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,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
]. 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
]. 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
Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol
2009; 104:S10S16.
An updated review on the studies that have examined the association of gastric
acidity blockers and enteric infections.
3 Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric
infection in patients taking acid suppression. Am J Gastroenterol 2007;
102:20472056.
4 Muir Gray JA. Evidences-based healthcare: how to make health policy and
management decisions. London: Churchill Livingstone; 1997.
5 Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppressing drugs
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5:14181423.
6 Doorduyn Y, Van Pelt W, Siezen CLE, et al. Novel insight in the association
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7 Forssman B, Mannes T, Musto J, et al. Vibrio cholerae O1 El Tor cluster in
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9 Cadle RM, Mansouri MD, Logan N, et al. Association of proton-pump
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10 Doorduyn Y, Van Den Bradhof WE, Van Duynhoven YTHP, et al. Risk factors
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tions in the Netherlands: predominant roles for raw eggs in Enteritidis and
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11 Berni Canani R, Cirillo P, Roggero P, et al. Therapy with gastric acidity
inhibitors increases the risk of acute gastroenteritis and community-acquired
pneumonia in children. Pediatrics 2006; 117:e817e820.
12
Schubert ML, Peura DA. Control of gastric acid secretion in health and
disease. Gastroenterology 2008; 134:18421860.
An excellent review on the physiology and pathophysiology of gastric acid
secretion.
19 IMS Health National Sale Prescription Web site. 2004 Year-End US Pre-
scription and Sales Information and Commentary. http://www.imshealthca
nada.com/htmen/3_2_28.htm. (Accessed 21 November 2005)
Gastric acidity suppression and intestinal infections Berni Canani and Terrin 35