doi:10.1111/j.1440-1746.2008.05758.

G A S T R O E N T E R O L O G Y jgh_5758 736..742

Effect of antibiotic prophylaxis on acute necrotizing

pancreatitis: Results of a randomized controlled trial
Ping Xue,* Li-Hui Deng,* Zhao-Da Zhang,† Xiao-Nan Yang,* Mei-Hua Wan,* Bing Song‡ and Qing Xia*
Departments of *Integrated Traditional Chinese and Western Medicine, †General Surgery and ‡Radiology, West China Hospital, Sichuan University,
Chengdu, Sichuan Province, China

Key words Abstract

acute necrotizing, antibiotic prophylaxis,
infection, randomized controlled trial,
pancreatitis.
Accepted for publication 17 November 2008.
Correspondence
Professor Qing Xia, Department of Integrated
Traditional Chinese and Western Medicine,
West China Hospital, Sichuan University,
Chengdu 610041, Sichuan Province, China.
Email: xiaqing@medmail.com.cn
Author’s contributions: Xue P, Zhang ZD,
Yang XN and Xia Q designed the trial; Xue P,
Deng LH, Wan MH and Song B performed
the trial; Yang XN and Xia Q monitored the
trial; Xue P and Deng LH collected and
analyzed the data; Zhang ZD and Xia Q
contributed to interpretation of the data; and
Xue P, Deng LH and Xia Q wrote the paper.
Background and Aims: This study addresses whether antibiotic prophylaxis is beneficial
for acute necrotizing pancreatitis.
Methods: This randomized, controlled trial enrolled 276 patients with severe acute pan-
creatitis. There were 56 patients with 30% or more necrosis proved by contrast-enhanced
computerized tomography who were eligible for randomization: 29 in the study group and
27 in the control group, who received i.v. imipenem–cilastatin (3 ¥ 500 mg/day) within
72 h of the onset of symptoms for 7–14 days, and no antibiotic prophylaxis, respectively.
The primary end-point was the incidence of infectious complication. The secondary end-
points were mortality, the incidence of necrosectomy for infected necrosis, the incidence of
organ complication and hospital courses.
Results: Characteristics of baseline data were similar in the two groups. No significant
differences were found in the incidence of infected pancreatic necrosis (37% vs 27.6%),
mortality (10.3% vs 14.8%) and the incidence of operative necrosectomy (29.6% vs 34.6%)
between the study group and the control group (P > 0.05). The incidence of extrapancreatic
infections, organ complications and hospital courses between the groups were also not
significantly different. However, a significantly increased incidence of fungal infection was
observed in the study group versus the control group (36.1% vs 14.2%, P < 0.05).
Conclusion: There was no benefit in the outcomes when antibiotic prophylaxis was
routinely used in patients with acute necrotizing pancreatitis.

Because of the inconclusive and inadequate evidence for the

Introduction
Acute necrotizing pancreatitis (ANP) continues to be a formidable
clinical problem, with a total mortality of 12–35% in patients with
acute pancreatitis (AP).1,2 Approximately 40–75% of patients with
pancreatic necrosis begin to develop complications related to
infection, 24% after the first week and 71% after the third week of
the illness.3,4 These complications due to infection are responsible
for up to 80% of the deaths in patients with AP.5–8
Antibiotic prophylaxis may possibly reduce the incidence of
infection, decrease mortality in pancreatitis patients, and even
improve the outcome of this disease. Randomized clinical studies
involving antibiotics during the past decade have not demonstrated
consistent results. Some studies have demonstrated the benefits of
prophylactic antibiotics in ANP,1,2,9 and consequently suggest that
patients with more than 30% proven pancreatic necrosis should
routinely receive prophylactic antibiotics10 such as imipenem or
meropenem.11 Others, however, show that prophylactic antibiotics
cannot reduce the morbidity of pancreatic or peripancreatic infec-
tion, and do not support early prophylactic antimicrobial
therapy.12,13
routine use of antibiotic prophylaxis, the present study aims to
investigate the effect of prophylactic antibiotics on the outcomes
of ANP.
Methods
Outcome measurements
The primary end-point is the incidence of infectious complication
during the hospital stay for severe acute pancreatitis (SAP). The
secondary end-points are mortality, the incidence of necrosectomy
for necrotic infection, major organ complication, use of a respira-
tor, duration of central venous catheterization and length of hos-
pital stay.
Selection of patients
This randomized controlled trial was conducted at West China
Hospital of Sichuan University (one of the largest treatment
centers for SAP in China). From January–December 2007,

