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Antibiotics in Acute Pancreatitis
181
c. Sphincter of oddi dysfunction (SOD). Is another common cause of AP.
SOD comprises two clinical entities: 1) SO increased basal pressure,
which refers to a structural alteration of the sphincter, as consequence
of a long-lasting inflammatory process with subsequent fibrosis
(stenosis); and 2) SO dyskinesia, referring to a transient primary
motor abnormality characterized mainly by sphincter hypertone. SOD
has been classified under three headings on the basis of clinical and
morphological parameters and may involve either the biliary or the
pancreatic segment of the sphincter [20].
d. Post – ERCP. Pancreatitis is the most common complication of ERCP
and carries a high morbidity and mortality. Asymptomatic
hyperamylasaemia occurs in 35%-70% of patients after the procedure
[21]. Risk is particularly high in young women with SOD. Meta-
analyses have helped screen for promising modalities of prophylaxis.
At present, evidence is emerging that pancreatic stenting of patients
with SOD and rectally administered nonsteroidal anti-inflammatory
drugs in a large unselected trial reduce the risk of post-procedure
pancreatitis. A recent meta-analysis have demonstrated that rectally
administered indomethacin, just before or after ERCP is associated
with significantly lower rate of pancreatitis compared with placebo
[24]. In another retrospective study analyzing 900 cases of patients
who underwent ERCP, AP developed in 3,7% of the cases [25].
e. Metabolic causes. Like hypertriglyceridemia and hypercalcemia.
There are many causes of hypercalcemia, but the majority of patients
who develop acute recurrent pancreatitis have hyperparathyroidism.
The diagnosis may be missed if calcium levels are not measured
during each attack. Typically, serum triglycerides have to exceed
1,000 mg/dL to precipitate an attack of AP [19].
f. Postraumatic AP. The typical clinical triad of pancreatic trauma is
upper abdominal pain, leukocytosis, and elevated serum amylase
level, that may be absent in adults during the first 24 hours and even
for several days [27]. Pancreatic trauma is difficult to recognize
because of coexisting injuries and the central retroperitoneal location,
presenting higher mortality rates than observed in injuries to other
intra-abdominal organs. In a patient with an isolated pancreatic injury,
even ductal transection may be initially asymptomatic or have only
minor signs.
g. Other acquired conditions. Benign and malignant tumors of the
papilla of Vater or pancreatico-biliary junction, organic strictures of
José R. O. Guillén, Ana P. Cano, María B.Martos et al.
182
the main pancreatic duct, and cystic neoplasms, including mucinous
ductal ectasia. Neoplastic strictures are found to induce AP in about
5% of cases [19, 21]. Choledochocele is a congenital or acquired
condition in which the intramural segment of the common bile duct is
dilated and herniates into the duodenal lumen. AP may develop when
the cystic dilation or bile duct sludge or stones obstruct the pancreatic
juice outflow. Ampullary choledochal cysts can develop when there is
SOD [19].
Many infectious agents are associated with AP, but no microorganism has
ever been identified within the pancreas [21]. Smoking has long been thought
to play a role in the induction of AP, but it was only recently that large
prospective studies have proved that cigarette smoking is an independent risk
factor and could be dose-dependent [27]. For a number of substances there is
general agreement on some relation with AP, and a recent review by the
Midwest Multicenter Pancreatic Study Group [28]
listed the following as
medications for which a strong association with AP is documented:
alphamethyldopa, azathioprine, cimetidine, cytosine arabinoside,
corticosteroids, estrogens, furosemide, isoniazid, mercaptopurine,
metronidazole, pentamidine, procainamide, sulfamethazole, sulindac,
tetracycline, trimethroprim/sulfamethoxazole and valproic acid. Another
causes of drug induced AP are azathioprine, mesalazine/sulfasalazine, 2-3-
dideoxyinosine (ddI), hydrochlorothiazide, and rifampicin [29].
Anatomical Variants
Pancreas divisum is the most common variant of pancreatic ductal
anatomy, occurring in up to 7% of autopsy series [21]. The dorsal duct of the
pancreas can drain through the major papilla via a communicating branch of
the ventral duct. However, this communication is generally narrow and may be
inadequate for draining the pancreatic secretion. The inability of minor papilla
to adapt the outflow of pancreatic juice when the gland is stimulated leads to
ductal hypertension that in some individuals may cause either recurrent pain,
elevation of amylase or AP. Dilatation of the dorsal duct confirms the presence
of some obstruction at the level of minor papilla and suggests a positive
outcome after sphincterotomy or stenting.
