Antibiotic Macrolides and lincosamides history,classification,mechanism of action and adverse effect

1. Macrolides and Lincosamides
AMIR SOHAIL

2. Macrolides
• History
• Chemistry
• Classification
• Mechanism of Action
• Antibacterial Spectrum
• Bacterial Resistance
• Pharmacokinetics
• Adverse Effects

3. Introduction
O
O O
O
CH3
HO
H3C
CH3
CH3
O
H3C
H3C
O
HO
CH3
N CH3
H3C
Picromycin
 The term Macrolide was originally given to antibiotics
produced by species of Streptomyces.
 In 1950 the first drug of this class was
isolated:Picromycin
 In 1952 Erythromycin and Carbomycin were introduced
into clinic.

4. General Structure
O
O
O
CH3
R1
H3C
CH3
CH3
O
H3C
OH
H3C
CH3
OH
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OR2
1 3
5
9
12
1`
1``
Erythromycin
Glycon
Aglycone
They all contain three characteristics parts in the molecule:
 A highly substituted macrocyclic lactone: aglycone.
 A ketone group.
 An amino deoxy sugar: glycon, and in some of the
macrolides, a neutral deoxy sugar which are glycosisically
attached to the aglycone ring.

5.  The lactone ring usually has 12, 14, or 16 atoms
and is often unsaturated having olefinic bonds
conjugated with the ketone group.
 Macrolides are water-insoluble molecules.
 Macrolides are stable in aqueous solutions at or
below room temperature. They are unstable in
acidic or basic conditions or at high temperatures.

6. Chemical Instability of Macrolide
Antibiotics
O
O
CH3
CH3
O
H3C
CH3
O
O
CH3
1 3
12 6
89
O
H3C
HO
H3C
Anhydroerythromycin
6,9;9,12-spiroketal
O OH
CH3
CH3
OR2
1``
O
HO
CH3
N
CH3
CH3
1`
• Macrolides are unstable under acidic conditions
and undergo an intramolecular reaction to form an
inactive cyclic ketal.

7. Chemical Instability..
 The cyclic ketal is the cause of intestinal
cramp which is reported after the use of
erythromycin.
 Water-insoluble salts and enteric coated
dosage forms of macrolides have less such a
side effect.
 Water insoluble forms cannot take part in the
reactions which occur in aqueous solutions.
 Stearate salt is an example of insoluble salts
of erythromycin.

8. Classification
Macrolides
• Erythromycin
• Clarithromycin
• Azithromycin
• Dirithromycin
• Telithromycin
• Troleandomycin
• Oleandomycin
• Tylosin

9. Lincosamides
Lincomycin
Clindamycin
Lincosamides are a group of
monoglycoside antibiotics containing an
amino acid like side chain.They resemble
macrolide antibiotics in several aspects
and are often considered with macrolides.
Limited use in human and veterinary
therapeutics because of their adverse

10. Mechanism of Action
• Macrolides attach to the 50s portion of
bacterial ribosomes and inhibit the protein
synthesis.
• Prevent translocation during elongation of
protein synthesis
• Their binding site is either identical or in
close proximity to that for clindamycin and
chloramphenicol.
• Macrolides are bacteriostatic.

11. Mechanism of action of erythromycin and clindamycin.

12. Spectrum of Antibacterial Activity
 Macrolides are similar to penicillins regarding their
spectrum of activity.
 They are effective against penicillin-resistant
strains.
 Macrolides are effective against most of the G(+)
bacteria, cocci or bacillus, they have antibiotic
activity against G(-) cocci ,especially Neisseria
Spp too.
 Macrolide antibiotics are effective against
Mycoplasma, Clamidia, Campylobacter and
Legionella in contrast to penicillins.
 They are less effective against G(-) bacteria,
though some strains of H. influenza and Brucella
are sensitive to the antibacterial activity of this
class of antibiotics.

