crop_square Key points

  • check_circle Bactericidal beta-lactam antibiotics with a 7-aminocephalosporanic acid core
  • check_circle Bind to penicillin-binding proteins (PBPs) inhibiting cell wall synthesis
  • check_circle Older generations: Narrow spectrum, mostly against gram-positives
  • check_circle Newer generations: Very broad coverage, some resistance to beta⁠-lactamases
  • check_circle Adverse effects: Potential cross-reactivity with other beta-lactam antibiotics

crop_square Background and biochemistry

Cephalosporin antibiotics, originally isolated from the fungus Acremonium strictum (used to be called Cephalosporium acremonium), share several characteristics with penicillin antibiotics. Both groups are beta-lactam antibiotics and the successive generations of cephalosporins remotely resemble the subgroups of penicillins with regards to their spectrum of activity. All cephalosporins consist of a beta-lactam ring and, unlike penicillins, of a dihydrothiazine ring. These rings form the basic cephalosporin structure called 7-aminocephalosporanic acid. There are many more cephalosporin antibiotics available throughout the world than there are penicillins.

crop_square Mechanism of action

The mechanism of action of cephalosporin does not differ fundamentally from other beta-lactam antibiotics. Cephalosporins bind to penicillin-binding proteins (PBPs) which disrupts the bacterial cell wall through interference with peptidoglycan synthesis. The interaction between cephalosporins and PBPs leads to the activation of autolytic enzyme and ultimately, cell death. Cephalosporins are bactericidal antibiotics. The production of beta-lactamases, alterations to PBPs and drug efflux pumps are all known bacterial resistance mechanism relevant to cephalosporins. Like other beta-lactam antibiotics, cephalosporins depend on active cell wall synthesis to function.

crop_square Drugs and spectrum of activity

First-generation cephalosporins
  • Cepha­lexin
  • Cefa­zolin
  • Ceph­radine
  • Cefa­droxil

First-generation cephalosporins are very active against gram-positive cocci including MSSA. Enterococci are intrinsically resistant to cephalosporins. Activity against Gram-negative rods is limited.

Second-generation cephalosporins
  • Cefuroxime
  • Cefmetazole
  • Cefaclor
  • Cefonicid

Second-generation cephalosporins show a spectrum of activity similar to first-generation cephalosporins with improved coverage against gram-negative bacteria. This generation of cephalosporins also covers some anaerobic organisms and may be considered for mixed anerobic-aerobic infections. However, widespread resistance and relatively high costs are limiting factors for clinical use.

Third-generation cephalosporins
  • Cefotaxime
  • Ceftriaxone
  • Ceftazidime
  • Cefixime

In contrast to the first and second generation, third-generation cephalosporins show limited activity against gram-positive cocci. Activity against gram-negative rods is superior. Most drugs in this group penetrate the blood-brain barrier and may be used to treat gram-negative bacterial meningitis, sepsis and complicated urinary tract infections.

Fourth-generation cephalosporins
  • Cefepime
  • Cefpirome
  • Cefclidine

Fourth-Generation Cephalosporin provide excellent cover against both gram-positive and gram-negative organisms including Pseudomonas aeruginosae. Activity against anaerobes is limited. Due to their molecular structure, they easily penetrate human tissue and accumulate in bacterial cell walls. They are resistant to many beta-lactamases and may be used, where available, for the empirical treatment of neutropenic septic patients.

Fifth-generation cephalosporins
  • Ceftaroline
  • Ceftopbiprole

The latest generation of cephalosporins have proven activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), and many gram-positive bacteria. They are active against common gram-negative rods. However, they do not cover extended spectrum beta-lactamase producing strains (usually gram-negative bacteria).

crop_square Pharmacokinetics

Cephalosporins can often only be given intravenously. Oral cephalosporins include Cefuroxime and Cephalexin. Bioavailability varies but may be as low as 50%. Tissue penetration is good in most cephalosporins. Many third- and fourth-generation cephalosporins cross the blood-brain barrier sufficiently but first- and second-generation cephalosporins do not. Most cephalosporins are excreted by the kidneys and have a rather short half-life. Ceftriaxone is a frequently used exception to these rules with only one dose required over 24h. This drug is hepatically metabolised and excreted via faeces.

crop_square Adverse drug effects

Cephalosporins are known to cause a variety of hypersensitivity reactions. Some are more concerning like anaphylaxis and haemolytic anaemia while others, like skin rashes, are more benign. Overall, anaphylaxis appears to occur somewhat less frequently in cephalosporins compared to penicillins. Patients with anaphylactic reactions to penicillins in the past should not be treated with cephalosporins. However, cephalosporins are mostly well tolerated in patients who had minor reactions to penicillins. Some sources state that cephalosporins are more strongly linked to antibiotics-associated Clostridium difficile infection than other antibiotics, however there is limited evidence to support this claim.