Annular pancreas is a rare anatomical condition that may be associated
with duodenal or biliary obstructive symptoms, as the consequence of the
Antibiotics in Acute Pancreatitis
183
entrapment of duodenum and common bile duct by the annular growth of the
gland. About one third of patients with annular pancreas also have pancreas
divisum, so it is not clear whether recurrent pancreatitis depends on the
annular variant or on the pancreas divisum. The presence of a common
pancreatico-biliary channel abnormally long without sphincters separating the
biliary and pancreatic ducts is a condition that facilitates free reflux of bile and
pancreatic juice into the alternative duct. This abnormality of the pancreatico-
biliary junction is easily diagnosed by magnetic resonance cholangio-
pancreatography or ERCP. Choledochal cysts and sigmoid configuration of the
main pancreatic duct are other anatomical causes of AP [20].
Autoinmune Pancreatitis
This is an autoinmune disorder caused by an infiltration of immune cells
into pancreatic tissue. The pancreas of a patient with autoinmune pancreatitis
is infiltrated by immune cells like cluster of differentiation CD 4-positive, T
cells, and granulocytes in type 2 or IgG4-producing plasma cells and B-
lymphocyte antigen CD20 in type 1. It can be divided into a) Type 1: more
frequent on adults, usually male, presenting elevated serum IgG4 levels, with a
high relapse rate and associated with lymphadenophaty, thyroiditis or
hypothyroidism, breast inflammatory pseudotumor or mastitis, chronic
gastritis, ampulla of Vater pseudotumor, sclerosing cholangitis and others
extra-pancreatic lessions; and b) Type 2: more frequent on children, regardless
of gender, presenting normal serum IgG4 levels, with normal relapse rate and
associated with inflammatory bowel disease. This type of AP responds to
steroid therapy successfully [30].
Genetic Causes
a. CFTR - gene mutations. This condition represents the most common
inherited disease of the exocrine pancreas. Exocrine pancreatic
insufficiency with no inflammatory changes is the most common
finding; AP may be the only clinical sign in some patients. CFTR
mutation plays its role in intraluminal pH regulation from bicarbonate
secretion and the flushing of ductal proteins [31]. Those with less
severe mutations in the CFTR gene risk developing pancreatitis,
which is estimated to be 40 to 80 times that in the general population.
José R. O. Guillén, Ana P. Cano, María B.Martos et al.
184
Heterozygotes for CFTR mutations are generally healthy but still have
a 3 to 4-fold risk over the general population for pancreatitis [20].
b. PRSS1 - gene mutations. Mutations in the cationic trypsinogen gene
have been found in patients with hereditary pancreatitis. In this
autosomal dominant disorder the pancreas is unable to protect itself
by premature or excessive trypsin activation in the gland; the lack of
this protective mechanism against premature activation of trypsin
predisposes individuals to recurrent bouts of pancreatitis in childhood
and frequent progression to chronic pancreatitis [20].
c. SPINK1 - gene mutations. SPINK1 polymorphisms are common in
the general population (~2%) and are significantly associated with
pancreatitis [32]. SPINK1 has a protective action in the pancreas since
it serves as an inhibitor of trypsin and plays a role in the prevention of
premature activation of zymogen that is catalyzed by trypsin within
the pancreatic duct system or the acinar tissue. These mutations have
been estimated to raise the risk for pancreatitis [20], but the results of
several studies are divergent depending on the geography [31].
5. MORTALITY
Mild form of AP accounts for 80% of the cases; 95% of deceased patients
for AP comes from the remaining 20% [33]. Although the mortality rate of
severe AP has decreased in recent years, it is still around 20 to 25% [34].
Advanced age has been considered an independent prognostic factor for
mortality in AP [34]. The presence of complications such as infected
pancreatic necrosis in the aged population is associated with a mortality rate of
up to 50% [35, 36]. Mortality rate has two peaks, early mortality (within the
first six days of hospitalization) and late mortality (after the sixth day). The
former is usually caused by a SIRS through shock and multiple organ failure,
effect of the circulating pancreatic enzymes and activated inflammatory
mediators (cytokines, interleukins, prostaglandins, etc.). SIRS can evolve
independently of the original injury and its management consists in the
treatment of the damages caused by systemic inflammation. Late mortality is
generally caused by local complications (necrosis infections or peripancreatic
collections infections) or distant complications (pneumonia, septicemia). For
some authors, late mortality has decreased because of better antibiotic
treatment and nutritional support and learned surgical decisions, while others
guess that mortality rate has not changed but moved from early to late peak.
