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Use of Acid-Suppressing Drugs and the Risk of Bacterial Gastroenteritis

2007; Elsevier BV; Volume: 5; Issue: 12 Linguagem: Inglês

10.1016/j.cgh.2007.09.010

1542-7714

Luis A. Garcı́a Rodrı́guez, Ana Ruigómez, Julián Panés,

Clostridium difficile and Clostridium perfringens research

Background & Aims: Gastric acid is a defense mechanism against gastrointestinal infections caused by ingested bacteria. Studies have suggested that the use of acid-suppressing drugs may increase the risk of gastroenteritis (GE). Methods: Patients aged 20−74 years with an episode of acute bacterial GE (n = 6414) were identified. A control group from the same study population without a diagnosis of GE (n = 50,000) was frequency-matched by age, sex, and calendar year to the case group. Unconditional logistic regression was used to calculate the adjusted relative risk (RR) of GE in patients using proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). Results: Current use of PPIs was associated with an increased risk of bacterial GE compared with nonuse, regardless of the treatment duration (RR, 2.9; 95% confidence interval [CI], 2.5−3.5), whereas no association was observed with H2RA use (RR, 1.1; 95% CI, 0.9−1.4). Doubling the PPI dose further increased the risk of developing bacterial GE (RR, 5.0; 95% CI, 2.7−9.3). The effect of PPI use did not vary significantly with regard to treatment indication. The increased risk associated with PPI use was similar for both omeprazole (RR, 3.0; 95% CI, 2.5−3.7) and lansoprazole (RR, 2.1; 95% CI, 1.4−3.0), whereas neither cimetidine nor ranitidine showed any increased risk. Campylobacter (n = 4124) and Salmonella (n = 1885) were the 2 species most frequently responsible for GE episodes in the case group. When analyzed separately, both species reproduced the increased risk associated with PPI use and not H2RA use. Clostridium GE cases were rare (n = 31). Conclusions: This study suggests that gastric acid suppression induced by PPIs but not H2RAs is associated with an increased risk of Campylobacter and Salmonella GE. Background & Aims: Gastric acid is a defense mechanism against gastrointestinal infections caused by ingested bacteria. Studies have suggested that the use of acid-suppressing drugs may increase the risk of gastroenteritis (GE). Methods: Patients aged 20−74 years with an episode of acute bacterial GE (n = 6414) were identified. A control group from the same study population without a diagnosis of GE (n = 50,000) was frequency-matched by age, sex, and calendar year to the case group. Unconditional logistic regression was used to calculate the adjusted relative risk (RR) of GE in patients using proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). Results: Current use of PPIs was associated with an increased risk of bacterial GE compared with nonuse, regardless of the treatment duration (RR, 2.9; 95% confidence interval [CI], 2.5−3.5), whereas no association was observed with H2RA use (RR, 1.1; 95% CI, 0.9−1.4). Doubling the PPI dose further increased the risk of developing bacterial GE (RR, 5.0; 95% CI, 2.7−9.3). The effect of PPI use did not vary significantly with regard to treatment indication. The increased risk associated with PPI use was similar for both omeprazole (RR, 3.0; 95% CI, 2.5−3.7) and lansoprazole (RR, 2.1; 95% CI, 1.4−3.0), whereas neither cimetidine nor ranitidine showed any increased risk. Campylobacter (n = 4124) and Salmonella (n = 1885) were the 2 species most frequently responsible for GE episodes in the case group. When analyzed separately, both species reproduced the increased risk associated with PPI use and not H2RA use. Clostridium GE cases were rare (n = 31). Conclusions: This study suggests that gastric acid suppression induced by PPIs but not H2RAs is associated with an increased risk of Campylobacter and Salmonella GE. Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) are potent drugs suppressing gastric acid secretion. Consequently, they are highly effective for treating acid-related disorders, but have raised concerns that suppression of gastric acid by these drugs will alter the bacterial flora of the upper-gastrointestinal tract and lead to complications such as malabsorption, enteric infections, and infections outside the gastrointestinal tract. A number of recent epidemiologic studies have reported an increased risk of Clostridium difficile infections in hospitalized patients1Dial S. Alrasadi K. Manoukian C. et al.Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies.CMAJ. 2004; 171: 33-38Crossref PubMed Scopus (486) Google Scholar and in the general population2Dial S. Delaney J.A. Barkun A.N. et al.Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease.JAMA. 2005; 294: 2989-2995Crossref PubMed Scopus (832) Google Scholar associated with the use of gastric acid–suppressing agents. However, conflicting data have been produced on the risk of bacterial enteral infections associated with the use of acid-suppressing drugs.3Neal K.R. Scott H.M. Slack R.C. et al.Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study.BMJ. 1996; 312: 414-415Crossref PubMed Scopus (135) Google Scholar, 4Laine L. Ahnen D. McClain C. et al.Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors.Aliment Pharmacol Ther. 2000; 14: 651-668Crossref PubMed Scopus (248) Google Scholar A recent review concluded that further research is required to more fully quantify the risk of enteric infections associated with the use of acid-suppressing drugs.5Williams C. McColl K.E. Review article: proton pump inhibitors and bacterial overgrowth.Aliment Pharmacol Ther. 2006; 23: 3-10Crossref PubMed Scopus (194) Google Scholar The widespread use of PPIs and other gastric-suppressing agents in the general population underscores the importance of evaluating their effect on the risk of bacterial gastroenteritis in the general population. We thus assessed whether the use of gastric acid–suppressant drugs is associated with an increased risk of bacterial enteral infections, whether the risk is dose dependent, and whether there are factors that could act as modifiers of this risk. We conducted a nested case-control study using the General Practice Research Database. The General Practice Research Database is a population-based database in the United Kingdom where general practitioners store their practice database with clinical information on their patients including demographics, diagnoses, and free text comments, referral information, and records of all prescriptions issued by them.6García Rodríguez L.A. Pérez-Gutthan S. Use of the UK General Practice Research Database for pharmacoepidemiology.Br J Clin Pharmacol. 1998; 45: 419-425Crossref PubMed Scopus (506) Google Scholar Data on about 3 million patients are recorded systematically and sent anonymously to the Medicines Control Agency. The Medicines Control Agency collects and organizes this information to be used for research projects. An additional requirement for participating practices is recording of the indication for new courses of therapy. A modification of the Oxford Medical Information System classification system is used to code specific diagnoses, and a drug dictionary based on data from the Prescription Pricing Authority is used to code drugs. Its completeness, validity, and quality of data have been widely reported by several studies in gastrointestinal diseases.7Hollowell J. The General Practice Research Database: quality of morbidity data.Popul Trends. 1997; 87: 36-40PubMed Google Scholar, 8Lewis J.D. Brensinger C. Bilker W.B. et al.Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease.Pharmacoepidemiol Drug Saf. 2002; 11: 211-218Crossref PubMed Scopus (156) Google Scholar We recently evaluated the risk of developing inflammatory bowel disease in patients after an episode of infectious gastroenteritis.9García Rodríguez L.A. Ruigómez A. Panés J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease.Gastroenterology. 2006; 130: 1588-1594Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar We used the same study population that comprised persons age 20–74 years of age between January 1992 and December 2001, who had been enrolled at least 2 years with the general practitioner (GP), had at least 1 year elapsed since their first computerized prescription, and were free of cancer, alcohol-related disease, inflammatory bowel disease (including specific inflammatory bowel disease therapy), previous episode of gastroenteritis, gastrointestinal infectious disease, or enteritis/colitis before start date. All study members were followed up from start date until they had a recorded entry of gastroenteritis, one of the earlier-mentioned exclusion criteria, 75th birthday, death, or until December 2001, whichever came first. For all patients identified with a code suggesting infectious gastroenteritis (GE), computerized patient profiles free of all personal identifiers were produced and reviewed. Finally, 6414 patients were considered to have documented bacterial gastroenteritis: this required the patient to present with symptoms compatible with an episode of gastroenteritis and to have a positive stool culture for a specific bacteria (Salmonella, Campylobacter, Shigella, Clostridium, or other bacteria). We used the day of first recording of GE as the index date. A more detailed description on case ascertainment can be found in our recent study.9García Rodríguez L.A. Ruigómez A. Panés J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease.Gastroenterology. 