In this study of community-acquired CDAD, with cases defined on the basis of the patient having received a prescription for oral vancomycin therapy (whose only indication is the treatment of CDAD), we observed an increased risk of CDAD associated with current use of proton pump inhibitors. The estimate of effect for H2
-receptor antagonists was not found to be statistically significant. Comorbid illnesses determined to be associated with CDAD in previous studies1,4
(i.e., renal failure, inflammatory bowel disease, cancer and MRSA infection) remained significantly associated with CDAD in this study.
As in the previous study,1
antibiotics presented the highest risk of all the medications assessed; however, 45% of the case subjects had not received a prescription for antibiotics in the 90 days before vancomycin prescription. Most studies of CDAD have involved patients in acute care hospitals, where the prevalence of antibiotic exposure is high,14
which has likely contributed to the high rates of antibiotic exposure among CDAD patients in this setting. Also, because antibiotics frequently cause diarrhea and are believed to be in the causal pathway of CDAD, selection and ascertainment bias may be occurring. Patients receiving antibiotics are more likely than those not taking antibiotics to be tested and therefore receive a diagnosis of CDAD, especially with recommendations that testing only be performed in patients with recent antibiotic exposure.15
In 3 studies performed in settings where the rate of antibiotic exposure in the source population was low (less than 15%), rates of prior antibiotic exposure of 49%,16
among the CDAD cases were observed. At a recent workshop on clostridial disease, low rates of antibiotic exposure among patients with community-acquired CDAD were also reported.19,20
Therefore, patients with community-acquired CDAD may be less likely than those with hospital-acquired CDAD to have been previously exposed to antibiotics.
The use of 3 different case definitions for CDAD from a validated research database — laboratory diagnosis based on a positive toxin assay result (n
= 833), physician diagnosis (n
= 400) and receipt of a prescription for oral vancomycin therapy (n
= 317) — yielded similar proportions of patients with prior proton pump inhibitor exposure (24%, 21%1
and 19%). The proportion of patients who had previously been exposed to antibiotics was higher among cases defined on the basis of vancomycin treatment (55%) than among those defined on the basis of a positive toxin assay result (34%) or physician diagnosis (38%).1
Because vancomycin is significantly more expensive than metronidazole and because metronidazole is suggested as the first-line agent for the treatment of CDAD, it is possible that a case definition based on a prescription for oral vancomycin therapy may have resulted in certain biases.8
For example, if being given oral vancomycin therapy is a marker for more severe CDAD, our estimates of drug effects may only be applicable to the risk of severe disease. It is possible that we included patients with relapses whose risk factors may have differed from those of patients with a first occurrence of CDAD. Also, if oral vancomycin therapy was prescribed as a second-line agent, these patients may have had diarrhea that was actually undiagnosed CDAD and in whom other antibiotic therapies (e.g., metronidazole or a quinolone) had failed. This could have increased our effect estimate of exposure to previous antibiotic agents (protopathic bias). This could also explain, in part, differences in the prevalence of antibiotic exposure between the cases seen in this study and those in a previous study, where the rate of prior antibiotic exposure was 37%.1
The UK health care system differs from the Canadian system in that general practitioners in the United Kingdom are responsible for overseeing the care of the patients in their practice, and budgetary adjustments are based on this premise. There may have been some unrecorded prescription information related to specialist visits, but it is unlikely to account for a high proportion of patients. Although the accuracy of the data is always a concern with database research, it has been reported that prescription information in the GPRD is extremely accurate11,13,21
and has been consistent throughout the period of study. Although the accuracy is shown to be of high quality for certain diagnoses,22
routine collection of such large amounts of data is inevitably subject to some constraints, since detailed diagnostic criteria cannot be laid down as in prospective studies. However, we believe that the consistency of the associations using the 3 different case definitions suggests that our definitions are valid.
In a community-based cohort, patients are less likely to be exposed to antibiotics and rarely receive multiple antibiotics concurrently. Under these conditions, it may be possible to gain a clearer estimate of the effect of nonantibiotic drugs on the risk of CDAD than in a hospital-based study, where antibiotic use is highly prevalent. The inability to demonstrate an association between acid suppressive agents23,24
and CDAD in some hospital-based studies could have been due to residual confounding by indication. This is highlighted by the fact that underlying disease severity,25
a known risk factor for CDAD (as well as other nosocomial complications) may be highly correlated with both broad-spectrum and multiple antibiotic use. Recent hospital-based studies3–5,26
and a large community study1
have described an increased risk of CDAD associated with proton pump inhibitor exposure. The results of this study, involving a different community cohort and a different case definition of CDAD, add additional weight to the evidence that proton pump inhibitor use is associated with an increased risk of CDAD.
@ See related article page 757