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Background: The rate of cardiovascular implantable electronic device infection (CIEDI) has increased, despite the use of preoperative antibiotics at the time of device placement or revision. Cefazolin, a beta-lactam antibiotic, is used as standard preoperative prophylaxis in the bulk of patients. Vancomycin is used in the small minority of patients who have IgE-mediated allergies to beta-lactams or have a history of colonization/infection with MRSA. As compared to cefazolin, vancomycin is less effective against methicillin-susceptible Staphylococcus aureus, has no gram-negative coverage, and has nephrotoxicity risk.Methods: A retrospective cohort study was performed to assess whether vancomycin use increased the risk of CIEDI in comparison to the standard preoperative prophylaxis. The VA Informatics and Computing Infrastructure (VINCI) database, which includes all veterans who underwent CIED placement or revision between 2008 and 2015, was used. A logistic regression model was constructed to estimate the adjusted risk of CIEDI among patients who received vancomycin after adjusting for confounding factors.Results: Overall, 10,454 CIED procedures were included, and 98% of them were performed in men with a mean age of 71 ± 12 years. Vancomycin was given in 40.6% of these procedures. The rate of diabetes mellitus, heart failure, and advanced chronic kidney diseases were 20.5%, 13.5%, and 2.3%, respectively. The logistic regression analysis showed that vancomycin increased the risk of CIEDI three-fold (OR 2.99 [1.76-5.06], P-value <0.001) as compared to the standard preoperative prophylaxis, after controlling for other effects including MRSA colonization.Conclusions: Our study revealed that among patients who received vancomycin as preoperative for CIED placement or revision, there was a three-fold increase in the risk of subsequent CIEDI.