MACROLIDES

Dr. Pratibha Omkar

Dept. of Pharmacology
Case scenario 1:
• On January 27, 2020, a 20 year old female presented
to emergency department in general hospital,
Thrissur, Kerala with one day history of dry cough
and sore throat.
• No history of fever, rhinitis and shortness of breath

• She revealed that she returned to Kerala from Wuhan

city, china on January 23, 2020.

• She was asymptomatic between 23rd to 26th

• No history of contact with anyone with respiratory
infections

• On examination: Normal

• Due to travel history oropharyngeal swab was

obtained and sent ICMR-National institute of
virology, Pune
 Case scenario 2

MJ is a 45-year-old female patient who has a history of

a purulent cough with a fever for 3 days. She
complained of chest pain and difficulty breathing, and
has no remarkable medical history. MJ made an
appointment to see her primary care physician, who
determined she had community-acquired
pneumonia.
• Antibiotics having a macrocyclic lactone ring with
attached sugars.
Includes -
• Natural – Erythromycin – 14 membered lactone ring
with 2 sugar moieties.
• Semi-synthetic - Roxithromycin - 14
Clarithromycin – 14
Azithromycin - 15
 Azithromycin
• Azalide congener of erythromycin

• Expanded spectrum, improved pharmacokinetics,

better tolerability and drug interaction profiles.

• More active than other macrolides against H.

influenzae, but less active against gram positive cocci.
• High activity on respiratory pathogens—
Mycoplasma, chlamydia pneumoniae, Legionella,
Moraxella and Campylobacter, Ch. trachomatis, N.
gonorrhoea.

• Not active against erythromycin resistant bacteria.

• Penicillinase producing Staph. aureus are inhibited

but not methicillin resistant ones.

• Good activity against MAC.

 Mechanism of Action

• Bacteriostatic at low but cidal at high concentrations.

• Sensitive gram positive bacteria, accumulate

intracellularly by active transport.

• Several fold more active in alkaline medium, because

the nonionized (penetrable) form of the drug is
favored at higher PH.
• Acts by inhibiting bacterial protein synthesis.

• It combines with 50S ribosome subunits and

interferes with 'translocation‘.
• After peptide bond formation between the newly
attached aminoacid and the nacent peptide chain at the
acceptor (A) site the
• elongated peptide is translocated back to the peptidyl
(P) site, making the A site available for next
aminoacyl tRNA attachment
• This is prevented by erythromycin and the ribosome
fails to move along the mRNA to expose the next
codon.
Peptide chain may be prematurely terminated: synthesis
of larger proteins is suppressed
 Pharmacokinetics

• Acid stable, rapid oral absorption

• Marked tissue distribution and intracellular
penetration.
• Concentration in most tissues exceeds that in plasma.
(except CSF)
• High concentrations in macrophages and fibroblasts
• Food interferes with absorption so give 1 hr before or
2 hrs after food
• Slow release from the intracellular sites contributes
to its long terminal t ½ of >50 hr.
• Does not inhibit cytochrome P-450 enzymes in liver
• It is largely excreted unchanged in bile, renal
excretion is < 10%.
• POSTANTIBIOTIC EFFECT

• higher efficacy, better gastric tolerance and

convenient once a day dosing, azithromycin is now
preferred over erythromycin
 Therapeutic use
• First choice drug for many infections such as:

• Legionnaire's pneumonia: 500 mg OD oral/

i.v. for 2 weeks.

• Chlamydia trachomatis: Nonspecific urethritis

and genital infections in both men and women —1 g
single dose is curative.
• Drug of choice: for chlamydial pneumonia and is
being preferred over tetracycline for trachoma in the
eye.

• Donovanosis – campylobacter granulomatis- 500mg

OD for 7 days per 1gm weekly for 4 weeks

• Chancroid and PPNG urethritis: single 1g dose is

highly effective
• Community acquired pneumonia : 500mg loading
dose - 250mg once daily for next 4 days

• Periapical abscess : 500mg for 3 days

 Other uses
• Pharyngitis , tonsillitis, sinusitis, otitis media,
pneumonias, acute exacerbations of chronic bronchitis,
streptococcal and some staphylococcaI skin and soft
tissue infections, and gonorrhoea.

