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3.ppt
- 2. Synthetic antimicrobials Bactericidal Primarily gram negative bacteria
- 3. Nalidixic acid • First member
- 4. Spectrum • Gram negative bacteria especially coliforms • E.coli • Proteus • Kleibseilla • Enterobacter • Shigella • X psuedomonas Bactericidal antibiotic
- 5. • Concentration of free drug in plasma & most tissues is non-therapeutic for systemic infections • Therapeutic concentrations attained in urine & gut lumen are lethal to common urinary pathogens & diarrhoea causing coliforms
- 6. Therapeutic uses • Urinary antiseptic • Diarrhoea caused by coliforms Norfloxacin/ciprofloxacin preffered Urinary tract infections for many years
- 7. Low potency Narrow spectrum and rapid developmemt of bacterial resistance. Limited therapeutic utility No longer used.
- 8. Fluoroquinolones • Fluorination of quinolone structure at position 6 & piperazine substitution at position 7 resulted in derivatives called fluoroquinolones • Important therapeutic advance
- 9. High potency Expanded spectrum/Broad antimicrobial activity Slow development of resistance Better tissue penetration & Good tolerability • Used for wide variety of infectious diseases
- 11. Mechanism of action Quinolones target bacterial DNA gyrase & Topoisomerase IV • Gram negative bacteria - DNA Gyrase • Gram positive bacteria - Topoisomerase IV
- 12. • Mammalian cells Topoisomerase II Low affinity for flouroquinolones Inhibited by quinolones only at much higher concentrations. Low toxicity to host cells
- 13. Mechanism of action • Double helical DNA • Two strands must separate to permit DNA replication / transcription • “over winding” / excessive positive supercoiling of DNA in front of point of seperation (mechanical hindrance) • faulty protein synthesis • Detrimental for bacterial growth.
- 14. DNA Gyrase has (A & B subunit) • A subunit - strand cutting function of DNA gyrase. • B subunit - introduces negative supercoils DNA Gyrase - introduces negative supercoils into DNA (checks mechanical hindrance) • A subunit reseals the strand
- 15. Quinolones • bind to A - subunit with high affinity & interfere with strand cutting & resealing function • Prevent replication of bacterial DNA during bacterial growth & reproduction.
- 16. • In addition bacterial DNA gyrase inhibition also leads to extensive filamentation vacuole formation & degradation of chromosomal DNA All this confers bactericidal activity to FQ’s
- 17. Mechanism of resistance • Chromosomal mutation bacteria produce DNA Gyrase/ Topoisomerase IV with reduced affinity for FQs • Efflux of these drugs across bacterial membranes • No quinolone modifying/inactivating enzymes have been identified in bacteria • Resistance is slow to develop
- 18. Spectrum Potent bactericidal against Gram negative bacteria: E.coli Salmonella Shigella Enterobacter Campylobacter & Neisseria Ciprofloxacin is more active against Pseudomonas aeruginosa
- 19. Flouroquinolones also have good activity against Staph. aureus but not against methicillin resistant strains Intracellular bacteria are also inhibited Chlamydia Mycoplasma Mycobacterium including Mycobacterium tuberculosis
- 20. • Levofloxacin • Gatifloxacin • Moxifloxacin Excellent Activity against streptococci Several - anaerobic bacteria • Gemifloxacin • Ofloxacin, Gatifloxacin & Moxifloxacin
- 21. • Rapid oral absorption • High tissue penetrability Concentration in lung, sputum, muscle, bone, prostrate, and phagocytes exceeds that in plasma • CSF & aqueous levels are low • Excreted in urine • Urinary & biliary concentrations are 10-50 fold higher than in plasma Pk
