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

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 ∼20% 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 multidrug-resistant Gram-positive organisms (25), has been disappointing for the treatment of bloodstream infections (12) and is considered only with reluctance for the treatment of endocarditis given its lack of bactericidal effect. With the worldwide emergence of community-associated MRSA (3, 8), the limits of our therapeutic armamentarium against MRSA endocarditis are a growing concern.Ceftobiprole (BPR) (formerly BAL9141), is a novel, broad-spectrum, bactericidal cephalosporin with MICs of ≤4 μg/ml for clinical isolates of S. aureus, including MRSA (5, 27). The anti-MRSA activity of ceftobiprole stems from its high affinity for PBP 2a, the penicillin binding protein chiefly responsible for the methicillin-resistant phenotype of staphylococci (1). In addition, ceftobiprole is stable to class A penicillinases produced by S. aureus. To improve solubility, ceftobiprole is administered as its dioxolenylmethyl carbamate prodrug, ceftobiprole medocaril (formerly BAL5788) (1). The purpose of the present study was to test the hypothesis that ceftobiprole would be superior to vancomycin, daptomycin, and linezolid for the treatment of MRSA in the rabbit model of aortic valve endocarditis.