Clostridium difficile Leaves the Hospital—What’s Next?

Since their introduction afterWorldWar II, antibioticshavebeen known to cause gastrointestinal problems, including nausea and diarrhea. By the late 1970s, Clostridium difficile was put forwardas the causeof a largeproportionof casesofdiarrhea,1 and the hunt began for an optimal control strategy.At first, control of the situationseemedeasy: clindamycin, an agent with potentanaerobicactivity,was implicated,aconnection thatmade biologicsenseandwassupportedbythenewlydevelopedhamstermodel.2 Better yet, less clindamycinuse resulted in lessC difficile, at least early on, and the problembriefly cameunder control.3 However, things were not as simple as they first seemed. Soon, additional antibioticswere incriminated, including ampicillin and third-generation cephalosporins and then fluoroquinolones, until eventually the list of associated antibiotics became almost synonymous with the hospital antibiotic formulary.Theclassic studybyMcFarlandet al,4using largerdata sets, found that advancedageandcomorbid illness, alongwith bowel perturbation,were associatedwithCdifficiledisease in hospitalized patients. Further progress in understandingwas made with the recognition that cases were occurring in the community, far from theharsh corridors of themodernmedical center.5 In the past few years, a new and disturbing smoking gun hasbeen identified. In2010, this journal ranapair of articles,6,7 along with a pointed editorial,8 about the health consequences of the overuse of a different class ofmedications: not antibiotics, but America’s third favorite drugs, proton pump inhibitors (PPIs), amultibillion-dollar product. Oneof theunexpected adverse effects was an increase in C difficile, with a corresponding dose response connecting the degree of acid suppression to the risk of C difficile–associated diarrhea. The link has proved to be of sufficient scope and significance that in February 2012 the Food and Drug Administration issued a safety announcement to inform the public that the “use of stomachaciddrugs knownasprotonpump inhibitors (PPIs) may be associated with an increased risk of Clostridiumdifficile–associateddiarrhea.”9Their evidencebasewas 28observational studies in 26 reports, aswell as their ownpassive Adverse Event Reporting System. In general, the risk ofC difficile–associateddiarrheawas 1.4 to 2.8 timeshigher among patientswhohad PPI exposure comparedwith thosewhodid not have PPI exposure. The importantarticlebyChitnisetal10 in this issueof JAMA Internal Medicine adds substantially more evidence. In a remarkably thoroughepidemiological study across 8 states, the authors determined risks for about 1000 cases of communityacquiredCdifficile–associateddiarrhea. Thepatientswere divided into thosewithhigh-level health care exposure (including recent hospitalization and dialysis or other invasive procedures), low-level exposure (such as a visit to a physician’sordentist’soffice),ornohealthcareexposureatall.Overall, more than one-third (36%) of the patients had no antibiotic exposure in the 12weeks before diagnosis, while 31%had received PPIs, a disturbingly high proportion. The investigators then zeroed in on the 177 patientswith no health care exposure in the 12 weeks before diagnosis. Of these, more than one-third were taking acid-reducing medications, including PPIs (24%) and H2-receptor antagonists (12%). This observation raises several important questions. The first is why America has such an upset stomach. Most of the use of PPIs is for symptoms well outside of the label indicaRelated article page 1359 Community-Associated Clostridium difficile Original Investigation Research