Macrolides

Macrolides are one of the most commonly used families of antibiotics, used to treat a wide variety of bacterial infections.

Source

Erythromycin is the first member obtained from strain of streptomyces erythrus.

Others are semisynthetic derivatives of erythromycin.

• Erythromycin (prototype)
• Clarithromycin
• Azithromycin
• Diirithromycin
• Roxithromycin
• Spiramycin –drug of choice in pregnant ladies against toxoplasmosis
• Carbomycin
• Oleandomycin
• Telithromycin.

Chemistry:

• Erythromycin contains a 14-member macrocyclic lactone ring to which are attached two sugar moieties, desosamine and cladinose at position 6.

• Clarithromycin differs from erythromycin by the methylation of a hydroxyl group at the 6- position of the lactone ring
• Erythromycin is destroyed in GIT by gastric acids, so has to be given 6 times a day.
• Clarithromycin is a 14- member macrolide with acid stability and improved antimicrobial and pharmacokientic properties.
• Primary metabolite is the 14- hydroxy epimere that possesses antimicrobial activity
• Azithromycin is an azalide, contains a 15- member lactone ring.
• Modification in structure results in better gastrointestinal tolerability and tissue penetration, decreased risk of interaction with other drugs and increased half life. Only once daily dose is required.
• Half life of erythromycin is one and a half hour, while elimination half life of charithromycin is 5 to 6 hours.

Mechanism of action

• Macrolides inhibit RNA dependent protein synthesis.
• Reversibly bind to the 50S ribosomal subunit of susceptible microorganisms
• They induce dissociation of peptidyl transfer RNA (t RNA) from the ribosome during elongation phase.
• RNA dependent protein synthesis is suppressed bacterial growth is inhibited.
• Macrolides are mainly bacteriostatic but can be bactericidal in high concentrations against very susceptible organisms. Aerobic gram positive organisms are more susceptible.
• Clindamycin and chloramphenicol also bind site near the level of peptidyl transfer RNA.

Spectrum of Activity

Mainly gram positive aerobic cocci and bacilli.

• Gram Positive
  Streptococci
  Staphylococci
  Pneumococci
  Corynebacterium diphtheriae

• Gram Negative
  Gonococci (N-Gonorrhoea)
  Pasteurella multocida
  Bordetella pertussis
• Other organisms
  Mycoplasma
  Chlamydia
  Legionella
  Campylobacter Jejuni (some resistant now in children)
  Helicobacter Pylori

• Atypical Mycobacteria
  M. Kansasii
  M. Avium intracellulare

Acquired Resistance to Macrolides May Occur

Common injudicious use alternative to penicillins in sensitive individuals. If patient is resistant especially streptococcus pneumoniae (60%) to penicillin, he is also resistant to erythromycin. Strong cross resistance occurs among members. There are different ways in which resistance can occur:

1. Chromosomal mutuations altering 50S ribosomal proteins.
2. Efflux of drug by an active pump mechanism
3. May induce/produce methylase enzyme that modifies the ribosomal target leading to decreased drug binding
4. Hydrolysis of macrolides by esterases produce by enterobacteriaceae

Preparations of Erythromycin

Oral

• Esters of Stearate, Estolate, Ethylsuccinate
• Estolate is only used in severe type and not in mild type of upper and lower respiratory tract infections as cholestatic hepatitis may be caused.
• Absorption of estolate is best having good bioavailability.

Parentral

• Lactobionate, Gluceptate –I/V
• Not given I/M as severe pain occurs at site of injection.
• Given I/V for legionellas, otitis media, life threatening cases.

Pharmacokinetics

• Erythromycin is incompletely absorbed
• Inactivated by gastric acid
• So administered as Enteric coated tablets.
• Erythromycin estolate is better absorbed
• Clarithromycin absorbed rapidly from GIT
• Bioavailability 50% due to rapid first pass metabolism
• Eliminated by renal & non renal mechanism so clarithromycin is safer in hepatic patients as chances of accumulation are less.
• Azithromycin absorbed rapidly and distributed through out the body except CSF
• Different from all other members as extensive tissue distribution high drug concentration within cells, due to accumulation in cells even phagocytic cells and fibroblasts.
• Biliary excretion is the major route of elimination
• Half life is 6-8 hours due to tissue binding and time dependent killing, elimination  half life is 40 to 68 hrs, due to tissue sequestration and binding, so single dose is given. It is present within cells and released continuously.
• Doxycylcline is used for community acquired pneumonia.
• Azithromycin action is time dependent.

Indications and Uses of Macrolides

Erythromycin:

1. Upper respiratory tract infection caused by streptococcus pyogenes or streptococcus pneumonia.
2. Lower respiratory tract infection caused by streptococcus pyogenes or streptoccus pneumonia.
3. Listeriosis caused by listeria monocytogenes.
4. Respiratory tract infections due to mycoplasma pneumoniae.
5. Skin and skin structure infections streptococcus pyogenes or staphylococcus aureus (resistance may develop with drug treatment)
6. Pertusis caused by bordetella pertussis. Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals, rendering them noninfectious.
7. Diphtheria infections due to corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers. Erythromycin is drug of choice.
8. Erythrasma. In the treatment of infections due to corynebacterium minutissimum
9. Intestinal amebiasis caused by entamoeba histolytica
10. Acute pelvic inflammatory disease caused by nesseria gonorrhoeae.
11. Infections caused by chlamydia trachomatis: conjunctivitis of the newborn pneumonia of infancy, and urogenital infections during pregnancy (clarithromycin, azithromycin, erythromycin)
12. The treatment of uncomplicated  urethral, endocervical, or rectal infections in adults due to chlamydia trachomatis.
13. Nongonococcal urethritis caused by ureaplasma urealyticum
14. Primary syphillis caused by treponema pallidium
15. Legionnaires’ disease caused by legionella pneumophila.