13. Typical therapeutic applications of macrolides.

14. Bacterial Resistance
• Methylation of a guanine residue on
ribosomal RNA leads to lower affinity toward
macrolides
• An active efflux system
• Presence of a plasmid-associated
erythromycin esterase.
• Clarithromycin and azithromycin show cross-
resistance with erythromycin, but
telithromycin can be effective
against macrolide-resistant organisms.
• Lack of cell wall permeability to macrolides is
the reason why G(-) bacteria are resistant to

15. Pharmacokinetics
• Absorption: Enteric coated preprations
protect the antibiotic from gastric acid
destruction allowing oral absorption
• Fate: Widely distributed to all tissues
except CNS.
• Excretion: Metabolized by liver and
excreted by bile .
• Tylosin and telmicosin excreted
unchanged in bile and urine.

16. Administration and fate of the macrolide antibiotics.

17. Some properties of the macrolide antibiotics.

18. Inhibition of the cytochrome P450 system by erythromycin,
clarithromycin, and telithromycin.

19. Pharmacokinetics
• Erthromycin
• Enteric coated tablets
• Enterohepatic cycling
• Ethromycin estolate
• Enternal toxicity mainly
• Enzyme inhibitors

20. Adverse Effects
• Epigastric distress: Common with erythromycin
• Cholestatic jaundice: Especially with the estolate form of
erythromycin
• Ototoxicity: Transient deafness associated with
erythromycin, at high dosages.
• Contraindications: Patients with hepatic dysfunction.
• Interactions: Inhibit the hepatic metabolism of a number
of drugs

21. Some adverse effects of macrolide antibiotics.

22. Clinical Application
of Erythromycin
It is used to treat
 The upper part of the respiratory tract infections,
 Soft tissue G(+) infections,
 Mycoplasma pneumonia caused pneumonia,
Campylobacter jejuni enteritis,
 Clamidia infections.
 Gonorrhoea.
It is a good choice for penicillin-sensitive cases.

23. Clarithromycin
O
O
O
CH3
HO
H3C
CH3
CH3
O
H3C
OH
H3C
O
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OH
1 3
5
9
12
1`
1``
Clarithromycin
H3C
CH3
6
 6-Methyl ether of erythromycin.
 Cannot undergo cyclic ketal formation, so doesn’t cause cramp in
GI.
 Higher blood concentrations.
 Lower doses with less intervals.

24. Azithromycin
O
O
CH3
HO
H3C
CH3
O
H3C
OH
CH3
OH
O
O
HO
CH3
N
CH3
CH3
O OH
CH3
CH3
OCH3
1 3
5
12
1`
1``
N
CH3
H3C
H3C
Azithromycin
 Azalide, a semisynthetic macrolide with a15 membered ring.
 Stable under acidic conditions, because it doesn’t form cyclic
ketal.
 In the treatment of urogenital infections caused by N.
gonorrhoeae and Chlamidia trachomatis.
 Longer half-life.

25. Troleandomycin
Oleandomycin
O
O
O
CH3
H3C
CH3
O
H3C
OH
H3C
H3C
O
O
RO
CH3
N
CH3
CH3
O OR
CH3
1 3
5
9
12
1`
1``
Oleandomycin, R=H
Troleandomycin R=COCH3
6
O
O
CH3
• Oleandomycin is isolated from Streptomyces antibuticus.
Troleandomycin is a prodrug of the macrolide antibacterial
oleandomycin
• Bacteriostatic effects the same as erythromycin.
• Oleandomycin is also used as feed additive for growth
promoting effect in food animals.

26. Clindamycin
• Mechanism same as that of erythromycin
• Clindamycin is a semisynthetic derivative of lincomycin
• Good for anaerobic organisms (Bacteroids)
• Resistance like erythromycin
• Well absorbed by the oral route.
• It distributes well into all body fluids except the CSF.
• Penetration into bone occurs even in the absence of
inflammation.
• The drug is excreted into the bile or urine .
• In addition to skin rashes, serious adverse effect is fatal
pseudomembranous colitis caused by C. difficile, which
is treated by metronidazole or vancomycin .

27. Administration and fate of clindamycin.