Evaluation of Ceftobiprole Activity against a Variety of Gram-Negative Pathogens, Including Escherichia coli, Haemophilus influenzae (β-Lactamase Positive and β-Lactamase Negative), and Klebsiella pneumoniae, in a Rabbit Meningitis Model

Abstract

Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a ␤-lactamase-negative Haemophilus influenzae strain. Against a ␤-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges. C eftobiprole, formerly BAL 9141, belongs to a new generation of broad-spectrum cephalosporins with additional activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus, and penicillin-resistant Streptococcus pneumoniae. Ceftobiprole is bactericidal against a broad range of clinically important pathogens, including major Gramnegative pathogens. Its special mechanism of action is based on inhibition of all essential transpeptidases, including penicillinbinding protein 2A (PBP 2A), the primary enzyme responsible for ␤-lactam resistance in MRSA, and PBP 2X in pneumococci (1, 17). In addition, ceftobiprole is a poor substrate for many class A and C ␤-lactamases (14).Currently, ceftobiprole has been studied in phase III trials for several indications, including complicated skin and skin structure infections (cSSSI) and lower respiratory tract infections, such as nosocomial infections and community-acquired pneumonia (CAP) in hospitalized patients.Although the pharmacokinetics of ceftobiprole has been studied in detail, little is known about its penetration into the cerebrospinal fluid (CSF). The aim of this study was to determine the penetration of ceftobiprole into inflamed and uninflamed meninges and to test its antibacterial activity against a variety of Gramnegative pathogens in the experimental rabbit meningitis model. MATERIALS AND METHODSStrains and antibiotics. Klebsiella pneumoniae (1173687), Escherichia coli (QK-9), and the two Haemophilus influenzae strains were kindly provided by the Institute for Infectious Diseases, University of Bern. E. coli and K. pneumoniae were grown in Mueller-Hinton broth. The two H. influenzae strains were grown in Mueller-Hinton broth supplemented with Haemophilus Test Medium Supplement (Oxoid SR0158E). Ceftobiprole was provided by Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ), and cefepime was purchased commercially. MICs were determined by broth dilution methods based on recommendations of the CLSI (Clinical and Laboratory Standards Institute).Experimental meningitis model. The experimental rabbit meningitis model described by Dacey an...

Management of post-neurosurgical meningitis: narrative review

“…The newer lipoglycopeptides have low CNS penetration: for telavancin CNS 0.1% in non-inflamed meninges and 2% in inflamed meninges [46] and for oritavancin 2%e5% in rabbit models of meningitis [47]. The newer cephalosporins with an anti-methicillinresistant S. aureus spectrum of coverage might hold promise as their CNS penetration is similar to that of other cephalosporins: for ceftaroline 3% in non-inflamed meninges and 14%e15% in inflamed meninges [48,49], and for ceftobiprole 2% and 16%, respectively [50], both in rabbit models. Clinical data are unavailable to date.…”

A Phase 3 Randomized Double-Blind Comparison of Ceftobiprole Medocaril Versus Ceftazidime Plus Linezolid for the Treatment of Hospital-Acquired Pneumonia

“…Ceftobiprole demonstrates in vitro activity against S. aureus resistant to linezolid, vancomycin, and daptomycin [15], and ceftriaxoneresistant S. pneumoniae [16,17]. It also demonstrates superior bactericidal activity to daptomycin, linezolid, and vancomycin in several animal models of endocarditis [18,19], osteomyelitis [20,21], meningitis [22], mediastinitis [23], and peritonitis [24], and good efficacy in animal models of pneumonia and skin infections [25,26]. Ceftobiprole is therefore a promising agent with potential utility for difficult-to-treat infections.…”

Ceftobiprole Perspective: Current and Potential Future Indications

“…In addition, little is known regarding the penetration of cerebrospinal fluid (CSF) for ceftobiprole. Stucki et al [ 65 ] found that ceftobiprole penetration was approximately 16% in inflamed meninges, compared to approximately 2% in uninflamed meninges in a model for rabbit meningitis. In primary meningitis caused by S. pneumoniae (including strains resistant to penicillin and ceftriaxone) and the secondary post-operatory meningitis that requires both Gram-positive and Gram-negative coverage, ceftobiprole may be a beneficial option.…”