• Prophylaxis and treatment of MAC in AIDS patients.

Dose : 500 mg once daily
 Side effects
• Mild gastric upset,
• Abdominal pain (less than erythromycin),
• headache
• Dizziness
 ERYTHROMYCIN
• Isolated from Streptomyces erythreus

• Used as alternative to penicillin

• Slightly water soluble; the solution remains stable

only when kept in cold.
 Antimicrobial spectrum

• It is narrow - mostly gram positive and few gram

negative organisms.

• Highly active against Str. Pyogenes and Str.

pneumoniae, N. gonorrhoeas, Clostridia,
C.diphtheriae, listeria.

• Most penicillin resistant Staphylococci and

Streptococci were initially sensitive, but have now
become resistant to erythromycin also.
• H.influenza, h.ducreyi, b. pertussis, chlamydia
trachomatis, str. Viridans, N. meningitidis, rickettsiae
are moderately sensitive.

• Enterobacteriaceae, other gram negative bacilli and

B. fragilis are not inhibited.
 Resistance
• Modification of receptor sites on 50 S ribosomes
through methylation- less binding of the drug

• Efflux systems are overactive

• Failure to permeate through bacterial cell membrane

 Pharmacokinetics
• Erythromycin base is acid labile.

• Given as enteric coated tablets to protect from gastric

acid , from which absorption is incomplete

• food delays absorption by retarding gastric emptying.

• Its acid stable esters are better absorbed.

• widely distributed in the body , enter cells and
abscess, crosses serous membranes and placenta but
not blood-brain barrier.

• It attains therapeutic concentration in prostate.

• It is 70-80% plasma protein bound, partly

metabolized
• excreted primarily in bile in the active form.
• Renal excretion is minor; dose need not be altered in
renal failure.

• Its plasma t ½ is 1.5 hr. but it persists longer in

tissues.
 Adverse effects

• GIT - Mild to severe epigastric pain specially children

on oral therapy, Diarrhoea is occasional.
•
Erythromycin stimulates motilin receptors in the
g.i.t.— induces gastric contractions, hastens
gastric emptying and promotes intestinal motility.
• Very high doses - reversible hearing impairment.

• Hypersensitivity rashes and fever are infrequent.

• Hepatitis with cholestatic jaundice -estolate easier
after 1-3 weeks.

• Incidence - pregnant women.

• It clears on discontinuation of the drug, and is

probably due to hypersensitivity to the estolate ester.
 Interaction

• Inhibits hepatic oxidation of many drugs.

• Rise in plasma levels -theophylline, carbamazepine,
valproate, ergotamine warfarin, terfenadine,
astemizole and cisapride.
• Q-T prolongation, serious ventricular arrhythmias and
death due to inhibition of CYP 3A4 by
erythromycin/clarithromycin resulting in high blood
levels of concurrently administered terfenadine,
astemizole, cisapride
 Uses
1. As an alternative to penicillin:
• (i) Streptococcal pharyngitis, tonsillitis, mastoiditis
and most respiratory infections caused by
pneumococci and Influenzas respond equally well to
erythromycin.
• alternative drug for prophylaxis of rheumatic fever
and SABI.
• many bacteria resistant to penicillin are also resistant
to erythromycin,
(ii) Diphtheria: acute stage and for carriers—7 day
treatment. Antitoxin is the primary treatment

(iii) Tetanus: as an adjuvant to antitoxin, toxoid therapy.

