Dig Dis Sci (2008) 53:394398

DOI 10.1007/s10620-007-9899-9

ORIGINAL PAPER

Association between Proton Pump Inhibitor Use and Spontaneous

Bacterial Peritonitis
Mical S. Campbell Keith Obstein K. Rajender Reddy
Yu-Xiao Yang

Received: 13 December 2006 / Accepted: 4 June 2007 / Published online: 7 July 2007

Springer Science+Business Media, LLC 2007

Abstract Proton pump inhibitors (PPIs) increase enteric

bacterial colonization, overgrowth, and translocation, all
effects which might predispose to spontaneous bacterial
peritonitis. We investigated whether PPI usage is associated with spontaneous bacterial peritonitis. Our retrospective case-control study included 116 consecutive cirrhotic
patients with ascites who underwent diagnostic paracentesis upon hospital admission (20022005). Spontaneous
bacterial peritonitis was defined as paracentesis yielding
250 polymorphonuclear leukocytes/ml. We performed
logistic regression to determine the risk of spontaneous
bacterial peritonitis by PPI usage. Of the 116 subjects, 32
had spontaneous bacterial peritonitis. Patient characteristics were similar between groups with and without
infection, with the exception of the Model for End-Stage
Liver Disease score (median: 23 and 18, respectively;
P = 0.002). Crude and adjusted odds ratios for the devel-

opment of spontaneous bacterial peritonitis by exposure to

PPIs were 1.22 (95% confidence interval: 0.522.87) and
1.05 (0.432.57), respectively. In conclusion, we did not
find a positive association between PPI use and spontaneous bacterial peritonitis.
Keywords Acid suppression
Ascites
Cirrhosis

Heartburn
Proton pump inhibitors
Spontaneous bacterial
peritonitis)
Abbreviations
H2RA Histamine 2 receptor antagonist
MELD Model for end-stage liver disease
PMN
Polymorphonuclear leukocytes
PPI
Proton pump inhibitor
SBP
Spontaneous bacterial peritonitis

Mical S. Campbell and Keith Obstein contributed equally to this

work.

Introduction

The study was not funded. Dr. Y.-X. Yang has served as a consultant
to AstraZeneca.

Spontaneous bacterial peritonitis (SBP) is a common and

serious infection occurring in cirrhotic patients with ascites
[1]. Intestinal permeability to bacteria is increased in patients
with cirrhosis[2, 3], and one mechanism that has been suggested to explain SBP in these patients is that it evolves
because bacteria translocate across the leaky gut [46].
Uncontrolled bacterial growth in ascitic fluid then develops
as a result of an impaired host immune response [7, 8].
Because of the significant morbidity and mortality
related to SBP, identifying predisposing factors is of great
importance. Gastric acid is a key defense against enteric
pathogens, and the suppression of gastric acid has been
associated with increased bacterial colonization and an
enhanced viability of pathogenic bacteria in the gastroin-

M. S. Campbell
K. Obstein
K. R. Reddy

Y.-X. Yang
Department of Medicine, University of Pennsylvania,
Philadelphia, PA, USA
Y.-X. Yang
Center for Clinical Epidemiology and Biostatistics, University of
Pennsylvania, Philadelphia, PA, USA
M. S. Campbell
K. R. Reddy
Y.-X. Yang (&)
Division of Gastroenterology, Hospital of the University of
Pennsylvania, 3 Ravdin, 3400 Spruce St, Philadelphia, PA
19104, USA
e-mail: [email protected]

