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Gastric acidity inhibitors and the risk of intestinal infections


Roberto Berni Canani
a,b
and Gianluca Terrin
a
Introduction
Gastric acid secretion is a phylogenetically old function
that developed about 500 million years ago [1]. Recent
years have seen widespread use of potent gastric acidity
inhibitors (GAIs) in the management of many upper
gastrointestinal disorders, also in pediatric patients. The
efcacy of these drugs has continued to improve as more
potent acid suppressants have been introduced, but
concerns have been raised with respect to the effects
of GAIs on host defenses and thus, on the risk of
infections. The concept of gastric microbicidial barrier
was introduced in 1925, subsequently, it has been
repeatedly reported that the suppression of gastric a-
cidity predisposes to infection by a variety of pathogens,
but only recently has the increased risk of infection
induced by GAIs been investigated systematically at
clinical and laboratory level [1]. The following is a
summary of the recent clinical studies performed in
adults, children, and neonates exploring the possible
association of GAI use with intestinal infections.
Updated pathogenetic hypotheses have also been
reviewed.
Clinical studies
Gastric juice consists of HCl and pepsin and can kill
bacteria within 15 min when the pH is less than 3.0. If the
pH is raised above 4.0, a state dened as hypochlorhydria,
bacterial overgrowth and infections are more common
[2

]. Different bacterial pathogens have been reported in


the studies investigating the side-effects of GAI use. Few
studies have focused on parasitic or fungal infections, and
no data are available on viral intestinal infections
[1,2

,3,4]. The most investigated associations of selected


pathogens with GAI use are reported in Table 1. In this
section, we will focus on more recent data on GAI-
associated intestinal infections occurring during different
ages of life. For systematic reviews see [1,2

,3].
Adults
The vast majority of the studies investigating effects of
GAI therapy on gastrointestinal infection susceptibility
were performed in adult patients. Diarrhea has been
reported to be a side-effect of proton pump inhibitor
(PPI) therapy since the rst study of surveillance. On
a multivariate analysis, the presence of diarrhea was
a
Department of Pediatrics and
b
European Laboratory
for the Investigation on Food Induced Diseases
University Federico II of Naples, Naples, Italy
Correspondence to Roberto Berni Canani, MD, PhD,
Department of Pediatrics, University of Naples
Federico II, Via Pansini 5, 80131 Naples, Italy
Tel/fax: +39 0817462680; e-mail: berni@unina.it
Current Opinion in Gastroenterology 2010,
26:3135
Purpose of review
We reviewed recent clinical studies performed in adults, children, and neonates
exploring the possible association of gastric acidity inhibitors use with intestinal
infections. Possible mechanisms have also been reported.
Recent ndings
Many studies and systematic reviews demonstrate an increased risk of bacterial
infection in adults taking acid suppressors. Little evidence is derived from the pediatric
population. The use of gastric acidity inhibitors has been associated with systemic
infections and necrotizing enterocolitis in preterm infants. Reduced gastric acidity,
delayed gastric emptying, increased gastric mucus viscosity, modication in microbiota,
and impairment of neutrophils functions, are all conditions determined by gastric acidity
blockers that potentially lead to an increased risk of gastrointestinal infections.
Summary
A proper utilization of these drugs, particularly for patients at high risk, is imperative in
order to reduce deleterious effects on infection risk and to optimize cost-effectiveness
ratio.
Keywords
Clostridium difcile, diarrhea, histamine 2 receptor antagonists, neonates, proton
pump inhibitors
Curr Opin Gastroenterol 26:3135
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0267-1379
0267-1379 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOG.0b013e328333d781
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
signicantly associated with the use of PPI [odds ratio
(OR) 2.97 (range 2.04.4)], second only to antibiotics in
terms of magnitude of the association. Although most of
these studies did not explore the cause of diarrhea, as
infections are the most common cause of acute diarrhea,
it is likely that some of these episodes were infectious
[2