2006; 130: 1588-1594Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar Controls were sampled randomly from the study population so that the likelihood of being selected as a control was proportional to the person-time at risk. Specifically, a date during the study period was generated at random for each of the members of the source population. If the random date of a study member was included in his or her eligible person-time, we used his or her random date as the index date and marked that person as an eligible control. The same exclusion criteria were applied to controls as to cases. Fifty thousand controls, frequency-matched to cases by age (within 1 year), sex, and calendar year were selected randomly from the pool of eligible controls. Exposure to PPI and H2RA were first considered independently and categorized as follows: current, when the supply of the most recent prescription lasted until the index date or ended in the week before the index date based on the length of drug therapy as prescribed by the GP; recent, when it ended 7–90 days before the index date; past, when it ended 91–365 days before the index date; and nonuse, when there was no recorded use in the year before the index date. Then, we created a single variable encompassing the use of any acid-suppressing drug (PPI and H2RA) with the following categories: nonuse was defined as no use of acid-suppressing drugs in the year before the index date; current single use of PPI was defined as use in the week before the index date conditional on no use of H2RA in the month before the index date; and current single use of H2RA was defined as use in the week before the index date conditional on no use of PPI in the month before the index date. Among current single users we studied the effect of duration, dose, and treatment indication. We evaluated the duration of use, adding the periods of consecutive prescriptions, defined as an interval of less than 2 months between 2 prescriptions. The effect of daily dose was studied in 3 categories: low, medium, and high, using the defined daily dose as a cut-off value. We also evaluated the risk among current single users of the most frequently used individual acid-suppressing drugs (omeprazole, lansoprazole, cimetidine, and ranitidine). Exposure to other drugs such as antidiarrheics, antibiotics, antacids, and nonsteroidal anti-inflammatory drugs also was evaluated using similar time windows as those for acid-suppressing drugs. We ascertained information from the database on gastrointestinal disorders any time before the index date. Body mass index, expressed in kilograms per square meter, was calculated from recorded height and weight (weight [kg]/(height —)2Dial S. Delaney J.A. Barkun A.N. et al.Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease.JAMA. 2005; 294: 2989-2995Crossref PubMed Scopus (832) Google Scholar). Alcohol intake and smoking status were used as directly recorded by the GP on computer files. We computed estimates of odds ratios and 95% confidence intervals (CIs) of bacterial GE associated with current use of PPI and H2RA compared with nonuse with unconditional logistic regression. Under our study design, the odds ratio was an unbiased estimator of the relative risk (RR). All estimates of RR were adjusted for age, sex, calendar year, and number of visits to the GP in the year before the index date. Adjustment for additional variables changed the estimates of acid-suppressing drugs by less than 10% and were not included in the final multivariate regression model. Specific subgroup analyses were performed by sex, age, and use of antidiarrheics. Finally, estimates of risk were computed according to the specific bacteria isolated in the stool culture. Selected characteristics of cases and controls are presented in Table 1. Because of the matching, cases and controls had a similar distribution of age and sex. Excessive alcohol consumers presented a greater risk than abstainers, as shown in Table 1. The risk of developing gastroenteritis was more than twice as great in summer than in the colder seasons. Leanness (body mass index < 20) conferred a close to 25% reduced risk of bacterial GE compared with normal-weight individuals. Current use of antidiarrheics was associated with a