736 Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors
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P Xue et al.
hospitalized male and female patients (ⱖ 18 years of age) with a
confirmed diagnosis of SAP were enrolled. The diagnostic criteria
formulated for SAP at the 2002 Bangkok World Congress of Gas-
troenterology in Thailand were adopted.14 Patients with 30% or
more necrosis of the pancreas, as proven by contrast-enhanced
computerized tomography (CECT), were eligible for inclusion
into the study. Patients were included within 72 h after the onset of
the symptoms.
Exclusion criteria were: (i) concurrent sepsis or (peri)pancreatic
infection caused by a second disease; (ii) direct transfer to the
intensive care unit due to multiple organ failure; (iii) recurrent or
endoscopic retrograde cholangiopancreatography (ERCP), or trau-
matic or operative pancreatitis; (iv) pregnancy, malignancy or
immunodeficiency; (v) a history of allergy to imipenem–cilastatin;
(vi) a history of antibiotic administration within 48 h prior to
enrollment; and (vii) possible death within 48 h after enrollment.
Patients who had been enrolled in the trial were withdrawn if
they died, received surgery because of a lack of response to inten-
sive care treatment within 72 h after admission, or had serious
adverse effects after administration of imipenem–cilastatin.
Study design
After informed consent had been given, the patients eligible were
randomized either to the study group or the control group using a
computer-derived random number sequence in a ratio of 1:1.
Within 72 h of the onset of symptoms, the patients in the study
group were given a dose of 500 mg imipenem–cilastatin (a ratio of
1:1) every 8 h by 30-min i.v. drip; the control group did not receive
any antibiotics. All 500 mg doses of imipenem–cilastatin powder
were diluted in 100 mL normal saline solution.
Study medication was planned to be given for 7–14 days.
During this period, the use of non-study antibiotics in the study
group or any antibiotics in the control group was not encouraged
until progressive pancreatitis was manifested by clinical deterio-
ration, and/or infection was microbiologically verified or strongly
suspected, or after an initial severe inflammatory response syn-
drome, a secondary rise in serum C-reactive protein (CRP) was
measured. Beyond that time, study medication was discontinued if
there was no evidence of infection proved by bacteriological test.
In patients who were switched to open antibiotic treatment, the
choice of antibiotic regime was at the investigator’s discretion, and
the recommendation of the study protocol was to use imipenem,
possibly in combination with vancomycin. If the presence of bac-
teria was confirmed, appropriate antibiotic therapy was guided by
the results of drug sensitivity testing.
Clinical treatment and parameters
measurement
During the hospital stay, all patients received daily intensive care
which consisted of monitoring of temperature, oxygen saturation,
central venous pressure via central venous catheter (CVC), liquid
intake and output, and were given supportive care and nutritive
administration.
Prior to randomization, CRP, Ranson’s score, Acute Physiology
and Chronic Heath Evaluation II (APACHE II) score and CECT
scan were assessed for disease severity according to the measure-
ments taken within 48 h of admission. Routine hematology,
Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Antibiotic prophylaxis in ANP
biochemical evaluations and CRP were followed up on the third,
seventh, 10th, 14th, 21st and 28th day, the day of discharge and
when clinically indicated.
Bacteriological testing in tissue or body fluid samples from the
suspect organ and a further CECT were performed when the fol-
lowing clinical signs of infection appeared: after the initial fluc-
tuation, a second continuous increase in temperature of 38.5°C or
more, white blood cell count of 20 ¥ 109 /L or more, or CRP of
30% or more was observed, or the patient showed signs of clinical
deterioration. Drug susceptibility tests were performed on original
isolates. Patients with a sign of ‘air bubbles’ in necrotic tissues as
shown by CECT underwent image-guided fine needle aspiration
(FNA) to confirm necrotic infection.
Operative necrosectomy was indicated if there were clinical
signs of infection with other infections ruled out, or if there were
positive isolates in pancreatic necrosis obtained by FNA.
Monitoring and follow up
Follow-up evaluations and procedures were performed for at least
1 month after hospital admission. Adverse events and clinical
laboratory values were monitored and recorded during the course
of the study. A data safety monitor reviewed all serious adverse
events, and all deaths, with particular attention paid to all non-
pancreatic infections and any deaths not attributed to pancreatitis.
A process was provided to notify the principal investigators if any
concerning trends were identified.
Ethics and informed consent
This study was conducted in accordance with the Declaration of
Helsinki (as revised in Edinburgh, 2000) and applicable regulatory
requirements. The protocol of this study was approved by the
medical ethics committee of West China Hospital of Sichuan Uni-
versity. The purpose and method of the trial, the expected effects
and risks, and other details were fully explained to the subjects.
Informed consent was obtained from all patients, either orally or
written, prior to the beginning of enrollment.
Statistical analysis
Non-stratified randomization numbers with a ratio of 1:1 were
generated by SAS software (SAS Institute, Cary, NC, USA). All
data were checked at the end of the study. The Fisher’s exact test,
unpaired Student’s t-test and c2-test were used to compare differ-
ences in baseline characteristics, the incidence of infectious com-
plications, mortality, the incidence of operative necrosectomy,
hospital courses and the level of serum CRP between the two
groups. P < 0.05 was considered statistically significant. Informal
descriptive analysis was used to summarize the spectrum of iso-
lates from the infected organs.
Results
A total of 1128 patients with AP were initially screened for entry
into the study. A total of 276 patients with SAP met the inclusion
criteria, in which 217 patients were excluded from the study. Of 59
patients who were enrolled into the study, 30 were randomized to
737
Antibiotic prophylaxis in ANP P Xue et al.