]. Subsequently, many studies have investigated


directly the association of gastrointestinal infections with
GAI use. Many of these investigations are casecontrol
studies, and only three were prospectively designed.
More recently, a systematic review including 25 studies
evaluating 29 748 participants was performed in order to
assess the risk of enteric infection in patients taking
GAIs. This meta-analysis showed an increased risk of
enteric infections in patients taking GAIs, to cure gastro-
esophageal reux disease (GERD), determined by the
prevalence of two well known acid-sensitive pathogens:
Salmonella and Campylobacter [OR 2.55, 95% condence
interval (CI) 1.534.26] [3]. Recent studies suggested
that increasing dosage and duration of GAI use determine
an increased risk of gastrointestinal infections [5]. Cam-
pylobacter or Salmonella infections in women and use of
PPI and a single-nucleotide polymorphism (SNP) in the
interferon-gamma gene (rs2430561) have been demon-
strated as independent risk factors for reactive arthritis
following enteric infection [6]. Another SNP in the
interferon-gamma gene (rs1861493) and the use of PPI
have been demonstrated as risk factors for recurrent
episodes of acute gastroenteritis [6]. There have been
no systematic reports of an association of GAIs and viral
gastroenteritis, Shighella, Escherichia coli, cholera, and
parasites. Recently, three cases of Vibrio cholerae O1 El
Tor infection, linked to the consumption of rawwhitebait
imported from Indonesia, have been described in Aus-
tralian women undergoing long-term PPI therapy [7].
Regarding parasites, there was a single study suggesting
an association between hypochlorhydria and Giardia
infection [8]. The use of H
2
receptor antagonists
(H
2
RA) has been associated with Strongyloides infections,
especially in immunosuppressed patients [2

]. Twenty-
seven studies have examined association with Clostridium
difcile infections. The vast majority of them (19 out of
27) have demonstrated a clear association with C. difcile
infection. Compared with the studies of other pathogens
that are all community based, the majority of C. difcile
investigations are hospital based, and improper choice of
controls of infections may contribute to the discrepant
results being obtained. A meta-analysis reports that there
was an increased risk of taking antisecretory therapy in
those infected with C. difcile (pooled OR1.94, 95%1.37
2.75). There was signicant heterogeneity between the
studies that was not explained by planned subgroup
analysis. The association was greater for PPI use (OR
1.96, 95% CI 1.283.00), compared with H
2
RA use (OR
1.40, 95% CI 0.852.29) [3]. Therapy with PPI is also
associated with an increased risk of recurrent C. difcile
colitis. Patients receiving PPIs have been found to be
4.17 times as likely to have recurrence as their counter-
parts not receiving them [9].
Children
A recent casecontrol study of risk factors for Salmonella
enteritidis in the Netherlands showed an increased risk of
gastroenteritis induced by these pathogens in children
taking GAIs (OR 3.6, range 1.96.9) [10]. A prospective
study performed in pediatric patients showing that the
use of GAIs is associated with an increased risk of acute
gastroenteritis and community-acquired pneumonia in
GERD-affected children has been recently published
by our group [11]. We obtained data on 186 participants
from four pediatric gastroenterology centers: 95 healthy
controls and 91 GAI users (47 on ranitidine and 44 on
omeprazole). The two groups were comparable for age,
sex, weight, length, and incidence of acute gastroenteritis
and pneumonia in the 4 months prior to enrollment. Rate
of acute gastroenteritis and community-acquired pneu-
monia was signicantly increased in patients treated with
GAIs compared with healthy controls (acute gastroenter-
itis: 47 vs. 20%, P0.001; pneumonia: 12 vs. 2%,
P0.03) during the 4-month follow-up period. In the
GAI-treated group, the rate of acute gastroenteritis (20 vs.
47%, P<0.0001) and community-acquired pneumonia (3
vs. 12%, P0.02) was increased when comparing the
rates 4 months before and after the enrollment. No
differences in acute gastroenteritis and pneumonia inci-
dence were observed between ranitidine and omeprazole
users in the previous 4 months and during the follow-up
period. On the contrary, in healthy controls, the incidence
of acute gastroenteritis and pneumonia remained stable.
It could be interesting to underline that in this study we
observed an increased incidence of intestinal and respir-
atory infections in otherwise healthy children taking
GAIs for GERD treatment. On the contrary, the majority
of the previous data showed that the patients most at risk
for pneumonia were those with signicant co-morbid
illnesses such as diabetes or immunodeciency, and this
32 Gastrointestinal infections
Table 1 Pathogens possibly responsible for gastrointestinal
infections in patients treated with gastric acidity inhibitors
Pathogen Drugs
a
Strength of
evidences
b
Bacteria
Clostridium difcile H
2
RA/PPI I
Nontyphoid Salmonella spp. H
2
RA/PPI I
Campylobacter jejuni H
2
RA/PPI I
Brucella spp. H
2
RA/PPI Vb
Vibrio cholera PPI Vb
Parasites
Giardia lamblia H
2
RA Vb
Strongyloides stercoralis H
2
RA Vb
Fungi
Candida albicans H
2
RA/PPI Vb
a
H
2
RA, histamine 2 receptor antagonists; PPI, proton pump inhibitor.
b
Strength of evidences based on [4].
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
points to the importance of gastric acidity suppression as a
major risk factor for infections. The effect on infection
susceptibility seems to be sustained even after the end of
therapy. We observed a similar incidence of acute gastro-
enteritis and pneumonia during the use of GAI drugs and
in the 2 months following the stop of their use as observed
previously in adult patients [12

