Orientation• All antibiotics inhibit the bacteria through three

main targets: Cell wall. Bacterial DNA. Bacterial ribosome.

1

2

• They affect the Bacterial ribosome.

Streptogramins

Introduction • What are streptogramins?

• Classification.

• Mechanism of action.

• When to use them?

• What problems patient may face ?

• Precautions should be taken in mind .

3

What are streptogramins?

• The streptogramin antibiotics :

Natural cyclic peptide antibiotics produced by certain sub-species of Streptomyces.

Structurally related to macrolides and lincosamides.

Strepogramins abstract Date of access 27/3/2012  http://dx.doi.org/10.2174/1389450023347678 4

 

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What are streptogramins?

(cont.)• The streptogramin antibiotics :

Discovered over 40 years ago.

The agent received accelerated approval by the FDA in late 1999[1]!!

[1]Koda-Kimble, Mary Anne; Young, Lloyd Yee; Alldredge, Brian K.; Corelli, Robin L.; Guglielmo, B. Joseph; Kradjan, Wayne A.; Williams, Bradley R.; Applied Therapeutics: The Clinical Use Of Drugs, Lippincott Williams & Wilkins.; Philadelphia; 9th Edition,2009 ; P.59p20.

Streptograminsclasses

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Cyclic peptides include two structurally unrelated

components

Group A

DalfopristinInhibit the early phase of protein

synthesis

Group B

Quinupristin Inhibits the late phase of protein

synthesis

Antibiotic classes date of access: 3/30/2012 http://www.bmb.leeds.ac.uk/mbiology/ug/ugteach/icu8/antibiotics/protein.html

Mechanism of action

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• The individual components are bacteriostatic.

• Their combination synergistically is bactericidal combination.

• Quinupristin/dalfopristin are available in combination of 3:7 ratio respectively[1] .

• Combination is concentration dependent mechanism with a long post-antibiotic effect.

[1]Sean C Sweetman; Martindale, The complete drug reference; Pharmaceutical Press; London , ,Chicago; Thirty-sixth edition; 2009; vol. 1; page 322

Mechanism of action (cont.)

Changes its conformation.

Inhibits the early phase of protein synthesis.

DalfopristinBinds to the 23S portion of the 50S ribosomal

subunit.

8Hugo and Russell's pharmaceutical microbiology Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman Edition: 7, illustrated Publisher: Wiley-Blackwell, 2004 ISBN: 0632064676, 9780632064670 Length: 481 pages

Mechanism of action (cont.)

Inhibits the late phase of protein synthesis

Prevents elongation of the polypeptideCausing incomplete chains to be released

QuinupristinBinds to a nearby site on the 50S ribosomal subunit

9Hugo and Russell's pharmaceutical microbiology Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman Edition: 7, illustrated Publisher: Wiley-Blackwell, 2004 ISBN: 0632064676, 9780632064670 Length: 481 pages

In market !!• Quinupristin/Dalfopristin

combination is available as sterile lyophilized

formulation for intravenous administration under trade

name of Synercid®.239$ per vial

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Therapeutic indications

• Synercid® is approved in the U.S. for treatment of:

Vancomycin-resistant Enterococcus faecium(but not E. faecalis) (VRE) induced bacteremia and complicated skin and skin-structure infection.

Infections caused by vancomycin resistant Staph. Aureus (VRSA)

11Laurence L. Brunton, PhD; Keith L. Parker, MD, PhD; Goodman & Gilman’s Manual of Pharmacology and Therapeutics; McGraw-Hill Companies, Inc; 11th edition; 2008; SECTION 46; page 779.

Therapeutic indications (cont.)

• In Europe, it is also approved for treatment of:

Nosocomial pneumonia and infections caused by methicillin-resistant strains of S. aureus.

• Used for patients with vancomycin-resistant enterococcal endocarditis[1] .

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[1] Koda-Kimble, Mary Anne; Young, Lloyd Yee; Alldredge, Brian K.; Corelli, Robin L.; Guglielmo, B. Joseph; Kradjan, Wayne A.; Williams, Bradley R.; Applied Therapeutics: The Clinical Use Of Drugs, Lippincott Williams & Wilkins.; Philadelphia; 9th Edition ,2009; P.59p20 .

Side effects Nausea and vomiting Skin rash, pruritus Hyperbilirubinemia and raised liver enzyme

values may occur. Arthralgias and myalgias in patients with

hepatic insufficiency Managed by reducing the dosing

frequency from q. 8hr to q.12 hr

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Side effects (cont.) Pain and phlebitis at the infusion site are most

common & minimized by[1]: Infusion through a central venous catheter. Dilution of preparation to 500-750ml solution

with D5W . Increase infusion duration

to 60 minutes.

14[1]Sean C Sweetman; Martindale, The complete drug reference; Pharmaceutical Press; London , ,Chicago; Thirty-sixth edition; 2009; vol. 1; page 322.

Side effects (cont.) Pain and phlebitis at the infusion site are most

common & minimized by[1]: The vein should be flushed with D5W after each

infusion.

Note that saline is in compatible with Synercid®.

15[1]Sean C Sweetman; Martindale, The complete drug reference; Pharmaceutical Press; London , ,Chicago; Thirty-sixth edition; 2009; vol. 1; page 322.

Precautions • Use synercid® with caution in case of:

o Hepatic impairment (avoid if severe).

o Cardiac patients e.g.: Congenital QT syndrome. Concomitant use of drugs prolong QT interval. Cardiac hypertrophy. Dilated cardiomyopathy.

16John Martin; BNF 57; BMJ Group & RPS Publishing; London, UK ; 57th Edition; 2009; vol. 5.1.1.; page 292.

Precautions (cont.)• Use synercid® with caution in case of:

o Hypokalaemia, hypomagnesaemia, brady-cardia.o Synercid® is pregnancy category B by FDA[1] .

17[1] pregnancy & reproductive studies date of access: 3/30/2012 http://www.drugs.com/pro/synercid.html

No adequate and well-controlled studies with Synercid in pregnant women., this drug should be used during pregnancy only if clearly

needed.

Conclusion • Streptogramins are class of natural cyclic

peptide antibiotics produced by certain sub-species of Streptomyces .

• They are 2 classes A & B.

• They inhibit bacterial protein synthesis by interfering 50S ribosomal binding sites.

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• Commercially available product is mixture of both Quinupristin/dalfopristin.

• Combination for bactericidal effect.

• Considered as the last resort against VRSA, VRE induced bacteremia ,endocarditis, ….etc.

Conclusion (cont.)

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• Most common side effect is the phlebitis and the pain during infusion.Dilution of the solution and vein flushing by

D5W are most effective management.

• Use with caution in case of hepatic impairment, cardiac arrhythmias.

• Synercid® is pregnancy category B drug.

Conclusion (cont.)

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Thank you

Kind regards