greatly increased risk of GE, but the risk completely disappeared with past use. When we analyzed the effect according to treatment duration among current users, the risk was restricted mainly to antidiarrheic treatment initiated within 1 week before the recording of GE: the estimate of RR among users with a treatment duration greater than 3 months was 1.4 (95% CI, 0.8–2.6). The same pattern was observed with antibiotic use although with a much smaller increased risk. Patients treated with antibiotics for longer than 1 week presented no increased risk of GE (1.0; 95% CI, 0.8–1.3).Table 1Descriptive Characteristics of Cases and Controls and Corresponding Estimates of Relative Risk of Bacterial GECharacteristicsCases (%) (N = 6414)Controls (%) (N = 50,000)Relative risk (95% CI)aAdjusted for age, sex, calendar year, and GP visits.Age, y 20–392765 (43.1)21,653 (43.3)NAbBecause of the frequency-matching, cases and controls had similar age and sex distributions. 40–592667 (41.6)20,691 (41.4) 60–74982 (15.3)7656 (15.3)Sex Male3143 (49.0)24,409 (48.8)NAbBecause of the frequency-matching, cases and controls had similar age and sex distributions. Female3271 (51.0)25,561 (51.2)Alcohol consumption, U/wk 0–11839 (28.7)15,673 (31.4)Reference 2–91424 (22.2)9662 (19.3)1.33 (1.23–1.43) 10–291041 (16.2)6660 (13.3)1.44 (1.32–1.57) ≥30210 (3.3)1251 (2.5)1.53 (1.31–1.80) Unknown1900 (29.6)16,754 (33.5)1.10 (1.02–1.18)Seasonal period January–April1415 (22.1)16,876 (33.7)Reference May–August2939 (45.8)17,019 (34.1)2.04 (1.91–2.19) September–December2060 (32.1)16,105 (32.2)1.50 (1.39–1.61)Body mass index <20250 (3.9)2624 (5.2)0.74 (0.64–0.85) 20–241979 (30.9)15,318 (30.6)Reference 25–291636 (25.5)11,046 (22.1)1.09 (1.01–1.17) ≥30686 (10.7)4657 (9.3)1.03 (0.94–1.13) Unknown1863 (29.0)16,355 (32.7)0.94 (0.88–1.01)GP visits (in year prior) 0–11276 (19.9)19,646 (39.3)Reference 2–42281 (35.6)16,287 (32.6)2.26 (2.10–2.43) 5–91860 (29.0)9929 (19.8)3.15 (2.91–3.40) ≥10997 (15.5)4138 (8.3)4.19 (3.82–4.60)Antidiarrheics use Nonuse4652 (77.2)49,152 (98.4)Reference Current1329 (20.7)172 (0.3)67.73 (57.52–79.75)Recent76 (1.2)213 (0.4)2.77 (2.12–3.62) Past use57 (0.9)463 (0.9)0.94 (0.71–1.24)Antibiotics use Nonuse3493 (54.5)32,936 (65.9)Reference Current499 (7.8)1322 (2.6)2.39 (2.14–2.68) Recent801 (12.5)5154 (10.3)0.96 (0.88–1.05) Past use1621 (25.2)10,588 (21.2)1.01 (0.95–1.08)a Adjusted for age, sex, calendar year, and GP visits.b Because of the frequency-matching, cases and controls had similar age and sex distributions. Open table in a new tab Table 2 shows the estimates of risk among users of PPI and H2RA. The RR of bacterial GE comparing current use of PPI with nonuse was 2.9 (95% CI, 2.5–3.5). Individuals who had stopped taking PPIs for longer than 3 months (past users) had a similar risk to that in nonusers (RR = 1.1; 95%, 0.9–1.4). The increased risk of GE observed among PPI users was fairly constant over treatment duration. Higher doses of PPI were associated with a greater risk. We analyzed the effect of dosage regimen among users of high-dose PPIs. Users of a high dose with a once-daily regimen presented a RR of 3.2 (95% CI, 0.5–19.4), and users of a high dose with a twice-daily regimen presented a RR of 5.3 (95% CI, 2.8–10.3). Yet, it should be noted that numbers were small in the high-dose category (2 cases on a once-daily regimen and 18 on a twice-daily regimen) and consequently CIs for the dose-specific RRs were overlapping with each other. The RR when comparing high daily dose of a PPI vs low-medium was 1.9 (95% CI, 1.0–3.6). Current use of H2RA was associated with a RR of 1.1 (95% CI, 0.9–1.4). The use of H2RA did not present an increased risk of GE irrespective of treatment duration or daily dose.Table 2Relative Risk of Bacterial GE According to Use, Daily Dose, and Duration of Acid-Suppressing DrugsCases (N = 6414)Controls (N = 50,000)Relative risk (95% CI)aAdjusted for age, sex, calendar year, and GP visits.PPI Current use212 (3.3)447 (0.9)2.91 (2.45–3.46) Recent use61 (1.0)254 (0.5)1.46 (1.10–1.95) Past use69 (1.0)407 (0.8)1.07 (0.82–1.38) Nonuse6072 (94.7)48,892 (97.8)RefH2RA Current use135 (2.1)696 (1.4)1.13 (0.93–1.37) Recent use94 (1.5)457 (0.9)1.16 (0.93–1.46) Past use167 (2.6)848 (1.7)1.11 (0.94–1.32) Nonuse6018 (93.8)47,999 (96.0)RefAcid-suppressing treatment duration Current PPI use 1 y77 (1.2)167 (0.3)3.05 (2.31–4.03)Current H2-antagonist use 1 y48 (0.7)302 (0.6)1.03 (0.75–1.41) Nonuse5802 (90.5)47,215 (94.4)RefAcid-suppressing daily dosebSpecific cut-off values for dose (in mg) were as follows: omeprazole 20, lansoprazole 30, pantoprazole 