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

Abstract

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...

In Vivo Synergism of Ceftobiprole and Vancomycin against Experimental Endocarditis Due to Vancomycin-Intermediate Staphylococcus aureus

“…Of note, ceftobiprole monotherapy was active when administered to animals at doses mimicking the treatment recommended in human (i.e., 500 mg b.i.d. ), thus confirming its intrinsic activity against VISA (4,15,45). On the other hand, it was not effective when used at low or very low doses, but these subtherapeutic doses could be Synergy between subtherapeutic doses of ceftobiprole and vancomycin against MRSA was also suggested in a recent meeting abstract (17).…”

“…Ceftobiprole is a novel broadspectrum cephalosporin with potent activity against Gram-positive pathogens, including MRSA and VISA (39), as well as Gram-negative pathogens. It has been reported to be efficacious in monotherapy against experimental endocarditis caused by both types of bacteria (4,15,45). It is therefore of interest to evaluate ceftobiprole as a potential partner with vancomycin for the treatment of endocarditis caused by MRSA or VISA.…”

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

“…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.…”

Antibiotics Against Endocarditis – Past, Present and Future (Experimental Data)

“…Endocarditis studies evaluating the activity of ceftaroline are very limited. However, Tattevin et al have assessed the activity of ceftobiprole (formerly BAL9141), the other anti-MRSA cephalosporin with high affinity for PBP2a, against MRSA in comparison with vancomycin, linezolid, and daptomycin (Tattevin et al, 2010). Using experimental conditions similar to the conditions used by Jacqueline et al, they showed that the burdens of organisms in vegetations were significantly lower in ceftobiprole-treated rabbits than in rabbits treated with vancomycin, linezolid, or daptomycin (4-day treatment) (Figure 13).…”