SYEDA MEMOONA GILLANI

Macrolides
 The macrolides are a family of safe, bacteriostatic
drugs that are generally used in the treatment of
community acquired infections.
 Erythromycin is the original agent and continues to

be used in different ailments.

Mechanism of Resistance
 Resistance has limited the use of this class of drugs
recently.
 Bacteria may be macrolide resistant due to a

permeability barrier (enterobacteriaceae).

 Active efflux pumps can expel the drug in Gram

positive species.
 A single step mutation in the 50 rRNA gene can confer

high level macrolide resistance in some species.

 Finally modification of the 50S rRNA subunit

decreases binding of erythromycin.

Indications for erythromycin
 Bacterial infections of the lungs (chest or lower respiratory
tract), eg bronchitis, bronchiectasis, pneumonia.
 Whooping cough. Erythromycin may also be prescribed to
prevent this infection in people who haven't been vaccinated
against whooping cough and who are in close contact with
someone who has it.
 Bacterial infection of the nasal passages, sinuses or throat
(upper respiratory tract infection), eg sinusitis, pharyngitis,
laryngitis, tonsillitis.
 Bacterial infection of the middle ear (otitis media) or outer ear
canal (otitis externa).
 Bacterial mouth infections, eg gum disease gingivitis.
 Bacterial infection of the eyelids (blepharitis).
 Bacterial infections of the skin or soft tissue, eg boils,
abscesses, cellulitis, impetigo, erysipelas.
 Bacterial infections of the stomach and intestines, eg
Campylobacter enteritis.
 Inflammation of the urethra due to bacterial infection
(urethritis).
 Inflammation of the prostate gland due to bacterial infection
(prostatitis).
 Chlamydia
 Syphilis ,Diphtheria, Scarlet fever
 Lyme disease
 Acne
 Usual Adult Dose of Erythromycin
 Mild to moderate infection: 250 to 500 mg (base,

estolate, stearate) or 400 to 800 mg (ethylsuccinate)

orally every 6 hours.

Severe infection: 1 to 4 g/day IV in divided doses

every 6 hours or by continuous infusion.
 Usual Pediatric Dose
 Neonatal 50 mg/kg/day orally in divided doses every

6 hours for at least 2 weeks.

Clarithromycin indication
 Tonsillitis/Pharyngitis
 Sinusitis
 Bronchitis
 Pneumonia
 Mycoplasma Pneumonia
 Skin and Structure Infection
 Helicobacter pylori Infection
 Mycobacterium avium-intracellulare - Prophylaxis
 Mycobacterium avium-intracellulare - Treatment
 Bacterial Endocarditis Prophylaxis
 Legionella Pneumonia
 Pertussis Prophylaxis
 Pertussis
Usual Adult Dose
 Immediate-release: 500 mg orally every 12 hours for 14 days
Extended-release: 1000 mg orally every 24 hours for 14 days
 for Helicobacter pylori Infection
 -In combination with omeprazole and amoxicillin:
Clarithromycin 500 mg orally every 12 hours for 10 days
 Usual Pediatric Dose
 Immediate-release:
6 months or older: 7.5 mg/kg orally every 12 hours for 10
days
Maximum dose: 500 mg/dose
Azithromycin indications
 Gonococcal Infection – Uncomplicated
 Nongonococcal Urethritis
 Chlamydia Infection
 Cervicitis
 Chancroid
 Pelvic Inflammatory Disease
 Chronic Obstructive Pulmonary Disease Acute
 Bronchitis
Usual Adult Dose
 -Immediate-release: 500 mg orally as a single dose on
day 1, followed by 250 mg orally once a day on days 2
to 5
-Extended-release: 2 g orally once as a single dose
Parenteral: 500 mg IV once a day as a single dose for at
least 2 days, followed by 500 mg (immediate-release
formulation) orally to complete a 7- to 10-day course
of therapy
 Gonococcal urethritis and cervicitis: 2 g orally as a