In mild cases Erythromycin is given. If recurrence occurs, we go for clarithromycin as is expensive.

Clarithromycin

1. Pharyngitis/tonsillitis due to streptococcus pyogenes
2. Acute maxillary sinusitis due to haemophilus influenzae, moraxella catarrhalis, or streptococcus pneumoniae
3.  Acute bacterial exacerbation of chronic bronchitis due to haemophilus influenzae, haemophilus parainfluenzae, moraxella, catarrhalis, or streptococcus pneumoniae (has more gram negative spectrum)
4. Community acquired pneumonia due to haemophilus influenzae, mycoplasma pneumoniae, streptococcus pneumoniae, or chlamydia pneumoniae .
5. Uncomplicated skin and skin structure infections due to staphylococcus aureus, or streptococcus pyogenes
6. Disseminated mycobacterial infections due to mycobacterium avium, or mycobacterium intracellulare in immunocompromised patients suffering from AIDS.
7. Acute otitis media  due to haemophillus influenzae, moraxella catarrhalis or streptococcus pneumoniae.

Azithromycin

1. Acute bacterial exacerbations of chronic obstructive pulmonary disease due to haemophlus influenzae, moraxella catarrhalis or streptococcus pneumoniae.
2. Toxoplasmosis gondii (Clarithromycin may be used as well)
3. Community acquired pneumonia of mild severity due to streptococcus pneumoniae or haemophilus influenzae
4. Streptococcal pharyngitis/tonsillitis due to streptococcus pyogenes
5. Uncomplicated skin and skin structure infections due to staphylococcus aureus, streptococcus pyogenes, or streptococcus agalactiae
6. Non gonoccal urethritis and cervicitis due to chlamydia trachomatis
7. Disseminated mycobacterium avium complex disease.

Adverse Reactions and Side Effects

1. GIT
a. Nausea,

b. Vomiting,

c. Abdominal discomfort,

d. Diarrhea and anorexia,

e. Pseudomembranous colitis,

f. Symptoms may occur during or after antibacterial treatment,

g. Hepatic dysfunction and or with abnormal liver function tests,

h. Cholestatic hepatitis

Food interferes with these agents, while with Clarithromycin it is less.

2. CVS
Erythromycin has been associated with (after I/V or with underlying cardiac problems):
a. QT prolongation and,
b. Ventricular arrhythmias
c. Torsades do pointes.
3. Allergic reactions
a. Allergic reactions with rash and eosinophilia can occur

b. Rarely fever and eosinophilia.

4. ENT
a. Transient auditory impairment
b. Astinnitus or deafness with I/V administration of large doses of erythromycin gluceptate or lactobionate or oral ingestion of large doses.

Drug Interactions

All macrolides except Azithromycin (due to difference in structure) inhibit cytochrome p450, decreasing the metabolism of drugs like

1. Warfarin
2. Theophylline
3. Steroids
4. Cyclosporine

Leading to toxicity

Erythromycin increases the bioavailability of digoxin.

Phenytoin and other inducers increase the metabolism of macrolides leading to therapeutic failure.

	Erythromycin	Clarithromycin	Azithromycin
Source	Natural	Semi-synthetic	Semi-synthetic
Structure	14 member lactone ring	14 member ring	15 member ring
Synthesis	Prototype	By adding CH3 to erythromycin	By adding methylated N2 to erythromycin
Acid stability	Acid labile (admin as enteric coated tablets)	Acid stable	Acid stable
Plasma levels	500 mg produces 10 mcg/ml	500 mg produces 2-3 mcg/ml	500 mg produces 0-4 mcg/ml
Half life	1.5 hours	6 hours	Tissue: 2-4 days Elimination: 3 days
Dose frequency	3-4 times daily	BD	OD
Drug interactions	Enzyme inhibitor	Enzyme inhibitor	Not significant
Prokinetic	Yes	No	No
Antibacterial spectrum
Cost		Most	Least

Ketoloides e.g. Telithromycin

Effects similar to erythromycin but different in structure.

In lactone ring, at C-3 the Cladinose sugar is replaced by keto group.

This leads to:

1. increased resistance to resistance mechanisms in bacteria
2. absorption of ketoloides is not affected by food
3. binds more strongly with 50S ribosomal subunit.
4. increased resistance as poor substrates of efflux pumps due to structural modifications.

Uses

Respiratory tract infections including:

1. Community acquired pneumonia
2. Sinusitis
3. Streptococcal pharyngitis
4. Acute exacerbation of chronic bronchitis

Adverse effects

1. QT prolongation
2. Hepatitis and liver failure