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
