Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Abstract

AIMTo perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI).METHODSWe conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran’s Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).RESULTSFifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).CONCLUSIONThis meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

“…In contrast, the odds for an increased occurrence of C difficile infection during PPI therapy are relatively low and PPI‐induced hypochlorhydria was shown not to affect C difficile spore integrity or germination . Instead, it has been hypothesized that PPI‐associated alterations in the gut microbiome may create a niche that facilitates the germination and disease initiation of C difficile infection.…”

“…In contrast, the odds for an increased occurrence of C difficile infection during PPI therapy are relatively low [8][9][10][11][12] and PPIinduced hypochlorhydria was shown not to affect C difficile spore integrity or germination. 14…”

“…The association of PPI use and Clostridium difficile infection appears evident. [8][9][10][11][12] However, due to limitations in study designs, low odds ratios (OR) and some uncertainties concerning biological plausibility, the available studies cannot ultimately provide sufficient evidence of causality of this association. 13,14 Then again, PPI use and communityacquired bacterial enteric infection show a strong association with a pooled OR of 4.28 (95% CI 3.01-6.08) for any infection, 4.84 (95% CI 2.75-8.54) for Salmonella infection and 5.09 (95% CI 3-8.64) for Campylobacter jejuni infection, as shown in a recent meta-analysis of nine observational studies 15 (Table 1, Figure 2).…”

“…The association of PPI use and Clostridium difficile infection appears evident . However, due to limitations in study designs, low odds ratios (OR) and some uncertainties concerning biological plausibility, the available studies cannot ultimately provide sufficient evidence of causality of this association .…”

The clinical drug candidate ebselen attenuates inflammation and promotes microbiome recovery after antibiotic treatment for Clostridium difficile infection

“…CDI is typically incited by antibiotic use, which induces dysbiosis in the commensal microbial communities of the gastrointestinal (GI) tract, allowing this pathogen to thrive. Risk factors such as antibiotic use, proton pump inhibitors (PPIs) and Westernized diets encourage GI inflammation and alter microbial commensals to reduce community robustness required for colonization resistance to enteric pathogens (Desai et al, 2016; Hryckowian et al, 2017; Hryckowian et al, 2018; Sonnenburg et al, 2016; Trifan et al, 2017).…”