Quinolones & Fluoroquinolones

Quinolones & Fluoroquinolones

• 1.
  QUINOLONES & FLUOROQUINOLONES DR. RESUNEHA REDDY POST GRADUATE MD PHARMACOLOGY
• 2.
  SULFONAMIDES
• 3.
  OBJECTIVES  Introduction  History Anti microbial spectrum  Classification  Mechanism of Action  Resistance  Pharmacokinetics  Therapeutic uses  Adverse Effects  Interactions
• 4.
  INTRODUCTION  The quinolonesare a family of synthetic, broad- spectrum antibiotic with bactericidal activity.  The term quinolone refers to potent synthetic chemotherapeutic antibacterial agent.
• 5.
  HISTORY  The 1stgeneration  Nalidixic acid (1962)  Urinary Tract Infections.  George Lesher and co-workers in an attempt at chloroquine synthesis. George Lesher
• 6.
  HISTORY  Nalidixic acid,not be used for systemic infections  98.5% protein bound,  Systemic levels were achieved only at the cost of toxicity.  In 1980’s this obstacle was overcome Fluoride group  Fluoroquinolones (ciprofloxacin)
• 7.
  QUINOLONES & FLUOROQUINOLONES CIPROFLOXACINNALIDIXICACID Fluorination Piperazine substitution
• 8.
  HISTORY Fluoroquinolones have  Broaderspectrum of action,  Fewer side effects  Relatively slower rate for microbial resistance.
• 9.
  ANTI MICROBIAL SPECTRUM
• 10.
  FIRST GENERATION SECONDGENERATION THIRD GENERATION Proteus, E.coli, Klebsiella, Shigella, Salmonella + ++ H. influenzae, H. Ducreyi, Legionella pneumophila, Pseudomonas aeruginosa Neisseria gonorrhea N. Meningitidis Vibrio cholerae(some extent) < Leigionella Staph. aureus (moderate) Bacillus anthracis (RECENT) Streptococcus pneumoniae Streptococcus Staphylococcus Enterococcus Mycobacterium tuberculosis Chlamydia trachomatis C. Pneumoniae < Chlamydia M. Tuberculosis M. avium complex in AIDS MRSA, Mycoplasma Anaerobes: Bacteroides Mycoplasma Mycoplasma pneumoniae Anaerobes
• 11.
  FIRST GENERATION SECONDGENERATION THIRD GENERATION Proteus, E.coli, Klebsiella, Shigella, Salmonella + ++ H. influenzae, H. Ducreyi, Legionella pneumophila, Pseudomonas aeruginosa Neisseria gonorrhea N. Meningitidis Vibrio cholerae(some extent) < Leigionella Staph. aureus (moderate) Bacillus anthracis (RECENT) Streptococcus pneumoniae Streptococcus Staphylococcus Enterococcus Mycobacterium tuberculosis Chlamydia trachomatis C. Pneumoniae < Chlamydia M. Tuberculosis M. avium complex in AIDS MRSA, Mycoplasma Anaerobes: Bacteroides Mycoplasma Mycoplasma pneumoniae Anaerobes
• 12.
  FOURTH GENERATION  Showenhanced activity against Gram Positive organisms  Penicillin / erythromycin resistant gram positive bacteria  Greater activity against Anaerobes  Gram negative organisms covered under all FQ’s
• 13.
  CLASSIFICATION FLUOROQUINOLONES FIRST GENERATION SECONDGENERATION NORFLOXACIN CIPROFLOXACIN OFLOXACIN PEFLOXACIN LEVOFLOXACIN MOXIFLOXACIN GEMIFLOXACIN PRULIFLOXACIN LOMOFLOXACIN SPARFLOXACIN PAZUFLOXACIN & BALOFLOXACIN
• 14.
  CLASSIFICATION According To BacterialSpectrum First Generation Norfloxacin, Lomefloxacin, Ciprofloxacin, Ofloxacin, Pefloxacin. Second Generation Levofloxacin, Prulifloxacin. Third Generation Gatifloxacin, Gemifloxacin, Sparfloxacin Fourth Generation Moxifloxacin, Trovafloxacin, Alatrofloxacin, Finafloxacin.
