Open Journal of Gastroenterology, 2013, 3, 276-280 OJGas
http://dx.doi.org/10.4236/ojgas.2013.35047 Published Online September 2013 (http://www.scirp.org/journal/ojgas/)
Incidence of Clostridium difficile-associated diarrhea in
patients using proton pump inhibitors: A Japanese study
Takatoshi Kitazawa*, Yusuke Yoshino, Ichiro Koga, Akari Isono, Takatsugu Yamamoto,
Yasushi Kuyama, Yasuo Ota
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
Received 10 July 2013; revised 9 August 2013; accepted 15 August 2013
Copyright © 2013 Takatoshi Kitazawa et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Objective: The incidence of Clostridium difficile-as-
sociated diarrhea (CDAD) has increased in many de-
veloped countries. In addition to previous use of an-
timicrobials, use of proton pump inhibitors (PPIs) is
thought to increase the incidence of CDAD. Howev er,
most previous studies that showed a positive rela-
tionship between PPI use and CDAD were conducted
retrospectively in Western countries. We investigated
whether the use of PPIs increases the incidence of
CDAD in Japan. Methods: The study was carried out
with all the patients admitted to the department of
internal medicine of Teikyo University Hospital from
April 2009 to June 2009. Clinical data were obtained
from medical records. CDAD was defined as detec-
tion of CD toxin from stool samples in diarrheal pa-
tients. PPI users were defined as patients that were
prescribed with PPI for more than 30 days at the de-
tection of CD toxin. The results of Clostridium difficile
(CD) toxin were collected until April 2011. Results: A
total of 793 patients were included, and PPIs were
prescribed to 489 patients (59.8%). The average age
of PPI users was higher than that of PPI nonusers
(68.9 vs. 63.1 years). Among the 489 PPI users, 19
patients developed CDAD, while 4 developed CDAD
among the 304 PPI nonusers. The relative risk of PPI
use on the incidence of CDAD was 3.20 in univariate
analysis (95% confidence interval, 1.10 to 9.32, p =
0.04), although the hazard ratio in multivariate analy-
sis was 1.23 (95% confidence interval, 0.35 to 3.83, p
= 0.82). Conclusions: There was no association be-
tween CDAD occurrence and PPI use in patients in
Japan.
Keywords: Cl ostridium difficile-Associated Diarrhea;
Proton Pump Inhibitors; Risk Factor
1. INTRODUCTION
Clostridium difficile is a gram-positive anaerobe that
causes a spectrum of diseases from asymptomatic car-
riage to mild diarrhea to severe pseudomembranous co-
litis. There has been a dramatic increase in the incidence
of C. difficile-associated diarrhea (CDAD) in many de-
veloped countries. Development of CDAD in hospital-
ized patients is associated with length of hospital stay,
resulting in higher health care costs [1]. The dominant
risk factor is antibiotic use [2,3], but other postulated risk
factors include advanced age, severe underlying illnesses
[4], hospitalization [2], non-surgical gastrointestinal pro-
cedures [5], antineoplastic chemotherapy and immuno-
suppressant agents. In addition to these risk factors, long-
term use of proton pump inhibitors (PPIs) has been sug-
gested to be a risk factor for CDAD [6-10]. However,
most previous epidemiological studies that showed a
positive relationship between PPI use and CDAD were
conducted retrospectively in Western countries. In this
study, we investigated whether use of PPIs increases the
incidence of CDAD at a single institution in Japan.
2. METHODS
2.1. Study Population
We enrolled all of the patients admitted to the Depart-
ment of Internal Medicine of Teikyo University Hospital
(teaching hospital, 1154 beds) in Japan from April 2009
to June 2009, and observed these patients from April
2009 to April 2011. This study design had hospital ethics
committee approval; informed consent was waived.
2.2. Case Definition
PPI users were defined as patients prescribed PPIs for
*Corresponding author.

T. Kitazawa et al. / Open Journal of Gastroenterology 3 (2013) 276-280 277
more than 30 days. CDAD was defined as detection of
CD toxin from stool samples in diarrheal patients. Usage
of immunosuppressants was defined as use of more than
20 mg of prednisolone for more than 30 days. Long
hospital stay was defined as a case of total hospitali-
zation for more than 30 days. Comorbid diseases were
defined as: renal failure, estimated glomerular filtration
rate (eGFR) <30 ml/min; diabetes mellitus, fasting blood
sugar levels of 126 mg/dl, or HbA1c ≥6.1%, or past
treatment history; solid tumors, radiologically or pathol-
ogically verified masses; hematological malignancy, pa-
thologically verified leukemia or lymphoma.