the study group and 29 to the control group. One death within 72 h
of admission were withdrawn from the study group; two were
withdrawn from the control group because one died within 24 h of
admission and one was transferred to operation due to disease
progression within 72 h of admission. None of the patients were
withdrawn due to loss of follow up or lack of severe adverse
events. Finally, 29 patients were eligible for analysis in the study
group, and 27 in the control group (Fig. 1).
The demographics and baseline clinical characteristics of the
patients are summarized in Table 1. The two groups had simi-
lar sex distributions. The age of the patients (mean ⫾ standard
deviation [SD]) was 48.4 ⫾ 15.1 years in the study group
and 47.5 ⫾ 12.3 years in the control group. Ranson’s scores
(mean ⫾ SD) in the study and control group were 4.8 ⫾ 1.5 and
5.3 ⫾ 1.7, respectively. APACHE II scores (mean ⫾ SD) evalu-
ated within 24 h of admission were 12.7 ⫾ 2.1 and 11.9 ⫾ 3.7 in

AP
Initial screen
(n = 1128)
•MAP
Failed initial screen
(n = 852)
SAP enrolled
(n = 276)
•Excluded (n = 217)
– Not meeting inclusion criteria
(n = 200)
– Refused to participate (n = 11)
– Other reasons (n = 6)
ANP to be randomized
(n = 59)

• Allocated to imipenem-cilastation • Allocated to imipenem-cilastatin non-

prophylaxis (n = 30) prophylaxis (n = 29)
• Withdrew within 72 hours of admission • Withdrew within 72 hours of admission
(n = 1) (n = 2)
– 1 died – 1 died and 1 transferred to operation due
to disease progression

Final analysis Final analysis

(n = 29) (n = 27)

Figure 1 Flowchart of enrolled and randomized patients. ANP: acute necrotizing pancreatitis; AP, acute pancreatitis; MAP, mild acute pancreatitis;
SAP, severe acute pancreatitis.

738 Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors
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P Xue et al. Antibiotic prophylaxis in ANP

