Oxazolidinones

Pharmacology PPT

1. Glycopeptide,Oxazolidinone , Lipopeptides,Polypeptides Dr. Chintan M Doshi

2. Glycopeptide Vancomycin M/A -acts by inhibiting bacterial cell wall synthesis It binds to the terminal dipeptide “D-ala-D-ala” sequence of peptidoglycan units Prevents its release from bactoprenol lipid carrier Assembly of the units at the cell membrane and their cross linking to form cell wall do not take place

3. Contd. Mechanism of resistance Enterococcal resistance due to plasmid mediated alteration of the dipeptide target site ,reducing its affinity for vancomycin Staph. Aureus may express reduced or intermediate susceptibility vancomycin due to abnormally thick wall and false targets for vancomycin

4. Antimicrobial activity Exclusively effective against aerobic and anaerobic gm (+) species like Strepto and staphylococci(including MRSA), enterococci,peptostreptococci,corynebacterium diptheriae , listeria , C.tatany,C perfringens,bacillus anthracis Gm(-) baciili –non responsive as –because of their larger molecular size they unable to penetrate the outer membrane

5. P/K Absorption Poorly absorbed orally Given i.v i.m it causes muscle damage Distribution PPB-30% Peak after 1 hr after i.v 1gm dose Appears in CSF and pleural,pericardial,synovial ascitic fluids Elimination 90% excreted through glomerular filtration T1/2-6 hrs

6. Uses and doses Orally 125-600 mg 6 hrly is the second choice drug to metronidazole for antibiotic associated pseudomembranous enterocolitis caused by C.difficile Systemically 500mg 6 hrly or 1gm 12 hrly infused i.v over 1 hr for serious MRSA infection And as a penicillin substitute for enterococcal endocarditis with gentamycin

7. Untoward effects Hyper sensitivity reactions Skin rashes,anaphylaxis,eosinophilia On i.v injection Flushing,tachycardia,hypotension,chills , fever, The extreme flushing that can occur is sometimes called " red-neck" or "red-man" syndrome. This is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine.

8. Contd. Auditory impairment Due to high concentration-permanent Nephrotoxicity , formerly very problematic due to the impurities in earlier formulations of vancomycin less common with modern formulations at standard dosages.

9. Teicoplanin Very similar to vancomycin in chemical structure,mechanism of action,spectrum of activity,route of elimination and uses

10. spectrum Active against gm(+) bacteria only More active against enterococci than vancomycin,equally active against MRSA Some VRE but not VRSA are susceptible to teicoplanin Listeria monocytogenes , Corynebacterium spp., Clostridium spp., and anaerobic gram-positive cocci inhibited

11. P/K i.m or i.v Largely excreted unchanged in urine T1/2-100 hrs Untoward effects Less than vancomycin Rashes,granulocytopenia,fever occasionally hearing loss Histamine release are rare

12. Use Entrococcal enocarditis MRSA Penicillin resistant streptococcal infection Osteomylitis As an alternative to vancomycin in surgical prophylaxis

13. Linezolid Approved in 2000 Spectrum Oxazolidinone VRSA,VRE,Penicillin resistant Strep.pyogens, Strep.viridans, Strep. Pneumoniae ,Cornebacterium,Listeria, Clostridia, Bact.fragilis, M.tuberculosis

14. Mechanism of action Linezolid inhibits protein synthesis: by binding to the 23S fraction of the 50S ribosom e preventing formation of ternary N- formylmethionine-tRNA( fMet-tRNA )-70S ribosomal initiation complex that initiates protein synthesis. Its unique binding site, located on 23S fraction of the 50S ribosom e , results in no cross-resistance with other drug classes.

15. Contd. Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA. Pharmacokinetics 100% bioavailability orally 30% protein-bound Volume of distribution :0.6-0.7 L/kg t1/2: 4-6 hrs

16. USES Serious hospital acquired pneumonia Febrile neutropenia Wound infections and others cause by gram +ve bacteria such as: VRSA VRE Resistant S. Pneumoniae Being bacteriostatic : not useful for enterococcal endocarditis

17. Contd. U sed for uncomplicated and complicated skin and soft tissue infections, C ommunity acquired pneumonias B acteremias and other drug resist a nt gram positive infections. XDR tuberculosis

18. Contd. Also approved in diabetic foot and pediatric patients in 2005 Dose:100 mg BD oral or i.v.

19. Adverse effects Hematological Toxicity Myelosuppression, including anemia, leucopenia, pancytopenia, and thrombocytopenia Thrombocytopenia in 2.4% in patients receiving courses of therapy lasting beyond 2 weeks Cause: drug binds to mitochondrial 70s ribosome

20. Contd. Other Toxic and Irritative Effects GI complaints, headache, rash Long-term (e.g., >8 weeks) treatment: peripheral neuropathy optic neuritis lactic acidosis

21. Interactions Reversible inhibitor of MAO-A and leads to cheese reaction with food containing tyramine Precipitate “serotonin syndrome” if used with SSRI Linezolid is neither a substrate nor an inhibitor of CYPs.

