Macrolides, Lincosamides and Vancomycin

1. Macrolides,Macrolides,
Lincosamide &Lincosamide &
GlycopeptideGlycopeptide
AntimicrobialsAntimicrobials
Dr. Sahil Kumar
Department of Pharmacology
Maulana Azad Medical College

2. INTRODUCTION
 Characterized by a macrocyclic lactone ring (usually
containing 14 or 16 atoms) to which deoxysugars
are attached.
 Prototype drug – Erythromycin.
Part APart A: Macrolides: Macrolides

3. 11.. AntimicrobialAntimicrobial spectrumspectrum ：：
 GG++
organismsorganisms
 GG--
cocci:cocci: Streptococcus pyogenes and pneumoniaeStreptococcus pyogenes and pneumoniae
 Mycoplasma pneumoniae and Legionnellapneumoniae and Legionnella etcetc.
2.2. Antimicrobial activity:Antimicrobial activity:
 Typically bacteriostatic activity.Typically bacteriostatic activity.
 Bactericidal at high concentrations against veryBactericidal at high concentrations against very
susceptible organismssusceptible organisms
 More active at alkaline pHMore active at alkaline pH
General properties ofGeneral properties of MacrolidesMacrolides

4. Mechanism of action:Mechanism of action:
macrolidemacrolidesubunitsubunit
• Inhibits protein synthesis by reversibly binding to
the 50s ribosomal subunit.
• Suppression of RNA dependent protein synthesis
by inhibition of translocation of mRNA.

5. Mechanism of resistance:Mechanism of resistance:
 Modification of the ribosomal binding siteModification of the ribosomal binding site
 Production ofProduction of esteraseesterase that hydrolyzethat hydrolyze
macrolides.macrolides.
 Reduced permeability of cell membrane orReduced permeability of cell membrane or
active effluxactive efflux system is involved.system is involved.
 Cross-resistance is complete betweenCross-resistance is complete between
erythromycin and the other macrolides.erythromycin and the other macrolides.

6. 1)1) AAbsorption:bsorption:
Stearate and ester of erythromycin areStearate and ester of erythromycin are
fairly acid-resistant and somewhat betterfairly acid-resistant and somewhat better
absorbed. Food interferes withabsorbed. Food interferes with
absorption.absorption.
Erythromycin base is destroyed byErythromycin base is destroyed by
stomach acid and must be given withstomach acid and must be given with
enteric coating.enteric coating.
PharmacokineticsPharmacokinetics

7. 2)2) DDistribution: does not cross BBB.istribution: does not cross BBB.
3)3) EElimination: it is concentrated in thelimination: it is concentrated in the
liver, where some is unactived, whileliver, where some is unactived, while
some is excreted in active form insome is excreted in active form in
the bile.the bile.
PharmacokineticsPharmacokinetics

8. Adverse response:Adverse response:
1)1) GI Effects: nausea, vomiting, abdominalGI Effects: nausea, vomiting, abdominal
crampscramps
2)2) Liver Toxicity: Cholestatic hepatitis.Liver Toxicity: Cholestatic hepatitis.
3)3) Cardiotoxic effectsCardiotoxic effects
4) Auditory impairment (Ototoxicity)4) Auditory impairment (Ototoxicity)
Hypersensitivity reactionsHypersensitivity reactions
SuperinfectionsSuperinfections
General properties ofGeneral properties of MacrolidesMacrolides

9. Drug interactionsDrug interactions
• Erythromycin metabolites canErythromycin metabolites can
inhibit cytochrome P450inhibit cytochrome P450
enzyme.enzyme.
General properties ofGeneral properties of MacrolidesMacrolides

10. • ErythromycinErythromycin
• AzithromycinAzithromycin
• ClarithromycinClarithromycin
• RoxithromycinRoxithromycin
• SpiramycinSpiramycin
• Ketolide: TelithromycinKetolide: Telithromycin
CLASSIFICATION

20. Therapeutic uses of Telithromycin
 Telithromycin is the first ketolide antibiotic to enter
clinical use.
 Used to treat community acquired pneumonia of mild
to moderate severity.
 After significant safety concerns, the US Food and Drug
Administration sharply curtailed the approved use of
the drug in early 2007.
 Liver failure, vision problems, blackouts, syncope, and
potentially fatal cases of myasthenia gravis.

