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Fluroquinolones.. Dr. kiran g. piparva
- 1. Dr. kiran G.piparva Assistant professor, Pharmacology department P . D. U. Government medical college, Rajkot
- 2. Contents…… • Introduction • Chemical structure • Classification • Antibacterial spectrum • Mechanism of action • Mechanism of resistance • Individual drugs
- 3. • Synthetic antimicrobial agent • Having quinolone structure • Primarily active against gram negative bacteria • First member is NALIDIXIC ACID
- 4. Breakthrough 1980- • Fluorination of quinolone structure at 6th position and addition of piperazine at 7th position resulting derivative called- “FLUROQUINOLONES”
- 5. Development of FQs…… • 1960s – Nalidixic acid • 1970s – Cinoxacin and Rosoxcin • 1980s – Norfloxacin , Ciprofloxacin, Ofloxacin • 1990s – Lomefloxacin, Sparfloxacin • 2000s – Lovofloxacin, Gatifloxacin, Trovafloxacin , Moxifloxacin, Gemifloxacin
- 6. FQs First generation One FLUORO substitution Effective against gram-ve organism Second generation - ADDITIONAL FLUORO and other substitutions .. Antimicrobial spectrum extendto gram +ve and anaerobes
- 7. FQs First generation Norfloxacin, Ciprofloxacin Pefloxacin Ofloxacin Second generation Levofloxacin, Lomefloxacin Sparfloxacin Gemifloxacin Moxifloxacin prulifloxacin Pazufloxacin and Balofloxacin in india
- 8. Bacterial DNA gyrase Subunit B Subunit A Site of action Mechanism of action of FQ…. Positive supercoiling Negative supercoiling
- 9. Mechanism of action of FQ Gram -ve Gram +ve
- 10. Less likely & very slow to develop Reduced permeability Increased efflux Chromosomal mutation producing a DNA gyrase/ topoisomerase IV with reduced affinity for FQs. Mechanism of Resistant
- 11. •For individual drugs… DIFFERENCES…. • Antimicrobial spectrum • Pharmacokinetic profile • ADR
- 12. CIPROFLOXACIN (prototype) • Most potent 1st generation FQ • Spectrum : • Aerobic gram – ve bacilli- Enterobacteriaceae and Neisseria
- 13. Antibiotic spectrum Higley susceptible Gram -ve bacilli Gram -ve cocci -E.Coli - Neisseria -Salmonella -H. influenzae -Shigella -H, ducreyi -Proteus -Compylobector - K. pneumoniae jejuni Moderately susceptible -Atypical organisms -Pseudomonas aeruginosa - Anthracis - Brucella - Chlamydia pneumophila - Listeria - Mycoplasma - Mycobacterium - Staph epidermidis Low or variable susceptibility (gm+Ve) - Strep. Pyrogens - Strep. Faecalis - Strep. Pneumoniae - MRSA - Mycobact. Kansasii - MAC RESISTANT : ANAEROBES
- 14. Pharmacokinetics • Absorption: good with empty stomach • Good tissue penetrability • Renal excretion : required dose reduction in kidney damage
- 15. ADR of FQ… • Good safety record…..Mild ADRs • GIT: N/V/A, bad taste • CNS: Dizziness, headache, restlessness, anxiety, insomnia, impairment of concentration, dexterity- seizure when high dose or predisposing factors • HST: hypersensitivity reaction- rash pruritis, photosensitivity, urticaria, swellings. • Tendonitis and tendon rupture: higher in age above 60yrs, patients receiving corticosteroids. Children, seizure, photosensitivity While driving C/I : pregnancy
- 16. Drug Interactions • Absorption: Other drugs reduce absorption of FQs : Antacids, sucralfate and iron salts • Norfox/ ciproflox/ pefloxacin raises theophylline, caffeine and warfarin concentration – Second generation are safe • NSAIDs may enhance the CNS toxicity of FQs; seizures are reported
- 17. Important features of FQs……… Bactericidal Rapid action Post antibiotic effect Mutational resistance is low Susceptible to Penicillin , cephalosporin, aminoglycoside resistant bacteria Activity is pH dependent – reduced activity at acidic pH
- 18. Therapeutic uses of FQs….. • Ciprofloxacin is highly effective because….. Wide spectrum Bactericidal activity Oral efficacy Good tolerability Best for gram –ve infections EMPIRICAL THERAPY DOSE:
- 19. Gram negative infections Urinary track infection Bacterial gastroenteritis Typhoid fever Bone & soft tissue, gynecological and wound infection Gram negative septicemia Conjunctivitis Gonorrhoea Meningitis
- 20. • Other infections: • Chancroid • Anthrax • Respiratory infection • Tuberculosis • Prophylaxis
- 21. Therapeutic uses……. 1. Urinary tract infection(UTI) • FQ are superior to Trimethoprim-sulfamethoxazole • Good concentration in urine • High cure rate even in complicated UTI • All FQ are equally effective 2. Bacterial gastroenteritis: Empirical therapy- most common 3. Gonorrhoea: 100% curative in PPNG/ NPPNG- not used now 4. Bone soft tissue, gynaecological and wound infection: high cure rate is obtained with prolonged Rx (6-8wk) with high dose (750mgBD)
- 22. 5. Typhoid fever • First line drugs • Ciprofloxacin is the drug of choice • 750mg BD orally or 200mg I.V. 12 hrly for 10-14 days Other options: • Ceftriaxone: fastest acting bactericidal, prevent relapse and carrier state, preferred over FQs in children, pregnant women & FQ resistant cases • Fluroquinolones: equally efficacious alternative ceftriaxone • Azithromycin: 2nd line alternative in multidrug resistant typhoid • Chloramphenicol: Resistant and unreliable • Cotrimoxazole: Resistant, rarely used.
