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.

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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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PharmacokineticsDistribution

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 InteractionsErythromycin 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 05/03/2023 RAHUL

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 toxicityUSES :•Atypical mycobacterial infections (MAC)•Resistant leprosy•Toxoplasmosis•H.Pylori induced peptic ulcers.05/03/2023 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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