Major Finding: Proton pump inhibitor use during treatment for incident C. difficile infection was associated with a 42% higher risk of C. difficile recurrence.

Data Source: 1,136 patients in the pharmacy and administrative databases of eight Veterans Affairs medical centers in New England.

Disclosures: Support was provided by the VA Cooperative Studies Program and the VA Boston Healthcare System. No financial conflicts of interest were reported.

Use of proton pump inhibitors appears to increase the risk of recurrent Clostridium difficile infection and may even have a causal effect, according to two cohort studies.

In the first study, PPI use during treatment for an incident C. difficile infection was associated with a 42% higher risk of recurrent C. difficile infection. The second study demonstrated a dose-response effect between increasing levels of acid suppression among inpatients taking PPIs and increasing risk for nosocomial C. difficile infection.

Neither study was designed to definitively establish causality; an adequately sized randomized controlled trial would be both prohibitively expensive and possibly unethical. But both of these studies add to the growing body of evidence linking PPIs with C. difficile infection, and their findings should prompt clinicians to take several reasonable, important steps to limit patients' exposure to PPI therapy, both groups of investigators noted.

In the first study, Dr. Amy Linsky of Boston Medical Center and her associates examined pharmacy and administrative databases for eight Veterans Affairs medical centers in New England. They identified 1,166 patients who began treatment for an index case of C. difficile during a 4-year period.

This included 527 patients (45%) who used an oral PPI at some time during the 14 days following diagnosis and 639 (55%) who did not use any PPIs during that interval. Omeprazole was the PPI used by 97% of patients who were given PPI therapy.

The primary end point was recurrent C. difficile infection during the 90 days following the incident diagnosis. This occurred in 25% of the PPI-exposed group, compared with 19% of the nonexposed group, a significant difference.

After the data were adjusted to account for patient age, initial antibiotic treatment, additional antibiotic treatment, duration of hospitalization, and differences in baseline comorbidities and medications, the hazard ratio for PPI exposure remained elevated at 1.42. This represents a 42% increase in risk for recurrent C. difficile infection for patients taking PPIs, Dr. Linsky and her colleagues said (Arch. Intern. Med. 2010;170:772-8).

In the second study, Dr. Michael D. Howell of Beth Israel Deaconess Medical Center, Boston, and his associates performed a secondary analysis of data prospectively collected on 101,796 discharges from their center in 2004-2008. Nosocomial C. difficile infection had developed in 665 (0.7%) of these cases.

In unadjusted analysis, the risk of acquiring the infection rose from 0.3% with no exposure to PPIs to 0.9% with daily use of PPIs to 1.4% with more frequent than daily use of PPIs.

This dose-response effect persisted after the data were adjusted to account for patient age, comorbid conditions, and receipt of antibiotics. The odds ratios were 1 (reference) for no exposure to PPIs, 1.74 for daily exposure, and 2.36 for more frequent exposure to PPIs. This represents more than a 70% increase in the risk of developing nosocomial C. difficile if a patient is taking a daily PPI, and more than a doubling of the odds if a patient is taking the drugs more frequently, Dr. Howell and his colleagues said (Arch. Intern. Med. 2010;170:784-90).

The findings suggest that “we should expect at least 1 additional case of nosocomial C. difficile infection for every 533 patients who receive a daily PPI, after controlling for other risk factors,” Dr. Howell and associates noted.

“Although this seems like a relatively large number-needed-to-harm, the magnitude of exposure is large. We found that 60% of patients received acid-suppressive therapy, similar to others' estimates,” the researchers added.

Given the widespread use of PPIs and the millions of hospital discharges every year, “the number of potentially attributable nosocomial C. difficile cases in the United States numbers in the tens of thousands per year,” they noted.

This figure is particularly alarming because research has shown that PPIs are not strictly indicated for more than two-thirds of inpatients who receive them, added Dr. Howell and his colleagues, who reported no conflicts of interest.

To limit unnecessary exposure to PPIs, physicians should ensure that every hospitalized patient is given the least-intense acid-suppressive therapy that is appropriate for his or her condition. “In particular, unless and until there is clear evidence that low-risk, noncritically ill patients receive benefit from stress ulcer prophylaxis, we should strive to minimize exposure to acid-suppressive medications in this group,” they said.

Hospitals should reexamine standing protocols that include stress ulcer prophylaxis, and also should ensure that such medications are discontinued at discharge, they added.

C. difficile Infection, PPI Link Strengthened