- 23. 6. Respiratory infections • Not as primary drug • DOC only for Atypical pneumonia due to Mycoplasma, legionella, H. influenzas, Chlamydia pneumonia • 2nd generation (Levofloxacin/ Gemifloxacin/ Moxifloxacin) – used 7. Tuberculosis • Moxifloxacin/ levofloxacin : 2nd line antitubercular drug & for combination drugs in MDR TB • Ciprofloxacin most active against MAC 8. Meningitis: Only for gm –ve bacterial meningitis especially in immunocompromised patients
- 24. Properties of 1st generation FQs • No activity against S. Pneumoniae & anaerobes • No significant CNS concentration • Short action – twice daily dosing • DI: Raises warfarin and theophylline concentration Common to Ciproflox/ Oflox / Pefloxacin
- 25. Properties of 2nd generation FQs • Spectrum: Active against Gm +ve bacteria & anaerobes • PK: Longer action – OD- good compliance • CNS concentration is poor • NO DI: Levoflox/ sparflox do not interact with warfarin and theophylline • ADR: • Prolongs QT interval/ Phototoxicity – sparflox/gatiflox/moxiflox/gemiflox
- 26. • Pefloxacin: • Better PK- lipid soluble, long t1/2- better CSF concentration • Metabolized to norfloxacin- dose adjustment required in liver disease but NOT in renal insufficiency • Ofloxacin: • More active on strep. Pyogenes and gram+ve / anaerobes, chlamydia, Mycoplasma, mycobacterium • MDR TB: Alternative therapy for multidrug resistant tuberculosis
- 27. • Levofloxacin • Levo isomer of ofloxacin - Good PK- 100% bioavailability orally – long half life- OD- NO Drug interaction - Primary indication: - CAP- community acquired pneumonia, pyelonephritis, prostatis, skin/ soft tissue infection - MDR TB : 2nd line antitubercular drug- combined regimen for MDR TB • Moxifloxacin: • MDR TB : Most potent against M. tuberculosis- used in MDR TB • Should not given to predisposed to seizure- QT prolongation 2nd generation FQs
- 28. • Sparfloxacin: • 2nd generation difluorinated quinolones • Phototoxic, QT prolongation • Lomefloxacin • 2nd generation difluorinated - higher phototoxicity- Q-T prolongation • Gemifloxacin: • Broad spectrum/ aerobic/ resistant orgasnim • QT prolongation, DI QT PROLONGATION, PHTOTOXICITY
- 29. • Prulifloxacin Prodrug- Good spectrum- Good PK NO QT - PROLONGATION • Pazufloxacin: • Only injectable formulation as “ Mesylate” • Rarely seizure- limit dose • Balofloxacin • Marketed only in India and few other countries
- 30. HEPATIC HEPATIC
- 31. Pharmacokinetics Absorption Distribution Metabolism Elimination Ciprofloxacin is well absorbed on empty stomach F= 70-95% except norfloxacin – 40% Excellent tissue penetration (lungs, sputum, prostate , muscle, bone) Poor penetration in brain and eyes Pefloxacin and Moxifloxacin , Trovafloxacin are metabolised by liver- require dose reduction in hepatic dysfunction (PMT) Most Quinolones are cleared by kidney - require dose reduction in renal dysfunction • Clinically significant post antibiotic effect (2-6 hours) • Sparfloxacin has longest action (18-20 hrs) • 1st generation drugs given twice a day – • 2nd generation drugs once only
- 32. Some withdrawn FQs • Gatifloxacin – Dysglycemia • Lomiflxacin/ sparfloxacin – photosensitivity & QT prolongation • Trovafloxacin – Hepatotoxicity • Grepafloxacin – Cardiotoxicity