unit 10.3: beta-lactam - cephalosporins

Cephalosporin

Cephalosporin

• Derivatives of 7-aminocephalosporanic acid

• With 2 sites of attachment for various R1 and R2 groups

• More stable to many bacterial β–lactamases, has broader spectrum of activity

Giuseppe Brotzu

• Isolated Cephalosporin C compound in from the fungus Acremonium, previously known as "Cephalosporium” in 1945.

  • Found in the sea near a sewage outfall in Su Siccu, by Cagliari harbour in Sardinia, Italy

R group at 7-position

alters antibacterial activity

R group at 3-position

modifies pharmacokinetic profile

• whether they can traverse the blood-brain barrier or not

• hydrophobic or hydrophilic

• biliary or urinary

• Cephalexin

• Cefazolin

• Cefadroxil

• Cephalotin

• Cephradine

• Cephapirin

First generation

• Cefuroxime

• Cefoxitin

• Cefotetan

• Cefamandole

Second generation

• Ceftriaxone

• Cefotaxime

• Cefoperazone

• Ceftazidime

• Cefixime

Third generation

Cefepime

Fourth generation

• Ceftaroline

• Ceftolozane

Fifth generation

Bind to PBPs

Mechanism of Action

inhibit cell wall synthesis, similar to penicillins

Structural differences

Mechanism of Action

___ render them less susceptible to penicillinases produced by staphylococci

MRSA

Mechanism of Action

resistant to cephalosporins

Most are parenteral

Pharmacokinetics

administered or occurring elsewhere in the body than the mouth and alimentary canal.

renal excretion

Pharmacokinetics

Major elimination

hepatic metabolism

Pharmacokinetics

some with side chains

Cefoperazone and ceftriaxone

Pharmacokinetics

excreted in the bile

1st- and 2nd-generation

Pharmacokinetics

Do not enter the CSF when the meninges are inflamed1st- and 2nd-generation

1st Gen: Cefazolin and cephalexin

Clinical Use

• against G+ cocci, E coli, K pneumoniae

• Surgical prophylaxis

• Minimal activity (Gram (-) cocci, Enterococci. MRSA, Most gram (-) rods)

Second Generation

Clinical Use

• Less activity against gram (+)

• Extended coverage for gram (-)

• Marked differences in activity occur among the drug

Cefotetan, Cefoxitin

Clinical Use: 2nd Gen

• Anaerobic coverage

• B. fragilis

Cefamandole, cefuroxime, cefaclor

Clinical Use: 2nd Gen

H influenzae, M catarrhalis

Ceftazidime, cefoperazone, cefotaxime

• penetrates BBB except cefoperazone, cefotaxime

Clinical Use: 3rd Gen

• Increased activity against gram (-) organisms resistant to other beta-lactam drugs

• Ability to penetrate the blood-brain barrier

Ceftriaxone

Clinical Use: 3rd Gen

• gonococcal urethritis - purulent discharge

• Single injection for acute otitis media

• As effective as 10 days of amoxicillin

Ceftriaxone (IV) and cefixime

Clinical Use: 3rd Gen

Drug of choice for gonorrhea

Cefepime

Clinical Use: 4th Gen

• more resistant to beta lactamases

• combines gram positive activity / coverage of 1st gen with wider gram neg

Ceftaroline

Clinical Use: 4th Gen

• active against MRSA that is resistant to Cephalosporins

rashes to anaphylactic shock

Toxicity

• Allergy

• Complete cross reactivity should be assumed

• less frequently than penicillins

5-10%

Toxicity: Allergy

• Partial cross reactivity between penicillin and cephalosporin

• Pain at IM injection site

• Phlebitis after IV injection

• Increase nephrotoxicity of aminoglycosides

Toxicity:

Other adverse effects

Cefamandole, cefoperazone, cefotetan

Toxicity: Other adverse effects

• Drugs containing a methylthiotetrazole group

• May cause hypoprothrombinemia

• Disulfiram-like reactions with ethanol

• Listeria

• Atypicals

• Methicillin-resistant staphylococcus aureus (MRSA)- except Ceftaroline

• Enterococcus

Cephalosporins are “LAME” because they are inactive against

Cephalexin

First Generation:

• effective against pharyngitis (above umbilicus infections) which (back then) were mostly gram-positive

• cell wall will be thicker for gram-positive

• gram-negative are resistant with beta lactams

Cefazolin

First Generation:

• parenteral route (IV)

• longer duration of action, but similar spectrum

Cefuroxime

Second Generation:

• given parenterally

• longer half life

• it can cross blood brain barrier

• used for community-acquired bronchitis & pneumonia

Cefuroxime axetil

Second Generation:

• twice daily

• quite resistant even against to beta-lactamase-producing organism

Ceftriaxone

Third Generation:

• effective against genital, anal and pharyngeal penicillin-resistant neisseria gonorrhoeae

• excreted through the bile

Ceftazidine

Third Generation:

• anti-pseudomonal coverage

  • Pseudomonas are hospital-acquired germ with numerous resistance

Cefotaxime

Third Generation:

• good choice for infections (bacterial encephalitis & bacterial meningitis)

Cefepime

Fourth Generation:

• anti-pseudomonal property

interstitial nephritis and tubular necrosis

• if combined with aminoglycoside (protein synthesis inhibitor

• cephalosporin don’t go along well w/ aminoglycoside

Adverse Reactions of Cephalosporins

Renal

Hypoprothrombinemia and bleeding disorders

Adverse Reactions of Cephalosporins

Hematologic