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Edmund Pezalla, MD, MPH, spoke with Physician’s Weekly about findings that show proton pump inhibitors may not increase risk for infections like C. difficile.

Researchers found no significant link between proton pump inhibitor (PPI) use and the risk of serious infections such as Clostridioides difficile infection (CDI), challenging previous concerns, according to a preprint published with The Lancet.

Based on the findings, PPIs—a staple in managing acid-related stomach issues—may not be as risky as earlier studies suggested.

Proton pump inhibitors are some of the most prescribed drugs globally, treating conditions such as acid reflux and ulcers. For years, studies have warned of potential adverse effects, including life-threatening infections and gut health issues. This new analysis, based on a randomized controlled trial—the gold standard of medical research—reveals a different story.

“This review fills an evidence gap because previous information on CDI was based on observational studies only, but PPIs are commonly used and recommended by the American College of Gastroenterology,” Edmund Pezalla, MD, MPH, tells Physician’s Weekly.

Study Findings

The meta-analysis reviewed seven randomized controlled trials with more than 25,000 participants. It found no significant increase in CDI risk for PPI users compared with those taking a placebo (risk ratio [RR], 0.94; 95% CI, 0.55-1.59). Similarly, four randomized controlled trials comparing PPIs with histamine H2-receptor antagonists (H2RAs) also showed no elevated risk (RR, 0.72; 95% CI: 0.49-1.07).

These results directly contradict findings from earlier observational studies, published by the NIH and in multiple large journals, suggesting PPI users were twice as likely to develop CDI. Experts now point to the limitations of observational studies, which can be prone to biases.

When it comes to other gut infections, the review highlighted a slightly increased risk among PPI users in long-term studies. In one randomized controlled trial, a modest rise in infection rates (RR, 1.33; 95% CI: 1.01-1.75) was reported, but the overall incidence remained low. Notably, comparisons with H2RAs and newer drugs such as potassium-competitive acid blockers revealed no significant differences.

Small intestinal bacterial overgrowth (SIBO), another condition tied to PPIs, had a clearer risk. In two randomized controlled trials, higher SIBO rates were reported among PPI users, with one study finding nearly triple the risk (RR, 2.95; 95% CI, 1.31-3.05). This reinforces concerns about PPIs’ impact on gut bacteria but highlights the need for more targeted research.

An Outside Expert’s Perspective

“In the United States, the vast majority of PPI use is over the counter,” Dr. Pezalla notes. “Patients who use PPIs are not seeing the data on bacterial overgrowth and CDI and other things that could be important. This review demonstrates that it doesn’t appear, at least from these select studies, that PPIs are creating more opportunity for patients to get CDI,”

However, Dr Pezalla added, “It does leave concerns over bacterial overgrowth of the small intestine and some other changes in the gastrointestinal biome that might have an impact on some types of patients.”

These findings could reshape how doctors approach PPI use. Previous warnings about CDI risk led to reduced use of these medications, even for patients who needed them. This new evidence suggests those concerns might have been overstated, according to the study results. For patients requiring acid suppression, the data provide reassurance that PPIs are unlikely to increase CDI risk significantly.

“For physicians who may be recommending the use of PPIs to patients, the data show that you don’t have to be particularly worried about CDI,” Dr. Pezalla said.

Although the review’s strengths include its focus on randomized controlled trials and large sample sizes, limitations remain, study investigators noted. Most trials didn’t specifically aim to study infections or SIBO, and there was significant variability in treatment duration and doses. The findings call for more targeted studies to clarify risks further. Dr. Pezalla added that it would have been beneficial to know the history of CDI or specify the included participants’ history more explicitly, if possible, as well as focus on SIBO.

Researchers stress the need for additional high-quality trials focusing on gut infections and long-term PPI use. Standardized methods for diagnosing conditions such as SIBO and extended follow-up periods would help provide clearer answers. Until then, clinicians are advised to prescribe PPIs judiciously, ensuring they’re used only when medically necessary, according to the investigators.