- 22. Pk • Excreted in urine – Dose adjustment in renal failure • Exception Pefloxacin & moxifloxacin – Metabolized by liver – Should not be used in hepatic failure
- 23. Dosage • 200-400 mg every 12 Hrs for Ofloxacin • 400 mg every 12 Hrs for Norfloxacin & Pefloxacin • 250-750 mg every 12 Hrs for Ciprofloxacin • 500 mg OD : Levofloxacin • 400 mg OD : Lomefloxacin • 200-400mg OD : Sparfloxacin • 320 mg OD: Gemifloxacin
- 24. Adverse effects • Generally safe – Nausea, vomiting, abdominal discomfort, bad taste • CNS: – headache, dizziness, rarely hallucinations, delirium. – & seizures have occurred predominantly in patients receiving theophylline or a NSAIDs
- 25. • Hypersenstivity; rashes including photosenstivity • Tendonitis & tendon rupture • Arthropathy in immature animals, – Use in children contraindicated Adverse effects
- 26. • QTc prolongation – Sparfloxacin – Gatifloxacin – Moxifloxacin • Cautious use in patients who are taking drugs that are known to prolong the QT interval tricyclic antidepressants phenothiazines and class I anti-arrhythmics Adverse effects
- 27. • Gatifloxacin Hypoglycaemia • Temafloxacin Immune hemolytic anaemia • Trovafloxacin Hepatotoxicity • Grepafloxacin Cardiotoxicity • Clinafloxacin Phototoxicity withdrawn
- 28. Drug interactions NSAIDs may enhance CNS toxicity of FQ’s – Seizures reported Antacids, Sucralfate, Iron salts reduce absorption of FQ,s
- 29. THERAPEUTIC USES Urinary tract infections • Most commonly used antimicrobials for UTI • Very effective against Gram negative bacilli like E.coli Proteus Enterobacter Psuedomonas • Norflox 400 mg bd Ciprofloxacin 500 mg bd Ofloxacin 400 mg bd
- 30. Prostatitis Norfloxacin Ciprofloxacin Ofloxacin All are effective. FQ’s administered for 4-6 wks.
- 31. Quinolones with activity against G +ve bacteria & anaerobes such as • Ofloxacin • Moxifloxacin can be used in infections of the oral cavity
- 32. Sexually transmitted diseases Active against N. gonorrhoea Chlamydia trachomatis H. ducreyi FQ’s lack activity against T. pallidum
- 33. GASTROINTESTINAL AND ABDOMINAL INFECTIONS • Traveller’s Diarrhoea • Shigellosis • Diarrhoea in cholera • Peritonitis
- 34. Salmonella typhi infection • Ciprofloxacin 500 mg bd x 10 days • Prevents carrier state also – 750 mg bd x 4-8 wks • IN MDR enteric fever- Ceftriaxone,Cefotaxime,Cefixime(oral) and oral Azithromycin can be used. Ofloxacin: 400 mg BD Levofloxacin: 500 mg OD/BD Pefloxacin: 400 mg BD Equally efficacious
- 35. Ceftriaxone • Most reliable • Fastest acting bactericidal drug for enteric fever • i.v 4g daily 2 days • 2g daily till 2 days after fever subsides • Preferred drug
- 36. Bone, joint, soft tissue & wound infections Skin & soft tissue infections Osteomyelitis & joint infections
- 37. • Respiratory infections – Pneumonia – Acute sinusitis – Chr. Bronchitis – Multi drug resistant TB. – Myco. Avium complex in AIDS pts. – & Leprosy
- 38. To conclude • Rapid bactericidal activity • High potency • Long post-antibiotic effect • Low frequency of resistance • Frequently prescribed • Effectively decrease infectious load in the community.
- 39. THANK YOU
- 40. Norfloxacin • Primarily used for urinary & genital tract infections. • Bacterial diarrhoeas: high concentration in gut & anaerobic flora of gut is not disturbed
- 41. Pefloxacin • Methyl derivative of norfloxacin • More lipid soluble • High concentrations in CSF • Preferred for meningeal infections
- 42. Postantibiotic effect • The antibacterial effect continues for approximately two to three hours after bacteria are exposed to these drugs, despite subinhibitory concentrations. • The duration of the postantibiotic effect may be increased with longer bacterial drug exposure and higher drug concentrations.