Cephalosporins

β-Lactams (Antibiotics)
Time Dependent Bactericidal Agents

Obtained from fungi Cephalosporium acremonium = Acremonium chrysogenum

3rd Generation Cephalosporins and 4th Generation Cephalosporins are Banned in Poultry

Structure:

• β-Lactams ring + Dihydrothiazine ring
  • The Dihydrothiazine ring provides resistance against bacterial β-Lactamase due to the Carboxyle group
    • Better effect against β-Lactams Resistant Bacteria
• Hydrophilic

Antibacterial spectrum: The higher the generation, the more resistant the Cephalosporins against bacterial β-Lactamase

• 1st Generation Cephalosporins: Gr+ (++++), Gr- (+)
  • Oral:
    • Cefalexin: 1st choice in Dermatology (along with Amoxicillin-Clavulanic Acid), also used for Mastitis and soft tissue infections
    • Cefadroxil: Off label
  • Parenteral:
    • Cefapirin: Intramammary infusion only
    • Cefalonium: Intramammary infusion only
    • Cefazoline: Perioperative Antimicrobial Prophylaxis
    • Cefalotin: Off label
• 2nd Generation Cephalosporins: Gr+ (+++), Gr- (++)
  • Oral:
    • Cefaclor: Excreted in the bile, Off label
    • Cefuroxime Axetil: Off label
  • Parenteral:
    • Cefuroxime: Off label
    • Cephamycins: Good for Anaerobic bacteria infections, not for food producing species
      • Cefoxitin
      • Cefotetan
• 3rd Generation Cephalosporins: Gr+ (+++), Gr- (+++)
  • Oral:
    • Cefixime: Off label
    • Cefpodoxime: Off label
    • Proxetil: Off label
  • Parenteral:
    • Cefoperazone: Antibiotics Acting Against Pseudomonas spp, Authorized as Intramammary infusion, excreted in the Bile
    • Cefotaxime: Off label, Crosses the BBB
    • Cefovecin: Very high protein binding, for Small animals
    • Ceftazidime: Antibiotics Acting Against Pseudomonas spp, Off label, crosses the BBB
    • Ceftiofur: Very high protein binding, for Farm animals
    • Ceftriaxone: Off label, Crosses the BBB, excreted in the Bile
• 4th Generation Cephalosporins: Gr+ (++++), Gr- (++++)
  • Parenteral:
    • Cefquinome
• (5th Generation Cephalosporins): Human medicine only

Mechanism of action: Identical as Penicillins (and other β-Lactams Antibiotics)

• The bacterial cell wall (Peptidoglycan) is made of NAG - NAM chains linked together by transpeptide bonds
  • Cephalosporins inhibit the formation of these transpeptide bonds by inhibiting the Transpeptidase and Carboxypeptidase (known as PBP Penicillins Binding Proteins)
    • This leads to rupture of the bacterial cell wall > Bactericidal Agents

Mode of action:

• Time Dependent Bactericidal Agents (give every 12h)
• Cmax should stay above MIC for 3-5 days
  • Long action is preferrable: Tablets or Depot Injections

Pharmacokinetics:

• 1st Generation Cephalosporins and 2nd Generation Cephalosporins: Hydrophilic
• 3rd Generation Cephalosporins and 4th Generation Cephalosporins: Lipophilic
  • Banned for Poultry
• Excreted in the kidney
  • Except: Cefaclor, Ceftriaxone, Cefoperazone excreted in the bile
• High plasma protein binding: Ceftiofur, Cefovecin
• Cross the BBB: Cefotaxime, Ceftazidime, Ceftriaxone

Resistant Bacteria:

• Ab ovo (=naturally resistant bacteria): No PBP to act on
  • Mycoplasma spp: They don’t have a cell wall
  • Acid-fast bacteria (Mycobacterium, Nocardia, Brucella, Chlamydia…): They have a unique type of cell wall made of Mycolic acid that the Cephalosporins can’t penetrate
  • Enterococcus (type of Streptococcus) causing UTI
  • Bordetella bronchiseptica (causing Kennel cough in Dogs and Atrophic rhinitis in Pigs)
• β-Lactamase production:
  • Unlike Narrow Spectrum Penicillins, Cephalosporins resist the β-Lactamase of Staphylococcus, they are a very good choice for Mastitis, Skin and Ear infections (Dermatitis) caused by this bacteria
    • Cephalosporins play a very important role in Dermatology
  • β-Lactamase producing Gr- bacteria: 4 generations of Cephalosporins have been developed against these Resistant Bacteria
    • E. coli is a β-Lactamase producing Gr- bacteria. It will resist against 1st Generation Cephalosporins but not against 3rd Generation Cephalosporins and 4th Generation Cephalosporins
    • ESBL Extended Spectrum β-Lactamase producing bacteria resist to all 4 generations of Cephalosporins (Resistant Bacteria)
      • The important ESBL enzymes are named (CTX-M, SHV, TEM)
      • Only Carbapenems (last resort Antibiotics) work against ESBL producing bacteria
• PBP gene mutation: Target modification, the Cephalosporins can’t bind the PBP > the bacterial cell wall synthesis isn’t inhibited
  • Frequent Resistance mechanism in the MRSA Methicillin Resistant Staphylococcus Aureus and MRSP Methicillin Resistant Staphylococcus Pseudointermedius. They are resistant to ALL β-Lactams Antibiotics
    • The Antibiotics used in MRSA/MRSP infections are Rifampicin (AMEG A) and Amikacin, Florfenicol (AMEG C)
    • In human medicine only, there is also 5th Generation Cephalosporins

Some Cephalosporins have a high protein binding which increases the Antibiotics hl and duration of action

Indication:

• Mastitis: 1st Generation Cephalosporins
• Dermatitis, Soft Tissue infections: Cefalexin (1st Generation Cephalosporins) is the 1st choice as well as Amoxicillin-Clavulanic Acid
• Respiratory infections: 3rd Generation Cephalosporins and 4th Generation Cephalosporins
• UTI: All Cephalosporins generations (except those which aren’t excreted in by the kidney: Cefaclor, Ceftriaxone, Cefoperazone)
• Preoperative prophylaxis, Osteomyelitis, Orthopedic surgery: Cefazoline 30-60 min before procedure
  • Osteomyelitis only: Cefalexin is suitable too
• Meningitis, Encephalitis: Those which cross the BBB: Cefotaxime, Ceftriaxone, Ceftazidime
• Septicaemia: All Cephalosporins generations

Adverse effects:

• Allergy in 5% of the cases: Cross allergy with Penicillins
• Dysbacteriosis: Clostridium spp overgrowth
  • Herbivorous rodents (Degu, Chinchilla, Hamster, Guinea pig, Rabbits) and Horses are very sensitive to Dysbacteriosis
    • It is not forbidden though, but use with care
• Tissue irritation: Problematic for Small animals, not Farm animals
• Mild nephrotoxicity (Especially if combined with Aminoglycosides)