Antibiotic Prophylaxis in Acute Necrotizing

Raffaele Pezzilli
Department of Internal Medicine, Sant'Orsola-Malpighi Hospital. Bologna, Italy
The risk of complications and death in
necrotizing pancreatitis is dependent on the
intensity of proteolytic insult and on variable
biological responses, also comprising the age
of patients, comorbity, and treatment. Earlier
studies on antibiotic treatment do not indicate
favorable effects on the outcome of acute
pancreatitis [1, 2, 3]. However these studies
were carried before the CT era [4], without
the possibility of exactly stratifying pancreatic
necrosis as sterile necrosis, infected necrosis
and pancreatic abscess [5], and before the
discovery that bacterial contamination of
pancreatic necrosis is the cause of a
significant increase of morbidity and
mortality [6]. Furthermore, these studies were
also not able to take into account the new
advances in antibiotic pancreatic penetration
[7, 8], especially during the acute phase of the
disease [9].
These achievements have enabled Pederzoli et
al. to design the first clinical trial on
antibiotic prophylaxis in acute pancreatitis
with a less empiric approach based on a
broad-spectrum antibiotic in which pancreatic
penetration at therapeutic minimal inhibitory
concentration was proved [10]. In this
randomized multicenter study, 74 patients
with computed tomographic scans
demonstrating necrotizing pancreatitis within
72 hours of onset were assigned to two groups
receiving no antibiotic treatment or 0.5 grams
of prophylactic imipenem administered
intravenously every eight hours for two
weeks. Pancreatic sepsis was always detected
by means of cultures (percutaneous computed
tomography or ultrasound-guided needle
aspiration and intraoperative samples). The
incidence of pancreatic sepsis was much
lower in treated patients (12.2% versus
30.3%, P<0.01); however, this study failed to
demonstrate a significant reduction in
mortality for sepsis even if the mortality in
the placebo group (12.1%) was higher than
that in the treated group (7.3%). Therefore,
the authors recommend prophylactic use of
imipenem in patients with acute necrotizing
pancreatitis.
After this study, several other multicenter [11,
12, 13, 14], as well as single-center [15, 16,
17, 18], studies were carried out. Except for
those of Sainio et al. [15] and Luiten et al.
[11], all these studies failed to demonstrate
any significance in the mortality rate between
the treated groups in comparison with the
placebo groups. Whereas in the Luiten et al.
study [11], late mortality was significantly
reduced using a selective decontamination of
the gut, in the Sainio et al. study [15], the
reduction in mortality was due not only to
antibiotic treatment but partly for adequate
fluid resuscitation and effective intensive care
combined with the correct timing and type of
surgical intervention, as suggested by the
same authors.
Subsequently, two meta-analyses appeared
[19, 20]. The first of these two papers
concluded that the use of prophylactic
antibiotics in severe alcoholic acute
pancreatitis significantly reduces the
incidence of severe infection [19]; the second
meta-analysis [20] confirmed the results of
the previous study regarding the reduction of
sepsis in patients with acute necrotizing