40, rabeprazole 20, cimetidine 800, famotidine 40, nizatidine 300, ranitidine 300. Doses less than the cut-off value were grouped under low doses, doses equal to the cut-off value were grouped under medium doses, and doses greater than the cut-off value were grouped under high doses. Current PPI use Low dose41 (0.6)101 (0.2)2.69 (1.85–3.91) Medium dose130 (2.0)296 (0.6)2.67 (2.16–3.31) High dose20 (0.3)22 (0.1)5.02 (2.71–9.31) Current H2-antagonist use Low dose32 (0.5)196 (0.4)1.03 (0.70–1.50) Medium dose88 (1.4)449 (0.9)1.17 (0.93–1.48) High dose4 (0.1)28 (0.1)0.81 (0.28–2.31) Nonuse5802 (90.5)47,215 (94.4)Refa Adjusted for age, sex, calendar year, and GP visits.b Specific cut-off values for dose (in mg) were as follows: omeprazole 20, lansoprazole 30, pantoprazole 40, rabeprazole 20, cimetidine 800, famotidine 40, nizatidine 300, ranitidine 300. Doses less than the cut-off value were grouped under low doses, doses equal to the cut-off value were grouped under medium doses, and doses greater than the cut-off value were grouped under high doses. Open table in a new tab Among individual acid-suppressing drugs, omeprazole and lansoprazole were associated with an increased risk, whereas this risk was not observed with use of ranitidine or cimetidine (Table 3). Current use of omeprazole and lansoprazole presented a RR of 3.0 (95% CI, 2.5–3.7) and 2.1 (95% CI, 1.4–3.0), respectively.Table 3Relative Risk of Bacterial GE According to Current Use of Individual Acid-Suppressing Drugs and Treatment Indication Among Current Users of PPI and H2RA UsersCases (N = 6414)Controls (N = 50,000)Relative risk (95% CI)aAdjusted for age, sex, calendar year, and GP visits.Individual acid-suppressing drug Omeprazole147 (2.3)290 (0.6)3.02 (2.46–3.71) Lansoprazole36 (0.6)117 (0.2)2.06 (1.41–3.02) Ranitidine66 (1.0)370 (0.7)1.07 (0.82–1.40) Cimetidine50 (0.8)247 (0.5)1.24 (0.91–1.69) Nonuse5802 (90.5)47,215 (94.4)RefTreatment indication PPI GERD132 (2.1)281 (0.6)2.93 (2.36–3.63) Peptic disease24 (0.4)56 (0.1)2.57 (1.58–4.20) UGI symptombUpper-gastrointestinal (UGI) symptoms include dyspepsia, epigastric pain, and other upper-GI symptoms (other than gastroesophageal reflux disease) in the absence of any organic upper gastrointestinal disease.23 (0.4)33 (0.1)3.87 (2.26–6.65) OthercOther includes treatment prescribed as prevention of nonsteroidal anti-inflammatory–related upper-gastrointestinal damage or treatment indication was unknown.12 (0.2)49 (0.1)1.60 (0.84–3.03) H2RA Gastroesophageal reflux disease35 (0.5)209 (0.4)1.00 (0.69–1.43) Peptic disease33 (0.5)195 (0.4)1.07 (0.73–1.55) UGI symptombUpper-gastrointestinal (UGI) symptoms include dyspepsia, epigastric pain, and other upper-GI symptoms (other than gastroesophageal reflux disease) in the absence of any organic upper gastrointestinal disease.25 (0.4)142 (0.3)1.07 (0.69–1.64) OthercOther includes treatment prescribed as prevention of nonsteroidal anti-inflammatory–related upper-gastrointestinal damage or treatment indication was unknown.31 (0.5)127 (0.3)1.44 (0.96–2.14) Nonuse5802 (90.5)47,215 (94.4)Refa Adjusted for age, sex, calendar year, and GP visits.b Upper-gastrointestinal (UGI) symptoms include dyspepsia, epigastric pain, and other upper-GI symptoms (other than gastroesophageal reflux disease) in the absence of any organic upper gastrointestinal disease.c Other includes treatment prescribed as prevention of nonsteroidal anti-inflammatory–related upper-gastrointestinal damage or treatment indication was unknown. Open table in a new tab The effect of PPI use did not seem to vary greatly according to treatment indication (Table 3). No increased risk of GE was observed across the various indications of H2RA therapy. We performed alternative analyses according to the bacteria responsible for the episode of GE: Campylobacter (N = 4124) and Salmonella (N = 1885) were the 2 most frequent species. Both the increased risk for bacterial GE associated with the use of a PPI and the lack of association with H2RA were replicated when analyzed separately (data not shown). There were limited data on other bacteria-related GE (312 Shigella and 31 Clostridium infections) to compute estimates of RR. We performed several stratified analyses by selected characteristics and the effect of increased risk with PPI use and lack of association with use of H2RA were not modified by sex, age, seasonal period, or numbers of visits to the GP in the year prior (data not shown). This large population-based study found that PPI use is associated with an increased risk of bacterial gastroenteritis. The hazard of GE quickly returns to the