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. 2015 May;70(5):1443-52.
doi: 10.1093/jac/dku547. Epub 2015 Jan 5.

Early Agr Activation Correlates With Vancomycin Treatment Failure in Multi-Clonotype MRSA Endovascular Infections

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Free PMC article

Early Agr Activation Correlates With Vancomycin Treatment Failure in Multi-Clonotype MRSA Endovascular Infections

Wessam Abdelhady et al. J Antimicrob Chemother. .
Free PMC article

Abstract

Objectives: Persistent MRSA infections are especially relevant to endovascular infections and correlate with suboptimal outcomes. However, the virulence signatures of Staphylococcus aureus that drive such persistence outcomes are not well defined. In the current study, we investigated correlations between accessory gene regulator (agr) activation and the outcome of vancomycin treatment in an experimental model of infective endocarditis (IE) due to MRSA strains with different agr and clonal complex (CC) types.

Methods: Twelve isolates with the four most common MRSA CC and agr types (CC5-agr II, CC8-agr I, CC30-agr III and CC45-agr I) were evaluated for heterogeneous vancomycin-intermediate S. aureus (hVISA), agr function, agrA and RNAIII transcription, agr locus sequences, virulence and response to vancomycin in the IE model.

Results: Early agr RNAIII activation (beginning at 2 h of growth) in parallel with strong δ-haemolysin production correlated with persistent outcomes in the IE model following vancomycin therapy. Importantly, such treatment failures occurred across the range of CC/agr types studied. In addition, these MRSA strains: (i) were vancomycin susceptible in vitro; (ii) were not hVISA or vancomycin tolerant; and (iii) did not evolve hVISA phenotypes or perturbed δ-haemolysin activity in vivo following vancomycin therapy. Moreover, agr locus sequence analyses revealed no common point mutations that correlated with either temporal RNAIII transcription or vancomycin treatment outcomes, encompassing different CC and agr types.

Conclusions: These data suggest that temporal agr RNAIII activation and agr functional profiles may be useful biomarkers to predict the in vivo persistence of endovascular MRSA infections despite vancomycin therapy.

Keywords: antibiotics; bacteria; resistance.

Figures

Figure 1.
Figure 1.
In vitro expression of agrA (a) and RNAIII (b) in all S. aureus strains studied at 2, 3, 4, 8 and 24 h of growth. Data were obtained by RT–PCR and relative transcript levels of agrA and RNAIII represent the mean (+SD) of at least two biological replicates (fold changes versus gyrB). Strains with strong δ-haemolysin activity are underlined.
Figure 2.
Figure 2.
S. aureus densities in the target tissues in the IE model in the presence versus absence of vancomycin therapy for 3 days (panels a, b and c represent clinical CC5, CC8 and CC30 S. aureus strains, respectively, and panel d represents four reference strains). Each dot represents one rabbit and the horizontal black bars indicate the means of the observations. Strains with strong δ-haemolysin activities are underlined. VAN, vancomycin.
Figure 2.
Figure 2.
S. aureus densities in the target tissues in the IE model in the presence versus absence of vancomycin therapy for 3 days (panels a, b and c represent clinical CC5, CC8 and CC30 S. aureus strains, respectively, and panel d represents four reference strains). Each dot represents one rabbit and the horizontal black bars indicate the means of the observations. Strains with strong δ-haemolysin activities are underlined. VAN, vancomycin.

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