macrolide antibiotics with detailed description of classification and individual drug with mechanism of action, pharmacokinetics, adverse effect, uses for undergraduates and post graduates

1. MACROLIDE
ANTIBIOTICS
By: BIBI
UMEZA

2. The macrolides are a class of
natural products
consist of
large macrocyclic lactone ring to
which one or more deoxy sugars,
usually cladinose and desosamine,
will be attached.
The lactone rings are usually
14-, 15-, or 16-membered.

4. Macrolides- General Consideration
Contain macrocyclic
lactone ring attached
to deoxy sugars.
These antibiotics are
bacteriostatic in
nature & act by
inhibiting protein
synthesis of bacteria.
obtained mainly from
certain actinomycetes
genus, such as-
Streptomyces.
Example-
Erythromycin,
clarithromycin,
azithromycin,
telithromycin 3

5. Macrolides are a
class of antibiotics
derived from
Saccharopolyspora
erythraea
(originally called
Streptomyces
erythreus),
soil-borne
bacteria.
Macrolides inhibit protein
synthesis in bacteria by
reversibly binding to
the P site of the 50S
unit of the ribosome.

6. Chemistry of
Macrolides
A macrocyclic lactone
ring containing 14
or 16 carbons
ketone group (O=) &
hydroxyl group (-OH).
2 deoxy sugars
attached by
glycosidic bond
with lactone ring.

8. view of the 50S ribosomal
subunit from D. Radiodurans
showing
erythromycin (red)
bound to the entrance of
the tunnel.
Blue, 23S rRNA
and 5S rRNA.
Gold, ribosomal
proteins.

10. ERYTHROMYCIN
Isolated from Streptomyces
erythreus in 1952.

11. Pharmacokinetics
 Route of Administration:
 Oral & parenteral.
 Absorption: Erythromycin is
poorly absorbed from GIT due to acid
sensitivity. Clarithromycin &
azithromycin are well absorbed from
GIT.
 Distribution: Rapidly distributed
into systemic circulation. They can
cross placenta but can’t cross BBB.
 Metabolism: Via liver.
 Excretion: Through bile mainly, but
clarithromycin is excreted through
urine

12. Erythromycin
Most common market
brand of erythromycin
are-
A-mycin
Eromycin
Etrocin
Macrocin etc.
 1st macrolide obtained
from streptomyces
erytherus in 1952.
 Active against G(+)
bacteria.
 Plasma half life: 2hrs.
 Dose: adult(250-500mg 6-
hourly).
 Unstable in stomac acid.
 Formulataed as enteric
coated tablet.

13. MECHANISM OF ACTION
Gram-positive bacteria accumulate
erythromycin intracellularly by
active transport which is
responsible for their high
susceptibility to this antibiotic.
Erythromycin is bacteriostatic at low but
cidal (for certain bacteria) at high
concentrations.

14. Macrolides are protein synthesis inhibitors.
• by preventing
peptidyltransferase
from adding the
growing peptide
attached to tRNA to
the next amino acid
• as well as inhibiting
ribosomal translation.
Another potential
mechanism is premature
dissociation of the peptidyl-
tRNA from the ribosome.

16. ANTIMICROBIAL SPECTRUM
It is narrow, mostly gram-positive and a few
gram-negative bacteria,
•highly active against Str.pyogenes and
•Str.pneumoniae,
• N.gonorrhoeae,
•Clostridia,
•C.diphtheriae,
•Listeria.campylobacter,
•legionella,
• Branhamella catarrhalis,

17. Macrolides ( cont. )
Antibacterial spectrum
Erythromycin – Mainly effective on G+ bacteria
A. Gram- positive bacteria
Staph. Aureus
S. pneumoniae
URTIs ( eg. Otitis media, pharyngitis )
LRTIs ( eg. Pneumoniae )
S. pyogens
C. diphtheria
B. Gram- negative bacteria
T. pallidum
C. Intracellular organisms
L. pneumophila
M. pneumoniae
C. trachomatis

18. Bacterial infections.
respiratory tract infections
chlamydia infections,
pelvic inflammatory disease,
Erythromycin - Uses

