality trials were thosewith the least potential effect of antibiotic prophylaxis,

indicating less likelihood of missing a real effect.

One possible limitation of this meta-analysis is

pooling data of patients without proven pancreatic

necrosis and patients with proven pancreatic necrosis.

But, even meta-analyses with the inclusion criterion

ceCT-proven necrosis included, at least in parts,

data of patients in which necrosis was not conrmed

by contrast-enhanced computer tomography (ceCT)

[39,36,37,4042]. Just one example, Sainio et al. [4]

stated in the result section of their publication that

. . .Five patients in the antibiotic group and seven in

the non-antibiotic group had plain CT only. . .

, i.e.

only 25 patients in the antibiotic group and 23 patients

in the non-antibiotic group had ceCT-proven necrosis

and not 30 patients per group, included in these meta-

analyses.

For a physician it is important to know whether an

antibiotic prophylaxis is benecial for a patient with

SAP, not only for a patient with ceCT-proven pan-

creatic necrosis. In clinical daily routine, it is often

impossible to perform a ceCT scan, e.g. due to

impaired kidney function.

A second possible limitation could be the timing of

antibiotic prophylaxis. L. Besselink et al. focused in a

cohort study on this topic and found that half of therelevant infections occur in the rst few days of the

disease and that these infections, especially bacterae-

mia, are associated with an increased risk of devel-

oping infected necrosis and death [43]. On the basis

of these ndings, Besselink et al. [43] concluded that

prophylactic strategies should focus on early interven-

tion. However, Manes and colleagues also addressed

this issue in a recent published randomized trial and

found only a statistically signicant decrease of extra-

pancreatic infection with antibiotic prophylaxis at

hospital admission [20]. The analysis of our included

trials showed in most cases imprecise data of timing of

prophylaxis (within 3 days, within 2 days, etc.)

and start of antibiotic prophylaxis ranged in the mean

from 1.5 to 5 days. Thus, a conclusive answer could

not be drawn from these data.

In summary, to date there is no statistically signif-

icant evidence that supports the routine use of anti-

biotic prophylaxis in SAP. However, in case of newly

developed sepsis or SIRS, newly developed failure of

two or more organ systems, proven pancreatic or

extrapancreatic infection, and an increase in serum

C-reactive protein in combination with evidence of

pancreatic or extrapancreatic infection an antibiotic

treatmentshould be considered, as recommended by

Isenmann et al. [1]. Nordback et al. demonstrated

that this on demand treatment might avoid or

postpone surgery [31].

Further, it is possible that a subgroup of patientsprot from an antibiotic prophylaxis, e.g. with large

pancreatic necrosis, but this is not evidence-based till

now. Thus, this issue and the impact of timing of

antibiotic prophylaxis should be the subject of further

well designed RCTs.

Declaration of interest: The authors report no

conicts of interest. The authors alone are responsible

for the content and writing of the paper.

References

[1] Isenmann R, Rnzi M, Kron M, Kahl S, Kraus D,

Jung N, et al. Prophylactic antibiotic treatment in patients

with predicted severe acute pancreatitis a placebo-

controlled, double-blind trial. Gastroenterology 2004;126:

9971004.

[2] Banks PA, Freeman ML. The Practice Parameters Commit-

tee of the American College of Gastroenterology: practice

guidelines in acute pancreatitis. Am J Gastroenterol 2006;

101:2379400.

[3] Pederzoli P, Bassi C, Vesentini S, Campedelli A.

A randomized multicenter clinical trial of antibiotic prophy-

laxis of septic complications in acute necrotizing pancreatitis

with imipenem. Surg Gynecol Obstet 1993;176:4803.

[4] Sainio V, Kemppainen E, Puolakkainen P, Taavitsainen M,

Kivisaari L, Valtonen V, et al. Early antibiotic treatment inacute necrotizing pancreatitis. Lancet 1995;346:6637.

[5] Dellinger EP, Tellado JM, Soto NE, Ashles SW, Barie PS,

Dugernier T, et al. Early antibiotic treatment for severe acute

necrotizing pancreatitis: randomized, double-blind,

placebo-controlled study. Ann Surg 2007;245:67483.

