This document discusses macrolide antibiotics, including erythromycin, clarithromycin, azithromycin, and telithromycin. It describes their mechanisms of action as protein synthesis inhibitors that bind reversibly to the 50S ribosomal subunit. It outlines their spectra of activity against various gram-positive and -negative bacteria as well as atypical pathogens. It also covers their pharmacokinetics, clinical uses, adverse effects, drug interactions, and mechanisms of resistance.

1. 1
Antibiotics-
Protein Synthesis Inhibitors:
Macrolides
Pharmacology L3
PHCL-L3-AntiMicro
Oct 2011

2. Learning Objectives
 Referring to the therapy of atypical pneumonia, single dose
management of Sexually Transmissible Infections and ,
► choose a drug (generic name) that could be recommended for
► As applicable,
• Cite a commercial name of the drug
• List various dosage forms as available
• Provide essential pharmacokinetic elements of the drug
• Describe the mechanism of action of the drug
• List the adverse effects of the drug
• List drug interaction facts of the drug
• List the contra-indications of the drug
• Describe a potential mechanism of resistance
2

3. 3
Ribosomal Targets

4. 4
Macrolides
• Erythromycin is a naturally-occurring macrolide derived
from Streptomyces erythreus
• Specific agents:
• Erythromycin
• Clarithromycin
• Azithromycin
• spiramycine
• Others (roxithromycine, josamycine, Troleandomycin)
• Ketolides (Telithromycin)
• Short comings of erythromycine:
• problems with acid lability, narrow spectrum, poor GI intolerance, short
elimination half-life
• Structural derivatives of erythromycine include
clarithromycin and azithromycin:
► Broader spectrum of activity
► Improved PK properties – better bioavailability, better tissue
penetration, prolonged half-lives
► Improved tolerability

5. Macrolide Structure
• binding irreversibly to a 50S subunit of the bacterial ribosome
- inhibition of the translocation step of protein synthesis -
bacteriostatic
ERYTHROMYCIN CLARITHROMYCIN AZITHROMYCIN

6. 6

7. 7
Macrolides versus Ketolides
O
O
OCH3
O
O Sugar
O
R
O
N
O
Ketolides
Cladinose
O
O
OR
O Sugar
O
HO
HO
3
6
11
12
3
6
11
12
Macrolides
C11-C12 Carbamate:
 potency, overcomes macrolide
resistance
Methoxy group:
 acid stability
Keto Group:
 acid stability, overcomes
macrolide resistance

8. 8
Ketolides
Ketolides are derived from
erythromycin by substituting the
cladinose sugar with a keto-group and
attaching a cyclic carbamate group in
the lactone ring.
These modifications give ketolides
much broader spectrum than other
macrolides.
• Telithromycin (the only available ketolide)

9. 9
Macrolides and Ketolides
Mechanism of Action
► Inhibits protein synthesis by
reversibly binding to the 50S
ribosomal subunit
• Suppression of RNA-dependent
protein synthesis
• Telithromycin (Ketek®) binds to 2
domains on 50S ribosome (10
times stronger binding to domain
II – may account for greater
spectrum of activity)
► Macrolides and ketolides
typically display bacteriostatic
activity, but may be bactericidal
when present at high
concentrations against very
susceptible organisms
► Time-dependent activity

10. 10
Macrolides and Ketolides
Mechanisms of Resistance
► Altered target sites– encoded by the erm gene
which alters the macrolide binding site on the
ribosome; confers high level resistance to all
macrolides, clindamycin and Synercid, but
telithromycin retains activity
► Active efflux– mef gene encodes for an efflux
pump which pumps the macrolide out of the
cell away from the ribosome;
► Cross-resistance occurs between all
macrolides

11. 11
Macrolide and Ketolide
Spectrum of Activity
Gram-Positive Aerobes
(Telithro>Clarithro>Erythro>Azithro)
• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae
• Group and viridans streptococci
• Bacillus sp., Corynebacterium sp.