the study and control group, respectively. Biliary origin was the ferent between the two groups (Table 1). In 65.6% (19/29) of the
most common etiology, followed by idiopathic, alcoholic and study group, 30–50% necrosis of (peri)pancreas was observed, and
hyperlipidemic association in both groups. None of these differ- 66.7% (18/27) of patients were similarly affected in the control
ences between the two groups was statistically significant. The group, while more than 50% necrosis of (peri)pancreas occurred in
extent of (peri)pancreatic necrosis was also not significantly dif- 41.4% (12/29) of the study group and 33.3% (9/27) of the control
group.
The differences in the incidence of infectious complications
Table 1 Patient demographics and baseline clinical characteristics in between the two groups were not significant (Table 2). All the
the two groups patients with infected (peri)pancreatic necrosis underwent FNA
Study group Control group
and were confirmed by positive isolates and/or operations. All
(n = 29) (n = 27) infectious complications were proven by positive isolates from
tissue or body fluid samples from the corresponding sites. The
Sex, n (male/female)* 14/15 14/13 incidence of infected pancreatic necrosis was 27.6% (8/29) in the
Etiology, n (%)† study group and 37.0% (10/27) in the control group. Regarding the
Biliary 15 (53.6) 14 (53.8) rate of infection in extrapancreatic organs in the study group and
Alcoholic 4 (14.3) 2 (7.7)
the control group, 24.1% and 22.2% were for the lung, respec-
Hyperlipidemic 2 (7.1) 2 (7.7)
tively; 20.7% and 25.9% for the blood, respectively; 6.9% and
Idiopathic 8 (27.6) 9 (33.3)
3.7% for the intestine, respectively; moreover, 10.3% and 3.7%
Age, years (mean ⫾ SD)‡ 48.4 ⫾ 15.1 47.5 ⫾ 12.3
were for the urinary tract, respectively.
Ranson’s score (mean ⫾ SD)‡ 4.8 ⫾ 1.5 5.3 ⫾ 1.7
24-h APACHE II score (mean ⫾ SD)‡ 12.7 ⫾ 2.1 11.9 ⫾ 3.7
Characteristics of the bacterial spectrum are shown in Table 3.
Pancreatic necrosis in CECT, n (%)†
Among eight infected patients in the study group, a total of 36
30–50% 17 (58.6) 18 (66.7) strains were isolated, versus 35 strains isolated from 10 infected
> 50% 12 (41.4) 9 (33.3) patients in the control group. Gram-negative bacteria were prepon-
derantly found, comprising 41.7% (15/36) of the isolated strains in
Differences in demographics and baseline clinical characteristics the study group and 68.6% (24/35) in the control group. Gram-
between the study group and the control group were not statistically
positive bacteria accounted for 22.2% (8/36) of the isolated strains
significant, P > 0.05. *Fisher’s exact test. †c2-test. ‡Unpaired Student’s
in the study group and 17.1% (6/35) in the control group. The
t-test. APACHE II, Acute Physiology and Chronic Heath Evaluation II;
differences in the incidence of Gram-negative and Gram-positive
CECT, contrast-enhanced computed tomography.
bacterial infection between the two groups were not statistically
significant. There was a higher rate of fungal infection that was
Table 2 The incidence of infectious complication in the two groups found to be statistically significant in the study group (36.1%,
13/36) versus the control group (14.2%, 5/35) (P < 0.05).
Infectious complication Study group Control group
The comparison of the secondary end-points between the two
(n = 29) (n = 27)
groups showed no significant differences (Table 4). The mortality
Infection of pancreatic necrosis, n (%) 8 (27.6) 10 (37.0) in the study group and the control group was 10.3% (3/29) and
Extrapancreatic infection, n (%) 14.8% (4/27), respectively. The two groups had no differences in
Lung 7 (24.1) 6 (22.2) the incidence of organ complications. The usage rate of respirator
Intestine 2 (6.9) 1 (3.7) in the study group was 32.1% (9/29) and 30.8% (8/27) in the
Blood 6 (20.7) 7 (25.9) control group. The incidence of operative necrosectomy was
Urinary tract 3 (10.3) 1 (3.7) 32.1% (9/29) in the study group and 34.6% (9/27) in the control
There were no statistically significant differences in the incidence of group. The duration of CVC was 23 days (range, 14–27 days) in
infectious complications between the study group and the control group the study group and 21 days (range, 15–29 days) in the control
(P > 0.05, c2-test). group. The duration of the hospital stay in the study group and the

Table 3 Spectrum of isolates from the infected organs in the two groups

Organ Study group (n = 8) Control group (n = 10)

- + -
Strains G G Fungi Strains G G+ Fungi

Lung 12 5 2 5 12 9 1 2
Pancreas 12 6 3 3 12 7 4 1
Intestine 2 1 0 1 1 1 0 0
Blood 7 2 3 2 9 7 1 1
UT 3 1 0 2 1 0 0 1
Total, n (%) 36 15 (41.7)* 8 (22.2)* 13 (36.1)† 35 24 (68.6) 6 (17.1) 5 (14.2)

*Difference in the incidence of G+ or G- bacterium infection between the study group and the control group was not statistically significant (P > 0.05,
c2-test). †Difference in the incidence of fungal infection between the study group and the control group was statistically significant (P > 0.05, c2-test).
G-, Gram-negative bacterium; G+, Gram-positive bacterium; UT, urinary tract.

Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors 739
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Antibiotic prophylaxis in ANP P Xue et al.

Table 4 Mortality, organ complications, and hospital courses in the

two groups

Study group Control group

(n = 29) (n = 27)

Mortality, n (%)* 3 (10.3) 4 (14.8)

Organ complication, n (%)*
ARDS 10 (34.5) 9 (33.3)
ARF 4 (13.8) 3 (11.1)
Hepatic insufficiency 13 (44.8) 10 (37.0)
Shock 1 (3.6) 1 (3.8)
Figure 3 Serum C-reactive protein (CRP) in patients with infected
Pancreatic pseudocyst 6 (20.7) 5 (18.5)
necrosis (n = 18) versus without infected necrosis (n = 38). *Patients
Use of respirator, n (%)* 9 (32.1) 8 (30.8)
with infected necrosis; **patients without infected necrosis. CRP at
Operative necrosectomy, n (%)* 8 (29.6) 9 (34.6)
each time point was higher in patients with versus without infected
Duration of CVC, days (median, range)† 23 (14–27) 21 (15–29)
necrosis (P < 0.05, unpaired Student’s t-test).
Hospital stay, days (median, range)† 28.3 (23–71) 30.7 (25–60)

Differences between the study group and the control group regarding
mortality, the incidence of organ complication, usage rate of respirator,
the incidence of operative necrosectomy, duration of CVC and hospital
stay were not statistically significant (P > 0.05, *c2-test, †unpaired Stu-
dent’s t-test). ARDS, acute respiratory distress syndrome; ARF, acute
renal failure; CVC, central venous catheterization.
All randomized patients who received at least one dose of study
treatment were included in the population safety analysis. There
were no proven treatment-related adverse events in the control
group. In the study group, however, pruritus developed in two
patients on the third and seventh day after admission, respectively.
They responded well when anti-allergic drugs were administered
and did not appear to experience any severe adverse events.

Figure 2 Comparison of the level of serum C-reactive protein (CRP)
between the study group and the control group. *Control group;
**study group. Difference in the level of serum CRP at each time point
between the study group and the control group was not statistically
significant (P > 0.05, unpaired Student’s t-test).
control group was 28.3 days (range, 23–71 days) and 30.7 days
(range, 25–60 days), respectively. During the follow-up period, the
rate of pancreatic pseudocysts in the study group and the control
group was 20.7% (6/29) and 18.5% (5/27), respectively.
The changes of CRP in the two groups are shown in Fig. 2. In
the two groups, serum CRP was remarkably beyond the upper
normal limit on the first day of admission, and reached a peak on
the third day. There was no significant difference in the level of
CRP at each time point between the two groups (P > 0.05).
Further, we evaluated CRP in patients with and without infected
necrosis (Fig. 3). CRP on the first, third, seventh and 10th days
presented a declining shape in these two subgroups of patients. On
the seventh and 10th days, it almost reduced to a normal value in
patients without infected necrosis, but did not do so in those who
had infected necrosis. CRP at each time point in patients with
infected necrosis was significantly higher than in patients without
infected necrosis (P < 0.05).
Discussion
We conducted this randomized controlled trial to compare the
outcomes of early prophylactic antibiotics with non-prophylactic
antibiotics in ANP, because there is no conclusive result available
on this issue. Early studies enrolled patients with a low risk of
infected necrosis or they employed antimicrobials that did not
have sufficient penetration into the pancreatic tissue, and therefore
lacked sufficient discriminatory power to properly evaluate antibi-
otic prophylaxis. From 1993–2007, there were a total of 11 pro-
spective randomized controlled trials that compared antibiotic
prophylaxis with non-prophylaxis or placebo in pancreatitis, but
only six are available for ANP.1,2,9,12,13,15–20 The first trial in the
comparison of early imipenem–cilastatin treatment with no anti-
biotic treatment in ANP patients (n = 74) demonstrated a signifi-
cant reduction in the incidence of pancreatic sepsis with treatment,
but no difference for surgical procedures or mortality.1 Another
study showed a reduction in infectious complications and mortal-
ity in ANP patients (n = 60) receiving prophylactic cefuroxime
versus non-prophylactic treatment.2 Although a study showed that
prophylactic antibiotics (ceftazidime, amikacine and metronida-
zole for 10 days) in severe alcoholic AP significantly reduced the
incidence of severe infection, pancreatic necrosis was not convinc-
ingly demonstrated in the inclusion criteria.20 Schwarz et al.
included 26 cases of SAP with the necrotic extent of 40% and
demonstrated that antibiotic prophylaxis (2 ¥ 200 mg/day ofloxa-
cin and 2 ¥ 500 mg/day metronidazole) neither prevented nor
delayed bacterial infection of the necrotic pancreas, but signifi-
cantly improved the clinical course if started before the onset of
infection in pancreatic necrosis.16 Another trial (n = 58), in which
the need for operation due to infected necrosis was defined as the
end-point, demonstrated that the incidence of operation, mortality
and overall number of major organ complications was significantly
lower in ANP patients receiving prophylactic imipenem–cilastatin

