Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains.

We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAPr) methicillin-resistant Staphylococcus aureus (MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent in vivo efficacy against DAPr MRSA isolates in this invasive endovascular infection model.

Comparative efficacy of telavancin and daptomycin in experimental endocarditis due to multi-clonotype MRSA strains.

BACKGROUND: MRSA strains of clonal complexes (CCs) 5, 8, 30 and 45 are leading causes of complicated endovascular infections associated with suboptimal clinical outcomes. Telavancin is a novel anti-MRSA agent that both inhibits bacterial cell wall synthesis and disrupts membranes by depolarization. METHODS: In this study, we compared the in vitro susceptibility and in vivo efficacy of telavancin versus daptomycin in an experimental rabbit infective endocarditis (IE) model caused by four MRSA strains representing each of the above CC types. RESULTS: All study strains were susceptible to telavancin (MICs of ≤0.12 mg/L) and daptomycin (MICs of ≤0.5 mg/L). In vitro time-kill analyses revealed that supra-MIC levels of telavancin were effective at preventing regrowth at 24 h of incubation. In the IE animal model for all CC types, treatment with telavancin produced significantly greater reductions in MRSA counts as compared with daptomycin-treated animals in all target tissues. Moreover, telavancin-treated animals had a significantly higher percentage of sterile tissue cultures versus daptomycin-treated animals (e.g. 78%-100% versus 0% sterile vegetations and 100% versus 0%-11% sterile kidneys and spleen, in the telavancin- and daptomycin-treated animals, respectively). CONCLUSIONS: These results suggest that telavancin exhibits significantly greater efficacies versus daptomycin in treating experimental IE caused by MRSA clinical isolates across four common CC types.

Impact of vancomycin on sarA-mediated biofilm formation: role in persistent endovascular infections due to methicillin-resistant Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is the most common cause of endovascular infections. The staphylococcal accessory regulator A locus (sarA) is a major virulence determinant that may potentially impact methicillin-resistant S. aureus (MRSA) persistence in such infections via its influence on biofilm formation. METHODS: Two healthcare-associated MRSA isolates from patients with persistent bacteremia and 2 prototypical community-acquired MRSA strains, as well as their respective isogenic sarA mutants, were studied for in vitro biofilm formation, fibronectin-binding capacity, autolysis, and protease and nuclease activities. These assays were done in the presence or absence of sub-minimum inhibitory concentrations (MICs) of vancomycin. In addition, these strain pairs were compared for intrinsic virulence and responses to vancomycin therapy in experimental infective endocarditis, a prototypical biofilm model. RESULTS: All sarA mutants displayed significantly reduced biofilm formation and binding to fibronectin but increased protease production in vitro, compared with their respective parental strains. Interestingly, exposure to sub-MICs of vancomycin significantly promoted biofilm formation and fibronectin-binding in parental strains but not in sarA mutants. In addition, all sarA mutants became exquisitely susceptible to vancomycin therapy, compared with their respective parental strains, in the infective endocarditis model. CONCLUSIONS: These observations suggest that sarA activation is important in persistent MRSA endovascular infection, potentially in the setting of biofilm formation.

Role of the LytSR two-component regulatory system in adaptation to cationic antimicrobial peptides in Staphylococcus aureus.

Many host defense cationic antimicrobial peptides (HDPs) perturb the staphylococcal cell membrane (CM) and alter transmembrane potential (ΔΨ) as key parts of their lethal mechanism. Thus, a sense-response system for detecting and mediating adaptive responses to such stresses could impact organism survival; the Staphylococcus aureus LytSR two-component regulatory system (TCRS) may serve as such a ΔΨ sensor. One well-known target of this system is the lrgAB operon, which, along with the related cidABC operon, has been shown to be a regulator in the control of programmed cell death and lysis. We used an isogenic set of S. aureus strains: (i) UAMS-1, (ii) its isogenic ΔlytS and ΔlrgAB mutants, and (iii) plasmid-complemented ΔlytSR and ΔlrgAB mutants. The ΔlytS strain displayed significantly increased in vitro susceptibilities to all HDPs tested (neutrophil-derived human neutrophil peptide 1 [hNP-1], platelet-derived thrombin-induced platelet microbicidal proteins [tPMPs], and the tPMP-mimetic peptide RP-1), as well as to calcium-daptomycin (DAP), a cationic antimicrobial peptide (CAP). In contrast, the ΔlrgAB strain exhibited no significant changes in susceptibilities to these cationic peptides, indicating that although lytSR positively regulates transcription of lrgAB, increased HDP/CAP susceptibilities in the ΔlytS mutant were lrgAB independent. Further, parental UAMS-1 (but not the ΔlytS mutant) became more resistant to hNP-1 and DAP following pretreatment with carbonyl cyanide m-chlorophenylhydrazone (CCCP) (a CM-depolarizing agent). Of note, lytSR-dependent survival against CAP/HDP killing was not associated with changes in either surface positive charge, expression of mprF and dlt, or CM fluidity. The ΔlytS strain (but not the ΔlrgAB mutant) displayed a significant reduction in target tissue survival in an endocarditis model during DAP treatment. Collectively, these results suggest that the lytSR TCRS plays an important role in adaptive responses of S. aureus to CM-perturbing HDPs/CAPs, likely by functioning as a sense-response system for detecting subtle changes in ΔΨ.

Reduced vancomycin susceptibility in an in vitro catheter-related biofilm model correlates with poor therapeutic outcomes in experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus is the most common cause of endovascular infections, including catheter sepsis and infective endocarditis (IE). Vancomycin (VAN) is the primary choice for treatment of methicillin-resistant S. aureus (MRSA) infections. However, high rates of VAN treatment failure in MRSA infections caused by VAN-susceptible strains have been increasingly reported. Biofilm-associated MRSA infections are especially prone to clinical antibiotic failure. The present studies examined potential relationships between MRSA susceptibility to VAN in biofilms in vitro and nonsusceptibility to VAN in endovascular infection in vivo. Using 10 "VAN-susceptible" MRSA bloodstream isolates previously investigated for VAN responsiveness in experimental IE, we studied the mechanism(s) of such in vivo VAN resistance, including: (i) VAN binding to MRSA organisms; (ii) the impact of VAN on biofilm formation and biofilm composition; (iii) VAN efficacy in an in vitro catheter-related biofilm model; (iv) effects on cell wall thickness. As a group, the five strains previously categorized as VAN nonresponders (non-Rsp) in the experimental IE model differed from the five responders (Rsp) in terms of lower VAN binding, increased biofilm formation, higher survival in the presence of VAN within biofilms in the presence or absence of catheters, and greater biofilm reduction upon proteinase K treatment. Interestingly, sub-MICs of VAN significantly promoted biofilm formation only in the non-Rsp isolates. Cell wall thickness was similar among all MRSA strains. These results suggest that sublethal VAN levels that induce biofilm formation and reduce efficacy of VAN in the in vitro catheter-associated biofilms may contribute to suboptimal treatment outcomes for endovascular infections caused by "VAN-susceptible" MRSA strains.