Abstract
BackgroundThe accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA.Methods40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 106 and 108 cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model.Results15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 106 cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 108 cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log10 CFU/ml for agr functional vs. 2.41 log10 CFU/ml for agr dysfunctional MRSA (p = 0.0007).ConclusionsDysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.
Highlights
The accessory gene regulator is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus
Dysfunction in agr was less common among CA-methicillin-resistant S. aureus (MRSA) vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA
Vancomycin MICs against HA-MRSA 7, 9, were 1.0, 2.0 mg/L and for CA-MRSA 26 and 20 were 1.0, and 1.0 mg/L. 15% (6 of 40) of isolates were dysfunctional in agr which was higher among HA-MRSA
Summary
The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. The accessory gene regulator (agr) is a quorum sensing cluster of genes which orchestrate the expression of cellsecreted and virulence factors, and several metabolic pathways in Staphylococcus aureus in a growth dependant fashion [1,2]. While a large proportion of HA-MRSA display dysfunctional in the agr loci, the prevalence of agr dysfunction among CAMRSA is relatively low from 3.5 to 9% [10,11] This may account for the enhanced virulence of CAMRSA as compared with HA-MRSA, whether dysfunction in agr would hamper vancomycin bactericidal activity among Canadian CA-MRSA has not been fully elucidated. The objectives of this current study were to compare vancomycin pharmacodynamics of agr dysfunctional versus functional CA-MRSA and HA-MRSA clinical isolates from the Canadian Nosocomial Infection Surveillance Program at low and high initial inoculum
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