Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus

• Published in: Annals of clinical microbiology and antimicrobials 2011-05, Vol.10 (1), p.20-20
• Main Authors: Tsuji, Brian T, MacLean, Robert D, Dresser, Linda D, McGavin, Martin J, Simor, Andrew E
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Canada; Care and treatment; Community-Acquired Infections - microbiology; Cross infection; Cross Infection - microbiology; Health aspects; Hemolysin Proteins - genetics; Hemolysin Proteins - metabolism; Humans; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Methicillin-Resistant Staphylococcus aureus - isolation & purification; Methicillin-Resistant Staphylococcus aureus - metabolism; Microbial Sensitivity Tests; Nosocomial infections; Reorganization and restructuring; Risk factors; Staphylococcal Infections - microbiology; Staphylococcus aureus infections; Trans-Activators - genetics; Trans-Activators - metabolism; Vancomycin; Vancomycin - pharmacokinetics
• ISSN: 1476-0711; 1476-0711
• DOI: 10.1186/1476-0711-10-20

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. 40 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 10(6) and 10(8) cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 10(6) cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 10(8) 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 log(10) CFU/ml for agr functional vs. 2.41 log(10) CFU/ml for agr dysfunctional MRSA (p = 0.0007). Dysfunction 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.