Macrolides
3
- Clarithromycin
- Azithromycin
- Roxithromycin
Ketolides
Telithromycin
Macrolides MOA
- bacterioSTATIC inhibitors of protein synth. (bind to ribosomes 50s)
- block transpeptidation
what about macrolides?
- large cyclic lactone ring structures with attached sugars
Clarithromycin Pharmacokinetics
- Elimination: hepatic metabolism and urinary excretion of intact drug
- 1/2 life: 6h
- Bioavailability: good oral bioavailability
- distribution: most body tissues
Azithromycin pharmacokinetics
- absorption is impeded by food (not good oral availability)
- distribution: the levels achieved in tissues and in phagocytes are higher than those in the plasma
- Elimination: in urine as unchanged drug
- 1/2 life: 2-4d
Antimicrobial activity of azithromycin and clarithromycin
- Campylobacter
- Chlamydia
- Mycoplasma
- Mycobacterium avium complex (MAC)
- Toxoplasma
- Legionella
- G+ cocci,
- some G- organisms
G+ resistance mechanisms
- efflux pump
- production of a methylase –> adds a methyl to the ribosomal binding site
what is special about Azithromycin?
- effective in gonorrhea (alternative to ceftriaxone)
- effective in syphilis (alternative to penicillin G)
Macrolides clinical uses?
- M. pneumoniae
- Corynebacterium
- Campylobacter jejuni
- Chlamydia trachomatis
- Chlamydophila pneumoniae
- Legionella pneumophila
- Ureaplasma urealyticum
- Bordetella pertussis
- G+ cocci (except PRSP)
- beta-lactamase producing staphylo (except MRSA)
special clinical uses of Azithromycin?
[ H&M ;) ]
more active against:
- H influenzae
- Neisseria
- Moraxella catarrhalis
also:
urogenital infections caused by
C trachomatis (because of long 1/2 life, single dose is given)
also:
community-acquired pneumonia
(4-d course)
special clinical uses of Clarithromycin
- Prophylaxis treatment of MAC
- component of drug regimens for ulcers caused by H pylori.
Macrolides Toxicity in general
- G.I. irritation (motolin rec. Stim)
- skin rashes
- eosinophilia
Clarithromycin toxicity?
- clarithromycin: inhibits several cyt.P450 which can increase the plasma levels of other drugs (ex. anticoagulants, carbamazepine, digoxin, theophylline)
Azithromycin Toxicity?
- azithromycin: The lactone ring structure is slightly different from other macrolides –> drug interactions are uncommon (azithro does not inhibit hepatic cyt.P450)
about Telithromycin?
ketolide structurally related to macrolides
Telithromycin MOA and spectrum
similar to Macrolides but narrower spectrum
why we use Telithromycin?
- some macrolide-resistant strains are susceptible to Telithro
- because it binds more tightly to ribosomes and is a poor substrate for
bacterial efflux pumps
Telithromycin clinical uses?
- used in community-acquired pneumonia (including MDRs)
Telithromycin pharmacokinetix
eliminated in the bile and the urine
Telithromycin Toxicity?
- hepatic dysfunction
- QTc interval prolongation
- inhibitor of the CYP3A4 (drug-metabolizing system)
Clindamycin MOA
- inhibits bacterial protein synth.
- binds 50S ribosome
- block transpeptidation
Resistance to Clindamycin ?
- binding site methylation on 50S
- enzymatic inactivation
- Clinda has poor penetration through the outer membrane of G- Aerobes!
Clindamycin Pharmacokinetix
- distribution: Good tissue penetration after oral absorption
- metabolism: hepatic
- Elimination: biliary and renal excretion for both intact drug and metabolites
