Cephalosporins

·        Chemistry.

·        Mechanisms of action.

·        Pharmacokinetics.

·        Adverse reactions.

Chemistry

1.       Cephalosporins are semi-synthetic antibiotic derivatives of cephalosporin C, a substance produced by the fungus Cephalosporium acremonium.

2.    The nucleus of the cephalosporins is the 7-amino-cephalosporanic acid which consists of:

a.       Dihydrothiazine ring.

b.    Beta lactam ring.

3.       Modifications at 3 and 7 positions of the nucleus produce cephalosporins that vary widely in spectrum of antibacterial activity and pharmacokinetic properties.

4.    2 antibiotics in this family which are technically not cephalosporins are:

a.       Cefoxitin: a cephamycin.

b.       Moxalactam.

Mechanism of action

1.    Act on growing bacterial cell wall therefore metabolically inactive cells are unaffected.

2.    Bind to penicillin-binding proteins (PBP) blocking final step in cell wall synthesis by inhibiting transpeptidation.

3.       Incapable of withstanding the osmotic gradient between its interior and its environment the cell swells and rupture.

4.       Bacterial resistance:

a.       Some bacteria produce beta-lactamases which break open the beta lactam bond and destroy activity of the drug.

b.       Other bacteria are resistant because they lack specific receptors for penicillin or they are impermeable to the drug.

Pharmacokinetics

1.       Absorption:

a.       Oral: cephalexin, cephradine, cefadroxil, cefaclor, cefprozil, cefdinir.

b.       Parenteral: cephalothin, cefazolin, cephaloridin, cefoxitin, cefamandole, cefuroxime, cefotaxime, ceftriaxone, moxalactam, cefoperazone, cefsulodin.

2.       Distribution:

a.    Wide distribution through most body fluids and tissues.

b.    Half-life: 6 – 14h.

c.    Poor penetration into CSF except for cefotaxime, moxalactam and ceftriaxone which achieve significant concentrations in CSF.

d.       Readily cross the placenta.

3.       Elimination:

a.       Excreted unchanged in the urine.

b.       Actively secreted by renal tubule.

c.    Dose should be reduced in patients with poor renal function.

d.       Cefoperazone is excreted mainly via the biliary tract.

Adverse effects

1.       Cephalosporins have low incidence of adverse effects.

2.       Hypersensitivity:

a.    5 – 20% cross sensitivity in patients allergic to penicillin.

b.       Anaphylaxis.

c.       Maculopapular or erythematous rash.

d.       Pruritus.

e.       Eosinophilia.

f.     Drug fever.

3.       Gastrointestinal:

a.       Diarrhoea.

b.       Pseudomembranous colitis.

c.       Cholelithiasis: ceftriaxone.

4.       Renal dysfunction and nephropathy: cephaloridin, cephalexin and cefazolin, but rare.

5.       Blood:

a.       Anaemia.

b.       Leukopeina.

c.       Thrombocytopenia.

d.       Hypoprothrombinaemia and platelet dysfunction: moxalactam, cefoperazone and cefamandole.

6.       Genitourinary:

a.       Vaginitis.

b.       Vaginal candidiasis.

c.       Genital pruritus.

d.       Menstrual irregularities.

7.    Drug interactions:

a.       Disulfiram-like reactions with alcohol: cefamandole, cefoperazone and cefotetan.

b.       Probenecid: increase cephalosporin levels.

c.       Aminoglycosides, vancomycin: increase nephrotoxicity.

Spectrum of antimicrobial activity

1.    1st generation cephalosporins:

a.       Good activity against gram-positive cocci but relatively limited activity against gram-negative bacilli.

b.    Used in infections caused by:

c.    1st generation cephalosporins are active against streptococci, staphylococcus aureus, enterobacteriaeae and anaerobes except Bacteroides fragilis.

d.    They are inactive against gram-negative cocci.

2.    2nd generation cephalosporins:

a.    Less activity against gram-positive bacteria compared to 1st generation cephalosporins.

b.       Greater activity than 1st generation cephalosporins against gram-negative bacilli but less than 3rd generation cephalosporins.

c.       Sensitive organisms: Haemophilus influenzae, Enterobacter spp, Proteus sp. (indole positive).

d.       Cefoxitin has good activity against anaerobes including Bacteroides fragilis.

3.    3rd generation cephalosporins:

a.       Activity against gram-positive cocci is decreased compared to the older cephalosporins.

b.       Greater activity against gram-negative bacilli than the 2nd generation cephalosporins.

c.       Remarkable activity against the enterobacteriaeae and some uncommon organisms: Aeromonas, Pasturella spp, Citrobacter, Providencia and Serratia.

d.       Ceftazidime, cefoperazone and cefsulodin are active against Pseudomonas aeruginosa.

e.       Inactive against MRSA, enterococci and Listeria monocytogenes.

4.    4th generation cephalosporins:

a.       Cefepime has an expanded spectrum of activity against gram-negative bacilli than its predecessors.

b.       Active against Pseudomonas aeruginosa and certain enterobacteriaeae that are generally resistant to third generation cephalosporins.

c.    More active against gram-positive bacteria than some third generation drugs.

d.       Expanded spectrum of activity is due to the fact that they penetrate outer membrane of gram-negative bacteria more rapidly than other cephalosporins and their resistance to inactivation by beta-lactamase.