we further analyzed data from a population - based case - control study that was constructed using the united kingdom s general practice research database ( gprd ) . gprd is a well - validated ( 7 ) clinical database that records information taken from general practice records . briefly , we identified all patients who had had cdad ( based on either clinical diagnosis or a positive toxin test result ) from 1993 through 2004 and who were registered for 2 years in a general practice anywhere in the united kingdom . approximately 90% of tests for c. difficile toxin had neither a positive nor negative result in the gprd ( the result was not recorded as a variable but included as case notes that we were unable to review ) , and so a clinical diagnosis often indicates a test result that was not available to the investigators . case - patients were defined as patients with community - acquired cdad , that is , patients who had not been not hospitalized during the year before their cdad diagnosis . each case - patient was matched by practice and age ( 2 years ) to 10 control - patients who also had not been hospitalized during the prior year . control - patients were also registered in the gprd . by matching these control - patients to specific case - patients , we could assess the antimicrobial use in the source population from which the case - patients arose . control - patients had the same index date as the case - patient to which they were individually matched , which enabled us to account for changing drug patterns and disease rates over time in this database . we used the british national formulary to define the following antimicrobial drug classes : penicillins , cephalosporins and other -lactams , tetracyclines , macrolides , sulfonamides and trimethoprim , fluoroquinolones , and all others . the results of antimicrobial exposure , by drug class , are presented in table 1 . the adjusted odds ratio ( or ) for cdad with use of any antimicrobial drug in the 90 days before the index date was 3.1 ( 95% confidence interval [ ci ] : 2.73.6 ) . adjusted ors for different classes of antimicrobial drugs were as follows : tetracyclines 0.85 , sulfonamides 1.88 , penicillins 1.89 , macrolides 2.15 , cephalosporins 2.21 , and fluoroquinolones 6.20 . the mean number of antimicrobial classes for those who received the drugs was 1.4 for case - patients and 1.2 for control - patients . with respect to patients who received at least 1 antimicrobial drug , 67% of case - patients and 82% of control - patients received only 1 class of antimicrobial drug ( compared with 50% of case - patients and 59% of control - patients among fluoroquinolone users who received only a single class of antimicrobial drug ) . * or , odds ratio adjusted for other antimicrobial drugs and prior antimicrobial drug use to ensure that all comparisons used the same reference group . adjusted for inflammatory bowel disease , diverticular disease , peptic ulcer disease and gastroesophageal reflux disease , helicobacter  pylori  associated disease , pernicious anemia , cancer including solid tumor and hematologic malignancies , diabetes mellitus , chronic  obstructive pulmonary disease , cirrhosis , nonsteroidal anti - inflammatory agents , aspirin , h2 blockers , proton pump inhibitors , and  antimicrobial drug use in the past 2 years . table 2 describes the residual effects after discontinuation of antimicrobial agents , fluoroquinolones in particular , as a function of the time since the last prescription . the risk ( or 3.1 , ci 2.73.6 ) with current antimicrobial drug use diminished after 3 months , dropped to or 1.8 ( 95% ci 1.42.3 ) , and essentially disappeared after 6 months ( or 1.3 , 95% ci 1.01.6 ) . this is much lower than the effect in the 90-day window before diagnosis with cdad . * or , adjusted for inflammatory bowel disease , diverticular disease , peptic ulcer disease and gastroesophageal reflux disease ,  helicobacter pylori  associated disease , pernicious anemia , cancer including solid tumor and hematologic malignancies , diabetes  mellitus , chronic obstructive pulmonary disease , cirrhosis , nonsteroidal anti - inflammatory agents , aspirin , h2 blockers , proton pump  inhibitors , and antimicrobial use in the past 2 years . to reduce the risk for protopathic bias ( 8) , we did a sensitivity analysis in which we considered any patient who had a recent ( 90-day ) diagnosis of infectious diarrhea to be unexposed to fluoroquinolones . this analysis reduced the size of the adjusted or for fluoroquinolone use from 6.2 ( 95% ci 4.48.8 ) to 5.0 ( 95% ci 4.47.2 ) . we also conducted sensitivity analyses based on the source of the cdad diagnosis ( test - based or clinical only ) . these analyses showed a similar effect for exposure to any antimicrobial agents for clinical and test - based diagnoses . among antimicrobial classes , although fluoroquinolones appear to have higher ors in the test - based group ( or 6.7 ; 95% ci 4.510.0 ) than in the group with clinically based diagnoses ( or 5.2 ; 95% ci 2.60.6 ) , this difference is not statistically different . all other antimicrobial agents were stronger risk factors for development of cdad when the definition of cdad was determined by clinical diagnosis alone , without a toxin - positive test result almost all antimicrobial drugs were associated with increased risk for community - acquired cdad . the risk associated with fluoroquinolones was particularly elevated , as has been found in other recent studies on cdad in hospital settings ( 2,911 ) . because broad - spectrum antimicrobial drugs are more commonly prescribed for patients with more severe infections , the underlying indications for fluoroquinolone prescription could also be contributing to the increased risk for cdad . that is , channeling of antimicrobial drugs toward sicker patients may result in confounding by indication ( 12 ) . however , the sharp reduction in residual risk among fluoroquinolone users suggests that any such health status confounding is likely to be minor . although the residual effects of antimicrobial prescriptions never drop to zero ( which may indicate a minor effect of confounding ) , they drop significantly and quickly . this does not exclude the possibility of confounding by indication due to the infection for which the fluoroquinolone was prescribed . in addition , our sensitivity analysis suggested some degree of robustness of this result because of misclassification , from either misdiagnosis of cdad as another form of diarrhea or from the source of the diagnosis . however , despite the high sensitivity and specificity seen in studies that use database codes to identify cdad cases ( 13 ) and the successful use of this approach in other studies ( 14,15 ) , more validation work on this endpoint remains to be done to completely describe the process of recording community - based cdad diagnoses . our results suggest that antimicrobial drugs are a risk factor for cdad , including community - acquired cdad . despite the high risk that appears to be associated with fluoroquinolone use , only 7% of the case - patients in this sample were exposed to a fluoroquinolone , and only 37% were exposed to any class of antimicrobial drug . therefore , while good prescribing practices for antimicrobial drugs should continue to be encouraged , these drugs are unlikely to be the primary driver of community - acquired cdad infections in this population . this study was funded by the canadian institutes of health research ( cihr ) and the canadian foundation for innovation . a chercheur national awardee , both from the fonds de la recherche en sant du qubec .
in a population - based case - control study of community - acquired clostridium difficile  associated disease ( cdad ) , we matched 1,233 cases to 12,330 controls . 
 cdad risk increased 3-fold with use of any antimicrobial agent and 6-fold with use of fluoroquinolones . 
 prior use of antimicrobial agent did not affect risk for cdad after 6 months .