Willems RPJ, van Dijk K, Ket JCF, et al. Evaluation of the Association Between Gastric Acid Suppression and Risk of Intestinal Colonization With Multidrug-Resistant Microorganisms: A Systematic Review and Meta-analysis. JAMA Intern Med. 2020 Feb 24. pii: 2761273. doi: 10.1001/jamainternmed.2020.0009. (Systematic review)

Importance: Acid suppressants inhibit gastric acid secretion and disrupt the intestinal microbiome. Whether acid suppression increases the risk of colonization with multidrug-resistant microorganisms (MDROs) is unclear.

Objectives: To systematically examine the association of use of acid suppressants with the risk of colonization with MDROs and to perform a meta-analysis of current evidence.

Data Sources: PubMed, Embase, the Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials were searched from database inception through July 8, 2019.

Study Selection: Study selection was performed independently by 2 authors (R.P.J.W. and C.M.J.E.V.-G.) on the basis of predefined selection criteria; conflicts were resolved by consensus or by an adjudicator (K.v.D.). Human observational studies (case control, cohort, and cross-sectional) and clinical trial designs were selected if they quantified the risk of MDRO colonization in users of acid suppressants in comparison with nonusers.

Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) recommendations were followed. Data were extracted independently by the same 2 authors, and adjudication was conducted when necessary. Risk of bias was assessed according to a modified Newcastle-Ottawa Scale. Pooled odds ratios (ORs) were estimated using random-effects models; heterogeneity was evaluated using the I2 method.

Main Outcomes and Measures: The primary outcome measure was intestinal colonization with MDROs of the Enterobacterales order (producing extended-spectrum ß-lactamases, carbapenemases, or plasmid-mediated AmpC ß-lactamases), vancomycin-resistant enterococci, methicillin-resistant or vancomycin-resistant Staphylococcus aureus, or multidrug-resistant Pseudomonas or Acinetobacter species.

Results: A total of 26 observational studies including 29?382 patients (11?439 [38.9%] acid suppressant users) met the selection criteria. Primary meta-analysis of 12 studies including 22?305 patients that provided adjusted ORs showed that acid suppression increased the odds of intestinal carriage of MDROs of the Enterobacterales order and of vancomycin-resistant enterococci by roughly 75% (OR = 1.74; 95% CI, 1.40-2.16; I2 = 68%). The odds were concordant with the secondary pooled analysis of all 26 studies (OR = 1.70; 95% CI, 1.44-1.99; I2 = 54%). Heterogeneity was partially explained by variations in study setting and the type of acid suppression.

Conclusions and Relevance: Acid suppression is associated with increased odds of MDRO colonization. Notwithstanding the limitations of observational studies, the association is plausible and is strengthened by controlling for confounders. In view of the global increase in antimicrobial resistance, stewardship to reduce unnecessary use of acid suppressants may help to prevent MDRO colonization.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Internal Medicine 6 / 7
Gastroenterology 5 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

This review is interesting in its methods, which appear to strictly follow standards for observational study reviews and data aggregation. I did not review the references; however, almost all studies were excluded for various reasons. Of the 23 evaluated, 15 were hospitals, 4 were travel clinics with unacceptably wide CIs, and 4 were community. Of those 4, at least two were reported as nursing homes. The relevance to free-living people is thus unclear. Of hospitals and other settings with increased communal exposures, many comments may be made - use of antibiotics, exposures to pathogens, wide use of prophylactic PPIs - but the one that cannot be made is that of causation. I will not use this data analysis to determine my outpatient prescribing, and I trust others will not also.

Gastroenterology rater

As the investigators note, association cannot establish causation. PPI users are sicker than non-users (and more likely to have been exposed to resistant bacteria). Also, while I assumed that the cohort studies compared otherwise matched patients who were or were not receiving acid-suppression, classic case-control studies compare groups with given outcomes (resistant bacteria present or absent) and look for different factors (acid reduction) in the two groups. However, to fit these data into this systematic review, didn't the investigators have to compare members with both outcomes who received acid reduction to the other members of both groups who did not, thereby losing the original matching? Also, how can a case-control study be prospective? Was there some other definition of case-control studies used? If so, this was not clear. Finally, while the message about overuse of PPIs is not new, why was nothing said about inappropriate use of antibiotics?

Gastroenterology rater

As a general surgeon and endoscopist, I feel these results are under-reported and not explained to patients as a risk of long-term acid suppression. Every gastroenterologist should read this article to understand the risk factors of long term medication use to treat GERD and refer to surgery when symptoms are long-standing or refractory.

General Internal Medicine-Primary Care(US) rater

Given the widespread use of PPIs, the findings of this study (although observational) are important for practitioners to be aware of, and should make them think twice before long-term refilling of PPI prescriptions.

Internal Medicine rater

Despite limitations, the study provides a very important message because PPIs are widely used.
Comments from EvidenceAlerts subscribers

Dr. Rudolph Napodano (3/2/2020 3:49 PM)

The article mentions PPIs. Did they study the association with other over-the-counter agents?