12. 12
Macrolide and Ketolide
Spectrum of Activity
Gram-Negative Aerobes – newer
macrolides with enhanced activity,
ketolides with poor activity
(Azithro>Clarithro>Erythro> Telithro)
• H. influenzae (not erythro or telithro), M.
catarrhalis, Neisseria sp.
• Do NOT have activity against any
Enterobacteriaceae

13. 13
Macrolide and Ketolide
Spectrum of Activity
Anaerobes – activity against upper airway
anaerobes
Atypical Bacteria – all macrolides have
excellent activity against atypical bacteria
including:
• Legionella pneumophila – DOC (dissolved organic carbon)
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma urealyticum
Other Bacteria – Mycobacterium avium
complex (MAC – only A and C), Treponema
pallidum, Campylobacter, Borrelia,
Bordetella, Brucella. Pasteurella

14. 14
Macrolides
Pharmacokinetics
Absorption
► Erythromycin – variable absorption (F = 15-45%);
food may decrease the absorption
• Base: destroyed by gastric acid; enteric coated tablets
• Esters and ester salts: more acid stable
► Clarithromycin – acid stable and well-absorbed (F =
55%) regardless of presence of food
► Azithromycin –acid stable; F = 38%; food decreases
absorption of capsules
► Telithromycin – only available PO; F = 57%

15. 15
Macrolides and Ketolides
Pharmacokinetics
Distribution
► Extensive tissue and cellular distribution – clarithromycin
and azithromycin with extensive tissue penetration
► Minimal CSF penetration
Elimination
► Clarithromycin is the only macrolide partially
eliminated by the kidney (18% of parent and all
metabolites); requires dose adjustment when CrCl < 30
ml/min
► Hepatically eliminated: ALL
► NONE of the macrolides are removed during
hemodialysis!
► Variable elimination half-lives (1.4 hours for erythro; 3 to
7 hours for clarithro; 68 hours for azithro, 10 hours for
telithro)

16. 16
Macrolides and Ketolides
Clinical Uses
 Respiratory Tract Infections
► Pharyngitis/ Tonsillitis – pen-allergic patients
(telithro not approved)
► Sinusitis, (azithro best if H. influenzae suspected),
Otitis Media
► Community-acquired pneumonia - atypical
 Uncomplicated Skin & Soft Tissue
Infections – Streptococcus C, E, A
 STDs – Single 1 gram dose of azithro
 MAC – Azithro for proph; Clarithro for RX

17. 17
Macrolides
Adverse Effects
• Gastrointestinal – up to 33 %
► Nausea, vomiting, diarrhea, dyspepsia
► Most common with erythro; less with new agents
• Cholestatic hepatitis - rare
► > 1 to 2 weeks of erythromycin estolate
• Thrombophlebitis – IV Erythro and Azithro
► Dilution of dose; slow administration
• Other: ototoxicity (high dose erythro); QTc
prolongation; allergy

18. 18
Ketolides
Adverse Effects
• Gastrointestinal
► Nausea (7%), vomiting (3%), diarrhea (10%)
• Central Nervous System
► Dizziness (3%), headache (2%)
• Hepatotoxicity – severe liver injury;
• Ocular – blurred vision, decreased
accommodation
• QTc prolongation

19. 19
Macrolides and Ketolides
Drug Interactions
Erythromycin, Clarithromycin and
Telithromycin – are inhibitors of cytochrome
p450 system in the liver; may increase
concentrations of:
Theophylline Digoxin, Disopyramide
Carbamazepine Valproic acid
Cyclosporine Terfenadine, Astemizole
Phenytoin Cisapride
Warfarin Ergot alkaloids
Tacrolimus
(NOT AZITHROMYCIN)

20. Summary
20

21. Macrolide antibiotic
• ERY
– as PNC G - especially G + bacteria and spirochaetes, N.gonorrhoae
– used in patients allergic to the PNCs
– intracellular - Chlamydia, Mycoplasma,Legionella, Corynebacterium diphterie
– Antistaphylococcal antibiotic – not MRSA
• Clarithromycin:
– similar to erythromycin, but it is also effective against Haemophilus influenzae.
– higher activity than ERY against intracellular pathogens (e.g., Chlamydia,
Legionella, Moraxella, Urea plasma species) and Helicobacter pylori
• Azithromycin:
– Less active against streptococci and staphylococci than erythromycin;
– more active against respiratory infections due to H. influenzae and Moraxella
catarrhalis.
– The preferred therapy for urethritis caused by Chlamydia trachomatis.
• Telithromycin:
– spectrum similar to azithromycin, less vulnerable to resistance