Cefetamet: Its In Vitro Activity and Interaction with β-Lactamases and Penicillin-Binding Proteins

Summary

Cefetamet pivoxil (pivoxyl) is an orally active cephalosporin in advanced clinical development sharing a 2-aminothiazolyl- and a methoxyimino-moiety as side chains, in common with other third generation cephalosporins. Consequently, cefetamet is highly active against various Gram-positive and Gram-negative pathogens such as β-haemolytic streptococci [serogroup A: median minimum concentration inhibiting 90% of pathogens (MIC₉₀) 0.06 mg/L; serogroup B: median MIC₉₀ 1 mg/L], Streptococcus pneumoniae, Haemophilus influenzae β-lactamase positive (median MIC₉₀ 0.25 mg/L), Enterobacteriaceae [Escherichia coli, Klebsiella spp., most Enterobacter spp., Proteus and Providencia spp., Salmonella spp., Shigella spp. and Yersinia enterocolitica (median MIC₉₀ ≤ 2 mg/L)]. Cefetamet is inactive against Staphylococcus spp., Pseudomonas aeruginosa, and most members of Bacteroides and Clostridia spp.

Cefetamet is not affected by most plasmid-mediated β-lactamases, such as the TEM-1/-2, OX A 1–3 and SHV enzymes. Moreover, it exhibits greater stability against the recently evolved ‘extended-spectrum’ β-lactamases than many other third generation cephalosporins; however, it is inactive against TEM-3 (synonym CTX-l)-producing isolates, although fully active against the ‘new’ SHV-enzyme-producing isolates. There was complete cross-resistance between Cefetamet and the third generation cephalosporins in cephalosporinase-(Richmond’s and Sykes class I classification) overproducing enterobacteria. On the contrary, Cefetamet was more stable against the class III P. vulgaris enzyme than most other oxyimino-cephalosporins. Cefetamet exhibited high affinity for the penicillin-binding proteins (PBPs) 3 [concentration required to decrease binding of ¹⁴C-benzylpenicillin by 50% (IC₅₀): 2.5 mg/L] and PBP la (IC₅₀: 4.2 mg/L) of E. coli W3110 and for the PBPs 3 (IC₅₀: 1.3 mg/L) and PBP la (IC₅₀: 0.3 mg/L) of E. cloacae 908 S, but had very low affinity for S. aureus PBPs (IC₅₀ ≥ 50 mg/L), thus explaining its lack of clinically relevant activity against staphylococci.