Telavancin in Therapy of Experimental Aortic Valve Endocarditis in Rabbits Due to Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus

Abstract

A number of cases of both methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains that have developed daptomycin resistance (DAP-R) have been reported. Telavancin (TLV) is a lipoglycopeptide agent with a dual mechanism of activity (cell wall synthesis inhibition plus depolarization of the bacterial cell membrane). Five recent daptomycin-susceptible (DAP-S)/DAP-R MRSA isogenic strain pairs were evaluated for in vitro TLV susceptibility. All five DAP-R strains (DAP MICs ranging from 2 to 4 g/ml) were susceptible to TLV (MICs of <0.38 g/ml). In vitro time-kill analyses also revealed that several TLV concentrations (1-, 2-, and 4-fold MICs) caused rapid killing against the DAP-R strains. Moreover, for 3 of 5 DAP-R strains (REF2145, A215, and B 2.0 ), supra-MICs of TLV were effective at preventing regrowth at 24 h of incubation. Further, the combination of TLV plus oxacillin (at 0.25؋ or 0.50؋ MIC for each agent) increased killing of DAP-R MRSA strains REF2145 and A215 at 24 h (ϳ2-log and 5-log reductions versus TLV and oxacillin alone, respectively). Finally, using a rabbit model of aortic valve endocarditis caused by DAP-R strain REF2145, TLV therapy produced a mean reduction of >4.5 log 10 CFU/g in vegetations, kidneys, and spleen compared to untreated or DAP-treated rabbits. Moreover, TLV-treated rabbits had a significantly higher percentage of sterile tissue cultures (87% in vegetations and 100% in kidney and spleen) than all other treatment groups (P < 0.0001). Together, these results demonstrate that TLV has potent bactericidal activity in vitro and in vivo against DAP-R MRSA isolates. (1,2,6,24,29). (Although the currently accepted term for reduced in vitro susceptibility to daptomycin is "nonsusceptible," we will use the terms "daptomycin resistant [DAP-R]" and "daptomycin susceptible [DAP-S]" in this paper for a more facile presentation.) Potential alternative regimens for such infections are limited to the bacteriostatic agent linezolid and the clinically cumbersome agent quinupristin-dalfopristin (Synercid) (17).Telavancin (TLV) is a novel lipoglycopeptide with bactericidal activity against Gram-positive pathogens, including S. aureus (4,9,18,19). The bactericidal action of TLV results from a dual mechanism that includes both cell wall synthesis inhibition and disruption of the target bacterial membrane (7,18). In the current investigation, we evaluated (i) in vitro efficacy of TLV against several recent clinical DAP-R MRSA strains, (ii) whether combinations of TLV and oxacillin (OXA) would enhance in vitro efficacy of these single agents against DAP-R MRSA strains, taking advantage of the so-called DAP-OXA "see-saw" phenomenon (38), and (iii) the in vivo efficacy of TLV in a prototypic rabbit IE model of invasive systemic infection caused by a DAP-R MRSA strain. MATERIALS AND METHODSBacterial strains and growth conditions. The S. aureus strains employed in this study are listed in Table 1. We used five recent clinically derived DAP-S/DAP-R MRSA strain pair...

Role of the LytSR Two-Component Regulatory System in Adaptation to Cationic Antimicrobial Peptides in Staphylococcus aureus

“…As observed in previous studies (6,39,47,48), S. aureus cell densities in cardiac vegetations were significantly higher than those in kidneys and spleens for each strain at 24 h postinfection (P Ͻ 0.01) ( Table 3). In the comparative virulence assessments, except for the ⌬lytSR complemented and ⌬lrgAB strains, which showed rather moderate decreases in cell densities in kidneys (Ͻ1 log 10 -fold; P Ͻ 0.05), no significant differences in bacterial densities were observed among the strain set in the three target tissues.…”

“…Fourth, our in vitro data above led us to evaluate the role of the LytSR TCRS in endovascular infections, using the IE model (6,41,43). In the current study, both the ⌬lytS and ⌬lrgAB strains were found to be equivalent to the parental strain in their capabilities to induce experimental IE, proliferate within the vegetative lesion, and then disseminate hematogenously to distant target organs.…”

“…Host defense CAPs (HDPs) are typically small amphipathic peptides (Ͻ50 amino acids) with a high net positive charge and are found in most mammalian tissues (3)(4)(5). In the context of bloodstream infections, HDPs localized within the skin, nasal mucosa, white blood cells and platelets are especially relevant in the initial successful colonization of S. aureus, as well as the subsequent hematogenous dissemination and organ invasion of this organism (3,(6)(7)(8). Therefore, for colonization of the host, the organism must resist the microbicidal action of a diverse cadre of HDPs.…”

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…In brief, its efficacy and superiority compared with vancomycin or daptomycin has been documented in murine models of bacteremia or pneumonia by MRSA [105,106], in murine subcutaneous infection models, in rabbit endocarditis caused by MRSA, VISA, or daptomycin non-susceptible staphylococci [107][108][109], as well as in rabbit meningitis caused by penicillin-resistant pneumococcus [110,111]. It was equivalent to vancomycin or linezolid in a model of rabbit osteomyelitis caused by MRSA [112].…”

Comparative Efficacies of Tedizolid Phosphate, Linezolid, and Vancomycin in a Murine Model of Subcutaneous Catheter-Related Biofilm Infection Due to Methicillin-Susceptible and -Resistant Staphylococcus aureus

“…In this investigation, we evaluated (i) the MICs (11) and in vitro killing activities (12,13) of tedizolid, linezolid, and vancomycin against lux mutant methicillin-susceptible S. aureus (MSSA) (Xen29) and MRSA (Xen30) strains (4,14,15), (ii) the influence of these antibiotics on biofilm formation (16,17), and (iii) the real-time in vivo efficacy of tedizolid versus that of linezolid and vancomycin in a well-characterized model of murine subcutaneous catheter-related infection (18) caused by the MSSA or MRSA strain by using a novel bioluminescence in vivo imaging system (IVIS).…”