]. How long this effect


can last remains to be dened in future studies. GERD is
commonly clinically diagnosed in children with many
nonspecic symptoms, and frequently the treatment is
empiric. These results could leave pediatricians with
some unanswered questions about how to handle GAIs
in selected patients with severe neurological impairment
or chronic lung diseases. These patients appear to be at
increased risk for reux and aspiration. Protecting these
selected patients fromaspiration pneumonia secondary to
untreated reux is probably more convenient than pro-
tecting against the risk of infection associated with GAI
therapy. At the same time, considering the high risk of
inappropriate treatment in children, the pediatrician
needs to consider kindly the increased risk of infection
before prescribing a gastric acid blocker.
Newborns
Many drugs used in neonatal age are either not licensed
for the use or are prescribed outside the terms of their
product license (off label prescribing) [13]. The use of
these drugs in neonatal intensive care units (NICUs)
seems to be far greater than in other pediatric settings.
It has been recently reported that at least 30%of neonates
received treatment with GAIs at the time of discharge
from NICU [14]. The European Parliament and the
European Medicines Agency (EMEA), aiming to
increase the information available on the use of medicinal
products in the pediatric population, indicates as priority
safety studies on GAI use in children and newborns.
These observations are particularly relevant for very
low birth weight infants (VLBW) in whom infections
contribute signicantly to morbidity and mortality.
Recently, Stoll et al. [15] examined the relationship
between postnatal steroid exposure and H
2
RA therapy
(beginning at 2 weeks of age) and late-onset sepsis in
VLBW infants into a randomized, controlled trial. They
observed that treatment with dexamethasone and H
2
RA
was associated with an increased risk of sepsis and
meningitis. The increased risk of infection in infants
treated with H
2
RA before randomization to the study
drug (steroid or placebo) was postulated to be the result of
a change in small-bowel colonization after the develop-
ment of hypochlorhydria. Similarly, in a prospective
observational study, Beck-Sague et al. [16] reported that
12 (36%) of 33 VLBW neonates who received H
2
RA
developed bloodstream infections, whereas only 30
(9%) of 343 of those not treated with H
2
RA developed
bacteremia. In logistic-regression analysis, the risk of a
bloodstream infection was independently associated with
lower birth weight, respiratory illness at the time of
admission, and receipt of H
2
RA. They postulated that
gastric acidity may be a protective mechanism against
respiratory and gastrointestinal tract colonization by noso-
comial pathogens and subsequent bacteremia. More
recently, a retrospective study has observed an additional
risk of infections and necrotizing enterocolitis (NEC) in
newborns treated with GAIs [14]. Unfortunately, in
VLBW infants, the diagnosis of GERD or of peptic
disease is based on the evaluation of nonspecic symp-
toms, and the empiric treatment represents frequently
the rst diagnostic test. In addition, there is no clear
evidence of benet of the use of H
2
RA in many clinical
conditions typical of neonatal age. These observations
suggest the importance of a more careful use of GAIs in
these patients, in particular, if other risk factors for severe
infections are present.
Possible pathogenetic mechanisms
The mechanism of the deleterious effects on the risk of
infections in patients receiving GAIs is still not comple-
tely elucidated. A number of experimental and clinical
evidences suggest a multifactorial pathogenesis (Fig. 1).
The preservation of gastric acid secretion during phylo-
genesis supports the biological importance of this highly
energy consuming system developed to inactivate
ingested microorganisms. Gastric acid is important in
the killing of ingested acid-sensitive organisms; in
addition, elevation in gastric pH may also induce other
deleterious effects on gastrointestinal host defense
including delayed gastric emptying, increased bacterial
translocation, decreased gastric mucus viscosity, and
changes in the normal microbial ora [2

