Meta-analysis Confirms Acid Suppressors Raise Recurrent CDI Risk

Clinicians should avoid prescribing acid-suppression medications in general, and especially proton-pump inhibitors, to patients with Clostridioides difficile infection, according to the study.

A recent systematic review supports the idea that acid suppression medications (ASMs) can increase a patient’s risk of developing recurrent Clostridioides difficile infection (CDI).

About 1 in 6 of the half-million Americans who develop CDI each year will experience at least one recurrence of the infection. Writing in the journal Clinical Infectious Diseases, corresponding author Luigi Brunetti, PharmD, MPH, of Rutgers University, and colleagues, explained that the use of medications like antibiotics and ASMs have been linked with an increased risk of recurrent CDI, but many of the studies supporting the link between ASMs and CDI have had small sample sizes and used different definitions of exposures and outcomes.

A meta-analysis of the studies is one way to solve that problem, but Brunetti and colleagues wrote that previous meta-analyses on the ASM question were less definitive because they used both inpatient and outpatient cases.

“This distinction is important because it is commonly seen that studies that contain an outpatient population often display less integrity or accuracy in terms of data, since compliance cannot be monitored,” they wrote.

The new meta-analysis focused exclusively on inpatients. A total of 9 studies were found that looked at CDI and included medication information. Together, the studies had a patient population of 5668 people. Of those, 17.7% of patients (1003) experienced recurrent CDI, a number in line with national averages.

The data showed those patients who were taking ASMs were 64% more likely to be among those patients experiencing CDI recurrence (OR, 1.64; 95% CI, 1.13–2.38; P = .009; I2 = 79.54%). Those taking proton-pump inhibitors had an even higher risk, at 84% (OR, 1.84; 95% CI, 1.18–2.85; P = .007; I2 = 83.4%).

One reason these findings are important, Brunetti and colleagues noted, is that ASM use is a modifiable factor, whereas other risk factors for CDI recurrence, such as older age and recent hospitalization, are not modifiable. ASMs are also chronically over-prescribed, Brunetti said, suggesting many patients could safely be taken off their ASM because they never needed it in the first place.

“In fact, 1 study reported that 65% of ASMs prescribed in inpatients were without indication,” the authors wrote. “ASM carries many risks, especially with long-term use, that are often ill-considered.”

Those risks include pneumonia, bone fractures, and, as the current meta-analysis showed, CDI.

The reason for the link between ASMs and CDI may have to do with the impact of altered pH on gut microbial diversity, Brunetti and colleagues said, rather than on acid suppression itself. Altered pH in the upper gastrointestinal tract causes the patient’s colonic microbiome to become more susceptible to CDI. It therefore follows that proton-pump inhibitors cause the greatest increase in CDI risk, the authors wrote, since proton-pump inhibitors have a stronger effect on gastric pH than the average acid suppressor.

Brunetti and colleagues noted a few limitations, including varying in the included studies’ definitions of CDI recurrence, and a lack of information about certain patient characteristics, such as age, which limited the types of subgroup analyses the authors were able to perform. Still, the investigators said the new analysis adds strength to the case that ASMs are problematic for patients with CDI.

“Clinicians should consider discontinuation of ASMs during the treatment of CDI whenever possible,” the authors concluded.


Mehta P, Nahass RG, Brunetti L. acid suppression medications during hospitalization as a risk factor for recurrence of Clostridioides difficile infection: Systematic review and meta-analysis. Clin Infect Dis. 2021;73(1):e62-e68. doi:10.1093/cid/ciaa545