21. • LincomycinLincomycin
• ClindamycinClindamycin
Part B:Part B: LincosamidesLincosamides

22. Antimicrobial propertiesAntimicrobial properties
• Resemble Erythromycin inResemble Erythromycin in
antibacterial spectrum, activity,antibacterial spectrum, activity,
mechanism and resistance.mechanism and resistance.
• Lincomycin is forerunner ofLincomycin is forerunner of
Clindamycin. Less potent; moreClindamycin. Less potent; more
diarrhea.diarrhea.
Lincomycin & ClindamycinLincomycin & Clindamycin

23. Mechanism of resistance:Mechanism of resistance:
 Modification of the ribosomal binding siteModification of the ribosomal binding site
 Antibiotic efflux isAntibiotic efflux is notnot an importantan important
mechanism of Clindamycin resistance.mechanism of Clindamycin resistance.
(unlike macrolides)(unlike macrolides)
 Cross-resistance is complete betweenCross-resistance is complete between
erythromycin and the other macrolides.erythromycin and the other macrolides.

24. Clinical UsesClinical Uses
• Severe anaerobic infectionSevere anaerobic infection
• Aerobic GAerobic G++
cocci infection (but not MRSA).cocci infection (but not MRSA).
• Combination with pyrimethamine for AIDS-Combination with pyrimethamine for AIDS-
related toxoplasmosis.related toxoplasmosis.
• Combination with primaquine for AIDS-relatedCombination with primaquine for AIDS-related
pneumocystis cariniipneumocystis carinii pneumonia.pneumonia.
Lincomycin & ClindamycinLincomycin & Clindamycin

25. Adverse response:Adverse response:
1) GI effects: Antibiotic-associated1) GI effects: Antibiotic-associated
colitiscolitis ((pseudomembranouspseudomembranous
colitis)colitis)..
2) Allergic reaction.2) Allergic reaction.
3) Impaired liver function.3) Impaired liver function.
Lincomycin & ClindamycinLincomycin & Clindamycin

26. Clindamycin, Erythromycin and
Chloramphenicol can exhibit mutual
antagonism, because their ribosomal
binding sites are proximal.

27. VancomycinVancomycin
TeicoplaninTeicoplanin
Part C: GlycopeptidesPart C: Glycopeptides

28. Antibacterial activityAntibacterial activity
Bactericidal for GBactericidal for G++
bacteria (especially Gbacteria (especially G++
cocci, including MRSA & MRSE)cocci, including MRSA & MRSE)
VancomycinVancomycin

29. • Antibacterial MechanismAntibacterial Mechanism
Inhibiting cell wall synthesis byInhibiting cell wall synthesis by
binding to thebinding to the DD-Ala--Ala-DD-Ala terminus-Ala terminus
of nascent peptidoglycan penta-of nascent peptidoglycan penta-
peptide.peptide.
• ResistanceResistance
Occurrs because of the alteration ofOccurrs because of the alteration of DD--
Ala-Ala-DD-Ala to the-Ala to the DD-Ala--Ala-DD-Ser.-Ser.
VancomycinVancomycin

30. Fig. Antibacterial MechanismFig. Antibacterial Mechanism of Vancomycinsof Vancomycins

31. • ADMEADME
• Oral administration (poorly absorbed).Oral administration (poorly absorbed).
• Intravenous administration, is excreted byIntravenous administration, is excreted by
glomerular filtration (accumulates when renalglomerular filtration (accumulates when renal
function is impaired).function is impaired).
• Widely distributed in the body, including CSFWidely distributed in the body, including CSF
when the meninges are inflamed.when the meninges are inflamed.
VancomycinVancomycin

32. Clinical UsesClinical Uses
1) Severe infection caused by MRSA1) Severe infection caused by MRSA etcetc..
2) Alternative for2) Alternative for ββ-lactam-lactam
3) Enterococcal or staphylococcal3) Enterococcal or staphylococcal
endocarditis (combination withendocarditis (combination with
gentamicin).gentamicin).
4)4) Pseudomembranous colitisPseudomembranous colitis
VancomycinVancomycin

33. Pseudomembranous
enterocolitis
Hurley and Ngueyn Arch Intern Med. 2002;162:2177-2184.
Pseudomembranous colitis.
Endoscopic en face view of colon wall
demonstrating several
pseudomembranes (arrows).

34. Focal ulceration can be seen at
the tips of the mucosa. The
exudate of fibrin and
inflammatory tissue.
Pseudomembranous enterocolitis
Normal

35. Adverse ReactionsAdverse Reactions
1) Hypersensitive reaction – it releases1) Hypersensitive reaction – it releases
histamine (e.g. red man syndrome)histamine (e.g. red man syndrome)
2) Ototoxicity2) Ototoxicity
3) Nephrotoxicity3) Nephrotoxicity
4) G4) Gl effects,l effects, etcetc..
VancomycinVancomycin

36. Teicoplanin
 Active against G+ bacteria only.
 MOA and spectrum similar to Vancomycin.
 More active than Vanco against
Enterococci and equally effective against
MRSA.
 Some VRE but not VRSA are susceptible to
Teicoplanin.
 Can be injected i.m. as well.
 Toxicity is less than Vancomycin.

37. Thanks!