(iv) Syphilis and gonorrhoea: other alternative drugs

including tetracyclincs cannot be used: relapse rates
are high.
(v) Leptospirosis : 250mg 6th hourly for 7 days
 First choice drug

(i) Atypical pneumonia caused by Mycoplasma

pneumonias, rate of recovery is hastened

(ii) Whooping cough: 1-2 week course for eradicating

B. pertussis from upper respiratory tract.

(iii) Chancroid: erythromycin 2 g/day for 7 days - drugs

of choice, as effective as cotrimoxazole or ceftriaxone.
3. As a second choice drug in:

(i)Legionnaire's pneumonia: 3 week erythromycin

treatment is effective( azithromycin/ ciprofloxacin are
preferred)

(ii) Chlamydia trachomatis infection of urogenital tract:

erythromycin 500 mg 6 hourly for 7 days is an
effective alternative to single dose azithromycin.
NEWER MACROLIDES
Roxithromycin –

• long acting acid stable macrolide (t1/2 12 hrs). Food

does not interfere.

• antimicrobial spectrum resembles with that of

erythromycin.

• more potent against Branh. Catarrhalis, Gard.

vaginalis and legionella but less potent against B.
pertussis.
 pharmacokinetics
• Good enteral absorption and tissue penetration

• plasma t ½ - 12 hr - suitable for twice daily

dosing, better gastric tolerability.

• Affinity for cytochrome P450 is similar to

erythromycin
 Uses
• Respiratory ,ENT, skin and soft tissue and genital
tract infections with similar efficacy as erythromycin.

• Dose - 150-300 mg.

 Clarithromycin
• The antimicrobial spectrum resembles erythromycin.

• in addition -Mycobact. avium complex (MAC), other

atypical mycobacteria, Mycobacteria leprae and
some anaerobes
• It is more active against sensitive strains of gram
positive cocci, Moraxella, Legionella, Mycoplasma
pneumoniae and Helicobacter pylori.
 Kinetics
• It is rapidly absorbed.

• oral bioavailability is 50% due to first pass

metabolism;
• food delays absorption.

• slightly greater tissue distribution than erythromycin

• Metabolized by saturation kinetics—t ½ is
prolonged from 3-6 hours at lower doses, 6-9 hours at
higher doses.
• An active metabolite is produced.

• About 1 /3 of oral dose is excreted unchanged in

urine,
• but no dose modification in liver & kidney failure.
 Uses
• Upper and lower respiratory tract infections,
sinusitis, otitis media, atypical pneumonia, skin and
skin structure infections due to Strep. pyogenes and
some Staph. aureus.

• Component of triple drug regimen - H.pylori

clarithromycin 500mg+omeprazole 20mg+
amoxycillin 1g 14 days )
• first line drug in combination regimens for MAC
infection in AIDS patients

• second line drug for other atypical mycobacterial

diseases and leprosy. (clarithromycin + minocycline)
• Dose: 250 mg BD for 7 days; severe- cases 500 mg
BD upto 14 days.
 Side effects
• similar to erythromycin
• Gastric tolerance is better.
• Pseudomembranous enterocolitis, hepatic
dysfunction or rhabdomyolysis are reported.

• safety in pregnancy and lactation is not known.

A pregnant mother had been admitted at the 15th week
of her pregnancy on account of a febrile illness,
symptoms of common cold, and enlargement of
submandibular lymph nodes. Serological testing of the
mother’s serum revealed positive IgG and IgM anti-
Toxoplasma antibodies. Amniotic fluid was taken and
evaluated by polymerase chain reaction (PCR) assay
with a direct amplification of the Toxoplasma URPT
gene which was found to be positive.

Toxoplasmosis
 Spiramycin
• resembles erythromycin in spectrum of activity and
properties.
• it has been found to limit risk of transplacental
transmission of Toxoplasma gonadii infection.
• specific use- toxoplasmosis and recurrent abortion in
pregnant women.
• Other indications are similar to erythromycin.
• Dose : 6-9 MU by mouth daily in 3 divided doses for
5 days

• Toxoplasmosis : 2-3 MU three times a day for 3

weeks, to be repeated after a gap of 2 weeks till
parturition.
 Side effects
• Gastric irritation,
• Nausea ,
• Diarrhoea
• Rashes .
THANK YOU