Table 1. Cont.Source Single Single Single Single Single Single Single Single Single Multicenter Hospital Single Single Multicenter Community Gen Pop Single Multicenter Community Elderly patients Multicenter Both Single Single Single Single Single Single Hospital Gen Inpatients Case control Hospital Gen Inpatients Case control Hospital Gen Inpatients Case control Hospital Gen Inpatients Case control Both Gen Pop Case control Both Gen Pop Case control Gen Pop Case control CDAD Diagnosis CDAD Diagnosis, onset during the pre-outbreak or outbreak periods, hospitalization Received at least 5 days of antibiotics prior to diagnosis of CDAD Nosocomial CDAD Nosocomial CDAD Nosocomial, onset during outbreak. Nosocomial, onset during outbreak. Case control Hospital Gen In-patient Cohort Case control, (R) Age:$18 yr Age:$18 yr; hospital acquired; non-psychiatric ward; exposed to antibiotics Age $65, Community Associated CDAD Community Gen Pop Case control, (R) Community acquired CDAD Hospital Gen In-patient Case control Nosocomial CDAD Gen In-patient Cohort Age:$18 yr; healthcare associated CDAD Hospital Gen In-patient Cohort , (R) Age:$18 yr; Recurrent CDAD Hospital Medical ICU Cohort, (R) All patients with CDAD diagnosis Hospital Case control, (R) Post Hip/Knee replacement, CDAD Hospital NA Case control NA Community Gen Pop & Hospital Cohort , (R) All patients with CDAD PPI PPI PPI PPI PPI PPI PPI Community Gen Pop & Hospital Cohort , (R) Recurrent CDAD PPI Hospital Gen In-patient Case control, (P) All hospitalized patients with CDAD PPI Hospital Gen In-patient Case control, (R) Age:$18 yr; CDAD PPI Community Gen Pop Case control, (R) 1 hospital admission for CDAD; Age $ 66yr; CDAD diagnosis within 60d of ABX therapyAcid suppressive therapy Acid suppressive therapy PPI PPI PPI PPI PPI PPI: During the 4 weeks before detection of CDAD PPI PPI being taken before the date of CDAD diagnosisNA: Data obtained from abstract Legend: OR: odds ratio; HR: harzard ratio; CDAD: Clostridium difficile-associated diarrhea; PPI: Proton pump inhibitor; H2RA: VA: Veteran Affairs; D: Durham County, P: Prospective; R: Retrospective, ABX: Antibiotic; GPRD: General Practice Research Database; ICU: Intensive care unit Metabolic processes are controlled by a variety of enzymes. For instance, cytochrome P450 monooxygenase could detoxify herbicides such as fenoxaprop-ethyl, diclofop-methyl, and bentazon in plants [22,23]. Polyphenol oxidase (PPO), commonly found in fungi and plants, refers to a group of enzymes that catalyze the oxidation of phenolic compounds [24]. Peroxidase (POD), another type of oxidative enzyme commonly present in plant and animal tissues, can oxidize phenols and aromatic amines in the presence of hydrogen peroxide. In contrast, the oxidation of phenolic compounds by PPO requires the presence of oxygen gas [25]. Both PPO and POD play important roles in the metabolism of aromatic compounds in soil and water [26,27]. However, little information is available regarding their function in the metabolism of PAHs by plants.
Figure 2. Forest Plot of the Meta analyses of The Association Between CDI and Proton Pump Inhibitors Based on 51 Observations. examined the potential effect of a residual confounding on the observed association using the rule-out approach. Finally, we interpret the results in the context of observed limitations and therefore, draw more careful conclusions. Contrary to other reviews and FDA alert, we conclude that current cumulative data constitutes very low quality evidence. Our results are helpful for guidelines writing committees and policy makersthat use the GRADE framework when formulating recommendations for use of PPI for different clinical indications.
Biologic Plausibility
The mechanism by which PPI therapy contributes to an increased risk of CDI is unclear, because gastric acid does not kill
Table 2. Influence of study type, country, weather effect estimate adjusted or not and PPI ascertainment method on the pooled effect estimate and its associated heterogeneity.This further makes a cause-effect relationship a less likely explanation for the observed association. It has been proposed that the vegetative form of C. difficile, which is killed by acid, plays a role in pathogenesis. Vegetative forms survive on surfaces and could be ingested by patients [47]. Survival of these acid-sensitive vegetative forms in the stomach could be facilitated by 2 main factors: (1) suppression of gastric acid production by acid-suppressive medications; and (2) presence of bile salts in gastric contents of patients on acid-suppressive therapy. Bile salts, which are mainly found in the small intestine,are present in gastric contents, particularly among patients with gastro-esophageal reflux disease (GERD). Moreover, PPI use can delay gastric emptying and predispose to bacterial overgrowth with associated high intragastric bile salts which could trigger spore germination in the stomach [48?0]. However, a recent in vitro experiment has challenged these postulated biological mechanisms for the observed association. In this experiment, aspirate of gastric contents from hospitalized patients with nasogastric tubes were collected.Figure 3. Contour enhanced funnel plot of the association between the effect-estimates and its standard errors: * Contour enhanced funnel plots with implementation of regression adjustment model (adjusted effect at top where SE is 0).* The contour lines differentiate the significance and non-significance regions in the plot at 1%, 5% and 10% significance levels. *Vertical lines show average effect-estimates from random effect (red), and fixed effect models (blue). *A regression line (black) is added for regression based adjustment (With adjusted effect estimate and 95% CI at top where SE is 0). Abbreviations: FEMA: Fixed effect meta-analysis, REMA: Random effect meta-analysis, Reg: Regression line. Figure 4. Influence of a hypothetical dichotomous confounder present in 20% (panel A) and 50% (panel B) of the study population, unaccounted for in the adjustments already performed in the individual studies. The graphs indicate what combinations of OREC and RR that would be necessary for the confounder to fully account for the observed association between proton pump inhibitor (PPI) use and CDAD after adjustment for publication bias. Abbreviations: OREC, odds ratio of exposure to the confounder in PPI non-users vs. acid-suppression users; RRCD, relative risk of CDAD in individuals exposed to the confounder vs. non-exposed.