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Objective Antibiotic use, particularly type and duration, is a crucial modifiable risk factor for Clostridium difficile . Cardiac surgery is of particular interest because prophylactic antibiotics are recommended for 48 hours or less (vs ≤24 hours for noncardiac surgery), with increasing vancomycin use. We aimed to study associations between antibiotic prophylaxis (duration/vancomycin use) and C difficile among patients undergoing coronary artery bypass grafting. Methods We extracted data on coronary artery bypass grafting procedures from the national Premier Perspective claims database (2006-2013, n = 154,200, 233 hospitals). Multilevel multivariable logistic regressions measured associations between (1) duration (<2 days, “standard” vs ≥2 days, “extended”) and (2) type of antibiotic used (“cephalosporin,” “cephalosporin + vancomycin,” “vancomycin”) and C difficile as outcome. Results Overall C difficile prevalence was 0.21% (n = 329). Most patients (59.7%) received a cephalosporin only; in 33.1% vancomycin was added, whereas 7.2% received vancomycin only. Extended prophylaxis was used in 20.9%. In adjusted analyses, extended prophylaxis (vs standard) was associated with significantly increased C difficile risk (odds ratio, 1.43; confidence interval, 1.07-1.92), whereas no significant associations existed for vancomycin use as adjuvant or primary prophylactic compared with the use of cephalosporins (odds ratio, 1.21; confidence interval, 0.92-1.60, and odds ratio, 1.39; confidence interval, 0.94-2.05, respectively). Substantial inter-hospital variation exists in the percentage of extended antibiotic prophylaxis (interquartile range, 2.5-35.7), use of adjuvant vancomycin (interquartile range, 4.2-61.1), and vancomycin alone (interquartile range, 2.3-10.4). Conclusions Although extended use of antibiotic prophylaxis was associated with increased C difficile risk after coronary artery bypass grafting, vancomycin use was not. The observed hospital variation in antibiotic prophylaxis practices suggests great potential for efforts aimed at standardizing practices that subsequently could reduce C difficile risk. [ABSTRACT FROM AUTHOR]