Confounding by indication affects antimicrobial risk factors for methicillin-resistant Staphylococcus aureus but not vancomycin-resistant enterococci acquisition

Abstract

Background: Observational studies rarely account for confounding by indication, whereby empiric antibiotics initiated for signs and symptoms of infection prior to the diagnosis of infection are then viewed as risk factors for infection. We evaluated whether confounding by indication impacts antimicrobial risk factors for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) acquisition. Findings: We previously reported several predictors of MRSA and VRE acquisition in 967 intensive care unit (ICU) patients with no prior history of MRSA or VRE who had an initial negative screening culture followed by either a subsequent negative screening culture (controls) or positive screening or clinical culture (cases). Within and prior to this acquisition interval, we collected demographic, comorbidity, daily device and antibiotic utilization data. We now re-evaluate all antibiotics by medical record review for evidence of treatment for signs and symptoms ultimately attributable to MRSA or VRE. Generalized linear mixed models are used to assess variables associated with MRSA or VRE acquisition, accounting for clustering by ward. We find that exclusion of empiric antibiotics given for suspected infection affects 17% (113/661) of antibiotic prescriptions in 25% (60/244) of MRSA-positive patients but only 1% (5/491) of antibiotic prescriptions in 1% (3/227) of VRE-positive patients. In multivariate testing, fluoroquinolones are no longer associated with MRSA acquisition, and aminoglycosides are significantly protective (OR = 0.3, CI:0.1-0.7). Conclusions: Neglecting treatment indication may cause common empiric antibiotics to appear spuriously associated with MRSA acquisition. This effect is absent for VRE, likely because empiric therapy is infrequent given the low prevalence of VRE.