Antibiotics in Acute Pancreatitis
185
Infection is widely accepted as the main reason for death in AP, mainly
infected pancreatic necrosis, although older patients and those with
comorbidities present high mortality attributed to others causes. The rate of
infection correlates with the extent of necrosis and, therefore, with the severity
of the disease. This infection has an enormous impact in mortality, multiplying
it by 4 to 15 times. In general, infections are involved in 80% of deaths caused
by AP. Mortality in patients without necrosis is nearly 0%, with sterile
necrosis is between 0 and 11%, and with infected necrosis reaches 40% [1].
6. ANTIBIOTIC PROPHYLAXIS
Antibiotic prophylaxis is the setting of pancreatic necrosis refers to the use
of antibiotics to avoid infection in severe AP [1]. This issue has remained
controversial for the lasts four decades. The most important questions raised
are about antibiotic indications, antibiotic selection and length of treatment.
Available studies are not conclusive although some have shown benefit
from antibiotic prophylaxis. These last studies used different antibiotic drugs,
different selection criteria, and different length of treatment. Also, definitions
of severe disease varied between trials although in each the aim was to deliver
antimicrobial prophylaxis to patients with severe AP and evidence of
pancreatic necrosis. Combinations of the number observed in these studies
suggests that there may be a significant reduction in complications and deaths
in patients with predicted severe AP treated with prophylactic antibiotics, but
this ignores the major inconsistences within and between these trials.
When there is less than 30% of pancreatic necrosis, the risk of infection of
necrosis and peripancreatic tissue is very low, so that the onset of antibiotic
prophylaxis is recommended when there is evidence from imaging test (CT) of
more than 30% of pancreatic necrosis, according to the American
Gastroenterology Association [37]. In the beginning is also accepted after
surgical necrosectomy, even without microbiological diagnosis to confirm the
infection [38].
The basis of antibiotic prophylaxis in severe pancreatitis is to avoid
infection and all the problems arising from it (major complications and death)
[39, 40], since the infection of pancreatic necrosis is a major determinant in
the prognosis of the patient [41]. Several prospective studies using broad-
spectrum antibiotic with good distribution in pancreatic tissue, exhibit a
significant decrease in the range of infected necrosis, sepsis and mortality
compared with the group of patients not receiving prophylaxis [42-44].
José R. O. Guillén, Ana P. Cano, María B.Martos et al.
186
Early trials show preference for use in severe pancreatitis grade, without
finding evidence of benefit in mild pancreatitis [45]. In recent studies, it is
established that the indication for initiating antibiotics must be based on the
clinical judgment of the physician [46].
In the main studies treatment duration ranges from 7 to 14 days, because
of longer treatments increases the prevalence of fungal infection. If there is no
evidence of infection after this period, treatment is finished; on the other side,
if we have evidence of infection for cultures, antibiotics based on the
antibiogram are mandatory [38].
The monobacterial infection occurs in about 55-60% of cases of infected
necrosis, the rest is multibacterial (Table 1). Abscesses are usually mainly
multibacterial [47]. Fungal infection is increasing, caused in most cases by
Candida. The major risk factors for the appearance of this type of infectious
agent is the use of broad-spectrum antibiotics, prolonged hospitalization and
surgical and / or endoscopic procedures.
Both for prophylaxis and treatment, the antibiotic chosen must be one with
good broad-spectrum diffusion in pancreatic tissue and also covers flora
involved in infected necrosis. In published studies they have used different
types of antibiotics, although the two groups have mainly been used
carbapenems, quinolones, metronidazole and high dose cephalosporines. Some
authors state that imipenem is the only antibiotic showing a significant
decrease in infection of pancreatic necrosis [48, 49].
Table 1. Etiologic agents in infected AP
Etiologic agents
Percentage
Gram-negative bacilii
Escherichia coli
Klebsiella spp
Enterobacter spp
Proteus spp
25-25%
10-25%
3-7%
8-10%
Etiologic agents
Percentage
Other gram-negative bacilii
Psuedomonas spp
11-16%
Gram-positive cocci
Staphylococcus
aureus
Enterococcus spp
14-15%
4-7%
Anaerobius
6-16%
Yeast
36%
Antibiotics in Acute Pancreatitis
187
The problems arising from use are increasing the prevalence of fungal
infection [38, 50, 51], and increasing the resistance and adverse effects
associated with antibiotic. The role of antifungal prophylaxis, despite being
debated in the last 15 years, is not well defined [38, 51-53]. So far there are no
randomized studies on fungal prophylactic therapy in acute pancreatitis.
