Dose-Dependent Impact of Proton Pump Inhibitors on the Clinical Course of Spontaneous Bacterial Peritonitis

Tammo L. Tergast; Anika Wranke; Hans Laser; Svetlana Gerbel; Michael. P. Manns; Markus Cornberg; Benjamin Maasoumy


Liver International. 2018;38(9):1602-1613. 

In This Article

Abstract and Introduction


Background & Aims: Spontaneous bacterial peritonitis is a severe complication in patients with cirrhosis leading to acute kidney injury, hepatic encephalopathy and a high mortality. In this study, we aimed to investigate the impact of proton pump inhibitors and the potential relevance of the taken dosage on the incidence and clinical course of spontaneous bacterial peritonitis.

Methods: Overall, 613 consecutive patients with decompensated cirrhosis were included. All patients were carefully evaluated for proton pump inhibitors intake including the applied dosage and were further followed up for spontaneous bacterial peritonitis development as well as for the incidence of clinical complications like hepatic encephalopathy, acute kidney injury and mortality.

Results: Cumulative spontaneous bacterial peritonitis incidence did neither differ between the proton pump inhibitors and the no-proton pump inhibitors group nor between those taking the high (>40 mg/d) and the low (10–40 mg/d) proton pump inhibitors' dose. However, proton pump inhibitors' intake was associated with an impaired clinical course of spontaneous bacterial peritonitis reflected by a higher likelihood for acute kidney injury (71% vs 43%; P = .002), severe hepatic encephalopathy (15% vs 0%; P = .04) and an increased mortality (24% vs 0%; P = .008) within 28 days after spontaneous bacterial peritonitis diagnosis. In particular, patients with proton pump inhibitors dosages >40 mg/d had an increased short-term risk for acute kidney injury (adjusted hazard ratio: 1.86; P = .009) and mortality (adjusted hazard ratio: 2.05; P = .02). In contrast, there was no effect of proton pump inhibitors on acute kidney injury, hepatic encephalopathy and mortality in patients without spontaneous bacterial peritonitis irrespective of the applied proton pump inhibitors dosage.

Conclusions: High dosages of proton pump inhibitors are associated with an adverse outcome in patients with spontaneous bacterial peritonitis. Thus, indication for high-dosage proton pump inhibitors therapy should be evaluated carefully in these patients.


Patients with cirrhosis have a significantly increased risk for developing a bacterial infection.[1] Furthermore, infections are a leading cause for hepatic decompensation and subsequent complications like hepatic encephalopathy (HE), acute kidney injury (AKI) and acute-on-chronic liver failure.[2–4] The most frequent type of infection in cirrhotic patients is a spontaneous bacterial peritonitis (SBP).[5] Immediate diagnosis as well as an urgent and adequate treatment is crucial to avoid further complications and maximize the chance of survival.[6] Over the last decades the optimal management of SBP has been intensively discussed.[7,8] As a result of the emergence of multidrug-resistant bacteria, antibiotic treatment of SBP has become more and more challenging. This has a particular relevance for nosocomial-acquired infections.[1,9] Most recently, the impact of comedication like proton pump inhibitors (PPI) and non-selective beta blockers (NSBB) on the incidence and clinical course of SBP has gained increasing interest.[10–12]

Proton pump inhibitors are widely used in cirrhotic patients. In general, PPIs are supposed to be well tolerated and serious adverse events are rarely reported. However, an undesired effect of PPIs is the neutralization of the gastric acid barrier and the opportunity for non-habitant pathogens to colonize the intestine.[13,14] It has been hypothesized that the alterations caused by PPIs might facilitate the translocation from the gut microbiota to mesenteric lymph nodes or the peritoneum, which may result in a higher risk for SBP, systemic inflammation and HE.[15,16] Indeed, a couple of studies reported an increase in SBP incidence in patients using PPIs. However, other studies did not observe any significant association.[17–20] After all, the impact of PPI intake on SBP development and associated complications like AKI, HE and death remains highly controversial. A cornerstone of evidence for a suggested clinical effect of a certain drug is a dose-dependent relationship. However, while several studies investigated the influence of any PPI intake in patients with cirrhosis, the impact of the applied PPI dosage has widely been neglected in the discussion, so far.

In this study, we aimed to further investigate the impact of PPI intake on the incidence and clinical course of SBP in patients with decompensated cirrhosis and ascites with a particular focus on relevance of the applied PPI dosage.