Vancomycin Heteroresistance and Clinical Outcomes in Bloodstream Infections Caused by Coagulase-Negative Staphylococci

Abstract

Coagulase-negative staphylococci (CoNS) are a common etiology of serious and recurrent infections in immunocompromised patients. Although most isolates appear susceptible to vancomycin, a single strain might have a subpopulation of resistant bacteria. This phenomenon is termed heteroresistance and may adversely affect the response to treatment. A retrospective cohort study was performed of pediatric patients with leukemia treated at St. Jude Children's Research Hospital who developed CoNS central line-associated bloodstream infection (CLABSI). Available isolates were sequenced and tested for vancomycin heteroresistance by population analysis profiling. Risk factors for heteroresistance and the association of heteroresistance with treatment failure (death or relapse of infection) or poor clinical response to vancomycin therapy (treatment failure or persistent bacteremia after vancomycin initiation) were evaluated. For 65 participants with CoNS CLABSI, 62 initial isolates were evaluable, of which 24 (39%) were vancomycin heteroresistant. All heteroresistant isolates were of Staphylococcus epidermidis and comprised multiple sequence types. Participants with heteroresistant bacteria had more exposure to vancomycin prophylaxis (P = 0.026) during the 60 days prior to infection. Of the 40 participants evaluable for clinical outcomes, heteroresistance increased the risk of treatment failure (P = 0.012) and poor clinical response (P = 0.001). This effect persisted after controlling for identified confounders. These data indicate that vancomycin heteroresistance is common in CoNS isolates from CLABSIs in pediatric patients with leukemia and is associated with poor clinical outcomes. Validation of these findings in an independent cohort and evaluation of alternative antibiotic therapy in patients with heteroresistant infections have the potential to improve care for serious CoNS infections.

Keywords: Staphylococcus epidermidis; child; heteroresistance; leukemia; staphylococci; vancomycin.

FIG 1

Vancomycin exposure in the 60 days before infection for heteroresistant and nonheteroresistant isolates (N = 62). Box plots show the differences between heteroresistant and nonheteroresistant infections with respect to vancomycin exposure (P = 0.11) and prophylactic vancomycin exposure (P = 0.026). The boxes represent the 25th to 75th percentiles, the whiskers extend up to 1.5 times the box height, and the circles and stars represent outliers and extreme outliers, respectively.

FIG 2

(a) Cumulative incidence of treatment failure in patients with CoNS bloodstream infection (N = 40). (b) Cumulative incidence of poor clinical response in patients with CoNS bloodstream infection (N = 40).