In conclusion, we can say that there is no evidence or consensus to support
the use of prophylactic antibiotics [49, 54-64]. They are not recommended by
international guidelines for the treatment of AP [65-67]. In particular, the
Working Group IAP / APA Guidelines Acute Pancreatitis of 2013, the use of
intravenous antibiotic is not recomemended as prophylaxis for the prevention
of infectious complications in AP with a degree of strong recommendation,
grade I. Some of these authors believe in the existence of subgroups of patients
who could benefit from using them, but more studies are needed to determine
them [68].
Since 1993, there have been 11 prospective, randomized trials with proper
study design, participants, and outcome measures that evaluated the use of
prophylactic antibiotics in severe AP [55]. From this meta-analysis, the
number needed to treat was 1,429 for one patient to benefit.
Based on the current literature, the use of prophylactic antibiotics to
prevent infection in patients with sterile necrosis (even predicted as having
severe disease) is not recommended.
7. ANTIBIOTIC TREATMENT
Three questions arise when we have to select an empirical treatment:
which one is more adequate for bacterial flora and bacterial resistance in our
hospital? When we must begin the treatment? For how long we keep the drug
without clinical or microbiological demonstration?
Antibiotic treatment only starts after confirmation of infected necrosis [67,
69, 70], based on the patient's clinical and imaging tests [51] that move fine
needle aspiration as the gold standard for the confirmation of infection. Thus,
the following clinical situations would be clear indication of the beginning of
antibiotic treatment:
a. Sepsis or SIRS.
b. Multi-organ failure.
José R. O. Guillén, Ana P. Cano, María B.Martos et al.
188
c. Extrapancreatic infection: pneumonia, intrabadominal infection,
urinary tract infection, sepsis of unknown focus, cholangitis, catheter-
acquired infections, bacteriemia, positive bronchoalveolar lavage.
d. After pancreatitis surgery to prevent persistent systemic sepsis [71,
72].
Fever, tachycardia, tachypnea, and leukocytosis associated with SIRS that
may occur early in the course of AP may be indistinguishable from sepsis
syndrome. When an infection is suspected, antibiotics should be given while
the source of the infection is being investigated [65]. However, once blood and
other cultures are found to be negative and no source of infection is identifed,
antibiotics should be discontinued.
It is necessary an antibiotic that covers the most common agents involved
and with good distribution within the pancreatic tissue. Büchler [73] studied
the concentrations of antibiotic in blood and pancreatic tissue finding high
concentrations with the use of ciprofloxacin, ofloxacin and imipenem.
Imipenem is the most widely used antibiotic in clinical routine [49, 68, 74,
75]. Also in the choice of treatment should be taken into account flora and
resistance of our own hospital. Therefore, the antibiotic selected should be one
broad spectrum, starting with a carbapenem [55, 56].
Tigecycline is an antibiotic used for intra-abdominal infections caused by
gram-positive, gram negative and anaerobius. It has proved its good
penetration into pancreatic tissue. Some studies described the possibility of
their use causing pancreatitis [76, 77] However, in 2014 a study concluded that
pancreatitis associated with use of this antibiotic is rare (below 1 was
published %), although it is a phenomenon that is still little studied [78]. Due
to the high resistance of hospital flora to carbapenems, tigecycline should
consider as an alternative in such cases [79].
The duration of treatment should not be more than 14 days without
laboratory confirmation of infection.
In summary, antibiotic treatment using carbapenems and quinolones is
indicated on demand in patients with severe AP and multiorgan failure at
admission and in those with hemodynamic shock. Antibiotics are also useful
with biliary AP, clinically acute cholecystitis and/or cholangitis, bacteriemia,
positive bronchoalveolar lavage, and urinary tract infection. Antibiotics of
choice are imipenem, meropenem or tigecycline in patients allergic to beta-
lactams. Fluconazole must be given if surgery is performed, if fungal isolation
in blood, drained fluids or tissue is obtained or when clinical improvement is
followed by the complications described in the treatment on demand.
Antibiotics in Acute Pancreatitis
189
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