Cephalosporins

history

· discovered in 1945

· Prof Giuseppe Brotzu found fungus called Cephalosporium acremonium in sewer in Kalgara, Sardinia

· found to inhibit growth of bacteria

· culture sent to Prof Abrahan in Oxford

· cephalosporin C isolated

chemistry

· belong to beta-lactam group

· together with penicillins

· dihydrothiazine ring rused with four-member beta-lactam ring

· divided into three groups

First generation

· cephalothin (Keflin)

· cephalexin (Keflex)

· cefazolin (Cefzol)

Second generation

· cefoxitin (Mefoxin)

· cefuroxime (Ceftin)

· cefomandole (Mandol)

Third generation

· cefotaxime (Claforan)

· ceftriaxone (Rocephin)

· ceftazidime (Tazidime)

mechanism of action

· bind to enzymes involved in cell wall biosynthesis

· called penicilln-binding proteins (PBPs)

spectrum of activity

· broad-spectrum

· wide range of activity against gram-positive and gram-negative organisms

· marked differences among cephalosporins

· none effective against methicillin-resistant staph species

First generation

· active against most gram-positives

· S aureus

· S epidermidis

· Strep pneumoniae

· Clostridium perfringens

· limited gram-negative activity but active against

· E coli

· Klebsiella pneumoniae

· Proteus mirabilis

· not effective against

· Step faecalis (enterococci)

· Pseudomonas aeruginosa

· Enterobacter

· Bacteroides fragilis

· limited effectiveness against Haemophilus influenzae

· inhibit but do not reach sufficient tissue concentrations to be effective against

· N meningitidis

· N gonorrhoeae

· Salmonella

· Shigella

· (oral) cephalexin has only 1/10 of antistaphylococcal activity of (IV) cephalothin

Second generation

· generally less gram-positive activity

· more effective against gram-negatives

· more active against H influenzae

· cefoxitin effective against B fragilis and other anaerobes

Third generation

· generally even less effective against gram-positive organisms and 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

pharmacological properties

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% to ceftriaxone 90%

· widely distributed

· interstitial and peritoneal fluids

· urine

· CSF (3rd generation only)

· all enter bone

· cephalothin has lowest reported concentration (?artifactual)

· cefazolin has high concentrations

· 3rd generations 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

· excreted through kidney

· active tubular secretion

· glomerular filtration

· probenocid alters excretion of 1st and 2nd generations

· accumulate with renal failure

· T1/2 of cephalexin increases from 1 hr to 20 hrs

Pharmacokinetics

· frequency of administration varies

· cefazolin q8h

· cephalothin, cephalexin and cefoxitin q6h

· cefotaxime q12 h

· ceftriaxone od

Adverse reactions

Hypersensitivity

· anaphylaxis and immediate reactions rare

· skin rash 1-5%

· cross-sensitivity with penicillin

· similar chemical structure

· cross-reaction low (<5%)

· no contraindication if delayed penicillin side-effect such as rash

· with immediate penicillin side-effect, because of seriousness, should avoid

GIT

· diarrhoea in 1-10%

· pseudomembranous colitis uncommon

· hepatotoxicity does not occur

Other

· haematological and CNS rare

· resistance to Pseudomonas seen

· cephalothin may potentiate nephrotoxicity of aminoglycosides

indications

Musculoskeletal infections

· useful as

· low toxicity

· high concentration in bone and synovial fluid

· effective against common infective agents

S aureus infections

· can be treated with 1st generation cephalosporin

· maybe should be treated with flucloxacillin if not allergic to penicillins

· cephalosporins clearly drug of choice in penicillin allergy

Strep infections

· can be treated with 1st generation cephalosporins

Other infections

· not effective against enterococci

· clostridial infections preferably treated with penicillins

· cefoxitin effective for anaerobic infections

· maybe should add metronidazole

· 3rd generation cephalosporins effective in gram-negative osteomyelitis

· ceftazidime useful for Pseudomonas osteomyelitis

· no need for serum aminoglycoside levels or serum creatinine

Septic arthritis

· 3rd generation cephalosporins can be used for gram-negative septic arthritis

· aminoglycosides less effective in acid pH or high numbers of leukocytes

Outpatient treatment

· ceftriaxone can be used once daily IM

· cheaper than inpatient therapy

Prophylaxis in orthopaedic surgery

· 1st generation cephalosporins are drugs of choice

· effective against organisms most commonly cultured in deep infections in elective surgery

· inexpensive

· low toxicity

· cefazolin is drug of choice

· longer half life than cephalothin

· 2nd generations have no advantage

Respiratory tract infection

· cefoxitin useful against aspiration pneumonias

· 3rd generation effective against hospital-acquired gram-negative pneumonias

Urinary tract infection

· 3rd generation effective against hospital-acquired UTIs

· useful where aminglycosides contraindicated