Antimicrobial

1. University of Kufa
College of Medicine
Department of pharmacology & therapeutics
Done by :-
Qassim A. Zigum

2. OUTLINE
 INTRODUCTION
 HISTORY
 VANCOMYCIN
◊◊ Mechanisms of Action
◊◊ Mechanisms of Resistance
◊◊ Antibacterial Activity
◊◊ Pharmacokinetics
◊◊ Clinical Uses
◊◊ Adverse Reactions
 OTHER GLYCOPEPTIDES 2

3. INTRODUCTION
 Glycopeptide are non-beta lactam cell wall
synthesis inhibitors antibiotics .
 are composed of glycosylated cyclic or
polycyclic nonribosomal peptides.
 include the :-
◊◊ anti – infective antibiotics ( vancomycin ,
teicoplanin, and telavancin)
◊◊ anti – tumor antibiotic ( bleomycin )
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4. HISTORY
 Vancomycin was isolated in 1953, and used
clinically from 1955. Approved in 1958 by FDA to
treat penicillin resistant staphylococci. MRSA first
seen in 1961.
 Bleomycin was first discovered in 1966.
 Teicoplanin was discovered in the early 1990s.
 Telavancin is a semi-
synthetic lipoglycopeptide derivative of vancomycin
(approved by FDA in 2009).
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5. VANCOMYCIN
 Vancomycin is an antibiotic produced by
Streptococcus orientalis and Amycolatopsis
orientalis.
 With the exception of Flavobacterium , it is active
only aginst gram-positive bacteria.
 Vancomycin is a glycopeptide of molecular weight
1500 dalton . It is water soluble and quite stable.
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6. MECHANISMS OF ACTION
 Vancomycin inhibits cell wall synthesis by binding
firmly to the D-Ala-D-Ala terminus of nascent
peptidoglycan pentapeptide .
 This inhibits the transglycosylase, preventing
further elongation of peptidoglycan and cross-
linking.
 The peptidoglycan is thus weakened, and the cell
becomes susceptible to lysis.
 The cell membrane is also damaged, which
contributes to the antibacterial effect.
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7. MECHANISMS OF ACTION
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8. BASES OF RESISTANCE
 Changing the D-Ala-D-Ala unite of the
peptidoglycane to D-Ala-D-Lactate which cannot be
bond to vancomycin.
 This results in the loss of a critical hydrogen bond
that facilitates high affinity binding of vancomycin to
its target and loss of activity.
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9. BASES OF RESISTANCE
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R
O
N
H
O
H CH3
O
O
O
H CH3
R
O
N
H
H
N
H CH3
O
O
H CH3
O
C-Terminus of D-Ala-D-Ala peptide
C-Terminus of D-Ala-D-Lactate peptide

10. ANTIBACTERIAL ACTIVITY
 Vancomycin is bactericidal for gram-positive bacteria in
concentrations of 0.5–10 mcg/mL.
 Most pathogenic staphylococci, including those
producing β lactamase and those resistant to nafcillin
and methicillin, are killed by 2 mcg/mL or less.
 Vancomycin kills staphylococci relatively slowly and
only if cells are actively dividing; the rate is less than
that of the penicillins both in vitro and in vivo.
 Vancomycin is synergistic in vitro with gentamicin and
streptomycin against Enterococcus faecium and
Enterococcus faecalis strains that do not exhibit high
levels of aminoglycoside resistance.
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11. ANTIBACTERIAL SPECTRUM
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12. PHARMACOKINETICS
 Vancomycin is poorly absorbed from the
intestinal tract and is administered orally only for
the treatment of antibiotic-associated colitis caused
by C. difficile .
 Parenteral doses must be administered
intravenously. A 1-hour intravenous infusion of 1 g
produces blood levels of 15–30 mcg/mL for 1–2
hours.
 The drug is widely distributed in the body.
Cerebrospinal fluid levels 7–30% of simultaneous
serum concentrations are achieved if there is
meningeal inflammation. 12