single dose
Usual Pediatric Dose
 6 months and older:
Immediate-release: 10 mg/kg (maximum: 500
mg/dose) orally on day 1, followed by 5 mg/kg (250
mg/dose) orally once a day on days 2 to 5
16 years and older:
Parenteral: 500 mg IV once a day as a single dose for at
least 2 days, followed by 500 mg (immediate-release
formulation) orally to complete a 7- to 10-day course
of therapy
Pharmacokinetics
 Absorption incomplete but adequate from
intestine
 Inactivated by gastric HCL, hence given as :
Enteric coated tablets or ester (stearate, ethyl succinate )
 Food delays absorption
 Not metabolized and actively secreted in bile ( major
route of excretion )
 Only 2-5 % is excreted in active form in urine
 Widely distributed into most tissues, except the brain
and CSF
 Cross the placental barrier
 Protein binding – 70- 80 %
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 %
 Advantage over erythromycin
 Lower frequency of GI intolerance
 Less frequent dosing ( twice daily )
Azithromycin
Pharmacokinetics
 Rapidly absorbed from GIT
 Food delays absorption
 Widely distributed ( extensive tissue distribution ),
except CSF
 Protein binding 51%
 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
Adverse Effects
 Erythromycin is significantly more likely to evoke
gastrointestinal side effects, largely through
stimulation of motility.
 Co-administration with food may reduce GI upset.
 High intravenous doses of erythromycin or
clarithromycin have been associated with hearing
loss and QT prolongation.
 Allergic reactions, headache, taste disturbance,

eosinophilia and hepatotoxicity are an infrequent

occurrence with all the macrolides.
Drug interactions
 Erythromycin and clarithromycin are strong
inhibitors of cytochrome P450 3A4 and may result
in elevated concentrations of many drugs.
Macrolides may be classified into 3 different groups in
causing drug interactions.
 The first group (e.g. troleandomycin, erythromycins)

are those prone to forming nitrosoalkanes and the

consequent formation of inactive cytochrome P450-
metabolite complexes.
 The second group (e.g. josamycin, flurithromycin,

roxithromycin, clarithromycin, miocamycin and

midecamycin) form complexes to a lesser extent and
rarely produce drug interactions.
 The last group (e.g. spiramycin, rokitamycin,
dirithromycin and azithromycin) do not inactivate
cytochrome P450 and are unable to modify the
pharmacokinetics of other compounds.
 It appears that 2 structural factors are important for a
macrolide antibiotic to lead to the induction of
cytochrome P450 and the formation in vivo or in
vitro of an inhibitory cytochrome P450-iron-
nitrosoalkane metabolite complex:
◦ the presence in the macrolide molecules of a non-
hindered readily accessible N-dimethylamino group
and
◦ the hydrophobic character of the drug.
 Erythromycin with;
 Clopidogrel: may reduce the metabolic activation of the prodrug
clopidogrel and its antiplatelet effects.(inhibition of CYP450 3A4
enzymatic activity, which is responsible for the conversion of clopidogrel
to its active metabolite.)
 Coadministration leads to increase the plasma concentrations of digoxin.

The proposed mechanism is inhibition of the P-glycoprotein-mediated

intestinal efflux and/or renal tubular secretion of digoxin.
 Coadministration increase the serum concentrations of theophylline,

which may result in toxicity. The proposed mechanism is macrolide

inhibition of CYP450 3A4, the isoenzyme partially responsible for the
metabolic clearance of theophylline.
 Coadministration significantly increase the plasma concentrations of

ergot derivatives. The mechanism is macrolide inhibition of CYP450 3A4,

the isoenzyme responsible for the metabolic clearance of ergotamine and
related drugs.
 Food may variably affect the bioavailability of
different oral formulations and salt forms of
erythromycin. The individual product package
labeling should be consulted regarding the
appropriate time of administration in relation to food
ingestion. Grapefruit juice may increase the plasma
concentrations of orally administered erythromycin.
The proposed mechanism is inhibition of CYP450
3A4-mediated first-pass metabolism in the gut wall
by certain compounds present in grapefruits.
Clarithromycin;

 Budesonide and clarithromycin; increase the absorption of

budesonide into the blood stream. (swelling, weight gain,
high blood pressure, high blood glucose, muscle weakness )
 Ciprofloxacin together with clarithromycin can increase the

risk of an irregular heart rhythm that may be serious and

potentially life-threatening.
 Clarithromycin may increase the blood levels of alprazolam.

This can increase the risk and/or severity of side effects

including excessive drowsiness, motor impairment,
amnesia, anxiety, hallucinations, and breathing difficulties
Azithromycin…..
 Atorvastatin: possible increased risk of myopathy
when azithromycin given with atorvastatin (serious
condition called rhabdomyolysis that involves the
breakdown of skeletal muscle tissue)
 Coumarins, azithromycin possibly enhances

anticoagulant effect of coumarins

 Colchicine, azithromycin possibly increases risk of

colchicine toxicity—suspend or reduce dose of

colchicine (avoid concomitant use in hepatic or renal)
 Antacid, absorption of azithromycin reduced by

antacids.