Proton Pump Inhibitors Associated With Increased Risk of Drug-Resistant Infections

Treatment with proton pump inhibitors is now associated with an increased risk of acquiring a drug-resistant infection, according to new research.1 

A team, led by Roel P. J. Willems, MD, Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Academic Medical Center, assessed the association between PPI treatment and the risk of acquiring drug-resistant Enterobacterales and examined the interactions with possible microbiome-altering agents.


In the past, PPI has been linked to an increased risk of colonization with drug-resistant bacteria. However, there is some doubt about this association, largely because of possible confounding by lifestyle-associated factors and disease severity. In addition, whether this risk is dose dependent is not currently known.

In the nested case-control study, the investigators examined 2239 hospitalized adult patients using data from the microbiology laboratory database of Amsterdam University Medical Centers between December 31, 2018 and January 6, 2021. The mean age was 60.9 years.

The case group had 374 patients with newly detected extended-spectrum β-lactamase (ESBL)– or carbapenemase-producing Enterobacterales (identified by clinical specimens).

The mean age of this group was 61.1 years.

The investigators assigned 1865 patients with negative results for ESBL- and carbapenemase-producing Enterobacterales to the control group using a risk-set sampling. The mean age of this group was 60.9 years. The control group was matched with a 5:1 ratio with patients in the case group by age and culture data.

They then conducted a second validation case-control study that included an equal match of 188 patients who were prospectively enrolled.

Each participant had clinical data from PPI use for 30 days and 90 days before the date of culture.

The Risk

The investigators estimated the adjusted incidence rate ratios (AIRRs) of ESBL- or carbapenemase-producing Enterobacterales acquisition by PPI dose and time risk windows using conditional logistic regression models.

These were estimated for 30 days for the primary outcome and 90 days for the secondary outcome.

The results show an aIRR of 1.48 (95% confidence interval [CI], 1.15-1.91) for PPI use overall at 30 days. After conducting a sensitivity analysis and an analysis of the pair-matched study with prospectively enrolled patients (aIRR, 2.96; 95% CI, 1.14-7.74), the investigators found similar results.

The findings were also consistent in subgroups and corroborated by a negative-control exposure analysis. On the other hand, the team did not identify an association with microbiome-disturbing agents and found laxatives and antibiotics were independently associated with a more than 2-fold increase in the acquisition risk (antibiotics: aIRR, 2.78; 95% CI, 2.14-3.59; laxatives: aIRR, 2.26; 95% CI. 1.73-2.94).

“In this study, after careful control for confounding and sensitivity analyses, PPI use was associated with increases in the risk of acquiring ESBL- or carbapenemase-producing Enterobacterales among adult hospitalized patients,” the authors wrote. “These findings emphasize the need for judicious use of PPIs.”


Willems RPJ, Schut MC, Kaiser AM, et al. Association of Proton Pump Inhibitor Use With Risk of Acquiring Drug-Resistant Enterobacterales. JAMA Netw Open. 2023;6(2):e230470. doi:10.1001/jamanetworkopen.2023.0470