Predictors of agr Dysfunction in Methicillin-Resistant Staphylococcus aureus (MRSA) Isolates among Patients with MRSA Bloodstream Infections

Abstract

Despite emerging evidence that dysfunction in the accessory gene regulator (agr) locus is associated with deleterious outcomes among patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections, factors predictive of agr dysfunction have not been evaluated. This study describes the epidemiology of agr dysfunction, identifies predictors of agr dysfunction in MRSA isolates among those with MRSA bloodstream infections, and describes the relationship between agr dysfunction and other microbiologic phenotypes. A cross-sectional study of patients with MRSA bloodstream infections at two institutions in upstate New York was performed. Clinical data on demographics, comorbidities, disease severity, hospitalization history, and antibiotic history were collected. Microbiologic phenotypes, including agr dysfunction, MIC values by broth microdilution (BMD) and Etest, and vancomycin heteroresistance (hVISA) were tested. Multivariable analyses were performed to identify factors predictive of agr dysfunction. Among 200 patients with an MRSA bloodstream infection, the proportion of strains with agr dysfunction was 31.5%. The distribution of MICs determined by both BMD and Etest were equivalent across agr groups, and there was no association between agr dysfunction and the presence of hVISA. Severity of illness, comorbidities, and hospitalization history were comparable between agr groups. In the multivariate analysis, prior antibiotic exposure was the only factor of variables studied found to be predictive of agr dysfunction. This relationship was predominantly driven by prior beta-lactam and fluoroquinolone administration in the bivariate analysis. Identifying these institution-specific risk factors can be used to develop a process to assess the risk of agr dysfunction and guide empirical antibiotic therapy decisions.The accessory gene regulator (agr) is a quorum-sensing operon which coordinates the expression of secreted and cellassociated virulence factors, and it controls several metabolic pathways in Staphylococcus aureus in a growth phase-related fashion (7,30). In vitro studies show that alterations in agr function result in several phenotypic changes in S. aureus, including diminished autolysis (21), attenuated vancomycin activity (20,22,29), vancomycin heteroresistance (22), and an increased proclivity for the development of intermediate resistance to vancomycin (7,22,29,30). There is also increasing clinical evidence showing that alterations in agr in S. aureus are a key risk factor for poor outcomes in patients with S. aureus bacteremia (7,25).Despite the poor outcomes associated with agr dysfunction, factors predictive of agr dysfunction have not been well described, and scant literature exists describing the relationship between agr dysfunction and other reduced vancomycin susceptibility phenotypes. This study describes the epidemiology of agr dysfunction, determines predictors of agr dysfunction in methicillin-resistant Staphylococcus aureus (MRSA) isolates among those with MRS...

What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?

“…Carriage of agr-defective strains is strongly associated with a hospital stay or prior use of antibiotics such as fluoroquinolones or beta-lactams. This indicates that the healthcare environment selects for loss of Agr function and is the principal source of agr-defective strains [29,34]. Recently, Chong et al [38] reported the spread of an agr-defective hospital-associated type II MRSA (Box 1) in a tertiary hospital in Korea, supporting this hypothesis.…”

“…agr-defective S. aureus is a frequent cause of bacteremia Despite the importance of Agr in many infections, strains lacking detectable Agr activity have been isolated in 3-82% of cases of S. aureus bacteremia [10,[26][27][28][29][30][31][32]. The methods used to determine Agr functionality vary from simple haemolysis assays on solid media to sequencing of the agr operon, which may contribute to the variation in their reported frequency ( Table 1).…”

Genetic and Molecular Predictors of High Vancomycin MIC in Staphylococcus aureus Bacteremia Isolates

“…Evidence of enhanced hemolysis between RN4220 and a test isolate was considered positive for delta-hemolysin production (20). The presence of agr dysfunction was defined as an absence or severe depression of delta-hemolysin production (21). The positive control was JKD6159, a fully sequenced S. aureus reference isolate known to have a functional agr operon, and the negative control was TPS3105, a sequenced S. aureus isolate with defective agr function (22).…”

A Novel δ-Hemolysis Screening Method for Detecting Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate S. aureus

“…Our aim was to develop a simple and rapid screening method for heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA), based on ␦-hemolysin production, to correctly identify and distinguish hVISA and VISA from vancomycin-susceptible S. aureus (VSSA), based on the observations that hVISA and VISA are characterized by a decreased functionality of the regulatory agr (accessory gene regulator) locus encoding ␦-hemolysin (1,2,7,8,(11)(12)(13)(14)(15).…”