background level after cessation of PPI treatment, is relatively constant over treatment duration, is greater with double-dose PPI therapy, and is of similar magnitude with the use of omeprazole and lansoprazole. By contrast, consumption of H2RA did not carry a greater risk of bacterial GE. All these associations were reproduced when subgroups of the population were analyzed separately according to different characteristics. A number of factors may explain the differential risk associated with the 2 classes of acid-suppressing drugs. First, it may be related to the degree of gastric acid suppression because H2RAs are associated with less suppression than PPIs, and it is known that the presence or absence of gastric acid has important implications for bacterial overgrowth. The amount of growth also correlates with the percentage of the day that the pH is greater than 4. If the pH is less than 4.0 for a few hours during each 24-hour period, bacterial growth is inhibited.10Hill M. Normal and pathological microbial flora of the upper gastrointestinal tract.Scand J Gastroenterol Suppl. 1985; 111: 1-6Crossref PubMed Scopus (38) Google Scholar In short-term studies, the proportion of time in which gastric pH is higher than 3 and higher than 4 is significantly greater in individuals treated with therapeutic doses of PPIs than in subjects receiving therapeutic doses of H2RAs.11Blum R.A. Shi H. Karol M.D. et al.The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion.Clin Ther. 1997; 19: 1013-1023Abstract Full Text PDF PubMed Scopus (66) Google Scholar The differential ability of PPIs and H2RAs to suppress gastric acid secretion has been shown to parallel the incidence of bacterial overgrowth, which has been detected in 53% of patients treated with omeprazole in comparison with 17% of patients receiving cimetidine, when both drugs are used after common therapeutic regimens.12Thorens J. Froehlich F. Schwizer W. et al.Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study.Gut. 1996; 39: 54-59Crossref PubMed Scopus (277) Google Scholar Therefore, the increased gastric suppression afforded by PPI will weaken the mechanism of gastric acid as a first line of defense against ingested organisms. The observed dose-dependent increase in the risk of bacterial GE associated with the consumption of PPI also supports the notion that the degree of acid suppression is a key determinant of the risk of Salmonella and Campylobacter GE, although the extent of increased gastric acid suppression with increasing doses of H2RAs is not sufficient to translate into a clinical risk of infection; yet, it should be noted that few individuals were taking double-dose H2RA therapy. However, this may not hold true for all types of bacteria, such as Shigella or Clostridium difficile. The use of acid-suppressing drugs has been associated with an increased risk of Clostridium GE in a previous study,2Dial S. Delaney J.A. Barkun A.N. et al.Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease.JAMA. 2005; 294: 2989-2995Crossref PubMed Scopus (832) Google Scholar but the small number of Clostridium cases in the current study precluded further analysis of this association as well as with other species. Also, although numbers were small to look at different dosage instructions among users of high-dose PPI, the data suggest an increased risk at least as great with a twice-daily regimen vs a once-daily regimen. This would support the theory that not only more potent suppression of gastric acid secretion translates into a greater risk of bacterial GE, but also more long-lasting suppression.13Shimatani T. Inoue M. Kuroiwa T. et al.Rabeprazole 10 mg twice daily is superior to 20 mg once daily for night-time gastric acid suppression.Aliment Pharmacol Ther. 2004; 19: 113-122Crossref PubMed Scopus (49) Google Scholar, 14Katz P.O. Hatlebakk J.G. Castell D.O. Gastric acidity and acid breakthrough with twice-daily omeprazole or lansoprazole.Aliment Pharmacol Ther. 2000; 14: 709-714Crossref PubMed Scopus (87) Google Scholar PPIs also have been shown to affect leukocyte function. A single dose of 40 mg of omeprazole reduces the bactericidal activity of neutrophils over Escherichia coli by 30%, and this reduction has been related to altered oxidant radical production.15Zedtwitz-Liebenstein K. Wenisch C. Patruta S. et al.Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity.Crit Care Med. 2002; 30: 1118-1122Crossref PubMed Scopus (177) Google Scholar By contrast, ranitidine does not affect oxidant production by neutrophils, and cimetidine and famotidine only marginally affect the function of these cells.16Mikawa K. Akamatsu H. Nishina K. et al.The effects of cimetidine, ranitidine, and famotidine on human neutrophil functions.Anesth Analg. 