1. Protein Synthesis Inhibitors
Dr. Naza M. Ali Lec-9

2. These drugs selectively inhibit bacterial protein synthesis.
The selectivity is due to the differences between bacterial and human ribosomal proteins, RNA, and associated enzymes.
Bacteria have 70S ribosomes with 50S and 30S subunits
Mammalian cells have 80S ribosomes with 60S and 40S subunits.

3. Classification of some antibacterial agents by their sites of action

4. Macrolides
The macrolides are a group of antibiotics with a Large cyclic lactone structure to which one or more deoxy sugars are attached.

6. Macrolides
-Erythromycin 125mg , 250mg, 500mg -Clarithromycin 500mg -Azithromycin 200mg, 250 mg, 500mg -Roxithromycin 150mg, 500mg -Spiramycin 1,500,000 IU 3,000,000 IU

7. Mechanism of action
Macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, inhibiting the translocation steps of protein synthesis.
Also interfere with transpeptidation steps.
Bacteriostatic, or bactericidal higher doses

9. Antibacterial spectrum
Erythromycin:
-is effective against many of the same organisms
as penicillin G
-it is used in patients who are allergic to the
penicillins (syphilis)
- It is used in Corynebacterium Diphtheriae

10. Clarithromycin: -Same of erythromycin, active H.influenzae
-Its has higher activity than that of erythromycin
against
Chlamydia,
Legionella,
Moraxella,
H. pylori

11. Azithromycin: -less active against strepto & staphyl than erythromycin
-more active against respiratory infections due to
H.influenzae , Moraxella catarrhalis.
-preferred therapy for urethritis due to Chlamydia
trachomatis (single dose).
-Community acquired pneumonia (4 day course )

13. Resistance 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.
3) The presence of a plasmid-associated erythromycin
esterase.

14. Pharmacokinetic: Absorption
The erythromycin base is destroyed by gastric acid
So, either enteric-coated tablets
or esterified forms of the antibiotic are administered.
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 & azithromycin, but can increase that of clarithromycin.

15. Distribution:
Erythromycin distributes well to all body fluids except CSF.
It is one of the few antibiotics that diffuses into prostatic fluid, and it also accumulates in macrophages.
Clarithromycin, azithromycin are widely distributed in the tissues.
Azithromycin concentrates in neutrophils, macrophages, and fibroblasts.

16. Azithromycin concentration in phagocyte
lysosomes can be 40 times higher than in blood and
they can enhanced intracellular killing of bacteria by
phagocytes
Inflammation allows for greater tissue penetration.
It has the longest half-life and the higher volume of distribution

17. Pharmacokinetics

18. Elimination:
Erythromycin and telithromycin are extensively metabolized hepatically.
They inhibit the oxidation of a number of drugs through their interaction with the CYP450 system.

19. Excretion:
Erythromycin and azithromycin are primarily concentrated and excreted in the bile as active drugs.
Partial reabsorption occurs through the enterohepatic circulation.
Clarithromycin and its metabolites are eliminated by the kidney as well as the liver.
The dosage of this drug should be adjusted in patients with renal impairment.

20. Excretion

21. Adverse effects 1. GIT irritation
2. Cholestatic jaundice: ( erythromycin estolate form)
3. Ototoxicity: transient deafness at high dosage

22. Contraindication:
Patients with hepatic dysfunction should be treated
with caution, because these drugs accumulate in the
liver.
Interactions:
-Erythromycin, telithromycin, clarithromycin inhibit
hepatic metabolism of a number of drugs, lead to
toxic accumulations of these compounds.

24. Telithromycin Clinical use:
-Is a ketolide structurally related to macrolides.
-same mechanism of action as erythromycin & a
similar spectrum of antimicrobial activity.
-some macrolide–resistant strains are susceptible
to telithromycin.
Clinical use:
Community acquired pneumonia,
other upper respiratory tract infections.
Telithromycin is given orally once daily.

25. Fidaxomicin
Is a macrocyclic antibiotic with a structure similar to the macrolides;
Mechansim of action
it has a unique mechanism of action.
-acts on the sigma subunit of RNA polymerase,
-thereby disrupting bacterial transcription,
- terminating protein synthesis,
-and resulting in cell death in susceptible organisms.

26. Fidaxomicin has a very narrow spectrum of activity limited to gram-positive aerobes and anaerobes.
it possesses activity against staphylococci and enterococci
It is used primarily against Clostridium difficile.
Following oral administration, has minimal systemic absorption and primarily remains within GIT .
This is ideal for the treatment of C. difficile infection, which occurs in the gut.

27. This characteristic also likely contributes to the low rate of adverse effects.
Hypersensitivity reactions may occur.
Fidaxomicin should be used with caution in patients with a macrolide allergy, as they may be at increased risk for hypersensitivity.