Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates

Abstract

An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.

FIG 1

Unrooted phylogram of 242 MSSA and MRSA bacteremia isolates and relationship to vancomycin MIC group, onset of SAB, methicillin susceptibility, and 30-day mortality. CC, clonal complex; ST, sequence type; LA-MSSA, livestock-associated MSSA.

FIG 2

Vancomycin Etest MIC according to clonal complex. Black circles indicate geometric mean MICs, boxes indicate interquartile range, error bars represent range between 10th and 90th percentiles, colored circles represent values outside the 10th to 90th percentiles, and the dotted line indicates vancomycin Etest MIC of 1.5 mg/liter. The y axis is on a log₂ scale. “Other” indicates the remaining clones (n = 21): CC7, CC9, CC25, CC50, CC59, CC80, ST93, CC97, CC361, CC398. CC188 includes one isolate for which a clonal complex was unassigned on microarray but clustered with CC188 on phylogenetic analysis. #, P < 0.001 for comparison of geometric mean MIC for CC8 versus CC22.

FIG 3

agr dysfunction (as measured by delta-hemolysin assay) according to clonal complex. n, number of isolates from each CC. CC188 includes one isolate for which a clonal complex was unassigned on microarray but clustered with CC188 on phylogenetic analysis.