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395

testinal tract [9, 10], thereby leading to an increased risk of

infection. For example, both community-acquired pneumonia and ventilator-related pneumonia among intensive
care unit (ICU) patients [11, 12] have been associated with
the administration of proton pump inhibitors (PPIs), presumably through increased bacterial colonization in the
stomach [12]. Moreover, PPI use has been identified as an
important risk factor for the development of Clostridium
difficile-associated disease in some [1315] but not all
[16, 17] studies. In addition, impairment of gastrointestinal motility by PPIs or histamine 2 receptor antagonists
(H2RAs) can predispose to bacterial overgrowth and bacterial translocation [5, 9, 18, 19]. Finally, PPIs may impair
neutrophil function, potentially predisposing to bacterial
infection [20, 21]. A recent study showed, as a secondary
finding, that acid-suppressive therapy was associated with a
trend towards a markedly increased risk for development of
SBP [9]. Against this background, we sought to specifically
determine whether PPI use was associated with SBP among
hospitalized cirrhotic patients who underwent diagnostic
paracentesis.

sis. Diagnostic paracentesis to identify SBP is standardly

performed on all cirrhotics with ascites admitted to our
hospital, regardless of the reason for admission. SBP was
defined as a paracentesis yielding 250 polymorphonuclear
leukocytes (PMN)/ml in the ascitic fluid. We did not
require positive ascitic fluid cultures to diagnose SBP. The
case group consisted of patients who met the SBP criteria
on their first paracentesis after admission. Patients with
ascites fluid PMN cell counts of <250 cells/ml were considered not to have SBP and constituted the control group.
We did not collect data on subsequent paracenteses
performed in the same patient.

Methods

Statistical analysis

Study population

Non-parametric data were compared using rank-sum tests.

Categorical data were compared with Fishers exact test.
Logistic regression was performed to determine the crude
and adjusted odds ratios (ORs) of developing SBP associated with use of PPI or any acid-suppressive agent (H2RA
or PPI). Multivariate analysis was performed to assess for
potential confounding effects of age, bilirubin, prothrombin time (INR), creatinine, Model for End-Stage Liver
Disease (MELD) score, diabetes mellitus, gender, race,
history of SBP, and etiology of liver disease. MELD scores
were calculated according to the method used by the
United Network of Organ Sharing (http://www.unos.org).
Histories of prior spontaneous bacterial peritonitis, diabetes
mellitus, and etiology of liver disease were obtained from
inpatient medical histories. Laboratory data at time of
admission were used. Only confounders affecting the
unadjusted point estimate by 10% or more were included in
the final multivariate model [22]. P-values < 0.05 were
considered to be significant, and two-sided tests were used.
All analyses were performed using STATA ver. 8.1 (Stata
Corp, College Station, Tex.).

We conducted a retrospective review of 214 consecutive

cirrhotic inpatients who underwent diagnostic paracentesis
within 5 days of admission to the University of Pennsylvania Health System from January 2002 to December
2005. Thirty of these patients were immunosuppressed due
to HIV infection or prior transplantation. Such patients may
have been more predisposed to developing SBP regardless
of PPI exposure and were therefore excluded from further
analysis. Seventy-eight patients had been exposed to antibiotics either within 2 weeks prior to hospitalization or
prior to paracentesis following hospital admission. These
patients were excluded because antibiotic administration
may have prevented the development of SBP, thus masking
a possible effect of PPI use on SBP development. A second
reason for this exclusion was that initiation of antibiotic
treatment may have rendered paracentesis insensitive for
the diagnosis of SBP. Of these 78 patients, ten met both
immunosuppression and antibiotic exposure exclusion
criteria. The remaining 116 patients were included in the
study.

Exposure
Exposure to PPIs and H2RAs was assessed by manually
reviewing medication history recorded in the inpatient
medical record upon hospital admission. We did not separate PPI or H2RA usage by individual drugs and daily
dosages, as there were too few patients in some of the strata
to yield interpretable results. In all cases, the medications
had been prescribed on a daily basis.

