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

Ceftobiprole

Ceftobiprole is an investigational "fifth"-generation cephalosporin with a broad spectrum of activity encompassing both gram-positive and gram-negative organisms. Like other ß-lactam antibiotics, ceftobiprole prevents cell wall formation by binding to and inhibiting penicillin binding protein (PBPs). However, ceftobiprole is structurally engineered to allow binding to PBP-2a expressed by the mecA cassette in MRSA isolates, which typically confers ß-lactam resistance.[18] As a result, ceftobiprole has bactericidal activity against methicillin-sensitive and -resistant S. aureus.[19] Ceftobiprole is also active in vitro against vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA).[20] The strong binding affinity of ceftobiprole to PBP-2x provides enhanced activity against penicillin-sensitive and -resistant S. pneumoniae and other streptococci.[21]

The development of ceftobiprole resistance in S. aureus was reported in a low frequency in early in vitro single-passage studies; however, in serial-passage studies with a high inoculum of organism, resistance to ceftobiprole mediated by mutations in PBP-2a has been observed.[22] The implications of in vitro generated resistance are unclear in the clinical setting.

Ceftobiprole generally exhibits potent activity against Enterobacteriaceae with the exception of Proteus vulgaris.[19] The antipseudomonal activity of ceftobiprole is similar to cefepime, displaying identical MIC50 and MIC90 in in vitro studies, although cefepime covers 1.5 to 5% more isolates. Elevated MIC values were reported to both ceftobiprole and cefepime for ceftazidime-resistant strains.[19,23] Ceftobiprole is a weak inducer but poor substrate of AmpC ß-lactamases, and therefore retains activity against organisms producing these enzymes.[23] Like other cephalosporins, ceftobiprole is inactive against ESBL-producing isolates.[23] Ceftobiprole also lacks activity against many nonfermentative gram-negative bacilli, including Acinetobacter spp., Burkholderia cepacia, and Stenotrophomonas maltophilia.[24] There are currently no published data regarding resistance development in P. aeruginosa.

After intravenous administration, the prodrug ceftobiprole medocaril is rapidly cleaved by plasma esterases to active ceftobiprole. The volume of distribution of ceftobiprole approximates the extracellular water compartment, and the estimated free fraction in plasma is 62%.[25] Ceftobiprole is predominantly excreted unchanged in the urine, has an elimination t ½ of 3 to 4 hours, and requires dosage adjustment for renal impairment.[25]

Ceftobiprole exhibits concentration-independent killing, and the PK-PD index predictive of clinical efficacy, as with other cephalosporins, is the T > MIC. Based on Monte-Carlo simulation, the proposed dosing strategy for complicated skin and skin structure infections (cSSSIs) (500 mg every 12 hours) has a high probability of achieving target PK-PD parameters for potential gram-positive pathogens, including MRSA.[25] Using the pneumonia dosing (500 mg every 8 hours as a 2-hour infusion) in the gram-negative organism analysis, the probability of target attainment varied by pathogen.[25] Target attainment was high for most Enterobacteriaceae; however, the probability of achieving bacteriostatic and near bactericidal effect was substantially lower for ESBL-, AmpC-producing organisms, and P. aeruginosa.

Ceftobiprole was generally safe and well tolerated in clinical studies. Frequently reported adverse effects included taste disturbances, nausea, and vomiting. There was no difference in ceftobiprole's effect on the QTc interval compared with placebo.[26]

Ceftobiprole has completed two phase III investigations for the treatment of cSSSIs demonstrating efficacy and noninferiority to vancomycin.[27,28] Ceftobiprole 500 mg IV every 8 hours as a 2-hour infusion was also compared with ceftriaxone with or without linezolid for the treatment of CAP in patients requiring hospitalization.[29] The clinical cure rates in the clinically evaluable population with moderate-severe diseases were 87% for ceftobiprole and 88% for ceftriaxone ± linezolid. For the treatment of HAP, a recently completed trial randomized patients to receive ceftobiprole 500 mg IV every 8 hours as a 2-hour infusion or ceftazidime plus linezolid for a total of 7 to 14 days.[30] The primary end point of clinical cure was reached in 69% of the ceftobiprole arm and 72% of the combination therapy arm, which met the predefined criteria for noninferiority. This trial included a subgroup analysis of patients with VAP in which the clinical cure rates were lower with ceftobiprole and noninferiority could not be established; further analysis of this subset of patients is ongoing.

Compared with cefepime, ceftobiprole has an expanded gram-positive spectrum with anti-MRSA activity but appears to be similar in gram-negative activity. The combination of the gram-positive (including MRSA) and gram-negative activity of ceftobiprole makes empirical monotherapy for HCAP an option for the first time.

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