Daptomycin Is Effective in Treatment of Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate
            <i>Staphylococcus aureus</i>

Beta lactam agents are the most active drugs for the treatment of streptococci and methicillin-susceptible Staphylococcus aureus endocarditis. However, methicillin-resistant S. aureus (MRSA) is resistant to all beta lactam agents licensed to date, and alternative treatments are limited. Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the penicillin binding protein that mediates the methicillin resistance of staphylococci and is active against MRSA. Ceftobiprole was compared to vancomycin, daptomycin, and linezolid in a rabbit model of MRSA aortic valve endocarditis caused by the homogeneously methicillin-resistant laboratory strain COL. Residual organisms in vegetations were significantly fewer in ceftobiprole-treated rabbits than in any other treatment group (P < 0.05 for each comparison). In addition, the numbers of organisms in spleens and in kidneys were significantly lower in ceftobiprole-treated rabbits than in linezolid-and vancomycin-treated animals (P < 0.05 for each comparison). Anti-MRSA beta lactam agents such as ceftobiprole may represent a significant therapeutic advance over currently available agents for the treatment of MRSA endocarditis.Endocarditis is one of the most difficult infections to treat in humans, with an in-hospital mortality rate of ϳ20% even in most recent series, despite significant advances in surgical treatment over the last decades (2, 17). In addition, Staphylococcus aureus, which has emerged as the most common cause of endocarditis worldwide (16), is associated with a high rate of severe complications, such as heart failure and central nervous system emboli. Guidelines for the treatment of streptococci and methicillin-susceptible S. aureus (MSSA) endocarditis include a beta-lactam agent whenever possible (2) because of the bactericidal effect of these drugs and the possibility to use high doses with most agents. However, none of the currently licensed beta-lactam agents are clinically active against methicillin-resistant S. aureus (MRSA), and the alternative agents available for the treatment of MRSA endocarditis are limited. Vancomycin, which remains the first choice in recent guidelines, has a narrow therapeutic index, while recent reports have documented a gradual increase in MICs for MRSA over time (10,33,34). Moreover, in vitro studies and clinical data suggest that vancomycin is less active than beta-lactams in the treatment of MSSA bacteremia (35). Daptomycin is an alternative, given its rapid bactericidal activity, but clinical data are limited in left-sided endocarditis (15), and the ideal dose has still to be determined, leaving clinicians "guessing" doses, frequently at even numbers of mg per kg of body weight per day. The emergence of resistance during daptomycin therapy and reports of cross-resistance in non-vancomycin-susceptible S. aureus are also of concern (4, 31, 32). Lastly, linezolid, which has proved its value in the treatment of pneumonia and complicated skin and skin structure infections due to multidrugres...

Section: Discussionmentioning

confidence: 73%

Ceftobiprole Is Superior to Vancomycin, Daptomycin, and Linezolid for Treatment of Experimental Endocarditis in Rabbits Caused by Methicillin-Resistant Staphylococcus aureus

Tattevin

Basuino

Bauer

et al. 2010

“…The antibiotics were administered to animals with IE using a computer-controlled infusion pump system designed to simulate human-equivalent serum levels following the administration of DAP at the FDA-approved dose for S. aureus bacteremia (6 mg/kg) (39) and GEN at the recommended synergistic dose for enterococcal IE (1 mg/kg i.v. every 8 h) (40).…”

Section: Methodsmentioning

confidence: 99%

Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis

García-de-la-Mària

Xiong

Pericàs

et al. 2017

Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be ␤-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAP s ) S. mitis/S. oralis strain and its daptomycin-resistant (DAP r ) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAP r variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAP s strain following treatment with daptomycin. The parental strain and the DAP r variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 10 6 -and 10 7 -CFU/ml challenge inocula, the parental strain outcompeted the DAP r variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAP s strain was completely eliminated, while the DAP r variant persisted in all target tissues. These data underscore that the acquisition of DAP r in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.

“…The numbers of CFU were counted to determine the tissue burdens of organisms. (8)(9)(10). The first dose of drug was administered 18 to 20 h after inoculation.…”

Section: Methodsmentioning

confidence: 99%

Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

Chan

Basuino

Dip

et al. 2015

Staphylococcus aureus is a common cause of skin and soft tissue infections and invasive disease, such as bacteremia and endocarditis. Tedizolid, the microbiologically active moiety of the prodrug tedizolid phosphate (TZD), is a novel oxazolidinone approved for treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria, including strains of methicillin-resistant S. aureus (MRSA). Tedizolid phosphate is rapidly cleaved in the bloodstream to yield the active component, tedizolid. It is approximately 4 times more active by weight than linezolid against S. aureus in vitro (1) and 16 times more active against cfr plasmid carrying linezolid-resistant staphylococci in vitro (2). Moreover, unlike the bacteriostatic activity of linezolid, tedizolid has been shown to have some bactericidal activity in a neutropenic mouse thigh model (3, 4). To assess further its potency and bactericidal activity in vivo, tedizolid was compared to vancomycin and daptomycin in a rabbit model of aortic valve endocarditis (AVE) caused by the MRSA strain COL. MATERIALS AND METHODSBacterial strains. S. aureus strain COL is a homogeneous, methicillinresistant strain. COL inoculum was prepared by diluting a frozen stock in 0.9% injectable sodium chloride. The frozen stock was prepared from an overnight culture grown in tryptic soy broth. Cells were washed and resuspended in phosphate-buffered saline with 10% glycerol and stored at Ϫ80°C.Susceptibility studies. Susceptibility studies were performed by broth dilution to determine the MICs using standard CLSI methods (5). Briefly, the bacteria and drugs were diluted in cation-adjusted Mueller-Hinton broth (CAMHB) and incubated at 37°C overnight. Ca 2ϩ supplementation was provided for daptomycin testing (6). The MIC was determined as the lowest concentration of drug that inhibited growth. Tedizolid and daptomycin standard powder for in vitro testing were provided by the manufacturers, and vancomycin was purchased from Sigma-Aldrich.Time-kill studies. Time-kill studies were conducted in duplicate at 37°C in 10 ml of CAMHB containing vancomycin at 5 g/ml (5ϫ MIC), daptomycin at 5 g/ml (5ϫ MIC), or tedizolid at 2 g/ml (16ϫ MIC) at a starting inoculum of 10 6 CFU/ml. Rabbit model of endocarditis. New Zealand White rabbits (2.5 to 3 kg) were used. Endocarditis was established by standard methods (7). Briefly, a cutdown was made over the right carotid artery. A polyethylene catheter was introduced via carotid arteriotomy, positioned into the left ventricle, and sutured in place. Forty-eight hours later, a 1-ml suspension of 10 7 to 10 8 CFU of S. aureus in 0.9% NaCl was injected intravenously (i.v.). On postinoculation day 1, approximately 16 to 18 h after infection, untreated control rabbits were sacrificed to determine pretreatment bacterial counts. The hearts, spleens, and kidneys were harvested. Aortic valves and endocardial vegetations and approximately 0.2-g samples of spleen and kidney were placed in 1.0 ml of 0.9% NaCl and homogenized with a tissue grinder. Ten-...