Adverse Effects of Proton Pump Inhibitor Drugs: Clues and Conclusions

Denis M. McCarthy


Curr Opin Gastroenterol. 2010;26(6):624-631. 

In This Article


Although a number of early studies suggested a weak association between community-acquired pneumonia (CAP) and PPI use, a recent survey of 70 RCTs, of which seven met strict criteria for inclusion into meta-analysis, found no association, although about half the studies showed a trend toward significant increases. In two separate studies, there appeared to be a high risk of CAP in the first 5–14 days of therapy, but nothing for longer times or with chronic exposure. There are no convincing data to indicate significant links with nosocomial or ventilator-associated pneumonias.[19] Despite abnormal gastric colonization in PPI users, and theoretical risks of increased micro-aspiration or translocation, no reports have appeared. Reports of increased leakage of the gastric mucosa (probably via tight junctions) caused by several PPIs so far apply only to molecules in the 500–4000 Da weight range and not to larger molecules or particles, but this may change:[20] this phenomenon is unlikely to affect bacteria.

Small Intestinal Bacterial Overgrowth

Despite long-standing suspicions that acid-suppressive therapy increases the risk of SIBO, it has been uncertain whether this risk is uniform in all users or is perhaps restricted to certain subgroups, such as the elderly, the H. pylori-infected or those with irritable bowel syndrome (IBS). There is growing acceptance of the presence of SIBO in 25–40% of patients with IBS-type symptoms, particularly gaseous bloating, excessive flatus and diarrhea, but also to a lesser extent in those in whom constipation or pain are dominant symptoms. Whether PPI use is an independent risk factor for SIBO in individuals free of IBS is not well studied. Furthermore, the type of overgrowth due to PPIs may be caused more by oropharyngeal flora rather than by the usual flora of the more distal gut and give rise to a different clinical picture. Despite such reservations, in a recent study of 450 patients with a positive glucose hydrogen breath test (GHBT), among 200 GERD patients on PPIs, GHBT was positive in 50% compared with 24.5% among 200 PPI nonusers with IBS and 6% among 50 normal controls, all differences between groups being highly significant.[21] Thus, even if there were IBS patients among the PPI users (unstated), the combination of IBS and PPI therapy carries at least twice the risk seen with IBS alone: an accompanying editorial identifies some additional reservations.

Although some other recent studies have not confirmed the observation, their designs [small numbers, use of lactulose breath test (LBT), etc.] do not allow confident rejection of the reported association. Furthermore, the association is strongly supported by a number of other observations, including chronic use of PPIs as an independent risk factor for SIBO in the elderly (OR 7.9), PPI therapy increasing the occurrence of relapses of SIBO after eradication by antibiotic therapy (OR 3.52) and PPI use an independent predictor of positive GHBT in 2000 non-IBS patients with a variety of diseases such as diabetes, cirrhosis, collagen vascular diseases or residua of previous gastric surgery (OR 1.27, P = 0.028). Older studies, culturing small bowel bacterial contents, also found increased risks of SIBO with H2RA therapy, greater for ranitidine than for cimetidine, and that the incidence of SIBO rose in scleroderma patients changed from H2RAs to PPIs.

In conclusion, although there is an undoubted need for randomized prospective studies in this area, it seems likely that chronic use of PPIs increases the risk of SIBO in a sizable number of individuals, the risk increasing with time on drug. This number may be influenced by a number of other factors including the presence of IBS, chronic gastritis, H. pylori infection, other comorbid conditions and exposure to antibiotics or to drugs or diseases that affect gastric emptying.

Spontaneous Bacterial Peritonitis

Although the pathogenesis of spontaneous bacterial peritonitis (SBP) is incompletely understood, translocation of bacteria across the intestinal wall is believed to be an important causative factor. It follows that alteration in intestinal flora, such as occurs with PPI use, may play an important role in SBP, although additional factors are clearly involved. It has been hypothesized that PPIs, widely used in cirrhotic patients, may favor intestinal bacterial overgrowth and translocation, increasing the risk of SBP. One recent retrospective case–control study of 70 cirrhotic, community-based patients with SBP, on multivariate analysis found that PPI use was associated with SBP with an OR of 4.31 (95% CI 1.34–11.7). Affected patients had advanced cirrhosis, and higher ascitic fluid protein was protective. Of interest was that 47% of patients had no indication for PPI treatment.[22]