- Cephalosporins function as cell wall inhibitors (same as penicillin). In general, there are 4 generations with each generation having increasing Gram-ve cover and lesser Gram+ve cover.
- The cephalosporins used to treat meningitis are cefotaxime and ceftriaxone.
- The cephalosporins used to treat pseudomonas are ceftazadime, cefoperazone and cefepime.
First generation (Cephazolin, cephalexin, cephalothin)
- Very active against GPC. Some activity against E.coli (GNR), Klebsiella (GNR) and Proteus (GNR). No activity against Pseudomonas. Therefore, the clinical indications are as follows:
- Staph/strep infections (soft tissue infections)
- Cephazolin is useful for surgical prophylaxis.
- *importantly, there is no penetration of first generation cephalosporins through the BBB, so cannot be used to treat meningitis.
- PK as follows:
- PO. Cephazolin is the only IV drug.
- Variable tissue level. Usually lower than serum.
- Renal, by glomerular filtration and tubular secretion. Dose adjustment is necessary in renal failure.
- Probenecid will reduce excretion.
Other than immediate hypersensitivity reactions, cephalosporins may be given to patients allergic to penicillins.
Second generation (cefaclor, cefuroxime)
- Very heterogeneous group with varying pharmacokinetics.
- In general, active against organisms that are inhibited by 1st generation, and also has extended Gram-ve coverage.
- Covers Klebsiella well.
- NO activity against Pseudomonas/enterococcus. Therefore, clinical indications as follows:
- Respiratory tract infections (sinusitis, otitis and LRTIs) as most are caused by Haemophilus and Moraxella.
- GIT infections – peritonitis and diverticulitis
Third generation (ceftriaxone, ceftazadime, cefotaxime and cefoperazone)
- Less activity against staph, but extended Gram-ve coverage. Effective against β-lactamase producing H.influenzae and N.meningitidis. Ceftazadime has activity against Pseudomonas. As such, the clinical indications are as follows:
- Ceftriaxone and cefotaxime cross the BBB, so may be used to treat meningitis caused by pneumococci, meningococci, haemophilus BUT NOT listeria.
- Can treat sepsis of unknown origin in immunocompetent hosts.
- Ceftazadime is the drug of choice for neutropenic sepsis.
- PK as follows:
- IV. Crosses BBB.
- Distributes well to body fluid and tissues (with the exception of cefoperazone)
- Ceftriaxone is excreted through biliary tract and therefore does not need dose adjustment in renal impairment. However the rest of the 3rd generation cephalosporins need dose adjustment.
Fourth generation (only one drug – cefepime)
- More resistant to hydrolysis by β-lactamases
- Extended coverage against enteric GNR
- Effective against Pseudomonas, Enterobacter, Staph, Strep, Haemophilus and Neisseria.
- Crosses the BBB and therefore can be used to treat meningitis.
- PK of cefepime are similar to ceftazadime.