Macrolides
Dr . Rahul KunkulolAsso. Prof .
Pharmacology
History • 1952 Erythromycin• 1970s Acetylspiramycin Medecamycin, Josamycin• 1980s Clarithromycin Roxithromycin Azithromycin
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Macrolides• Belong to the Polyketide class of natural products.• A group of antibiotics consisting of a macrolide ring• A large lactone ring to which one or more
deoxy sugars, are attached.• The lactone ring can be either 14, 15 or 16
membered.
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Erythromycin• Naturally-occurring macrolide
derived from Streptomyces erythreus
• Problems with erythromycin• Acid labile• Narrow spectrum• Poor GI tolerance • Short elimination half-life
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Structural derivativesClarithromycin and Azithromycin
• Broader spectrum of activity• Improved PK properties –
• Better bioavailability• Better tissue penetration• Prolonged half-lives
• Improved tolerability
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Mechanism of Action
• Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit • Suppression of RNA-dependent protein synthesis by inhibition of translocation of mRNA
•Typically bacteriostatic activity•Bactericidal at high concentrations against very susceptible organisms
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Macrolide Spectrum of Activity
Gram-Positive Aerobes : Erythromycin & clarithromycin display the
best activity (Clarithro>Erythro>Azithro)
• Methicillin-susceptible Staphylococcus aureus• Streptococcus pneumoniae (only PSSP) –
resistance is developing• Group and viridans streptococci• Bacillus sp.
• Corynebacterium sp. 04/11/2023 RAHUL
Macrolide Spectrum of Activity
Gram-Negative Aerobes – Newer macrolides with enhanced activity
(Azithro>Clarithro>Erythro)• H. influenzae (not erythro), • M. catarrhalis, • Neisseria sp.• Do NOT have activity against any
Enterobacteriaceae
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Macrolide Spectrum of Activity
Anaerobes – Upper airway anaerobesAtypical Bacteria – All have excellent activity • Legionella pneumophila - DOC• Chlamydia sp.• Mycoplasma sp.
• Ureaplasma
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Macrolide Spectrum of Activity
Other Bacteria –• Mycobacterium avium complex
(MAC – only A and C),
• Treponema pallidum, • Campylobacter• Borrelia, Bordetella• Brucella• Pasteurella
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Macrolide Spectrum of Activity
Activity Erythro Azithro Clarithro
H. infuenzae ++ +++ ++
Moraxella catarahalis
++ +++ ++
Mycoplasma ++ +++ ++
Legionella ++ +++ ++
Strepto/staph
+++ ++ +++
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PharmacokineticsAbsorptionErythromycin – variable absorption, food may decrease the absorption • Base: destroyed by gastric acid; enteric coated• Esters and ester salts: more acid stable
Clarithromycin – acid stable and well-absorbed regardless of presence of food
Azithromycin –acid stable; food decreases absorption of capsules
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Pharmacokinetics
Distribution Extensive tissue and cellular
distribution clarithromycin and
azithromycin with extensive penetration
Minimal CSF penetration
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PharmacokineticsElimination
Clarithromycin is the only macrolide partially eliminated by the kidney (18% of parent and all metabolites)
Hepatically eliminated: ALL NONE of the macrolides are removed during
hemodialysis !.... Variable elimination half-lives
1.4 hours for erythr3 to 7 hours for clarithro; 68 hours for azithro
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Adverse Effects• Gastrointestinal – up to 33 %
Nausea, vomiting, diarrhea, dyspepsiaGastic pain, crampsMost common with erythro; less with new agents
• Cholestatic hepatitis - rare > 1 to 2 weeks of erythromycin estolate
• Thrombophlebitis – IV Erythro and AzithroDilution of dose; slow administration
• Other: Ototoxicity (high dose erythro ); QTc prolongation; Allergy
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Drug Interactions
Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of:
Theophylline Digoxin, DisopyramideCarbamazepine Valproic acidCyclosporine Terfenadine, AstemizolePhenytoin CisaprideWarfarin Ergot alkaloids
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Therapeutic Use• ENT infections , Tonsillitis, URTI• Mycoplasma pneumonie infections• Legionnaires Disease• Chlamydial infections (any macrolides)• Diphtheria (erythromycin)• Pertussis (erythromycin)
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Therapeutic Use
• Strep/Staph Infections; alternatives in patients allergic to Penicillin
• Prophylaxis against endocarditis in dental procedures
• Campylobacter/ Helicobacter Infections :clarithro
• Tetanus: in patients allergic to Penicillin
• Mycobacterial Infections: Clathri / Azithro Ist choice
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Clinical Uses of Erythromycin
“Drug of Choice” for Mycoplasma pneumoniaeLegionella pneumophila Chlamydia pneumoniae, C. trachomatisBordetella pertussis (whooping cough)C. diphtheriae
Esters of erythromycin -sterate/estolate/ethylsuccinate are resistant to inactivation.
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New macrolides antibiotics
• Advantages :•Broader spectrum, higher activity•Orally effective•High blood concentration•Longer t 1/2
•Less toxicity•Mainly used in respiratory tract infection
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Azithromycin • Strongest activity against mycoplasma
pneumoniae.• Less effective against gram (+) bacteria
than erythro /clarithro.• More effective on Gram-negative bacteria,
H.influenzae, Legionella.• Excellent action against Toxoplasma gondii• Well tolerated• T1/2 :35~48h once daily• Mainly used in respitory tract infection
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Clinical Uses of Azithromycin
• Excellent tissue concentration : 10- to 100- fold higher conc. than serum•prolonged persistence of good conc. in cells•3- or 5-days therapy is possible (except for severe Legionella pneumonia)
• Pregnant women infected with Scrub typhus : Azithromycin can substitute for doxycycline
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Roxithromycin• 1987 France• Reaches highest blood concentration • Bioavailability upto 72%~85%• Respiratory tract infection and soft tissue infection• Low adverse effects
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Clarithromycin• Has the strongest activity on Gram-positive
bacteria, Legionella pneumophila, Chlamydia pneumoniae and H.pylori
• Good pharmacokinetic property• Low toxicity
USES :•Atypical mycobacterial infections (MAC)•Resistant leprosy•Toxoplasmosis•H.Pylori induced peptic ulcers.04/11/2023 RAHUL
Doses• Erythromycin: 1-2 g/ day divided into 4 doses
• Clarithromycin: 250-500 mg twice a day.
• Azithromycin: 250 mg/ day
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