New Antibiotics for Healthcare-Associated Pneumonia

Elizabeth A. Neuner, Pharm.D.; David J. Ritchie, Pharm.D.; Scott T. Micek, Pharm.D.

Disclosures

Semin Respir Crit Care Med. 2009;30(1):92-101. 

In This Article

Ceftaroline

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.[31]

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.[31] 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.[32] In contrast, resistant mutants of E. cloacae and E. coli were readily selected with phenotypes of AmpC-derepressed and TEM ß-lactamase producers, respectively.[32]

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.[36] 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.[37] The PK-PD profile of ceftaroline is similar to that for ceftobiprole and the other cephalosporins.[38] 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.[38]

Ceftaroline demonstrated similar clinical cure rates to vancomycin ± aztreonam in a phase II study for the treatment of cSSSIs.[39] 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.

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