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JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 5, No. 3 – May 2004
162
pancreatitis irrespective of the etiology, and,
even more importantly, was also able to
demonstrate that, aggregating the data of the
studies of Pederzoli et al. [10], Sainio et al.
[15] and Schwarz et al. [16], antibiotic
prophylaxis was also able to decrease the
mortality. Thus, the authors suggested that
prophylaxis with an antibiotic with proven
efficacy in necrotic pancreatic tissue should
be given to all patients with acute necrotizing
pancreatitis.
However, some points have unanswered
questions: what is the antibiotic of choice
(imipenem [10], cefuroxime [15], ofloxacin
plus metronidazole [15])? What is the time-
duration of antibiotic prophylaxis? What is
the optimal route of antibiotic administration?
What are the complications of antibiotic
prophylaxis such as incidence of infection
with fungi and the possibility of
nonsusceptible bacteria? Finally, in the case
of primary fungal infection which accounts
for percentages ranging from 37 to 74% of
patients with necrotizing pancreatitis [21, 22],
should antibiotics be given together with
prophylactically antifungal therapy?
Another consideration should be taken into
account; none of the studies published until
recently were carried out as double blind
studies. However, the first double blind
multicenter study on the use of antibiotic
prophylaxis in acute pancreatitis has been
now published [23]. In this study, a total
sample size of 200 patients was calculated
with a power of 90% in order to demonstrate
that antibiotic prophylaxis reduces the
proportion of patients with infected pancreatic
necrosis from 40% of placebo to 20% of
combined therapy with ciprofloxacin/
metronidazole. One hundred and 14 patients
with acute pancreatitis in combination with a
serum C-reactive protein exceeding 150 mg/L
and/or necrosis on contrast-enhanced
computed tomography scan were enrolled and
received either intravenous ciprofloxacin
(2x400 mg/day) plus metronidazole (2x500
mg/day) or placebo. Study medication was
discontinued and switched to open antibiotic
treatment when infectious complications,
multiple organ failure sepsis, or systemic
inflammatory response syndrome occurred.
After half of the planned sample size was
recruited, an adaptive interim analysis was
performed, and recruitment was stopped
because the trend in the incidence of infected
pancreatic necrosis was in the opposite
direction of the assumptions of the study.
Fifty-eight patients received ciprofloxacin/
metronidazole therapy and 56 patients
received a placebo. Twelve percent of the
ciprofloxacin/metronidazole group developed
infected pancreatic necrosis as compared to
9% of the placebo group (P=0.585), and the
authors concluded that there is no benefit in
antibiotic prophylaxis for protecting against
the risk of developing infected pancreatic
necrosis. Regarding the secondary endpoints
of the study such as incidence of death,
incidence of extrapancreatic infection,
surgical treatment for necrotizing pancreatitis,
duration of stay in the intensive care unit,
duration of hospitalization, there were no
statistical differences between the treated
group and the placebo group; this may be due
to the small sample of the subjects enrolled
demonstrating that, for these parameters, the
study had no adequate statistical power. Some
points of this study are not clear; the use of C-
reactive protein to stratify necrotizing
pancreatitis is questionable. In fact, of the 114
patients who were enrolled in the study, 45
were recruited on the basis of elevated serum
C-reactive protein only and, in this group,
only six patients developed pancreatic
necrosis (13.3%). Furthermore, a high
percentage of subjects of the placebo group
(26/56, 46%) were treated with antibiotic
therapy during the course of the study period
and 16 out of 58 (28%) treated subjects
received antibiotics different from those of
the study protocol; thus, this large crossover
rate could have introduced a bias in the study.
On the other hand, why did the authors
choose antibiotics such as fluoroquinolones
which, in a previous clinical study [12], did
not demonstrate efficacy similar to
imipenem? Finally, how many patients were
fed enterally? Enteral nutrition has been
demonstrated to decrease the risk of bacterial
translocation in patients with severe acute

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163
pancreatitis; enteral feeding repairs the
mucosal damage of fasting and started very
early, it preserves epithelial integrity and
bacterial ecology, thereby helping to maintain
gut barrier function [24, 25, 26, 27, 28, 29],
but, in this study, there is no mention as to
whether or not this procedure was applied.
In conclusion, it cannot not be affirmed on the
basis of this study that another myth bites the
dust; this study only demonstrate that the road
to Rome is too long.
Keywords Antibiotic Prophylaxis; Clinical
Trials; Controlled Clinical Trial; Meta-
Analysis; Pancreatitis, Acute Necrotizing
Correspondence
Raffaele Pezzilli
Dipartimento di Medicina Interna
Ospedale Sant'Orsola-Malpighi
Via G. Massarenti, 9
40138 Bologna
Italy
Phone: +39-051.636.4148
Fax: +39-051.549.653
E-mail: pezzilli@orsola-malpighi.med.unibo.it
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