[6] Garcia-Barrasa A, Borobia F, Pallares R, Jorba R, Poves I,

Busquets J, et al. A double-blind, placebo-controlled trial of

ciprooxacin prophylaxis in patients with acute necrotizing

pancreatitis. J Gastrointest Surg 2009;13:76874.

[7] Moher D, Liberati A, Tetzlaff J, Altman DG, The

PRISMA Group (2009). Preferred reporting items for sys-

tematic reviews and meta-analyses: The PRISMA Statement.

Open Med 2009;3(3);123130.

[8] Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute

pancreatitis: value of CT in establishing prognosis. Radiology

1990;174:331

6.

[9] Bradley EL III. A clinically based classication system for

acute pancreatitis. Summary of the International Symposium

on Acute Pancreatitis, Atlanta, Ga, September 11 through

13, 1992. Arch Surg 1993;128:58690.

[10] Toouli J, Brooke-Smith M, Bassi C, Carr-Locke D,

Telford J, Freeny P, et al. Working party of the program

committee of the Bangkok World Congress of Gastroenter-

ology 2002. Guideline for the management of acute pancre-

atitis. J Gastroenterol Hepatol 2002;17(Suppl):s1539.

[11] Higgins JPT, Green S. Cochrane handbook for systematic

reviews of interventions 5.0.1. Chichester: JohnWiley &

Sons; 2008.



10/11

[12] Higgins JPT, Green S. Cochrane handbook for systematic

reviews of interventions 5.0.2 [updated September 2009].

The Cochrane Collaboration; 2008.

[13] Mantel N, Haenszel W. Statistical aspects of the analysis of

data from retrospective studies of disease. J Natl Cancer Inst

1959;22:71948.

[14] DerSimonian R, Laird N. Meta-analysis in clinical trials.

Control Clin Trials 1986;7:177

88.

[15] Egger M, Davey SG, Schneider M, Minder C. Bias in

meta-analysis detected by a simple, graphical test. BMJ

1997;315:62934.

[16] Begg CB, Mazumdar M. Operating characteristics of a rank

correlation test for publication bias. Biometrics 1994;50:

1088101.

[17] Craig RM, Dordal E, Myles L. The use of ampicillin in acute

pancreatitis. Ann Intern Med 1975;83:8312.

[18] Howes R, Zuidema GD, Cameron JL. Evaluation of pro-

phylactic antibiotics in acute pancreatitis. J Surg Res 1975;

18:197200.

[19] Finch WT, Sawyers JL, Schenker S. A prospective study to

determine the efcacy of antibiotics in acute pancreatitis.

Ann Surg 1976;183:66771.

[20] Manes G, Uomo I, Menchise A, Rabitti PG, Ferrara EC,Uomo Gl. Timing of antibiotic prophylaxis in acute pancre-

atitis. A controlled randomized study with meropenem. Am J

Gastroenterol 2006;101:134853.

[ 21] Manes G , Rabitti PG , Menchise A, R icco E,

Balzano A Uomo G. Prophylaxis with meropenem of septic

complications in acute pancreatitis: a randomized, controlled

trial versus imipenem. Pancreas 2003;27;7983.

[22] Maravi-Poma E, Gener J, Alvarez-Loma F, Olaechea P,

Blanco A, Dominguez-Munoz JE. Early antibiotic treatment

(prophylaxis) of septic complications in severe acute necro-

tizing pancreatitis: a prospective, randomized, multicenter

study comparing two regimes with imipenem-cilastatin.

Intensive Care Med 2003;29:197480.

[23] Bassi C, Falconi M, Talamini G, Uomo G, Papaccio G,

Dervenis C, et al. Controlled clinical trial of peoxacin versusimipenem in severe acute pancreatitis. Gastroenterology

1998;115:151317.

[24] Swidnicka-Siergiejko A, Wereszczyska-Siemiatkowska U,

Daabrowski A. The efcacy of different modes of anti-

biotic prophylaxis in the prevention of complications in

severe acute pancreatitis. Gastroenterologia Polska 2007;

14:17983.

[25] Grezebieniak Z, Rudnicki J, Skalski A. Evaluation of selected

antibiotics in the treatment of acute pancreatitis. Adv Clin

Exp Med 2003;12:42333.

[26] Spicak J, Hejtmankova S, Cech P, Hoskovec D, Kostka R,

Lefer J, et al. Antibiotic prophylaxis in large pancreatic

necrosis: multicenter randomized trial with ciprooxacin

and metronidazole or meropenem. Gastroenterology 2004;

126:A-229.

