Study links acid suppressants to colonization with multidrug-resistant bacteria

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A new study suggests that medications used to control heartburn and other gastrointestinal issues may increase the risk of acquiring multidrug-resistant bacteria in hospital patients.

The study, published today in JAMA Network Open, found that hospitalized patients using proton pump inhibitors (PPIs) had a nearly 50% increased risk of acquiring extended-spectrum beta-lactamase (ESBL)- or carbapenemase-producing Enterobacterales, with a slightly higher risk among patients who used PPIs twice a day.

The study authors say the findings add to a growing body of evidence that overuse or misuse of PPIs may be linked to an increased risk of colonization with these multidrug-resistant organisms (MDRO), which can cause severe, difficult-to-treat infections.

Does acid suppression foster MDROs?

To investigate the association between the use of PPIs and the risk of acquiring ESBL- or carbapenemase-producing Enterobacterales, a team led by researchers from the University of Amsterdam Medical Centers conducted a study involving 2,239 adult patients treated at the hospital's two tertiary medical centers from Dec 31, 2018, to Jan 6, 2021.

In a previous review and meta-analysis of observational studies, the same team had found that use of PPIs and histamine-2 receptor antagonists (H2RAs) was associated with a more than 70% increase in the odds of MDRO colonization in the intestinal tract. One potential explanation they offered for the link was that the suppression of gastric acid by these medications—which are frequently prescribed for heartburn and gastrointestinal reflux disease but include over-the-counter medications like Prilosec, Nexium, and Zantac—may enable MDROs to survive in the stomach and intestinal tract.

To address some of the limitations of that study, including varying control for modifying factors like unhealthy lifestyle, they conducted a nested case-control study to verify the association with PPIs and examine a possible dose-response association. They also looked at potential interactions with other microbiome-altering medications, such as antibiotics, laxatives, and immunosuppressant medications.

After identifying all the patients in the study who had positive results for ESBL- or carbapenemase-producing Enterobacterales during their hospitalization, the researchers randomly matched up to 5 patients who tested negative for those organisms to a control group. They then examined PPI use within 30 days before the index date in the two groups.

The primary analysis adjusted for confounding factors such as sex, body mass index, presence of inflammatory bowel disease, Charlson Comorbidity Index score (which estimates risk of death based on underlying health conditions), and length of intensive care unit stay.

A nearly 50% increased risk

Among the 2,239 patients, 374 (51.6% male, mean age 61.1 years) were in the case group and 1,865 (51.0% male, mean age 60.9) were in the matched control group.

In the primary analysis, the adjusted incident rate ratio (aIRR) for acquiring ESBL- or carbapenemase-producing Enterobacterales with PPI use was 1.48 (95% confidence interval [CI], 1.15 to 1.91) at 30 days, with a higher risk among those with two daily PPI doses (aIRR, 1.75; 95% CI, 1.03 to 2.97). Use of H2RAs, which was much less common among patients, was not associated with an increased risk.

These findings emphasize the need for judicious use of PPIs

Sensitivity analyses and the analysis of a pair-matched study with prospectively enrolled patients (aIRR, 2.96, 95% CI, 1.14 to 7.74) yielded similar results as the primary analysis, and the findings were consistent in subgroups and corroborated by a negative-control exposure analysis. The use of other microbiome-altering medications together with PPIs did not reveal additional risks, but antibiotics (aIRR, 2.78; 95% CI, 2.14 to 3.59) and laxatives (aIRR, 2.26; 95% CI, 1.73 to 2.92) were independently associated with more than a twofold increased risk of acquiring ESBL- or carbapenemase-producing Enterobacterales. 

The authors note that unmeasured confounding remains a possibility and that the risks apply to hospitalized patients. But they say their study—which focused on correcting for confounding factors and included multiple levels of analysis—corroborates the findings from their previous study and supports the role of PPI use as an independent risk factor for acquiring ESBL- or carbapenemase-producing Enterobacterales. While carriage of these organisms doesn't always lead to illness, it can increase the risk of infection.

They also say the findings reinforce the need for clinicians to be cautious with these microbiome-altering medications, which are estimated to be overprescribed in 30% to 50% of cases.

"These findings emphasize the need for judicious use of PPIs," they wrote.

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