University of Kufa College of Medicine Department of pharmacology & therapeutics

Done by :- Qassim A. Zigum

GLYCOPEPTIDE ANTIBIOTICS

2

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

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 )

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).

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.

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.

7

MECHANISMS OF ACTION

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.

9

BASES OF RESISTANCE

R

O

NH

O

H CH3

O

O

O

H CH3

R

O

NH

HN

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.

11

ANTIBACTERIAL SPECTRUM

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.

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.

14

PHARMACOKINETICS

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 .

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.

17

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.

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.

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.

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.

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.

23

DALBAVANCIN TELAVANCIN TEICOPLANIN VANCOMYCIN PARAMETERS

IV IV IV,IM IV,PO Rout of adm.

6-11days 8hr 45-70hr 6-8hr Half life

Category C Category CTeratogenic

Category C Category C Pregnancy

lipoglycopeptide , derived from teicoplanin

Lipoglycopeptide ,derived from vancomycin

Glycopeptide Glycopeptide Nature

Approved by FDA in May 2014

approved by FDA in 2009

early 1990s Approved in 1958

History

24