[27] Rkke 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 2007;42:7716.

[28] Yang X, Deng LH, Xue P, Zhao L, Jin T, Wan M, et al.

Non-preventive use of antibiotics in patients with severe

acute pancreatitis treated with integrated traditional Chinese

and Western medicine therapy: a randomized controlled

trial. J Chin Interg Med 2009;7:3303.

[29] Delcenserie R, Yzet T, Duccroix JP. Prophylactic antibiotics

in treatment of severe acute alcoholic pancreatitis. Pancreas

1996;13:198201.

[30] Schwarz M, Isenmann R, Meyer H, Beger HG. Antibiotika

bei nekrotisierender Pankreatitis. Ergebnisse einer kontrol-

lierten Studie. Dtsch Med Wochenschr 1997;122:35661.

[31] Nordback I, Sand J, Saaristo R, Paajanen H. Early treatment

with antibiotics reduces the need for surgery in acute nec-

rotizing pancreatitisa single-center randomized study.

J Gastrointest Surg 2001;5:11318.

[32] Spicak J, Hubaczova M, Antos F, Bartova J, Cech P,

Kasalicky M, et al. Antibiotics in the treatment of acute

pancreatitis-ndings from a randomized multi-center pro-

spective study. Ces Slov Gastroent Hepatol 2002;56:1839.

[33] Spicak J, Hejtmankova S, Hubaczova M, Antos F, Bartova J,

Cech P, et al. Antibiotic prophylaxis of infectious complica-

tions of acute pancreatitis-the results of a randomised study

by meropenem. Ces Slov Gastroent Hepatol 2003;57:2227.

[34] Barreda L, Targarono J, Milian W, Portugal J, Sequeiros J,

Pando E, et al. Is the prophylactic therapy with imipenemeffective for patients with pancreatic necrosis? Acta Gastro-

enterol Latinoam 2009;39:249.

[35] Xue P, Deng LH, Zhang ZD, Yang XN, Wan MH,

Song B, et al. Effect of antibiotic prophylaxis on acute

necrotizing pancreatitis: results of a randomized controlled

trial. J Gastroenterol Hepatol 2009;24:73642.

[36] Jafri NS, Mahid SS, Idstein SR, Hornung CA, Galandiuk S.

Antibiotic prophylaxis is not preventive in severe acute pan-

creatitis: a systematic review and meta-analysis. Am J Surg

2009;197:80613.

[37] Villatoro E, Mulla M, Larvin M. Antibiotic therapy for

prophylaxis against infection of pancreatic necrosis in acute

pancreatitis. Cochrane Database Syst Rev 2010:CD002941.

[38] de Vries A, Besselink MG, Buskens E, Ridwan B,

Schipper M, van Erpecum KJ, et al. Randomised controlledtrials of antibiotic prophylaxis in severe acute pancreatitis:

relationship between methodological quality and outcome.

Pancreatology 2007;7:5318.

[39] Mazaki T, Ishii Y, Takayama T. Meta-analysis of prophy-

lactic antibiotic use in acute necrotizing pancreatitis. Br J

Surg 2006;93:67484.

[40] Villatoro E, Bassi C, Larvin M. Antibiotic therapy for pro-

phylaxis against infection of pancreatic necrosis in acute

pancreatitis. Cochrane Database Syst Rev 2006:CD002941.

[41] Bai Y, Gao J, Zou DW, Li Z. 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;

103:104110.

[42] Heinrich S, Schafer M, Rousson V, Clavien PA. Evidence-

based treatment of acute pancreatitis: a look at established

paradigms. Ann Surg 2006;243:15468.

[43] Besselink MG, van Santvoort HC, Boermeester MA,

Nieuwenhuijs VB, van Goor H, Dejong CHC, et al. Timing

and impact of infections in acute pancreatitis. Br J Surg 2009;

96:26773.

Supplementary material available online

Appendix A.



11/11

Copyright of Scandinavian Journal of Gastroenterology is the property of Taylor & Francis Ltd and its content

may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express

written permission. However, users may print, download, or email articles for individual use.

Download - 2011 - Systematic Review and Meta-Analysis of Antibiotic Prophylaxis in Severe AP

Top Related