19. syphilis
electron micrograph of
Treponema pallidum
during pregnancy to prevent Group B
streptococcal infection in the newborn
An eye ointment is routinely
recommended after delivery to
prevent eye infections in the
newborn

20. ADVERSE EFFECTS
1. Gastrointestinal especially children, on oral therapy.
2. Hypersensitivity.
Hepatitis with cholestatic jaundice resembling viral
hepatitis or extrahepatic biliary obstruction occurs
with the estolate ester
Incidence is higher in pregnant women.
 rare with stearate ester
It clears on discontinuation is due to hypersensitivity.

21. Hepatitis with cholestatic jaundice

22. NVD
arrhythmia with prolonged QT intervals, including torsades de pointes, and
reversible deafness. Allergic reactions range from urticaria to anaphylaxis.
Cholestasis, Stevens–Johnson syndrome, and toxic epidermal necrolysis are
some other rare side effects that may occur.

23. toxic epidermal necrolysis

24. RESISTANCE
Less permeable to erythromycin or acquire the capacity to pump it out.
Produce an erythromycin esterase.
Alteration in the ribosomal binding site for erythromycin by plasmid
encoded methylase enzyme is an important mechanism in gram-
positive bacteria.

25. RESISTANCE All the types of resistance are
• plasmid mediated,
• change in the 50S ribosome has also been found.
• Resistance to erythromycin
• are resistant to other macrolides as well cross resistance with
clindamycin and chloramphenicol also occurs.

26. Plasmid mediated resistance

27. The mechanism of macrolide antibiotic
resistance in S. antibioticus

28. INTERACTION
Erythromycin inhibits hepatic oxidation of
many drugs.
Rise in plasma levels of
•theophylline,
•carbamazepine,
•valproate,
•ergotamine and
•warfarin.

29. Q-T prolongation

30. Indications for erythromycin
1. Alternative to penicillin in allergic pts (
Staph.Aureus, S. pyogens, S.pneumoniae or
T.pallidum )
2. Diphtheria & whooping cough – drug of choice
3. Legionnaires disease- drug of choice
4. Pneumoniae ( M. pneumoniae ) – children
5. Chlamydia trachomatis

32. Chlamydia trachomatisDiphtheria

33. Atypical pneumonia
child with whooping cough paroxysms
(coughing with the characteristic
‘whoop’)

34. NEWER MACROLIDES
Limitations of erythromycin narrow
spectrum, gastric intolerance,
gastric acid lability,
low oral bioavailability,
poor tissue penetration and short half-life,
a number of semisynthetic macrolides have
been produced.

35. Erythromycin related compounds
Azithromycin Carbomycin Cethromycin
Clarithromycin Dirithromycin Mitemcinal
Oleandomycin Roxithromycin Spiramycin
Telithromycin Tylosin

36. CLARITHROMYCIN
Spectrum of similar to erythromycin, in addition, it
includes Mycobact avium complex (MAC), atypical
mycobacteria, Mycobact.leprae.

37. Clarithromycin
 Clarithromycin is derived
from erythromycin by
addition of methyl group.
Active against both
G(+)
& G(-) bacteria.
It is more active against
Mycobacterium avium
complex (MAC).
It is stable in stomac
acid.
Plasma Half-life: 6 hrs
Dose: 250-500mg twice
daily for 7 days.
Most common
market brands of
Clarithromycin-
 Binoclar
 Clarin
 Claricin etc.
8

38. Clarithromycin
Pharmacokinetics
Acid stable
Food delays absorption but does’nt alter its extent
Metabolized by the liver to 14- hydroxy clarithro. ( active )
Widely distributed, except brain and CSF
Protein binding 40 – 70 %
Excreted in Urine – unchanged 20 – 40 %
14- H. clarithromycin 10 – 15 %
Biliary Half- life clarithromycin 3 – 7 hr
14 – H. clarithromycin 5- 9 hr
Advantage over erythromycin
Lower frequency of GI intolerance
Less frequent dosing ( twice daily )

