Comparison of ceftaroline fosamil, daptomycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus

Université de Nantes, Nantes Atlantique Universités, Thérapeutiques Cliniques et Expérimentales des Infections, EA3826, F-44000 Nantes, France.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.31). 03/2011; 66(4):863-6. DOI: 10.1093/jac/dkr019
Source: PubMed


The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis.
The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed.
Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log(10) cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals.
The novel β-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains.

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    • "Following a 4-day course of ceftaroline fosamil in a rabbit endocarditis model, ceftaroline demonstrated superior bactericidal activity against MRSA and heterogeneous VISA when compared to vancomycin and linezolid [9]. Similarly, ceftaroline fosamil demonstrated significant bactericidal activity against MRSA and VISA, with a greater than 5 log10 colony-forming unit/g reduction of vegetation, which was comparable to that of daptomycin and superior to that of tigecycline [24]. When compared to vancomycin and linezolid, ceftaroline demonstrated improved bacterial killing of vancomycin-sensitive and vancomycin-resistant E. faecalis in both time–kill experiments and a rabbit endocarditis model [8]. "
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    ABSTRACT: Ceftaroline is a novel cephalosporin with a favorable tolerability profile and broad in vitro activity against many resistant Gram-positive and common Gram-negative organisms. Ceftaroline fosamil is the first cephalosporin to be approved by the United States Food and Drug Administration (FDA) for the treatment of adults with acute bacterial skin and soft tissue infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). It is also approved by the FDA for the treatment of adults with community-acquired bacterial pneumonia, including cases caused by Streptococcus pneumoniae (with or without concurrent bacteremia), although there are no data at this time to support the use of ceftaroline fosamil for the treatment of pneumonia caused by MRSA. Ceftaroline fosamil is likewise approved by the European Commission for the treatment of adults with complicated skin and soft tissue infections or community-acquired pneumonia. This review summarizes the pharmacokinetic and microbiologic properties of ceftaroline, as well as the safety and efficacy data that led to its approval by the FDA in 2010 and the European Commission in 2012. Future directions to be addressed are also highlighted.
    12/2013; 2(2):95-110. DOI:10.1007/s40121-013-0010-x
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    • "Experimental endocarditis studies played a major role in the exploration and assessment of new antistaphylococcal drugs beginning with the oxazolidinone, linezolid, in the early 2000s, and were critical to the recent approval of the promising anti-MRSA cephalosporin ceftaroline by the United States Food and Drug Administration (FDA). The endocarditis model is referenced in approximately 100 PubMed publications, most of which are assessments of the in vivo activity of new therapeutic options against Staphylococcus aureus such as linezolid (Jacqueline et al., 2002), quinupristindalfopristin (Batard et al., 2002), moxifloxacin (Entenza et al., 2001), daptomycin (Sakoulas et al., 2003), tigecycline (Murphy et al., 2000; Jacqueline et al., 2011), ceftobiprole (Tattevin et al., 2010) and ceftaroline (Jacqueline et al., 2007). Staphylococcus aureus is the most common cause of endocarditis worldwide and methicillin-susceptible Staphylococcus aureus (MSSA) is detected in up to two-thirds of cases (Fowler et al., 2005). "
    Endocarditis, 01/2012; , ISBN: 978-953-307-901-1
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    ABSTRACT: The efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate Staphylococcus aureus (VISA) strains, PC3 and Mu50, in rats with experimental endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (P < 0.001 versus controls). In comparison, LD-ceftobiprole sterilized 10 of 11 (91%) vegetations infected with PC3 (P < 0.01 versus controls) but only 3 of 12 (25%) vegetations infected with Mu50 (P > 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (P < 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA experimental endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.
    Antimicrobial Agents and Chemotherapy 09/2011; 55(9):3977-84. DOI:10.1128/AAC.00402-11 · 4.48 Impact Factor
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