Antibiotic Prophylaxis in Severe Acute

Raffaele Pezzilli
Department of Digestive Diseases and Internal Medicine,
Sant'Orsola-Malpighi Hospital. Bologna, Italy
Several guidelines on acute pancreatitis suggest that
carbapenems should be used prophylactically and
should be continued for 14 days, and that the
development of infected necrosis should be assessed
using fine-needle aspiration and the sample should be
cultured for germ isolation and characterization [1]. In
routine clinical practice, antibiotics are used to cure
both extrapancreatic infections which appear during the
course of acute pancreatitis and infected pancreatic
necrosis and also as a prophylaxis in those patients who
have pancreatic necrosis in order to prevent possible
infection from the necrosis. In the treatment of
extrapancreatic infections, the most used antibiotics
were cephalosporins whereas carbapenems,
glycopeptides and antifungal antibiotics were the most
used antibiotics in the treatment of proven infected
pancreatic necrosis [2]. Moreover, there are very few
topics in pancreatology which cause as much debate as
that regarding the utility of antibiotic prophylaxis in
severe acute pancreatitis. There are very few human
randomized studies and there are more meta-analyses
published than studies published. Of course, the cost of
a meta-analysis is much less than carrying out a study
on the efficacy of antibiotics in severe acute
pancreatitis. Thus, I would like to discuss the latest
meta-analytic study coming from the United States [3].
In brief, the authors carried out a systematic search of
MEDLINE, EMBASE, and the Cochrane Central
Register of Controlled Trials, using PubMed, Google
Scholar, and Ovid as search engines without language
restriction until the end of May 2008. They screened
367 articles of which 55 were found to be relevant to
pancreatitis and antibiotics; of these latter 55 articles,
only eight met the inclusion criteria: randomized
controlled studies; severe acute pancreatitis diagnosed
with contrast-enhanced computed tomography and any
of the severity criteria such as Acute Physiology And
Chronic Health Evaluation II (APACHE II), Imrie
classification and increased C-reactive protein levels
greater than 120 mg/L; necrosis evaluated by contrast-
enhanced computed tomography; prophylactic
antibiotics administered intravenously; defined length
of antibiotic treatment, and morbidity and mortality
measured objectively. Sensitivity analysis was applied
to the results to determine heterogeneity among the
studies. The authors pooled 502 patients from 8 studies
[4, 5, 6, 7, 8, 9, 10, 11]. The majority of the patients
(56%) had alcoholic pancreatitis, followed by biliary
pancreatitis (24%) and pancreatitis due to other causes
(20%). The age of these patients ranged from 43 to 59
years and the length of hospital stay ranged from 18 to
95 days. There were 253 patients with severe acute
pancreatitis who received prophylactic antibiotics, and
249 patients were randomized to the placebo arm.
Overall, there was no protective effect of antibiotic
treatment with respect to mortality. With respect to
morbidity, antibiotic prophylaxis did not protect
against infected necrosis or surgical intervention. There
was, however, an apparent benefit as regards non-
pancreatic infections, with a relative risk reduction of
40%, absolute risk reduction of 15%, and number
needed to treat of 7. Some comments are necessary;
first of all, there was heterogeneity in the studies
considered and only 5 studies [5, 6, 8, 10, 11] were
considered to be of high quality according to the Jadad
et al. scale [12]. Thus, very few studies were available
for a meta-analytic study. Regarding the antibiotics
used as prophylaxis, only half of the studies used
carbapenems [4, 5, 8, 11], other studies used
cefuroxime [6] ofloxacin [7] and ciprofloxacin [10,
11], associated or not with metronidazole, and the last
one, published in abstract form only, used meropenem
Key words Antibiotic Prophylaxis; Clinical Trials; Controlled
Clinical Trial; Meta-Analysis; Pancreatitis, Acute Necrotizing
Correspondence Raffaele Pezzilli
Department of Digestive Diseases and Internal Medicine,
Sant’Orsola-Malpighi Hospital, Via Massarenti, 9, 40138 Bologna,
Italy
 

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or ciprofloxacin plus metronidazole [9]. This is a
crucial point, because the differences in the ability of
the various antibiotics to penetrate into necrotic
pancreatic tissue are well known. In fact, the choice of
antibiotics in preventing infected necrosis during
necrotizing pancreatitis should be based on their
antimicrobial activity, penetration rate, persistence and
therapeutic concentrations in the necrotic pancreatic
area; these requisites are provided by pefloxacin and
metronidazole and, to a variable extent, by imipenem
and mezlocillin [13]. Finally, two studies considered in
the meta-analysis [10, 11] did not reach the number of
patients required by the calculated sample size. One
study was stopped after an adaptive interim analysis
[10] and, as pointed out by the authors themselves, the
sample size was not large enough to detect potential
beneficial effects of low magnitude or potential
benefits involving infrequent secondary end points
such as mortality, pancreatic necrosis, shock, and renal
insufficiency; a second study [11] was stopped due to
restriction of resources for continuing the trial.
It is also important to note that an apparent benefit was
found in the meta-analysis regarding the development
of non-pancreatic infections. In a recent multicenter
study from the Dutch Acute Pancreatitis Study Group
[14], it was found that the mortality rate was higher in
patients with pneumonia, bacteremia, infected necrosis
and pancreatic necrosis when patients with each
specific infection were compared to all other patients in
the study. As it is now clear that half of relevant
infections occur in the first few days of acute
pancreatitis, prophylactic strategies should be initiated
immediately after admission and randomized
controlled trials of antibiotic prophylaxis, commencing
treatment in the first 72-120 h after onset of symptoms
[10, 11], need to be repeated with a much earlier start
of prophylaxis. In fact, results from a recent
randomized trial, showing a significant reduction in
‘extrapancreatic sepsis’ by starting antibiotic
prophylaxis on admission to hospital, support this
hypothesis [15].
As pointed out by the authors themselves of the meta-
analyses published to date [3], other limitations of the
studies considered in the meta-analysis were inherent
in the primary study design such as inclusion criteria,
duration and dosing of antibiotics, assessment of
severity of disease, nutritional support, and
resuscitative measures, the relatively small number of
patients in each individual study, and different outcome
measurements. In addition, the inclusion of non-
blinded studies limits the findings because these
patients should have received surgical intervention
when investigators realized that they were not
receiving antibiotics. In conclusion, we do not need
more meta-analytic studies on this topic; on the
contrary, additional and well-carried out studies are
required to explore the benefits of antibiotic
prophylaxis in severe acute pancreatitis, also taking
into account the adverse effects, the effects of the
varying duration of the therapy, and whether the
outcome of the infection is related to the etiology.
Conflict of interest The author has no potential
conflicts of interest
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