Proton Pump Inhibitor Use and Clostridium difficile Infections -- More Harm Than Good?

David A. Johnson, MD


August 19, 2010

Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection

Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA
Arch Intern Med. 2010;170:772-778

Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection

Howell MD, Novack V, Grgurich P, et al
Arch Intern Med. 2010;170:784-790

Study Summaries

The incidence and severity of Clostridium difficile infections (CDI) are increasing at an alarming rate. Because the gastric acid barrier is one of the defense mechanisms for protecting the integrity of the normal gut microflora environment, acid-suppression therapy has beensuggested as treatment for a number of intestinal pathogenic infections -- including C difficile -- but this remains controversial.

These 2 reports suggest that the increased risk for CDI with proton pump inhibitors (PPIs) is not at all modest, and that gastric acid is potentially important in protecting against infection from this pathogen.

The study by Linsky and colleagues is a pharmacoepidemiologic cohort trial in which a secondary analysis was performed with data collected prospectively on 101,796 patients discharged from a tertiary care medical center during a 5-year period. As use of acid-suppression therapy increased, the reported risk for nosocomial CDI also increased, from 0.3% (95% confidence interval [CI], 0.21%-0.31%) in patients who did not receive acid-suppression therapy, to 0.6% (95% CI, 0.49%-0.79%) in those who did receive histamine2-receptor antagonist (H2RA) therapy, to 0.9% (95% CI, 0.80%-0.98%) in patients who received daily PPI treatment, and to 1.4% (1.15%-1.71%) in those who received more frequent PPI therapy.

Despite adjustment for comorbid conditions, age, antibiotic use/exposure, and likelihood of receipt of acid-suppression therapy on the basis of propensity score, the association persisted, increasing from an odds ratio (OR) of 1 (reference value for no acid suppression) to 1.53 (95% CI, 1.12-2.10) for H2RA therapy, to 1.74 (95% CI, 1.39-2.18) for daily PPI therapy, and to 2.36 (95% CI, 1.79-3.11) for more frequent PPI use. Similar estimates were found with a matched cohort analysis and with nested case-control techniques.

The report by Howell and associates involved a 5-year, retrospective, cohort study using administrative databases of the New England Veterans Healthcare System, in which 1166 inpatients and outpatients with metronidazole- or vancomycin hydrochloride-treated incident CDI were identified. From this cohort, 527 patients (45.2%) received oral PPIs within 14 days of diagnosis and 639 (54.8%) did not. The investigators report a hazard ratio (HR) for recurrent CDI, defined by a positive toxin finding in the 15 to 90 days after incident CDI.

Recurrent CDI was more common in patients exposed to PPIs than in those not exposed (25.2% vs 18.5%). The adjusted HR of recurrent CDI was higher in those exposed to PPIs during treatment (1.42; 95% CI, 1.11-1.82). Risks among exposed patients were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15-3.01) and those receiving antibiotics not targeted to C difficile during follow-up (HR, 1.71; 95% CI, 1.11-1.64).

The investigators concluded that increasing levels of pharmacologic acid suppression are associated with increased risk for nosocomial CDI. They suggest that the evidence of a dose-response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection.


A recent meta-analysis evaluated the data for the relative risk for CDI associated with PPI use and also concluded that risk may be increased (OR 1.94, 95% CI, 1.37-2.75).[1]

Before jumping on the "one more harm" bandwagon, however, I would urge scrutiny of the data. First, these studies are observational and retrospective, which limits their scientific reliability. In particular, the OR of < 2 could potentially be explained by unrecognized or unaccounted for study bias for the patient groups. The study by Howell and colleagues suggests that, compared with no acid suppression, the number needed to treat (NNT) to avoid a new case of CDI related to PPI use is 533. That means that in practice, clinicians should expect at least 1 additional case of nosocomial CDI for every 533 patients who receive a daily PPI, after controlling for other risk factors.

Before accepting that even this number is appropriate, I would suggest a process for synthesis of the evidence. First, is the scientific hypothesis correct? Given that C difficile is an acid-resistant spore, it does challenge the notion that acid modification would make a difference. Second, the biological plausibility from the literature is still subject to debate, specifically retrospective studies with post hoc analysis and relatively low ORs for reported risk. Furthermore, it would seem that the risk for CDI would be greater in patients with surgical or medical achlorhydria (eg, atrophic gastritis or pernicious anemia). No nested cohort data have evaluated this risk before we began to evaluate risks of lesser acid suppression. Finally, does this risk make sense from your clinical practice experience? Do you as a clinician sense that C difficile is more prevalent in your patients with surgical or medical achlorhydria?

Clearly, PPIs are overused in many patients. However, meaningful and clinically significant benefits are possible with appropriate use of these drugs. A recent report suggests that hospitalizations in patients receiving PPIs along with NSAIDs are reduced, as is the severity of upper gastrointestinal events.[2] At present, it would be inappropriate and premature to restrict PPI use in appropriate patients because of concern over possible CDI risk.