Proton pump inhibitor use and Clostridium difficile colitis: cause or coincidence?

It is now widely recognized that the incidence of Clostridium difficile-associated disease (CDAD) and its severity have risen markedly since 1990. This is reflected in the rising diagnosis of both community-acquired and hospital-acquired cases and in their severity, as judged by frequent identification of several hypervirulent strains, higher rates of recurrence, resistance to antibiotics, complications (toxic megacolon, septic shock, intestinal perforation), prolongation of hospital stay, morbidity, case fatality, and overall mortality.1–4 In the face of declining use of antibiotics, these risks have increased 3to 5-fold, particularly in the elderly, but there has also been a major rise in community-acquired disease5 involving younger and healthier cases: in some recent studies community-acquired infections have accounted for 40% or 50% of the total, with upward of 40% of patients having no history of prior exposure to antibiotics.5 A large number of risk factors have been identified, many of which are changing.3 In this issue of the journal, Kim et al6 provide startling information that recurrence of CDAD in patients taking a proton pump inhibitor (PPI) for at least 1 week after resolution of their bowel symptoms was 47.6%. This was compared with 4.8% in CDAD patients without recurrence, an odds ratio (OR) of 18.8 [95% confidence interval (CI): 2.05, 161.38; P=0.009]. The number of cases involved was small, but it adds this study to a rapidly growing number of reports identifying PPI use as a risk factor for CDAD. What does this mean? With over 30 papers of varying quality already published on the association of PPI use with development or recurrence of CDAD, it behooves us to seek evidence for causality that may emerge from essentially epidemiologic studies. Space does not allow a detailed application of Bradford Hill’s classic criteria for causation,7 but a few of the more important of these are of particular relevance, namely, temporal relationship, strength of association, consistency, dose-response relationship, and biological plausibility. Although PPIs first became available in the late 1980s, initial use was relatively small, and no consistent International Classification of Diseases coding existed for C. difficile infection (CDI) before 1993. Since that time PPI use has risen enormously and so has the incidence of CDI, but the rise of the latter was modest until about 2000, after which the rise was steep.1 Although studies have drawn attention to an apparently close temporal association between PPI use and CDAD,8,9 it must be noted that, around the same period that PPIs became generic, available over-the-counter and the third most used drug in the United States, fluroquinolone antibiotics, especially levoquin, were also being widely used, with C. difficile becoming increasingly resistant to them. More virulent toxigenic strains were also being increasingly identified, particularly in institutional outbreaks. Transmission of CDI by hospital personnel was not widely emphasized then. It is therefore difficult to exclude confounding of the temporal association by these or other factors. Nevertheless, in one carefully executed observational study of the incidence of CDAD among 76,908 hospitalized patients in New Jersey between 2001 and 2005 (inclusive), incidence increased from 5.08 to 8.42 cases/10 admissions (P<0.0005). 9 During the time period, there was a decline in the use of H2-receptor antagonists (H2RAs), with a concomitant increase in the use of PPIs for prophylaxis of stress ulcers. In 2005 (the last year of the study), a carefully designed case-control analysis showed that PPI use, either before or during admission, was associated with CDAD, with an adjusted OR of 2.75 (95% CI: 1.68, 4.52): the association with H2RAs was not significant: adjusted OR.0. 95 (95% CI: 0.39, 2.34). It is noteworthy that the usage of PPI correlated exactly with the increased incidence of CDAD