740 Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors
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P Xue et al.
therapy than in the observation group (P = 0.04).18 Two double-
blind, randomized, placebo-controlled trials recently reported by
Isenmann et al. (n = 76) and Dellinger et al. (n = 100) demon-
strated no advantage of early antibiotic prophylaxis and did not
support prophylaxis administration in patients with ANP.12,13 These
studies, using different inclusion criteria and different end-points
to evaluate the efficacies of various antibiotic therapies, resulted in
self-conflicting contradictory outcomes.
Different conclusions have been generated from evidence-based
studies on antibiotic prophylaxis. Four meta-analyses suggested a
decrease in infection-related morbidity, but there was bias in these
studies which ignored either catheter sepsis or catheter manage-
ment, and reached statistical significance only on the basis of the
results in the included study.21–24 Moreover, these four meta-
analyses were performed prior to two recent double-blind studies.
Including the data from Isenmann et al. and Heinrich et al. in the
2008 Cochrane review performed by Bai et al., the differences
between prophylactic antibiotics and placebo lose statistical sig-
nificance both in the infected pancreatic necrosis and mortality in
ANP patients.25 But the heterogeneity of the studies has made it
difficult to interpret these meta-analyses in detail, and has empha-
sized the need for further clinical trials to provide adequate evi-
dence for the routine use of antibiotic prophylaxis in SAP.26–28
In the present study, overall ‘infectious complication’ was
chosen as the primary end-point, because infection in pancreatitis
not only involves local pancreatic or peripancreatic tissue, but also
systemic extrapancreatic organs; that is, lung, blood, intestine and
urinary tract. Moreover, this is in accordance with the mechanism
that such complications are secondary to bacterial translocation
refluxing from the gastrointestinal tract as well as the biliary tract,
via lymphatic or hematogenic avenues to systemic organs.15,29
To compare early antibiotic prophylaxis with non-prophylactic
treatment, a maximum of 72 h between the onset of symptoms and
the start of treatment was defined. Because the CECT severity
index represents a powerful indicator for a high risk of infection in
AP,30,31 the present study rigorously defined that SAP patients were
eligible for randomization if CECT proved that there was 30% or
more necrosis of the pancreas.
The results of this study are largely consistent with previous
trials, which assessed mortality and infected necrosis, with no
significant difference demonstrated between early prophylaxis and
no antibiotic treatment.12,13 Our study also showed no significant
difference in infection of extrapancreatic organs during antibiotic
prophylaxis therapy, which was supported by three studies that
evaluated extrapancreatic infection.12,13,18
In this study, antibiotic prophylaxis did not reduce the incidence
of necrosectomy. Of five previous studies which provided the data
of operation, four showed no significant reduction in operation
rates.1,2,12,13 In the Nordback et al. trial,18 patients with sterile
necrosis of the pancreas were randomized to the observation group
or the prophylactic imipenem–cilastatin group to compare the
need for operation. Delayed imipenem–cilastatin resulted in an
increase in necrosectomy, but mortality was not significantly dif-
ferent (15% vs 8%). Furthermore, after imipenem–cilastatin treat-
ment, 64% of patients with infected necrosis in the observation
group did not require operation. Because follow-up data are not
provided, it was unclear whether these patients required operation
for infected necrosis in a later stage. Thus, in case of suspected or
provable necrotic infection, the primary treatment could be
Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Antibiotic prophylaxis in ANP
adjusted antibiotics. Operation is required in patients with infected
