PPIs induced Risk of Recurrent Clostridium difficile Infections and Rationale for Use of Probiotics: Review

Clostridium difficile associated diarrhea (CDAD) in India is still an under-recognized etiology of diarrhea. This is largely due to lack of clinical suspicion, difficulty in culturing the organism, and the non-availability of cost-effective diagnostic assays. (1)  The incidence of CDAD is as high as 16% in some of the studies reported in India. It contributes to significant morbidity among hospitalized patients as it is responsible for more than 1 in 6 cases of diarrhea among hospitalized patients.(2)

Proton Pump Inhibitors(PPIs) Increase Risk of Clostridium difficile infections (CDIs) – Implications of gastric pH > 4

Gastric acid suppression therapies are used for conditions such as dyspepsia, gastroesophageal reflux disease (GERD), stress ulcer prophylaxis, laryngopharyngeal reflux, peptic ulcer diseases (PUD), and H.pylori infections. It is accomplished through direct inhibition of the proton pump of gastric parietal cells or indirectly through inhibition by blockage of histamine, the former being more effective at increasing gastric pH. (3) Typical acid secretion creates a gastric pH of about 1.4. (4) A gastric p.H. > 4 is the generally accepted treatment goal of acid suppression therapy for the above-mentioned indications. (5) Commonly used Proton Pump Inhibitors (PPIs) achieve this goal. However, pH > 4 has been shown to increase bacterial survival, specifically for the spores of Clostridium. (6) Furthermore, in vitro studies have demonstrated that PPIs impair neutrophil function and inhibit chemotaxis and phagocytosis. (7)  Although acid suppression is beneficial for several medical conditions, it may lead to an increased risk of enteric infections and CDIs.(8)

Association of Long-term PPI use & Increased Risk of Clostridium difficile infections(CDI): Plethora of Evidence

Hypochlorhydria was implicated in the transmission of C. difficile as early as 1982(9)  and therapeutic acid suppression was first identified as a risk factor for CDI by Brown, et. al in 1990(10).  A recent meta-analysis evaluated incident and recurrent CDI among PPI users as well as the relative influence of concurrent antibiotic use. Forty-two observational studies were systematically reviewed which included 313,000 patients and indicated a clear association between PPI use and risk of CDI (OR 1.74, 95% CI 1.47 – 2.85) or risk of recurrent CDI (OR 2.51, 95% CI 1.16 – 5.44). When antibiotics and PPIs were used together, the risk of developing CDI rose above that with the effect of PPI alone (OR 1.96, 95% CI 1.03 – 3.70). An additional risk of 19% was attributed to the interaction between the two drug types, independent of the effect of either drug in isolation. (11)

PPIs Use & Clostridium difficile infections (CDIs) Risk: US FDA Communication

In February 2012, the US Food and Drug Administration (FDA) issued a safety announcement regarding the use of PPIs, which was based on the review report from the Adverse Event Reporting System (AERS). Based on these reports, the FDA alerted health care professionals and patients that the use of PPIs may increase the risk for CDAD in vulnerable patients(12).

Clinical Evidence for Use of Probiotics in Clostridium difficile Infections (CDIs)

The probiotic strains reported with a potential beneficial role against C. difficile infections include Lactobacillus, Saccharomyces, and Bifidobacterium. The mechanisms underlying the clinically beneficial effect of probiotics against C. difficile include inhibition of growth of C. difficile, degradation, and modulation of the immune response against clostridial toxins. The mode of action of probiotics on CDI may vary among different probiotic strains. (13)

Lactobacillus species including Lactobacillus rhamnosus GG (LGG) have also been studied in several studies for the prevention of CDI. LGG has been shown to excrete biosurfactants, organic acids including lactic acid, bacteriocins, and hydrogen peroxide to inhibit colonization and growth of pathogens. LGG has shown beneficial effects in the prevention and treatment of diarrhea of various etiologies in children and adults. Gorbach et al published an initial case series reporting successful treatment with Lactobacillus rhamnosus (LGG) among patients with multiple recurrences of CDI. In yet another study, Biller et al reported that children with multiple recurrences of CDI had resolution of their infection after 2 weeks of LGG administration. (14) The Mexican Consensus on Probiotics cites that Lactobacilli have been listed in the group of probiotics as beneficial for the prevention of recurrence of diarrhea in children and adults due to C. difficile infection(15).

In Summary

It seems biologically plausible that an increase in pH with a decrease in barrier function of the gastric environment could increase the risk for CDIs, thus affirming the scientific rationale behind the association of PPIs use and augmented risk of CDAD. Observational studies confirm that patients undergoing pharmacologic acid suppression are at increased risk of developing CDIs. PPI use is associated with an approximately two-fold increased CDIs risk (3). Probiotics may have a protective role in reducing the incidence of CDIs with published evidence with genus Lactobacillus, Saccharomyces, and Bifidobacterium. (12)

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