Antibiotics

Macrolide

د. شذى هاني
Ph.D. candidate

-The macrolides are a group of antibiotics with a macro cyclic lactone ring (14-16 atoms) to which one or more deoxy sugars are attached.
-Erythromycin is the prototype of these drugs
-newer members of this family, Clarithromycin (a methylated form of erythromycin).
-Azithromycin (having a larger lactone ring), have some features in common with others

Telithromycin , This ketolide with structural modification neutralizes the most common resistance mechanisms (methylase mediated and efflux-mediated) that make macrolides ineffective

Mechanism of action

The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis. Generally considered to be bacteriostatic, they may be bactericidal at higher doses

Resistance: Several mechanisms have been identified:

1) the inability of the organism to take up the antibiotic or the presence of an efflux pump, both of which limit the amount of intracellular drug
2) a decreased affinity of the 50S ribosomal subunit for the antibiotic
i.e. modification of ribosomal binding site.
3) the presence of a plasmid-associated erythromycin esterase that hydrolyze macrolides.


Both clarithromycin and azithromycin show cross-resistance with erythromycin, but telithromycin can be effective against macrolide-resistant organisms.

Pharmacokinetics

Administration:
- erythromycin base is destroyed by gastric acid. Thus, either enteric-coated tablets or esterified forms (estolated) of the antibiotic are administered orally .
-All are adequately absorbed upon oral administration . Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and are readily absorbed.
.

-Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin.
Azithromycin is available for intravenous infusion, but intravenous administration of erythromycin is associated with a high incidence of thrombophlebitis

Distribution:

- Erythromycin distributes well to all body fluids except the CSF.
it has the unique characteristic of accumulating in macrophages.
- All four drugs concentrate in the liver.
-cross placenta and reaches the fetus.

Excretion: Erythromycin and azithromycin are primarily concentrated and excreted in an active form in the bile.
Partial reabsorption occurs through the enterohepatic circulation.
Inactive metabolites are excreted into the urine. In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver, and it is recommended that the dosage of this drug be adjusted in patients with compromised renal function.


Erythromycin:
Pharmacokinetic:
-Erythromycin base is destroyed by stomach acid and must be administered with enteric coating.
-Food interfere with absorption .
-Erythromycin is available as estolate ,stearate propionate and succinate salts.
-Absorption after oral administration is best with erythromycin estolate ,even if there is food in the stomach.

-Although erythromycin estolate is the best absorbed salt, it impose the greatest risk of adverse reaction.
Therefore , the stearate or succinate salt may be preferred.
-Widely distributes to all body fluids except brain and CSF cross placenta and reaches the fetus.
-Erythromycin is available in enteric –coated tablets, slow-release capsules, oral suspension, ophthalmic solution, ointments, gels and injections.
-iv. form of erythromycin lead to increase incidence of thrombophlebitis.

Antimicrobial activity of erythromycin :

1-Gr+ve cocci including pneumococci streptococci and staphylococci (Haemophilus influenza is less susceptible)
2-it is also active against :mycoplasma pneumonia, Chlamydia trachomatis and Legionella species , corynebactrium diphtheria, and helicobacter .
3-Gr –ve organisms such as Neisseria species, Bordetella pertussis ,some rickettsia species &campylobacter species.

Clinical Uses:

Erythromycin is the drug of choice for:
- Mycoplasma pneumoniae in children, although inadults a tetracycline may be preferred.`
- Legionella spp. with or without rifampicin
- Diphtheria (including carriers).
- Pertussis (whooping cough).
-some chlamydial infections.-


-In gastroenteritis caused by Campylobacter jejuni
erythromycin is effective in eliminating the organism
from the faces
-Erythromycin is an effective alternative choice for
penicillin-allergic patients infected with Staphylococcus
aureus, Streptococcus pyogenes, Streptococcus
pneumoniae
-1ry syphilis by Treponema pallidum.

Adverse effects

1)Epigastric distress: This side effect is common and can lead to poor patient compliance for erythromycin.
Clarithromycin and azithromycin seem to be better tolerated by the patient.
2)Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin, presumably as
the result of a hypersensitivity reaction to the estolate form .
3)Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages.

Contraindications:

-Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver.
note:Dose adjustment of clarithromycin in renal impairment is needed .

Interactions:
Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulations of these compounds.


Clarithromycin
1- acts like erythromycin and has a similar spectrum of antibacterial activity, i.e. mainly
against Gram-positive organisms, although it is
usefully more active against Haemophilus influenzae.

2- It is rapidly and completely

absorbed from the gastrointestinal tract, 60% of a
dose is inactivated by metabolism and the remainder is eliminated in the urine.

3- Clarithromycin is used for

respiratory tract infections including atypical pneumoniasand soft tissue infections.
4- It is concentrated intracellularly achieving concentrations which allow effective therapy in combination for mycobacterial
infections such as Mycobacterium
in patients with AIDS and with pyrimethamine
for some Toxoplasim infections

5- It causes fewer gastrointestinal tract adverse effects (7%) than erythromycin.

6- Interactions: as erythromycin.
7-cost:clarithromycin is more expensive .
8-given twice daily while erythromycin
Four times/ day because it have longer half life .


Azithromycin
1)Obtained by adding methylated nitrogen to lactone ring of erythromycin
2) is usefully active against a number
of important Gram-negative organisms including
Haemophilus influenzae and Neisseria gonorrhoeae, and also against Chlamydiae, but is a little less effective than erythromycin against Gram-positive organisms.

3) Azithromycin achieves high concentrations in

tissues relative to those in plasma. It remains
largely unmetabolised and is excreted in the bile
and faces (t1/2 , 50h) that’s allow once daily dosing & hence short course of treatment .
4) Azithromycin is used to treat
respiratory tract and soft tissue infections, and
sexually transmitted diseases, especially genital
Chlamydia infections.

5) Gastrointestinal effects (9%)

are less than with erythromycin but diarrhea,
nausea and abdominal pain might occur.
6)Interactions: not act as an enzyme inhibitors as erythromycin.