INHIBITORS OF PROTEIN SYNTHESIS (50S)

MACROLIDES and KETOLIDES

I. Classification;
A. Macrolides
1. Erythromycin
1.1. Oral
1. Erythromycin base
2. Erythromycin stearate
3. Erythromycin estolate
4. Erythromycin ethylsuccinate

1.2. Parenteral
1. Erythromycin ethylsuccinate
2. Erythromycin lactobionate
3. Erythromycin gluceptate

2. Clarithromycin
3. Azithromycin
4. Roxithromycin

B. Ketolides
1. Telithromycin

II. ERYTHROMYCIN

A. Preparations:

B. Chemistry:
 consists of 2 sugar moieties attached to a 14 – atom lactone ring

C. Mechanism of Action
 Inhibition of RNA - dependent protein synthesis by binding to 50s
ribosomal subunits.

D. Pharmacokinetics
1. Absorption:
 active form - base
 rapid inactivation by acid – what modifications are done to prevent this?
 not intended for IM use – WHY?

2. Distribution:
 widely distributed with the exception of brain and CSF

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  concentration in middle ear exudate reaches only 50% of serum
concentration
3. Metabolism:
 demethylation in the liver

4. Excretion
 largely in feces
 urine - 2.5 % (oral);12-15 % (IV)
 half-life is 1.6 hrs.

E.Spectrum of Activity

Sensitive Organisms: Resistant Organisms:

Gm (+) except Staph. Aureus
Mycoplasma P. Gm (-) bacilli
Actinomyces
Treponema P.
Legionella P.
Rickettsia
Chlamydia

F. Clinical Uses
1. Conditions where Erythromycin is the drug of choice:

2.Conditions where Erythromycin is considered an alternative treatment:

G. Adverse Reactions
1. Hepatotoxicity
 cholestatic hepatitis
 hypersensitivity reaction to estolate ester
2. GI toxicity
 epigastric distress
 nausea, vomiting, diarrhea
3. Cardiac toxicity
 cardiac arrhythmias
4. Allergic reactions
 fever, skin reashes
5. Transient hearing loss

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H. Drug Interactions
1. Due to Inhibition of CYP3A4: Potentiates the effects of:
1.1. Theophylline 1.6. Ergot alkaloids
1.2. Carbamazepine 1.7. Triazolam
1.3. Corticosteroids 1.8. Valproate
1.4. Cyclosporine 1.9. Warfarin
1.5. Digoxin
2. Antagonism with:
2.1. Lincosamides
2.2. Chloramphenicol

III. CLARITHROMYCIN
A. Chemistry
 methyl group added to the hydroxyl group at the C-6 position
B. Pharmacokinetics
1. DISTRIBUTION
 concentraiton in the middle ear is higher
2. METABOLISM
 undergoes rapid first pass metabolism to an active metabolite,
14 – hydroxyclarithromycin
3. ELIMINATION
 half-life is 3 – 7 hours
 maybe given 2 times a day
C. Antibacterial activity
 more potent against Erythromycin sensitive strains of Streptococcus and
Staphylococcus
 modest activity against H. Influenzae and N. gonorrheac
 more active against Mycobacterium avium complex

III. AZITHROMYCIN
A. Chemistry
 methylsubstituted nitrogen atom added to the lactone ring
B. Pharmacokinetics
1. DISTRIBUTION
 extensive tissue distribution
 high drug concentration within cells exceeding serum conc.
2. ELIMINATION
 half life is 68 hours
 biliary route is major route of elimination
 may be given once a day
C. Antibacterial Activity
 less active than Erythromycin against gm (+) organisms
 more active than Erythromycin and Clarithromycin against
H. Influenzae and Campylobacter
 highly active against Chlamydia

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 LINCOSAMINES

I. Clindamycin:

1. Mechanism of Action:
 inhibits protein synthesis by binding to the 50S ribosomal subunit

2. Mode of Action: Bacteriostatic

1. Pharmacokinetics:
 rapidly and virtually absorbed from the GIT (90%)
 food does not affect absorption
 Palmitate preparation - prodrug (rapidly hydrolyzed to active form in
the blood)
 water soluble
 60% bound to plasma proteins
 high levels in all tissues and fluids EXCEPT in the CSF even if the
meniges are inflamed.
 metabolized mainly in the liver
 excreted in the urine with 10% unchanged

2. Antimicrobial Spectrum:
Sensitive to:
1. ANAEROBES – most important
2. Nonenterococcal Streptococci
3. Staphylococcus aureus
4. Corynebacterium diphtheriae
5. Bacillus anthracis

Resistant to:
1. All gram (-) bacilli
2. Mycoplasma pneumoniae

5. Mechanisms of Resistance:
5.1. Inability to penetrate cell envelope (esp. in Enterobacteriaceae)
5.2. alteration of ribosomal binding site

6. Clinical Uses:
6.1. Anaerobic infections - MOST IMPORTANT
6.2. Mixed (aerobic & gram-negative) infections
- synergistic with Aminoglycosides or Aztreonam
6.3. Alternative to Penicillin G for Actinomycosis
6.4. Questionable use in acne preparations

7. Adverse Reactions:
7.1. GI effects - most frequent
7.2. allergic reactions – RARE
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 CHLORAMPHENICOL

I. Mechanism of Action
 inhibits bacterial protein synthesis by reversibly binding to the 50S
ribosomal subunit

II. Pharmacokinetics
A. Absorption
 75-90 % from the GIT
 oral preparation-palmitate
 parenteral preparation -succinate
 serum level: IV = oral

B. Distribution
 45% protein bound
 achieves high concetntration in the brain and CSF, aqueous and
vitreous humor, synovial, pleural, ascitic fluid
 traverses placental barrier and is secreted in the breast milk

C. Metabolism / Elimination
 90 % by glucoronide conjugation
 2 % by deacetylation
 8% excreted in the urine

III. Spectrum of Activity

 cidal against H. influenza, N. meningitides and S. pneumonia
 active against V. chokera, some strains of slamonella and Shigella
 active against most anaerobic bacteria, including gram-positive cocci
and Clostridium spp., and gram-negative rods including B. fragilis
 also active against N. gonorrhoeae, Brucella spp., and Bordetella
pertussis, Mycoplasma, Chlamydia, and Rickettsia.

IV. Adverse Reactions

1. Hematologic
1.1. dose related – anemia, leucopenia, thrombocytopenia
1.2. idiosyncratic reaction – aplastic anemia, fatal pancytopenia
2. Hypersensitivity reactions
2.1. skin rashes
2.2. Jarisch-Herxheimer reactions with use of chloramphenicol for syphilis,
brucellosis, and typhoid fever
3. Gray Syndrome
4. GIT
4.1. Nausea and vomiting
4.2. unpleasant taste
4.3. diarrhea

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V. Clinical Uses where Chloramphenicol is the drug of choice (DOC)
1. Typhoid fever
2. CNS Infections: Meningitis ( H. Influenza ), Brain Abscess
3. Anaerobic Infections
4. Deep ocular Infections
5. Rickettsial diseases

V. Drug Interactions:
1. Inhibition of hepatic CYPs – Potentiates the effecst of:
1.1. warfarin
1.2. dicumarol
1.3. phenytoin
1.4. chlorpropamide, tolbutamide
1.5. antiretroviral protease inhibitors
1.6. rifabutin

2. Decrease Chloramphenicol effects with simulatanoeus administration of

Phenobarbital and Rifampicin

3. Antagonism with Macrolides and Lincosamides