Cases and controls

Results

We reviewed consecutive inpatient records of all patients

admitted to the University of Pennsylvania Health System
who had ascites and had undergone diagnostic paracente-

Of the 116 eligible study subjects 32 patients had SBP, and

84 did not. Clinical characteristics of the two groups are
summarized in Table 1. SBP patients tended to have higher

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Dig Dis Sci (2008) 53:394398

Table 1 Clinical chacteristics of patients with and without spontaneous bacterial peritonitis
Variablea

SBP present (n = 32)b

SBP absent (n = 84)b

P-value

PMN count in ascites (cells/ml)

2077 (739, 4,183)

13 (5, 41)

<0.001*

17 (53%)

48 (57%)

Acid suppression
None

0.89

Proton pump inhibitor

13 (41%)

30 (36%)

H2RA

2 (6%)

6 (7%)

Age (years)

53.9 10.1

54.9 11.0

Male gender

23 (72%)

55 (65%)

Race

0.65
0.66
0.42

Caucasian

23 (72%)

49 (58%)

AfricanAmerican

5 (16%)

21 (25%)

Other or unknown

4 (13%)

14 (17%)

HCV alcohol

20 (63%)

42 (51%)

Alcohol

5 (16%)

17 (20%)

NASH/Cryptogenic
PBC/PSC/AIH

3 (9%)
2 (6%)

10 (12%)
4 (5%)

Hepatitis B

0 (0%)

5 (6%)

Other

2 (6%)

5 (6%)

Diabetes mellitus

10 (31%)

19 (23%)

History of SBP

3 (9%)

2 (2%)

INR

1.8 (1.6, 2.3)

1.5 (1.3, 1.8)

<0.001*

Etiology of liver disease

0.77

0.35
0.13

Creatinine (mg/dl)

1.3 (0.9, 2.3)

1.1 (0.8, 2.0)

0.48

Bilirubin (mg/dl)

4.1 (2.6, 7.0)

2.6 (1.3, 5.6)

0.01*

MELD score

23 (18, 29)

18 (13, 22)

0.002*

15

5 (16%)

30 (36%)

1624

14 (44%)

40 (48%)

25

13 (41%)

14 (17%)

MELD group

0.02*

* P < 0.05
a

SBP, Spontaneous bacterial peritonitis; H2RA, histamine 2 receptor antagonist; HCV, hepatitis C virus; NASH, non-alcoholic steatohepatitis;
PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis; INR, international normalized ratio; MELD,
Model for End-Stage Liver Disease; INR, prothrombin time; PMN, polymorphonuclear leukocytes

Values are given as the median (25%, 75%), or as n (%)

INR, bilirubin, and MELD scores than subjects without

SBP (Table 1). The two groups were otherwise similar.
Moreover, rates of PPI and H2RA use were similar
between those with and without SBP; 41% of SBP patients
and 36% of subjects without SBP were taking PPIs
(Table 1).
The crude ORs for the development of SBP among PPI
users versus non-users was 1.22 [95%confidence interval
(95% CI): 0.52, 2.87], P = 0.64 (Table 2). Broadening the
definition of acid suppression to also include those exposed
to H2RAs did not significantly alter this point estimate
(Table 2). Multivariate analysis did not result in either
MELD or its separate components (bilirubin, INR, and
creatinine) significantly affecting our unadjusted point

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estimate. The only significant confounder was race, which

was included in the final multivariable model. After
adjusting for race, the ORs for SBP among subjects taking
PPIs was 1.05 (95%CI: 0.43, 2.57), P = 0.91 (Table 2).

Discussion
We did not find evidence in this study that the use of PPIs
was associated with a markedly increased risk of development of SBP. Biologically, PPI use might be expected to
predispose to infection because gastric acidity is an
important defense against enteric pathogens. Some investigators have demonstrated positive associations between

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397

Table 2 Risk of spontaneous bacterial according to acid suppression

a

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

PPI

1.22 (0.52, 2.87)

1.05 (0.43, 2.57)

PPI or H2RA

1.18 (0.52, 2.67)

1.03 (0.44, 2.40)

OR, Odds ratio; 95% CI, 95% confidence interval; PPI, proton pump
inhibitor; H2RA, histamine 2 receptor antagonist
a

