Cephalosporins

Discovered in 1945 in Sardinian sewer
Semisynthetic derivatives of fungus Cephalosporium
Morphology
- ß-lactam AB like Penicillin
- Dihydrothiazine ring fused with four-member beta-lactam ring

Three Groups

Same for Penicillins & Cephalosporins (ß lactam AB)
- inhibition of Cell Wall Synthesis
- Bacteriocidal
Bind to enzymes involved in cell wall biosynthesis called Penicillin-binding proteins (PBP)
PBP catalyse transpeptidation that is final step in cell wall synthesis
- Also plays role in maintenance of cell shape
- Also plays a role in cell division
Leads to weakening of cell wall & death

Active against most Gram Positive
Cephalexin 1/10 of anti-staphylococcal activity of Cephalothin
Limited Gram Negative activity but active against
- E coli
- Klebsiella
- Proteus
Not effective against
- Streptococcus faecalis (Enterococcus)
- Pseudomonas
- Enterobacter
- Bacteroides fragilis
Limited effectiveness against
- Haemophilus influenzae
Inhibit only
- Nisseria meningitidis
- Nisseria gonorrhoea
- Salmonella
- Shigella

Generally even less effective against Gram Positive
More effective against Gram Negative organisms
Effective against Gram Negative enterics
- Klebsiella
- Proteus
- Enterobacter
- Serratia
Cefotaxime has similar Gram positive activity to 1st Generation
Ceftazidime is effective against Pseudomonas

Route
- Most not orally absorbed
  - Except Cephalexin, which is absorbed by mouth
- Given IV or IM
  - Except Cephalothin, which is painful IM
Distribution
- Variable protein binding
  - Cephalexin 15%
  - Ceftriaxone 90%
- Widely distributed
  - Interstitial & Peritoneal fluids
  - Urine
  - CSF (3rd Generation only)
  - All enter bone (no true blood bone barrier)
- 1st Generation
  - Cefazolin has high concentrations
  - Cephalothin has lowest reported concentration
- 3rd Generation
  - Have just above MIC for Gram positive inhibition
  - But well in excess of MIC for Gram negative inhibition
    - All have excellent synovial fluid concentrations
Metabolism
- Cephalothin converted to less active Desacetyl derivative
- Cefotaxime converted to very active Desacetyl derivative
Excretion
- Via kidney
- Glomerular filtration +
- Active tubular secretion
- Probenecid alters excretion of 1st & 2nd generations
- Impedes excretion & prolongs T½
- Accumulate with CRF
- T½ of Cephalexin ↑ from 1 hour to 20 hours
Pharmacokinetics
- Frequency of administration varies
- Cefazolin q8h
- Cephalothin, Cephalexin, Cefoxitin q6h
- Cefotaxime q12h
- Ceftriaxone daily

Staphylococcus aureus Infections
- Can be treated with 1st Generation
- Drug of choice in Penicillin allergy
Streptococcal Infections
- Can be treated with 1st Generation
Other Infections
- Treat Clostridia with Penicillin
- Cefoxitin effective for anaerobic infections
- Maybe should add Metronidazole
3rd Generation effective in Gram negative OM
- Ceftazidime for Pseudomonas OM
Septic Arthritis
- 3rd Generation can be used for Gram negative septic arthritis
- Aminoglycosides less effective

Hypersensitivity
Anaphylaxis rare
Skin rash 1-5%
Cross sensitivity with penicillin 5-10%
- No contraindication if delayed penicillin side effect ie. Rash
- Avoid with immediate penicillin side effect ie. Anaphylaxis
GIT
Diarrhoea in 1-10%
Pseudomembranous colitis
- Uncommon
- Occurs with use of broad spectrum AB
Other
- Haematological & CNS rare
- Resistance to Pseudomonas seen
- Cephalothin may
  - Cause ATN in high doses