39. Clarithromycin
Antibacterial spectrum
A. Gram- positive bacteria
Staph. Aureus
S. Pneumoniae
S. Pyogens
B. Gram- negative bacteria
H. influenzae
H. Pylori
M. catarrhalis
C. Intracellular organisms
M. pneumoniae
L. Pneumophila
Indications
Pharyngitis / tonsilitis
Otitis, sinusitis
Adjunct in treatment of duodenal ulcer ( H. pylori )

40. Adverse Effect of Macrolides
In case of therapeutic dose:
 Gastrointestinal discomfort
 Anorexia
 Nausea
 Vomiting
 Diarrhea
 Mild allergic reaction.
In case of toxic dose:
 Reversible hearing loss
 Liver toxicity
 Jaundice
Main adverse effects
 Ventriculararrhythmia.

41. Mycobact avium complex (MAC),atypical mycobacteria

42. •More active against sensitive strains
of
• gram-positive cocci,
•Moraxella,
• Mycoplasma pneumoniae and
Helicobacter pylori.

43. gram-positive cocci

44. CLARITHROMYCIN
Triple drug regimen eradicates
H.pylori.
First line drug in combination regimens for MAC
infection in AIDS.
Gastric tolerance is better.
High doses can cause reversible hearing loss.

45. Triple drug regimen
eradicates H.pylori

46. AZITHROMYCIN
• Congener of erythromycin expanded spectrum, improved
pharmacokinetics, better tolerability and drug interaction
profiles.
• More active against H.influenzae.
• High activity is Mycoplasma,
• Chlamydia pneumoniae,
• Legionella, Morexella,
• Campylobacter,
• Ch.trachomatis H.
• ducreyi, Calymm,
• granulomatis,
• N. gonorrhoeae.

47. This includes middle ear infections,
strep throat,
pneumonia,
traveler's diarrhea, and certain other intestinal
infections.
It can also be used for a number of sexually
transmitted infections,
It can be taken by mouth or intravenously with doses
once per day.

48. Azithromycin
Pharmacokinetics
Rapidly absorbed from GIT
Food delays absorption
Widely distributed
( extensive tissue distribution ),
except CSF
Protein binding 51%

49. Undergo some hepatic metabolism ( inactive )
Biliary route is the major route of elimination
Only 6% is excreted unchanged in the urine
Half- life approx. 3 days
Advantage over erythromycin &
clarithromycin
Once daily dosing
No inhibition of cytochrome P- 450

51. Good activity against MAC. Acid-stability,
rapid oral absorption,
marked tissue distribution and intracellular
penetration.
Concentration in most tissues exceeds that in
plasma.

52. Azithromycin
Mainly effective on G- bacteria but less active against
G+(s.pneumoniae & s.pyogenes) than erythromycin
Antibacterial spectrum
A. Gram- positive bacteria
Staph. Aureus
S. Pneumoniae
S. Pyogens
B. Gram- negative bacteria (> erythromycin)
M. catarrhalis
H. influenzae
C. Intracellular organisms (> erythromycin)
L. Pneumophila
M. pneumoniae
Chlamydia species

53. Indications
•Pharyngitis/ tonsilitis ( s. pyogens ), otitis,
• sinusitis ( Staph. Aureus & H. influenzae )
•Uncomplicated genital chlamydial infections

54. First choice drug for infections such as:
a. Legionnaires’ pneumonia.
b. Chlamydia trachomatis.
c. Donovanosis caused by
Calymmatobacterium granulomatis.
d. Chancroid and PPNG urethritis.

55. Legionnaires’ pneumonia

56. Symptoms of
Legionellosis

57. SPIRAMYCIN It is used to treat Toxoplasmosis.
•The antibacterial
spectrum comprises
Gram
•positive cocci and rods,
• Gram-negative cocci
and
•also Legionellae,
• mycoplasmas,
• chlamydiae,
•Toxoplasma gondii
Cryptosporidium sp,
•Enterobacteria,
•pseudomonads and
pathogenic
•moulds are resistant. Its
action is mainly
•bacteriostatic, on highly
sensitive strains it exerts a
•bactericide action.

58. Toxoplasmosis