13. PHARMACOKINETICS
 Ninety percent of the drug is excreted by glomerular
filtration.
 The drug has a serum elimination half-life of about
6 hours.
 In the presence of renal insufficiency, striking
accumulation may occur .
 In functionally a nephric patients, the half-life of
vancomycin is 6–10 days.
 A significant amount (roughly 50%) of vancomycin
is removed during a standard hemodialysis run
when a modern, high-flux membrane is used.
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14. PHARMACOKINETICS
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15. CLINICAL USES
 Blood stream infections and endocarditis caused by
methicillin-resistant staphylococci MRSA.
 enterococcal endocarditis in a patient with serious
penicillin allergy( in combination with gentamicin) .
 meningitis suspected or known to be caused by a
penicillin-resistant strain of pneumococcus(in
combination with cefotaxime, ceftriaxone, or
rifampin)
 Oral vancomycin, 0.125–0.25 g every 6 hours, is
used to treat antibiotic
associated pseudomembranous colitis caused by
C. difficile .
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16. ADVERSE REACTIONS
 Adverse reactions are encountered in about 10% of
cases (Most reactions are minor).
 Vancomycin is irritating to tissue, resulting in
phlebitis at the site of injection.
 Chills and fever may occur.
 Ototoxicity is rare and nephrotoxicity uncommon
with current preparations.
 “red man” or “red neck” syndrome.
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18. OTOTOXICITY AND NEPHROTOXICITY
 Ototoxicity is rare and nephrotoxicity
uncommon with current preparations.
 However, administration with
another ototoxic or nephrotoxic drug,
such as an aminoglycoside, increases
the risk of these toxicities.
 Ototoxicity can be minimized by maintaining
peak serum concentrations below 60 mcg/mL.
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19. “RED MAN” OR “RED NECK” SYNDROME.
 This infusion-related flushing is
caused by release of histamine.
 It can be largely prevented by
prolonging the infusion period
to 1–2 hours or pretreatment
with an antihistamine such as
diphenhydramine.
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20. TEICOPLANIN
 Teicoplanin is a glycopeptide antibiotic that is very
similar to vancomycin in mechanism of action and
antibacterial spectrum.
 Unlike vancomycin, it can be given intra- muscularly
as well as intravenously.
 Teicoplanin has a long half-life (45–70 hours),
permitting once-daily dosing .
 This drug is available in Europe but has not been
approved for use in the United States.
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21. TELAVANCIN
 Telavancin is a semisynthetic lipoglycopeptide
derived from vancomycin.
 The half-life of telavancin is approximately 8 hours,
which supports once-daily intravenous dosing.
 Telavancin is approved for treatment of complicated
skin and soft tissue infections at a dose of 10 mg/kg
IV daily.
 Telavancin is potentially teratogenic, so
administration to pregnant women must be avoided.
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22. DALBAVANCIN
 Dalbavancin is a semisynthetic lipoglycopeptide
derived from teicoplanin.
 It is not active against most strains of vancomycin-
resistant enterococci.
 Dalbavancin has an extremely long half-life of 6–11
days, which allows for onceweekly intravenous
administration.
 Development of dalbavancin has been put on hold
pending additional clinical trials.
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23. DALBAVANCIN
TELAVANCIN
TEICOPLANIN
VANCOMYCIN
PARAME
TERS
IV
IV
IV,IM
IV,PO
Rout of
adm.
6-11days
8hr
45-70hr
6-8hr
Half life
Category C
Category C
Teratogenic
Category C
Category C
Pregnancy
lipoglycopeptide ,
derived from
teicoplanin
Lipoglycopepti
de ,derived
from
vancomycin
Glycopeptide
Glycopeptide
Nature
Approved by FDA
in May 2014
approved by
FDA in 2009
early 1990s
Approved in
1958
History
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