2.3. Evaluation of Clinical Background Data
Clinical data were obtained from medical records, and
the results of C. difficile toxin analysis were collected
until April 2011. Clinical courses of the patients were
retrospectively reviewed to determine the following de-
mographic characteristics: age; gender; comorbid dis-
eases; usage of drugs; hospital stay and occurrence of
CDAD.
2.4. Statistical Analysis
The student’s t-test for continuous variables and chi-
squared test were used when appropriate to compare
proportions. For multivariate analysis, the logistic re-
gression analysis was used. All p values were two-sided
and were considered to be statistically significant when p
< 0.05.
3. RESULTS
3.1. Clinical Factors in PPI Users and Nonusers
A total of 793 patients were included in this study.
PPIs were prescribed to 489 patients (61.6%) (Ta b l e 1 ).
The average age of PPI users was higher than that of
PPI nonusers (68.9 ± 13.8 vs. 63.1 ± 17.8 years, p <
0.01), and the proportion of male patients among PPI
users was also higher than that among PPI nonusers
(male/female ratio, 2.26 vs. 1.36, p = 0.04). Among the
487 PPI users, 19 patients developed CDAD, while 4
developed CDAD among the 304 PPI nonusers. The
relative risk of PPI use on the incidence of CDAD was
3.20 (95% confidence interval, 1.10 to 9.32, p = 0.04).
The proportion of patients with ICU stay was higher
in PPI users than that of PPI nonusers (8% vs. 4%, p
= 0.03). Multiple logistic regression analysis showed
that age, sex, use of H2 receptor antagonists, long
hospital stay, and ICU stay were associated with use of
PPI (Table 2). We could not demonstrate association
between use of antibiotics, CDAD and use of PPI (Table
2).
Table 1. Clinical characteristics of proton pump inhibitor users
and nonusers.
Categories PPI user
(n = 489)
PPI nonuser
(n = 304) p
Age (years, mean ± S.D.) 68.9 ± 13.8 63.1 ± 17.8<0.01
Sex (male) 338 189 0.04
Cormobid diseases
Renal failure 14 8 0.85
Diabetes 41 32 0.31
Solid tumor 32 21 0.84
Hematological malignancy 25 10 0.22
Inflammatory bowel disease2 2 0.53
Peptic ulcer 16 7 0.43
Collagen disease 15 12 0.51
Cirrhosis 7 3 0.59
Usage of drugs
Antibiotics (duration; days) <0.01
<4 229 183
4 - 14 72 50
>14 186 71
H2 receptor antagonist 21 66 <0.01
Laxative 78 54 0.51
Immunosuppresant 62 34 0.53
Anticancer drug 53 34 0.88
Hospital stay
Long stay (>30 days) 246 71 <0.01
ICU stay 40 13 0.03
CDAD 19 4 0.04
Abbreviations: PPI, proton pump inhibitor; S.D., standard deviation; ICU,
intensive care unit; CDAD, Clo storidi um difficile-associated diarrhea.
Table 2. Clinical characteristics of proton pump inhibitor users
and nonusers.
Categories HR 95% CI p
Age (≥65 years) 1.21 1.29 - 2.51 <0.001
Sex (male) 1.71 1.22 - 2.40 0.002
Usage of drugs
Antibiotics (duration; days)
<4 1.00
4 - 14 1.26 0.72 - 1.77 0.61
>14 1.00 0.58 - 1.73 0.99
H2 receptor antagonist 0.10 0.06 - 0.18 <0.001
Hospital stay
Long stay (>30 days) 0.19 0.12 - 0.32 <0.001
ICU stay 2.86 1.42 - 5.78 0.006
CDAD 1.23 0.35 - 3.83 0.82
Abbreviations: HR, hazard ratio; ICU,CI, confidence interval; ICU,
intensive care unit; CDAD, Clo storidi um difficile-associated diarrhea.

T. Kitazawa et al. / Open Journal of Gastroenterology 3 (2013) 276-280 278
3.2. Incidence of CDAD during the Study Period
The cumulative incidence of CDAD during the study
period is shown in Figure 1. The onset of CDAD in
more than half patients was within 200 days after
admission in both PPI users and nonusers, although there
were no significant differences between the two groups
(12 cases in 19 PPI users, 2 cases in 4 PPI nonusers, p =
0.62).