22. Tedizolid Approved by the FDA on June 20, 2014 Structural analogue of linezolid 4-6 time more active than linezolid for staphylococci and enterococci infections Low thrombocytopenia rates Lower potential for monoamine oxidase interaction

23. Lipopeptides Daptomycin is a novel cyclic lipopeptide fermentation product of Streptomyces roseosporus It was discovered 3 decades (1980) ago at for the treatment of infections caused by Gram-positive bacteria .

24. Mechanism

25. Antibacterial activity. Bactericidal against all clinically relevant Gram-positive bacteria including multiple-drug resistant pathogens: MRSA and vancomycin -resistant S. aureus (VRSA) , vancomycin -resistant strains of enterococci ( VRE)

26. Phramacokinetics Poorly absorbed orally and should only be administered intravenously Direct toxicity to muscle precludes intramuscular injection P rotein binding is 92%. Serum half-life is 8 to 9 hours Approximately 80% of the administered dose is recovered in urine; a small amount is excreted in feces.

27. Uses Complicated skin and soft-tissue infections. Pulmonary surfactant antagonizes daptomycin , and it should not be used to treat pneumonia . Staphylococcus aureus bloodstream infections (bacteremia)

28. Untoward Effects Damage to the musculoskeletal system In humans, elevations of creatine kinase may occur Rhabdomyolysis has been reported to occur rarely.

29. Polypeptide antibiotics

30. Low molecular weight cationic polypeptide antibiotics Powerful bactericidal agent Not used systematically because high chance of toxicity All are produced by bacteria

31. Drugs Polymixin B Colistin Bacitracin

32. Polymixin B and colistin Active against gram - ve bacteria Proteus ,serratia and Neisseria are not inhibited Colistin is more potent against pseudomonas, salmonella and shigella

33. Mechanism of action Detergent like action on cell membrane High affinity for phospholipids Peptide molecule orient between phospholipid and proteins Causes membrane distortion Amino acids and ions leak out

34. Adverse effects Orally: nausea, vomiting and diarrhea Systemic: Flushing, paresthesias Kidney damage Neurological disturbances Neuromuscular blockade

35. Uses Topically Skin infections Burns Otitis externa Conjunctivitis Corneal ulcer

36. Contd. Orally: Gram- ve bacillary diarrheas mainly in infants and children Pseudomonas superinfection enteritis

37. Bacitracin Active against gram+ ve bacteria Inhibit bacterial cell wall synthesis Bactericidal Uses: Topically: infected wounds, ulcers, eye infections generally combination with neomycin and polymixin B Not penetrate intact skin No value in boils, carbuncles and furunculosis

38. Contd. Boil carbuncle

39. Urinary antiseptics

40. Some orally antimicrobials attain antibacterial concentration only in urine with no systemic antibacterial effect They are concentrated in kidney tubules and useful in lower urinary tract infections This are called urinary antiseptics

41. Nitrofurantonin Primary bacteriostatic Bactericidal at higher concentration and in acidic urine Gram – ve bacteria are susceptible M/o : bacteria enzymatically reduce nitrofurantonin to generate reactive intermediates which damages DNA

42. Contd. Pharmacokinetics: Well absorbed orally T1/2:30-60 min Metabolized in liver Excreted unchanged in urine

43. Contd. Adverse effect Nausea, epigastric pain, and diarrhoea Acute reaction: Fever, chills and leucopenia Hemolytic anemia with G6PD deficiency Peripheral neuritis on chronic use Liver damage and pulmonary fibrosis are rare Urine turns dark brown on exposure to air

44. Use Uncomplicated lower UTI not associated with prostatitis Acute infection with E.coli : treated by 50-100mg TDS for 5-10 days 100 mg bed time given prophylaxis of UTI following catheterization and women with recurrent cystitis

45. Methenamine Hexamethylene - tetramine Decompose slowly in acidic urine to release formaldehyde which inhibits all bacteria Acidic urine is essential for its action Administered enteric coated tablets to prevent gastritis Dose:1 g TDS with fluid restriction

46. Use Chronic resistant type of UTI Adverse effect Gastritis due to release of formaldehyde in stomach Chemical cystitis and hematuria on high doses CNS symptoms occasionally

47. Urinary analgesic Phenylzopyridine Orange dye which exerts analgesic action in urinary tract and afford symptomatic relief in burning sensation, dysuria and urgency Not have antibacterial property Side effects: nausea and epigastric pain

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