necrosis if antibiotic treatment is incompatible with the general
status of these patients.
Fungal infection has been correlated with antibiotic prophy-
laxis, but up to 25% of patients with ANP who do not receive
antibiotics also develop fungal infection. The incidence of fungal
infection is associated with the extent of necrosis as well as the
severity at the time of admission in these patients. Three random-
ized trials on i.v. antibiotic prophylaxis provided the incidence of
fungal infection, which showed no strongly increased preponder-
ance with therapy.1,2,14 But in our study, a significantly higher rate
of fungal infections was observed when antibiotic prophylaxis was
administered versus non-prophylaxis (36.1% vs 14.2%, P < 0.05).
The broad spectrum antibacterial action of imipenem–cilastatin
may promote the potential risks of superinfection. Thus, it is
critical to adjust the antibiotic in accordance with microbiological
testing.
This study showed a significantly higher level of CRP at each
time point in patients with versus without infected necrosis
(Fig. 3). The results support previous studies that show a positive
relation of CRP to disease severity, and strongly indicate the risk of
infection in SAP.32,33 But CRP at each time point in the study group
was not found statistically different from that in the control group
(Fig. 2), which indicates that antibiotic treatment in the initial
stage does not cut off the acute inflammatory reaction or even
increase the risk of infection.
One limitation of this study is that the sample size was not large
enough to sufficiently detect potentially significant differences of
low magnitude in the various experimental parameters. Thus,
studies with a larger sample size are needed to test conclusively
whether a lack of antibiotic prophylaxis will significantly affect
outcomes.
In conclusion, antibiotic prophylaxis did not demonstrate any
significant reduction in the incidence of infectious complications,
mortality, operative necrosectomy, major organ complications or
hospital course. However, an increase in the fungal infection rate
caused by antibiotic prophylaxis was observed in our series of
patients. Thus, this study does not favor the routine use of prophy-
lactic antibiotics in ANP.
Acknowledgments
We thank all medical and nursing staff who contributed to the
collection of information during the follow up of patients in the
trial. We also thank the staff at West China Hospital, Sichuan
University, China, where the trial was performed. We thank
Sichuan Province Science and Technology Tackling Key Project
(no. 05SG011-021-1) for providing financial support for the trial
and the publication of the paper. We thank Dr Wei Huang for
assistance in preparation of the manuscript.
References
1 Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized
multicenter clinical trial of antibiotic prophylaxis of septic
complications in acute necrotizing pancreatitis with imipenem. Surg.
Gynecol. Obstet. 1993; 176: 480–3.
2 Sainio V, Kemppainen E, Puolakkainen P et al. Early antibiotic
treatment in acute necrotising pancreatitis. Lancet 1995; 346: 663–7.
741
Antibiotic prophylaxis in ANP
3 Gloor B, Müller CA, Worni M, Martignoni ME, Uhl W,
Büchler MW. Late mortality in patients with severe acute
pancreatitis. Br. J. Surg. 2001; 88: 975–9.
4 Olah A, Belagyi T, Issekutz A, Gamal ME, Bengmark S.
Randomized clinical trial of specific lactobacillus and fibre
supplement to early enteral nutrition in patients with acute
pancreatitis. Br. J. Surg. 2002; 89: 1103–7.
5 Schmid SW, Uhl W, Friess H, Malfertheiner P, Buchler MW. The
role of infection in acute pancreatitis. Gut 1999; 45: 311–16.
6 Mifkovic A, Pindak D, Daniel I, Pechan J. Septic complications of
acute pancreatitis. Bratisl. Lek. Listy 2006; 107: 296–313.
7 Baron TH, Morgan DE. Acute necrotizing pancreatitis. N. Engl. J.
Med. 1999; 340: 1412–17.
8 Carnovale A, Rabitti PG, Manes G, Esposito P, Pacelli L, Uomo G.
Mortality in acute pancreatitis: is it an early or a late event? JOP
2005; 6: 438–44.
9 Bassi C, Falconi M, Talamini G et al. Controlled clinical trial of
