Ceftaroline is another broad-spectrum cephalosporin with activity against MRSA.
Like ceftobiprole, ceftaroline inhibits bacterial cell wall synthesis and has enhanced binding affinity for PBP-2a resulting in anti-MRSA activity. Ceftaroline possesses potent bactericidal activity against many staphylococci, including both MSSA and MRSA.[31,32] In addition, ceftaroline retains activity against S. aureus with heterointermediate resistance to vancomycin (hVISA) and VISA.[31,33] Ceftaroline is active against S. pneumoniae, including penicillin-intermediate and -resistant strains.
Ceftaroline is active against many common gram-negative respiratory pathogens, including Haemophilus influenzae, Escherichia coli, Salmonella spp., Citrobacter freundii, Morganella morganii, Proteus mirabilis, and Klebsiella pneumoniae.[31,32] Importantly, ceftaroline does not possess activity against P. aeruginosa and exhibits reduced activity against E. cloacae, P. vulgaris, and Providencia spp compared with ceftobiprole. Unlike cefepime and ceftobiprole, ceftaroline is vulnerable to AmpC ß-lactamases, ESBLs, and some classical penicillinases. This, along with the inoculum effect, which can trigger rising MICs, limits the utility of ceftaroline when targeting many gram-negative organisms causing HCAP.
Using single-step and multistep passages, no resistant mutants were selected with ceftaroline in staphylococci, pneumococci, or H. influenzae. In contrast, resistant mutants of E. cloacae and E. coli were readily selected with phenotypes of AmpC-derepressed and TEM ß-lactamase producers, respectively.
In human plasma the prodrug ceftaroline acetate rapidly undergoes hydrolysis to the active compound ceftaroline. Ceftaroline has limited protein binding (1 to 19%) and achieved good lung penetration (~40%) in a rabbit model.[34,35] The major route of elimination is renal excretion and the average t ½ is 2.6 hour. In patients with mild renal impairment, no dose adjustment is necessary; however, further study is required to determine the appropriate dosage adjustment for moderate and severe renal disease. The PK-PD profile of ceftaroline is similar to that for ceftobiprole and the other cephalosporins. In animal models, dosages mimicking a human dose of 600 mg every 12 hours achieved the target PK-PD parameters for maximal efficacy for most organisms and validated the use of this dosing strategy in further research.
Ceftaroline demonstrated similar clinical cure rates to vancomycin ± aztreonam in a phase II study for the treatment of cSSSIs. Phase III studies for the treatment of community-acquired pneumonia and cSSSIs are currently under way.
Pharmacokinetic studies in animals demonstrate ceftaroline achieves good lung penetration, and pending results from ongoing clinical trials will impact whether ceftaroline has a role as monotherapy in serious CAP or HCAP infections where MRSA is a potential etiologic organism. The lack of activity against P. aeruginosa, ESBLs, and AmpC-producing Enterobacteriaceae limits its use as monotherapy for the empirical treatment of HCAP.
Semin Respir Crit Care Med. 2009;30(1):92-101. © 2009 Thieme Medical Publishers
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