1999; 89: 218-224PubMed Google Scholar PPIs also may affect recruitment of inflammatory cells to sites of inflammation, a key process in the defense against infections. Circulating leukocytes are recruited to sites of infection by a highly regulated multistep process governed by adhesion molecules expressed on the surface of the endothelium and leukocytes.17Panés J. Granger D.N. Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease.Gastroenterology. 1998; 114: 1066-1090Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar PPIs, but not H2RAs, have been shown to down-regulate the expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 on the endothelium and b2 integrins on the surface of white cells, resulting in decreased firm adhesion in response to endothelial cell activation.18Yoshida N. Yoshikawa T. Tanaka Y. et al.A new mechanism for anti-inflammatory actions of proton pump inhibitors–inhibitory effects on neutrophil-endothelial cell interactions.Aliment Pharmacol Ther. 2000; 14: 74-81Crossref PubMed Scopus (176) Google Scholar However, the implications of this in vitro study are unclear because the concentrations used were far greater than the in vivo concentrations used in clinical practice. Our estimate of risk for PPI derived from the current study is higher than that from a previous study performed by our group that also used the General Practice Research Database.19García Rodríguez L.A. Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk?.Epidemiology. 1997; 8: 571-574Crossref PubMed Scopus (42) Google Scholar Several differences between the 2 studies need to be noted. The current study is much larger (33 PPI-exposed cases of GE in the old study vs 212 in the present one), and consequently the precision of the measures of association in this study afford greater confidence. Other noteworthy differences are the time period and the study population. The previous study was performed in the early 1990s, when acid-suppression was much less prevalent and with different indications than the ones in this study (70% of cases occurred in the second half of the 1990s in the current study). Finally, the study population was truly population based in our current study whereas we used a cohort of ever-users of acid-suppressing drugs in the earlier study. Among variables that may act as independent risk factors for bacterial enteral infections we found that recent antibiotic use, within the previous week, was associated with an increased risk of bacterial GE. Although the explanation that altering the normal commensal flora as a result of antibiotic treatment may predispose to invasion by pathogens is plausible, we may not rule out the alternative explanation that some antibiotics could have been prescribed for treatment of early symptoms suggestive of GE before the diagnosis was established formally. Indeed, the risk virtually disappeared when treatment was initiated more than 1 week before the diagnosis of GE. Also, the observation that consumption of antidiarrheal drugs was associated with a major increased risk of GE strongly favors the latter interpretation. We also found that alcohol consumption slightly, but significantly, increases the risk of bacterial GE. This observation is in line with the hypothesis that chronic alcoholism may disturb the function of the immune system and predispose to infections in general,20de Roux A. Cavalcanti M. Marcos M.A. et al.Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia.Chest. 2006; 129: 1219-1225Crossref PubMed Scopus (131) Google Scholar and to bacterial GE in particular, as a consequence of an altered gastric acid barrier, that has been associated with a high prevalence of bacterial overgrowth21Hauge T. Persson J. Danielsson D. Mucosal bacterial growth in the upper gastrointestinal tract in alcoholics (heavy drinkers).Digestion. 1997; 58: 591-595Crossref PubMed Scopus (60) Google Scholar as a risk factor for infectious complications. We do not have an explanation for the apparent protective effect of a low body mass index, except hypothesizing that lean individuals are at a smaller risk of developing gastrointestinal infections as a result of their eating habits. In summary, the current study indicates that PPI therapy but not H2RA therapy is associated with an increased risk of Salmonella and Campylobacter enteric infections and this is consistent with the role of gastric acid as a major mechanism of defense against ingested organisms.