Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Microbiology

Ceftobiprole has in vitro activity against a wide range of gram-positive, gram-negative, and anaerobic bacteria, including MRSA, community-acquired MRSA, methicillin-resistant Staphylococcus epidermidis (MRSE), S. pneumoniae, penicillin-resistant S. pneumoniae, vancomycin-resistant Enterococcus faecalis, non–extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, P. aeruginosa, Fusobacterium nucleatum, and Clostridium perfringens ( Table 1 ).^{[11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]} Although official breakpoints have not been determined by the Clinical and Laboratory Standards Institute, in vitro analyses to this point have used conservative breakpoints at 4 µg/mL or less for enterococci, Enterobacteriaceae, nonenteric gram-negative bacilli, and Staphylococcus; however, current breakpoints for extended-spectrum cephalosporins were used for Haemophilus (2 µg/mL) and streptococci (1 µg/mL).^[12]

Gram-Positive Organisms

Ceftobiprole is very active against staphylococci, with the majority of isolates having a 90% minimum inhibitory concentration (MIC ₉₀ ) of 4 µg/mL or less, although some Staphylococcus haemolyticus isolates have an MIC ₉₀ of 8 µg/mL.^{[11,12,13,14,15,16]} In addition, activity toward S. aureus remains in MRSA, community-acquired MRSA, vancomycin-intermediate (VISA) and vancomycin-resistant (VRSA) isolates.^{[15,17,18,19,20]} Activity against S. pneumoniae is very high, even when penicillin-resistant isolates are tested.^{[11,12,21,22]} Mutations in PBP1a, PBP2x, and PBP2b may increase the MIC, but ceftobiprole remains active against the majority of penicillin-resistant, macrolide-resistant, and fluoroquinolone-resistant S. pneumoniae.^[21,22] Ceftobiprole is active against ampicillin-susceptible isolates of E. faecalis and Enterococcus faecium, while only remaining active against vancomycin-resistant E. faecalis, but not vancomycin-resistant E. faecium (VRE).^{[11,12,18,23,24]} Ceftobiprole differentiates itself from ampicillin by retaining activity at a high inoculum.^[23]

Gram-Negative Organisms

Ceftobiprole has activity in gram-negative organisms similar to that of some existing extended-spectrum cephalosporins, such as ceftriaxone and ceftazidime. Organisms producing ESBLs and enzymes with carbapenemase activity (KPC, IMP, VIM) are expected to be resistant to ceftobiprole. Ceftobiprole may be active against bacteria producing class A (TEM, SHV) and AmpC β-lactamases.^[25] In vitro data suggest activity against most Enterobacteriaceae, with reduced activity to Enterobacter spp., Serratia marcescens, indole-positive Proteae, and especially ESBL-producing E. coli and Klebsiella pneumoniae.^[11,12,26] Ceftobiprole may have similar activity to cefepime and ceftazidime against P. aeruginosa and limited activity against Acinetobacter baumannii, Burkholderia cepacia, and Stenotrophomonas maltophilia.^[11,12,27] Ceftobiprole is active against both non– and β-lactamase–producing Haemophilus influenzae and Moraxella catarrhalis, and Neisseria spp.^[11,12,28]

Anaerobes

Interpreting anaerobic activity of ceftobiprole is difficult due to reporting of mixed species, and in vitro activity may depend on the isolate source (intraabdominal vs diabetic foot).^[29] In summary, ceftobiprole is active against mixed anaerobic isolates. Bacteroides spp., Lactobacillus spp., and Prevotella spp. are not therapeutic targets.^{[11,12,27,28,29,30,31]} In general, activity includes Propionibacterium acnes, peptostreptococci, Finegoldia magna, Fusobacterium nucleatum, and C. perfringens.^{[12,27,28,29,30,31]} Ceftobiprole does not have in vitro activity against Clostridium difficile; thus, monitoring for C. difficile infection is necessary.^[31]

Bactericidal Activity

Bactericidal activity is defined by a 99.9%, or 3-log ₁₀ or greater, reduction in colony-forming units from the starting inoculum after a proper incubation interval. The concentration where bactericidal activity first occurs is defined as the minimum bactericidal concentration (MBC). The bactericidal activity of ceftobiprole has been assessed against gram-positive and gram-negative
isolates.^{[18,20,24,32]}

Deshpande et al.^[18,32] tested over 100 staphylococci, streptococci, enterococci, and gram-negative isolates. Ceftobiprole showed bactericidal activity against MSSA, MRSA, coagulase-negative staphylococci, hetero-VISA, penicillin-susceptible S. pneumoniae, penicillin-resistant group B streptococci, ampicillin-susceptible enterococci, H. influenzae, and E. faecalis isolates. Some Staphylococcus isolates displayed a decreasing rate of killing at concentrations above the MBC, or "eagle effect," which may occur with β-lactam antibiotics. Forty-five percent of penicillin-nonsusceptible S. pneumoniae and 3 of 5 isolates of S. marcescens had an MBC:MIC ratio greater than 4, and 1 ampicillin-susceptible E. faecium isolate was bacteriostatic. Other investigators verified bactericidal activity of ceftobiprole at 4 times the MIC for susceptible MRSA, community-acquired MRSA, VISA, and VRSA strains.^[20] Bactericidal activity against β-lactamase–producing and vancomycin-resistant E. faecalis has been confirmed.^[24]

The Annals of Pharmacotherapy. 2008;42(6):806-816. © 2008  Harvey Whitney Books Company