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Proton Pump Inhibitor Use Linked to Clostridium Difficile Infection

I have been taking acid suppressants, both H2 blockers (Ranitidine) and proton pump inhibitors (Omeprazole) for nearly 9 years. I see many here are also on these. The GERD I get in their absence is pretty miserable, but I have always believed that radically altering the chemistry of digestion with acid blockers is a generally bad idea, especially from the standpoint of potential GI infections. The 2 studies described below would seem to lend credence to this belief. Stomach acid exists primarily to disinfect. I would suspect that these drugs increase the risk of infection (or at least an over abundance) of many microorganisms, in addition to C. difficile, some of which may be harmful.

Arch Intern Med. 2010;170:747-748, 772-778, 784-790.

Use of proton pump inhibitors (PPIs) is linked to Clostridium difficile infection, according to the results of 2 studies reported in the May 10 issue of the Archives of Internal Medicine. The articles describing this prospective analysis are part of a series about PPIs in the Archives of Internal Medicine entitled "Less Is More."

First Study: Howell and Colleagues

"The incidence and severity of Clostridium difficile infections are increasing," write Michael D. Howell, MD, MPH, and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts. "Acid-suppressive therapy has been suggested as a risk factor for C difficile, but this remains controversial."

In this pharmacoepidemiologic cohort study, the investigators conducted a secondary analysis of prospectively collected data from 101,796 patients who were discharged from a tertiary care medical center during a 5-year period. Acid suppression treatment was the primary exposure of interest, classified by intensity (no acid suppression, histamine2-receptor antagonist [H2RA] treatment, daily PPI use, and PPI use more often than daily).

The risk for nosocomial C difficile infection increased with increasing level of acid suppression. This risk was 0.3% (95% confidence interval [CI], 0.21% - 0.31%) in patients not receiving acid suppressive treatment, 0.6% (95% CI, 0.49% - 0.79%) in those receiving H2RA treatment, 0.9% (95% CI, 0.80% - 0.98%) in those using PPIs daily, and 1.4% (95% CI, 1.15% - 1.71%) in patients using PPIs more often than daily.

The association persisted after adjustment for comorbid conditions, age, antibiotics, and propensity score–based likelihood of receiving no acid suppression treatment. The odds ratio was 1 for no acid suppression (reference), 1.53 for H2RA treatment (95% CI, 1.12 - 2.10), 1.74 for daily PPI use (95% CI, 1.39 - 2.18), and 2.36 for more frequent PPI use (95% CI, 1.79 - 3.11). A matched cohort analysis and nested case-control techniques resulted in similar estimates.

"Increasing levels of pharmacologic acid suppression are associated with increased risks of nosocomial C difficile infection," the study authors write. "This evidence of a dose-response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection."

Limitations of this study include observational design, possible residual confounding or selection bias, and lack of data about use of acid suppressive medications or antibiotics before admission.

Second Study: Linsky and Colleagues

The second study, by Amy Linsky, MD, from Boston Medical Center in Massachusetts, and colleagues, was a retrospective cohort study using administrative databases of the New England Veterans Healthcare System. From October 1, 2003, through September 30, 2008, there were 1166 inpatients and outpatients treated with metronidazole or vancomycin hydrochloride for incident C difficile infection.

Of these patients, 527 (45.2%) were given oral PPIs within 14 days of diagnosis, and 639 (54.8%) were not. The investigators measured the hazard ratio (HR) for recurrent C difficile infection, which was defined as a positive toxin result in the 15- to 90-day period after incident C difficile infection.

Compared with patients not using PPIs, those using them were more likely to have recurrent C difficile infection (25.2% vs 18.5%), with an adjusted HR of recurrent C difficile infection of 1.42 (95% CI, 1.11 - 1.82), based on Cox proportional survival methods.

Among patients exposed to PPIs, risks for recurrent C difficile infection were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15 - 3.01) and among those given antibiotics not targeting C difficile during follow-up (HR, 1.71; 95% CI, 1.11 - 1.64).

"...PPI use during incident CDI [C difficile infection] treatment was associated with a 42% increased risk of recurrence," the study authors write. "Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI."

Limitations of this study include use of observational databases, possible misclassification of exposure, and potential misclassifications of a positive test result for C difficile toxin alone as a clinically relevant recurrence.

Editorial: Risk Increase Not Modest

In an accompanying editorial, Mitchell H. Katz, MD, from the San Francisco Department of Public Health, San Francisco, California, describes these studies as well as the others described in the series, "Less Is More."

"The increases in the risk of Clostridium difficile infection with PPIs are not at all modest, reflecting the likely importance of gastric acid in protecting against infection from this pathogen," Dr. Katz writes.

"A pharmacoepidemiologic study of more than 1,000,000 hospital discharges in this issue of the Archives demonstrates a dose-response curve between level of acid suppression and C difficile infection.... Another article in this issue extends this association by demonstrating that the use of PPIs during treatment for C difficile infection was associated with a 42% increase in the rate of C difficile recurrence."

The authors of the study by Howell and colleagues have disclosed no relevant financial relationships. The study by Linsky and colleagues was supported by the resources of the Veterans Affairs Cooperative Studies Program and using the facilities of the Veterans Affairs Boston Healthcare System. The authors of the study by Linsky and colleagues have disclosed no relevant financial relationships.