]. Impaired
gastric acid secretion has been shown to increase the
colonization by several bacterial and parasitic agents.
More recently, two experimental studies of C. difcile
infection showed that in a mouse model, pretreatment
with GAI before inoculation with C. difcile resulted in
similar rates of infection, toxin production, and colon
injury compared with a group of mice pretreated with
ampicillin. In addition, spore germination was noted to be
favored by elevated pH levels (pH6) and by the
presence of potassium chloride and inorganic phosphate.
As the proton pumps in the stomach exchange potassium
for hydrogen ions, it is possible that their blockage,
besides resulting in higher gastric pH levels, may also
result in increased intraluminal potassium [2

]. Direct
effects of GAI on several leukocyte functions have been
demonstrated, including decreased adhesion to endo-
thelial cells, reduced bactericidal killing of microbes,
and inhibition of neutrophil phagocytosis and phagosome
acidication. This could be particularly important in
elderly and neonatal age when immunity is still largely
immature. A direct effect of histamine on intestinal
immune response to selected pathogens has been
Gastric acidity suppression and intestinal infections Berni Canani and Terrin 33
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
demonstrated in animal model. To test whether inhi-
bition of gastric acid was involved in the effects of H
2
signaling on the mouse response to Yersinia enterocolitica,
Handley et al. [17] compared the effects of cimetidine
with the PPI omeprazole in the orally infected mouse
model. The authors identied no effect of omeprazole
under their conditions, suggesting that gastric acid pro-
duction is not involved in the effects of cimetidine on Y.
enterocolitica infection, but rather that the H
2
antagonism
likely plays a role in regulating the innate immune
response to infection at the level of the Payers patches
[17]. Increased production of histamine is important for
controlling the infection, specically through H
2
recep-
tor. This increase in histamine could stimulate a signi-
cant inux of mast cells or basophils. After stimulation,
the histamine, upon cellular release, would bind to cells
expressing H
2
. Activation of H
2
has been shown to have a
variety of effects including altering the production of
inammatory cytokines and disrupting the Th1Th2
balance during the immune response. The Th1Th2
balance is known to be important for controlling such
infection. A negative inuence on the immune system
could be the consequence also of the modication of
quantitative and qualitative composition of intestinal
microora [17]. A study of the numbers and type of
bacteria in nasogastric tubes of patients receiving GAI
demonstrated an increased number of bacteria including
beta hemolytic Streptococcus, a known cause of com-
munity-acquired pneumonia [12

]. Considering the
information on the cross-talk between intestinal micro-
ora and immune system functions, it is important that
this aspect should be investigated in a more incisive
manner in the future. Concomitant risk factors including
pre-existence of chronic diseases, hospitalization, and
antibiotic use could contribute to an increased risk of
infections in patients taking GAIs (Fig. 1). Finally, it has
been demonstrated that when PPIs are prescribed to
patients with Helicobacter pylori infection, the acid inhi-
bition is more profound than in patients without H. pylori
infection [18

]. Patients with H. pylori infection may,


therefore, be at greater risk for infection.
Conclusion
GAI use accounts for signicant cost expenditure in
western countries, including over-the-counter and pre-
scription formulations [3,19]. With the increasing use of
GAIs, the demonstration of an association with an
increased risk of intestinal and extraintestinal infections,
and increasing concerns of multiresistant pathogens,
public and professional education is needed to stress
the importance of appropriate use of antisecretory drugs.
Because no drug is without side-effects, physicians have
to satisfy themselves that the benets of treatment out-
weigh the potential risks. Further pharmacovigilance
studies exploring all the possible variables inuencing
the impact of GAI therapy on the risk of infections
are necessary, together with more basic and clinical
34 Gastrointestinal infections
Figure 1 The multifactorial pathogenesis of the increased risk of gastrointestinal infections in patients treated with gastric acidity
inhibitors
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
investigations on the mechanisms of these GAI-related
problems and on possible prophylactic measures to pre-
vent them.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 74).
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Gastric acidity suppression and intestinal infections Berni Canani and Terrin 35