pefloxacin versus imipenem in severe acute pancreatitis.
Gastroenterology 1998; 115: 1513–17.
10 UK Working Party on Acute Pancreatitis. UK guidelines for the
management of acute pancreatitis. Gut 2005; 54: iii1–9.
11 Heinrich S, Schäfer M, Rousson V, Clavien PA. Evidence-based
treatment of acute pancreatitis: a look at established paradigms. Ann.
Surg. 2006; 243: 154–68.
12 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:
997–1004.
13 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: 674–83.
14 Toouli J, Brooke-Smith M, Bassi C et al. Guidelines for the
management of acute pancreatitis. J. Gastroenterol. Hepatol. 2002;
17: S15–39.
15 Maravi-Poma E, Gener J, Alvarez-Lerma F et al. Early antibiotic
treatment (prophylaxis) of septic complications in severe acute
necrotizing pancreatitis: a prospective, randomized, multicenter study
comparing two regimens with imipenem-cilastatin. Intensive. Care
Med. 2003; 29: 1974–80.
16 Schwarz M, Isenmann R, Meyer H, Beger HG. Antibiotic use in
necrotizing pancreatitis. Results of a controlled study. Dtsch. Med.
Wochenschr. 1997; 122: 356–61.
17 Takeda K, Matsuno S, Ogawa M, Watanabe S, Atomi Y. Continuous
regional arterial infusion (CRAI) therapy reduces the mortality rate
of acute necrotizing pancreatitis: results of a cooperative survey in
Japan. J. Hepatobiliary Pancreat. Surg. 2001; 8: 216–20.
18 Nordback I, Sand J, Saaristo R, Paajanen H. Early treatment with
antibiotics reduces the need for surgery in acute necrotizing
742
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
P Xue et al.
pancreatitis a single-center randomized study. J. Gastrointest. Surg.
2001; 5: 113–18.
19 Manes G, Rabitti PG, Menchise A, Riccio E, Balzano A, Uomo G.
Prophylaxis with meropenem of septic complications in acute
pancreatitis: a randomized, controlled trial versus imipenem.
Pancreas 2003; 27: e79–83.
20 Delcenserie R, Yzet T, Ducroix JP. Prophylactic antibiotics in
treatment of severe acute alcoholic pancreatitis. Pancreas 1996; 13:
198–201.
21 Golub R, Siddiqi F, Pohl D. Role of antibiotics in acute pancreatitis:
a meta-analysis. J. Gastrointest. Surg. 1998; 2: 496–503.
22 Sharma VK, Howden CW. Prophylactic antibiotic administration
reduces sepsis and mortality in acute necrotizing pancreatitis: a
meta-analysis. Pancreas 2001; 22: 28–31.
23 Bassi C, Larvin M, Villatoro E. Antibiotic therapy for prophylaxis
against infection of pancreatic necrosis in acute pancreatitis.
Cochrane Database Syst. Rev. 2003; 4: CD002941.
24 Zhou YM, Xue ZL, Li YM, Zhu YQ, Cao N. Antibiotic prophylaxia
in patients with severe acute pancreatitis. Hepatobiliary Pancreat.
Dis. Int. 2005; 4: 23–7.
25 Bai Y, Gao J, Zou DW, Li ZS. 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: 104–10.
26 Villatoro E, Bassi C, Larvin M. Antibiotic therapy for prophylaxis
against infection of pancreatic necrosis in acute pancreatitis.
Cochrane Database Syst. Rev. 2006; 4: CD002941.
27 Dambrauskas Z, Gulbinas A, Pundzius J, Barauskas G.
Meta-analysis of prophylactic parenteral antibiotic use in acute
necrotizing pancreatitis. Medicina (Kaunas) 2007; 43: 291–300.
28 de Vries AC, Besselink MG, Buskens E et al. Randomized
controlled trials of antibiotic prophylaxis in severe acute pancreatitis:
relationship between methodological quality and outcome.
Pancreatology 2007; 7: 531–8.
29 Beger HG, Bittner R, Block S, Büchler M. Bacterial contamination
of pancreatic necrosis: a prospective clinical study. Gastroenterology
1986; 91: 433–8.
30 Balthazar EJ, Robinson DL, Megibow AJ, Ranson JHC. Acute
pancreatitis: value of CT in establishing prognosis. Radiology 1990;
174: 331–6.
31 Triester SL, Kowdley KV. Prognostic factors in acute pancreatitis. J.
Clin. Gastroenterol. 2002; 34: 167–76.
32 Schütte K, Malfertheiner P. Markers for predicting severity and
progression of acute pancreatitis. Best Pract. Res. Clin.
Gastroenterol. 2008; 22: 75–90.
33 Nakamura M, Takahashi M, Ohno K et al. C-reactive protein
concentration in dogs with various diseases. J. Vet. Med. Sci. 2008;
70: 127–31.
Journal of Gastroenterology and Hepatology 24 (2009) 736–742 © 2009 The Authors