Cephalosporins

Cephalosporins & Generations

1. Definition, source & chemistry

• Cephalosporins are a group of semisynthetic, bactericidal β-lactam antibiotics derived from cephalosporin C, a natural product of the fungus Cephalosporium acremonium (now Acremonium chrysogenum) (KDT 8e Ch.52, p.775).
• Historical origin: Cephalosporium acremonium was isolated in 1948 by Giuseppe Brotzu from sea water near a sewage outlet off the Sardinian coast; crude culture filtrates inhibited S. aureus in vitro and cured staphylococcal infection and typhoid fever in humans. Culture fluid yielded three antibiotics — cephalosporin P, N and C — of which cephalosporin C proved the useful lead (G&G 14e Ch.58, p.1155).
• The active nucleus of cephalosporin C is 7-aminocephalosporanic acid (7-ACA), structurally analogous to the 6-aminopenicillanic acid (6-APA) of penicillins; addition of side chains to 7-ACA generated semisynthetic agents far more potent than the parent (G&G 14e Ch.58, p.1155; Katzung 16e Ch.43, p.841).
• Core structure: a β-lactam ring fused to a six-membered dihydrothiazine ring (the cephem nucleus), in contrast to the β-lactam–thiazolidine (five-membered) fusion of penicillins (KDT 8e Ch.52, p.775).
• Two side-chain positions govern the molecule's properties (G&G 14e Ch.58, p.1155; KDT 8e Ch.52, p.775):
  • Position 7 of the β-lactam ring (R₁) — modifications alter the antibacterial spectrum and β-lactamase stability.
  • Position 3 of the dihydrothiazine ring (R₂) — modifications alter metabolism and pharmacokinetic properties (e.g. half-life, protein binding).
• Cephamycins (e.g. cefoxitin, cefotetan, cefmetazole) are closely related but carry an additional 7-α-methoxy group on the β-lactam ring of the 7-ACA nucleus, conferring enhanced stability to some β-lactamases and anti-anaerobic activity (G&G 14e Ch.58, p.1155).
• Compared with penicillins, cephalosporins are water-soluble, relatively acid-stable, and inherently more resistant to penicillinase regardless of side chain — although susceptibility to the broader β-lactamase family is variable (G&G 14e Ch.58, p.1155; R&D 10e Ch.52).