4. DISCUSSION
PPIs are the major treatment for gastroesophageal
diseases. From American College of Gastroenterology
guidelines and a review article, indications for PPI use
are as follows: gastroesophageal reflux disease, with
complications such as Barrett’s esophagus; presence of
peptic ulcer disease (PUD) in the stomach or duodenum;
use of non-steroidal anti-inflammatory drugs (NSAIDs)
or aspirin, and at least one other risk factor (among age
over 70 years, medical history or complications of PUD,
untreated Helicobacter pylori infection with a history of
PUD, and/or medical history of gastric hemorrhage or
perforation); and simultaneous use of antiplatelet agents,
corticosteroids, anticoagulant drugs or selective sero-
tonin reuptake inhibitors. In Japan, approximately half of
physicians did not use international guidelines [11], and
the most frequently chosen drug for comedication with
NSAIDs was a mucoprotective drug with an approxi-
mately equal frequency of either PPI or H2-receptor anta-
gonist use [12]. In this study, the proportion of PPI use
was 61.6%, which was higher than that in other reports
in Japan. We believe that the reason for the higher pro-
Figure 1. Cumulative incidence of Clostridium difficile-asso-
ciated diarrhea (CDAD) during the study period. CDAD oc-
curred continuously both in proton pump inhibitor (PPI) users
and nonusers.
portion of PPI use is that patients with coronary disease
are aggressively treated. Craig et al. noted that the ma-
jority of intravenous PPI prescriptions in hospital were
inappropriate, particularly when initiated for non-upper
gastroesophageal bleeding indications.
We did not investigate the appropriateness of PPI use
in PPI users. If patients with inappropriate use of PPI
were excluded from this study, the incidence of CDAD
in PPI users may have been higher, as CDAD patients
used PPI more frequently than non-CDAD patients, and
the patients met the indications for PPI use. Among other
risk factors for CDAD incidence, short duration (<4 days)
of antibiotic administration was pre-dominant in PPI
users and PPI nonusers in this study (47% and 62%,
respectively). Stevens et al. reported that cumulative an-
tibiotic exposure appears to be associated with the risk of
CDAD, although the ratio of short duration of antibiotic
use was 9% and 22%, respectively [13]. The high pro-
portion of patients with short duration of antibiotic use
might be due to prophylaxis for coronary intervention.
Our study showed that PPI users tended to have
multiple risk factors for CDAD occurrence when com-
pared with PPI nonusers. A previous cohort study re-
ported that in addition to a higher incidence of CDAD,
PPI users tended to stay in surgical or medical wards
longer and were exposed to more than one antibiotic,
which was consistent with our study [14]. However,
among our data, average hospital stay in PPI users was
shorter than that of PPI nonusers. We speculated this
tendency because patients with coronary diseases were
included among PPI users for the purpose of coronary
angiography. From this finding, we believe that it is
difficult to evaluate the influence of PPI usage on all
hospitalized patients prospectively because more PPI
users tend to receive intensive care, which can be biased
towards the relationship between PPI usage and CDAD.
To lessen the influence of other risk factors on CDAD
occurrence by PPI usage, subanalysis of more patients
may be required.
On univariate analysis, usage of PPIs was a significant
risk factor for the onset of CDAD, but no such rela-
tionship was seen on multivariate analysis in this study.
Several reports have noted that usage of PPI was signi-
ficantly related to CDAD [6-9]. In contrast, several other
reports have found no relationship between PPI usage
and CDAD occurrence [15,16]; however, these studies
used cohorts of elderly subjects. Age is also a risk factor
for CDAD [17,18]. In our study, the average age of the
patients was 66.5 years, which is consistent with other
studies. Yearsley et al. reported that CDAD was inde-
pendently associated with acid suppression therapy with
PPI in the case-control study. The average age of the
cases in the study was higher than that of our study, and
ratio of the cases who had received antibiotics was high

T. Kitazawa et al. / Open Journal of Gastroenterology 3 (2013) 276-280 279
(92%) [19]. Patients using PPIs tended to develop CDAD,
but the statistical significance was weak. A meta-analysis
conducted by Janarthan et al. suggested that PPIs in-
creased the incidence of CDAD [20]. This analysis was
included in the retrospective hospital-based studies and
population-based case-control studies. Clinical back-
grounds of the subjects influence the results in the study
about association between PPIs and the incidence of
CDAD.
In our study, CDAD occurred both soon after admis-
sion and later during hospitalization. Acquisition of C.
difficile and occurrence of CDAD are considered to
occur by two routes. The first route is that C. difficile
intrinsically colonizes the host intestine and proliferates
under selective pressure such as antibiotic exposure. The
second route is that C. difficile is transmitted exogen-
ously by the medical environment and proliferates after
reductions in host microflora. We believe that CDAD
mainly occurs by exogenous transmission rather than
intrinsic proliferation.
In conclusion, there were trends observed between
CDAD incidence and PPI use in patients with advanced
age, antibiotic usage and shorter hospital stays, although
statistical association between CDAD incidence and PPI
use was not demonstrated.
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