Proton Pump Inhibitor Therapy Predisposes to Community-acquired Streptococcus pneumoniae Pneumonia

C. P. C. de Jager; P. C. Wever; E. F. A. Gemen; M. G. H. van Oijen; A. B. van Gageldonk-Lafeber; P. D. Siersema; G. C. M. Kusters; R. J. F. Laheij


Aliment Pharmacol Ther. 2012;36(10):941-949. 

In This Article

Abstract and Introduction


Background The pathophysiological mechanisms which contribute to an increased risk of community-acquired pneumonia (CAP) in patients using proton pump inhibitors are not well established.
Aim To examine differences in microbial etiology in patients with CAP between patients with and without proton pump inhibitor (PPI) therapy and its possible impact on disease severity.
Methods All individuals consulting the emergency care unit were prospectively registered and underwent chest radiography. Sputum, urine, nose-throat swabs and blood samples were obtained for microbial evaluation. We evaluated the association between use of proton pump inhibitors, etiology of CAP and severity of illness with multivariate regression analysis.
Results The final cohort comprised 463 patients, 29% using proton pump inhibitors (PPIs). Pathogens regarded as oropharyngeal flora were more common in CAP patients using PPI therapy compared to those who did not (adjusted OR: 2.0; 95% CI: 1.22–3.72). Patients using proton pump inhibitors more frequently had an infection with Streptococcus pneumoniae (28% vs. 14%) and less frequently with Coxiella burnetii (8% vs. 19%) compared to nonuser of PPI. Adjusted for baseline differences, the risk of PPI users being infected with S. pneumonia was 2.23 times (95% CI: 1.28–3.75) higher compared to patients without PPI's. No risk between PPI use and any other microbial pathogen was found. There was no difference in severity of CAP between patients with and without using PPI therapy.
Conclusions Proton pump inhibitor therapy was associated with an approximately 2-fold increased risk to develop community-acquired pneumonia possibly as a result of S. pneumoniae infection.


Community acquired pneumonia (CAP) is one of the most common infectious diseases in the Western World. Over the years, it remains a major reason for hospitalization and a common cause of mortality. Aging, cigarette smoking and co-morbidity such as chronic obstructive pulmonary disease (COPD) are well known causes for the development of CAP.[1]

Proton pump inhibitors (PPI's) are the major treatment for many gastroesophageal diseases. Since the first introduction in the late 1980s PPI's usage is widespread worldwide.[2] We have previously shown that gastric acid suppressive therapy, such as PPI's or histamine-2 receptor antagonists (H2RA's) also predispose to CAP.[3] The reduction of gastric acid secretion seem to have an important effect on the risk of developing CAP, with the lowest relative risk among patients using a lower defined daily dose and the highest relative risk among patients using a higher defined daily dose.

This observation was subsequently confirmed in several other observational studies and summarized in a recent meta-analysis.[4] In this meta-analysis, the results of six studies including approximately 1 million subjects showed that patients using PPI therapy have an estimated 36% higher risk to develop CAP compared to subjects not using PPI's. However, significant heterogeneity between the studies limited the interpretation of the estimated risk ratio. Furthermore, a retrospective analysis of the original safety data from several randomized clinical trials has shown that patients using esomeprazole did not have an increased risk for developing CAP compared to patients using placebo.[5]

Community acquired pneumonia is an infection of the pulmonary parenchyma that can be caused by various pathogens including bacteria, viruses, fungi and parasites.[6] Thus CAP is not a single disease entity but covers a group of specific infections, each with its own specific clinical features. The pathophysiological mechanisms, which contribute to an increased risk of CAP during PPI therapy, are not well established. There are several supposed mechanisms like anti-infective, anti-inflammatory and immunomodulatory effects that could potentially affect the susceptibility to bacterial infections in patients using PPI including CAP but also enteric infections.[7–9] In a previous study we hypothesized that PPI therapy impairs the immune system leading to an increased susceptibility to infections.[3] The low pH of the intra-gastric environment constitutes a major non-specific defense mechanism of the body against pathogen invasion of the gastrointestinal tract. Decreasing the gastric acidity may result in insufficient eradication of ingested pathogens through several mechanisms like alteration of the gut microflora, enhanced bacterial translocation altering various immunomodulatory and anti-inflammatory effects.[10,11]

The result of this may well be that patients on acid suppressive therapy often have pathogen colonization in the stomach.[12] Reduction of gastric acid secretion by PPI therapy led in almost 60% of patients to bacterial overgrowth in the stomach with predominantly gram-positive potential pathogenic microorganisms, and in particular pathogens normally found in the oropharyngeal cavity.[13] If our pathophysiological hypothesis is indeed true, then one would expect that patients using PPI's more often are being or becoming infected with microorganisms originating from the oropharyngeal cavity. Although the aforementioned mechanisms (backflow and overgrowth) are suggested in several reports this remains speculative in CAP patients.[14–16] A recent study did not confirm an increased presence of gastrointestinal nor oropharyngeal bacteria in CAP patients using PPI.[17] In the present study, we examined the difference in microbial etiology of CAP between patients with and without PPI's in a population based prospective cohort study.