Adjusted for race

the administration of acid suppression therapy and the

development of Clostridium difficile-associated diseases as
well as community-acquired and nosocomial pneumonia
[1115], although the association between PPI therapy and
the risk of infection remains controversial. [16, 17]
Furthermore, a small-scale previous study suggested a
markedly increased risk of SBP with the use of PPIs
(OR = 7.0, P = 0.08) [9]. Although we did not observe an
increase of such a large magnitude in the risk of SBP
associated with PPI therapy in this study, we could not rule
out the possibility of a modest increase in SBP risk due to
acid-suppressive therapy. Given how commonly acid-suppressive therapy is used in cirrhotics with ascites, it will be
important for other studies to exclude a possible small
increased risk of SBP in PPI users.
Our study has several important strengths. Compared to
the previous study that addressed the association between
SBP risk and PPI therapy in a secondary fashion, our study
was specifically designed to investigate this issue. Our
study also included more patients than the previous study,
which may have enhanced the precision of our point
estimates.
SBP is a common infection among cirrhotics and often
presents with subtle manifestations. As a standard of
practice, diagnostic paracentesis to identify SBP is
performed on all cirrhotics with ascites admitted to our
hospital, regardless of the reason for admission. Therefore,
we were able to capture all cases of SBP in our study
cohort. Patients who have been immunosuppressed or
recently exposed to antibiotics might be more or less likely,
respectively, to develop SBP, independent of PPI exposure.
We excluded all such patients so that our results are more
generalizable to the average end-stage liver disease
(ESLD) patients with ascites.
As expected, the median MELD score in SBP patients
was higher 23 than that in non-SBP patients 18. This
difference was statistically significant and likely reflects
the fact that patients with more advanced liver disease are
more likely to develop life-threatening complications such
as SBP. An alternative plausible explanation is that SBP
may lead to transiently worsening hepatic synthetic

function and renal function, resulting in a higher MELD

score on presentation. In any case, MELD score was not a
significant confounder in the association between PPI
therapy and SBP.
A diagnosis of SBP was made for patients with 250
PMN/ml of ascites fluid. We did not use ascites fluid culture data to aid in the diagnosis because the reliability the
culture data in our cohort is questionable. Ascites cultures
have a high yield when done properly (i.e., in blood culture
bottles with an adequate inoculum of 10 cc at bedside) [23,
24]. However, uniform proper techniques and high yield
are attainable only when relatively few people who are
also well-trained are involved. Given the large volume
and high turnover rate of the housestaff and students
involved in our institution, one cannot be confident that
proper culture collection techniques were followed consistently. In any case, since neutrocytic ascites has the same
clinical course as culture-positive ascites, it is not likely we
over-diagnosed SBP in the absence of a positive culture.
Moreover, bacterascites, defined as a positive culture
without an elevation in ascitic fluid neutrophil count, may
in some cases represent a contaminant in culture media.
Our definition of SBP may have lead to misclassification of
early SBP cases as controls. However, given the rarity of
bacterascites, it is unlikely to have biased our results significantly.
Several other potential limitations of our study warrant
consideration. We relied on nursing and physician admission notes to identify exposure to acid-suppressive therapy.
It is possible that other methods of identifying medication
exposure, such as corroboration with pharmacy records or
outpatient physician records, may have enhanced reporting
accuracy. Such an approach was impractical for our study.
We do not suspect that patients ultimately diagnosed with
SBP would have been more or less likely to have reported
acid-suppressive therapy on their hospital admission histories compared with the controls. We did not perform
separate analyses for different PPI formulations because of
the limited sample size, but there is no obvious reason why
the risk, if any, would be different among different formulations. Lastly, we were unable to perform an analysis
of PPI dosage and frequency of administration upon
development of SBP due to lack of sufficient statistical
power. Therefore, we instead report whether patients were
regularly taking PPI or H2RA prior to hospital admission.
In conclusion, our study addressed an important clinical
question, as PPI use is very common in cirrhotic patients
with ascites. We did not find a relationship between acidsuppressive therapy and the development of SBP in this
patient population. Further studies are needed to confirm
our results.

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