Dr. Katz is an independent consultant for Health Management Associates.
Thanks David,

Your post may have helped someones child in New Jersey.

I know that seems confusing, but the child has some kind of stomach infection, and the doctors are not getting anywhere, and I have been trying to help her.

I never thought of C-Diff, but your post gave at least one other possible pathogen, and the child is taking a proton pump inhibitor, and has been on antibiotics for Lyme Disease. Antibiotics alone can trigger this infection.

I should have thought of it a while ago.

D Bergy said:
Thanks David,

Your post may have helped someones child in New Jersey.

I know that seems confusing, but the child has some kind of stomach infection, and the doctors are not getting anywhere, and I have been trying to help her.

I never thought of C-Diff, but your post gave at least one other possible pathogen, and the child is taking a proton pump inhibitor, and has been on antibiotics for Lyme Disease. Antibiotics alone can trigger this infection.

I should have thought of it a while ago.

Hope it helps. Let me know how it works out!

Might also want to search Zollinger-Ellison Syndrome.

Also this:

Viewpoints in Infectious Diseases: Antibiotic Use and Clostridium difficile

This Viewpoint takes a look at the link between certain antibiotics and development of C difficile infections, but also cautions about drawing conclusions based on pharmacy database records.

Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection.
CMAJ. 2008; 179(8):767-72 (ISSN: 1488-2329)
Article Summary

This study sought to determine the precipitating cause of Clostridium difficile infection (CDI). The investigators' emphasis was on the use or non-use of antibiotics and the specific agents used. The study linked health databases using the Canadian system for pharmacy records for persons over 65 years and the provincial hospital discharge summary database, which was screened for persons admitted with CDI. For each case, investigators randomly selected 10 controls from the study population and matched for time of hospital admission. The pharmacy records were reviewed for antibiotic prescriptions given during the 45-day period before the date of hospitalization.

The screening process found 836 cases of CDI and 442 of these (53%) had no history of antibiotic exposure during the previous 45 day period according to pharmacy records. Antibiotic exposure was associated with a risk for CDI of 10.6. With regard the individual agents, clindamycin was associated with the greatest risk; for tetracycline and trimethoprim-sulfamethoxazole the risk was virtually nil. These results are summarized for the antibiotics in the following table .

Of note, the risks specified in the table represent the relative risk for the specified agent compared with 8,360 controls. Of additional interest is the risk associated with proton pump inhibitors and antacids, which were 1.6 and 1.5, respectively.

The authors conclude that CDI is common without previous antibiotic exposure, thus emphasizing the need to accept this possibility in patients who deny the most commonly recognized risk factor.

I always worry about studies that match databases based on my assumption that many patients keep antibiotics in their cupboards, borrow, or have alternative methods that would escape detection by review of pharmacy records for the 45 days before hospital presentation. Nevertheless, this study makes some important observations:

* The infection is relatively frequent in outpatients despite emphasis on the role of the hospital;
* Clindamycin, cephalosporins, and fluoroquinolones continue to be the "big 3";
* Of importance, this study was done in Quebec where an astonishing number of cases have involved the NAP-1 strain since 2004. This strain is resistant to fluoroquinolones, which may account for their relatively large numbers as inducing agents in this as well as other more recent reports; and
* Although non-antibiotic use seems to be prominent, it should be noted that these cases clearly do occur and the NAP-1 strain appears to be the most common pathogen in such cases; my skepticism is simply based on the large numbers here because 50% seems high and the possibility of missing some cases with a 45-day review of pharmacy records may obviously miss some of the cases

BACKGROUND: Previous observations have indicated that infection with Clostridium difficile occurs almost exclusively after exposure to antibiotics, but more recent observations have suggested that prior antibiotic exposure may be less frequent among cases of community-acquired disease. METHODS: We used 2 linked health databases to perform a matched, nested case-control study of elderly patients admitted to hospital with community-acquired C. difficile infection. For each of 836 cases among people 65 years of age or older, we selected 10 controls. We determined the proportion of cases that occurred without prior antibiotic exposure and estimated the risk related to exposure to different antibiotics and the duration of increased risk. RESULTS: Of the 836 cases, 442 (52.9%) had no exposure to antibiotics in the 45-day period before the index date, and 382 (45.7%) had no exposure in the 90-day period before the index date. Antibiotic exposure was associated with a rate ratio (RR) of 10.6 (95% confidence interval [CI] 8.9-12.8). Clindamycin (RR 31.8, 95% CI 17.6-57.6), cephalosporins (RR 14.9, 95% CI 10.9-20.3) and gatifloxacin (RR 16.7, 95% CI 8.3-33.6) were associated with the highest risk. The RR for C. difficile infection associated with antibiotic exposure declined from 15.4 (95% CI 12.2-19.3) by about 20 days after exposure to 3.2 (95% CI 2.0-5.0) after 45 days. Use of a proton pump inhibitor was associated with increased risk (RR 1.6, 95% CI 1.3-2.0), as were concurrent diagnoses of inflammatory bowel disease (RR 4.1, 95% CI 2.6-6.6), irritable bowel syndrome (RR 3.4, 95% CI 2.3-5.0) and renal failure (RR 1.7, 95% CI 1.2-2.2). INTERPRETATION: Community-acquired C. difficile infection occurred in a substantial proportion of individuals with no recent exposure to antibiotics. Among patients who had been exposed to antibiotics, the risk declined markedly by 45 days after discontinuation of use.