Relationship of agr Expression and Function with Virulence and Vancomycin Treatment Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Abstract

The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of Staphylococcus aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment, is controversial. Interestingly, agr dysfunction has been associated with reduced vancomycin responses.

Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

“…The 10 MRSA bloodstream study isolates are listed in Table 1; these strains have been described in detail previously (15)(16)(17). All 10 strains had VAN MICs within the susceptible range (0.5 to 1.0 g/ml).…”

“…All 10 strains had VAN MICs within the susceptible range (0.5 to 1.0 g/ml). The five Rsp strains were defined as isolates in which VAN treatment caused a Ն5-log 10 CFU mean reduction per gram of vegetation and Ն3-log 10 CFU mean reduction per gram of kidney or spleen in a rabbit IE model (15,17). The five non-Rsp strains were defined as isolates in which Ͻ1.5-log 10 CFU mean reductions per gram of vegetation, kidney, and spleen were observed due to VAN treatment in the IE model (15,17).…”

“…However, VAN treatment outcomes in vivo for these strains were dramatically different (15). Thus, despite equivalent in vivo virulence profiles, five of these strains were highly susceptible to VAN therapy in this model (responders [Rsp]), while the remaining five isolates were substantially resistant to VAN therapy (nonresponders [non-Rsp]) (15). Thus, the current study was designed to evaluate the mechanism(s) that may contribute to these disparate VAN treatment outcomes previously observed in experimental IE, aqnd we focused on biofilm-associated phenotypes and events.…”

“…All 10 MRSA strains were VAN susceptible (MICs of 0.5 to 1.0 g/ml) and nontolerant to this agent in vitro. However, VAN treatment outcomes in vivo for these strains were dramatically different (15). Thus, despite equivalent in vivo virulence profiles, five of these strains were highly susceptible to VAN therapy in this model (responders [Rsp]), while the remaining five isolates were substantially resistant to VAN therapy (nonresponders [non-Rsp]) (15).…”

“…In a recently published investigation, we evaluated the efficacy of VAN against 10 MRSA clinical bloodstream isolates in a catheter-induced IE model in rabbits (15). All 10 MRSA strains were VAN susceptible (MICs of 0.5 to 1.0 g/ml) and nontolerant to this agent in vitro.…”