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

Abstract

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-...

Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

“…Accordingly, antitoxin antibodies plus protein synthesis inhibitors, like linezolid and tedizolid phosphate, are expected to work together to further enhance survival outcomes by neutralizing preformed toxins and preventing their cytotoxic effects in the lungs, as well as inhibiting the bacterial production of these toxins. The superior protective efficacy of tedizolid phosphate over that of vancomycin in the rabbit MRSA USA300 pneumonia model stands in contrast to the superior protective efficacy of vancomycin over that of tedizolid phosphate in the rabbit model of aortic valve endocarditis (20). One potential explanation for this discrepancy could be that the USA300/SF8300 clinical strain used in the rabbit pneumonia model is known to naturally hyperproduce alpha-toxin and PVL (21), which together play critical roles in the pathogenesis of necrotizing pneumonia (5,7).…”

Activity of Tedizolid in Methicillin-Resistant Staphylococcus epidermidis Experimental Foreign Body-Associated Osteomyelitis

“…We demonstrated that the combination of tedizolid plus rifampin or vancomycin plus rifampin was more active than no treatment in this model, in which the infected foreign body was retained. Although the activity of tedizolid against methicillin-resistant S. aureus (MRSA) has been analyzed in several experimental studies, such as in a model of experimental endocarditis in rabbits (17) and a model of catheter-related biofilm infection in mice (18), the role of tedizolid against MRSE in experimental osteomyelitis has not been well studied. Successful animal models of osteomyelitis and foreign body infection have been established in rabbits, dogs, chicks, guinea pigs, and rats (19,20).…”

Absorption, Distribution, Metabolism, and Excretion of the Novel Antibacterial Prodrug Tedizolid Phosphate

“…In nonclinical studies, tedizolid phosphate demonstrated promising efficacy results across a range of animal infection models (Chan et al, 2009;Louie et al, 2011;Lepak et al, 2012); phase 3 trials showed that administration of intravenous or oral tedizolid phosphate (200 mg once daily) for 6 days achieved noninferior efficacy in acute bacterial skin and skin structure infections compared with 10 days of linezolid therapy (Prokocimer et al, 2011Fang et al, 2013).…”