• 15.
  MECHANISM OF ACTION
• 16.
  MECHANISM OF ACTION
• 17.
  MECHANISM OF ACTION
• 18.
  MECHANISM OF ACTION
• 19.
  MECHANISM OF ACTION
• 20.
  MECHANISM OF ACTION
• 21.
  MECHANISM OF ACTION
• 22.
  MECHANISM OF ACTION
• 23.
  MECHANISM OF ACTION
• 24.
  MECHANISM OF ACTION
• 25.
  MECHANISM OF ACTION
• 26.
  MECHANISM OF ACTION
• 27.
  MECHANISM OF ACTION
• 28.
  MECHANISM OF ACTION
• 29.
  MECHANISM OF ACTION
• 30.
  MECHANISM OF ACTION
• 31.
  FQ’s RESISTANCE
• 32.
  POINT TO BENOTED  Fluoroquinolones inhibit only prokaryotic DNA gyrase at therapeutic doses.  Eukaryotic DNA topoisomerase II is inhibited only at very high concentrations which are toxic to man.
• 33.
  PHARMACOKINETICS RFRF
• 34.
  PHARMACOKINETICS  Bioavailability: 80-100% for most of the drugs; except Norfloxacin : 30-35%  Plasma protein binding : 20-40%  T½ : 8-10hrs approx. for most of the drugs; except norfloxacin 3-5hrs.  Post antibiotic effect : 3-6hrs  Metabolized in liver; excreted through kidney.  Concentrated - mucosal tissues of GIT, genitourinary tract, respiratory tract, prostate, lungs, heart & macrophages.  FQ conc. in CSF, bone, prostatic fluid < serum conc.  Pefloxacin, Ofloxacin levels in ascites fluid ~= serum conc  Ciprofloxacin, Ofloxacin, Pefloxacin, Trovafloxacin  Human breast milk.  Penetrate placental barrier and get concentrated in amniotic fluid.
• 35.
  URINARY TRACT INFECTION Uncomplicated Norfloxacin400mg BD Ciprofloxacin 500mg BD Ofloxacin 400mg BD Orally for 4-6 Weeks Pefloxacin 400mg BD Lomefloxacin 400mg OD Complicated lower UTI Prulifloxacin 600mg OD ACUTE BACTERIAL DIARRHOEA Do not disturb normal gut flora and provide high fecal concentration. Norfloxacin 400mg BD Ciprofloxacin 500mg BD Orally for 5 days Ofloxacin 200mg BD THERAPEUTIC USES
• 36.
  SALMONELLA TYPHI One ofthe most preferred drug for typhoid –  High efficacy, low incidence of Complications and least chances of relapse.  Good intracellular accumulation, adequate levels in bile and feces. Ciprofloxacin 500mg BD Orally for 10 days Ofloxacin 400mg BD Pefloxacin 400mg BD Norfloxacin 400mg BD Orally for 14 days  If patient is unable to take orally, administer; Ciprofloxacin 200mg iv BD; followed by oral route after defervescence.  Resistance to FQ’s in typhoid is also being observed. THERAPEUTIC USES
• 37.
  SEXUALLY TRANSMITTED DISEASES Norfloxacin800mg Ciprofloxacin 250-500mg Ofloxacin 400mg Single oral dose Pefloxacin 800mg Provides ~95% cure rate from Lomefloxacin 400mg Neisseria gonorrhoea, Gonococcal urethritis, cervicitis and proctitis. Ciprofloxacin 500mg BD x 3 days : ~98% cure from Chancroid (Hemophilus ducreyi) Only Ofloxacin is effective against both Chalmydia trachomatis and Neisseria gonorrhoea (400mg OD x 7days) THERAPEUTIC USES
• 38.
  SOFT TISSUE &WOUND INFECTIONS Ciprofloxacin 500mg BD x 7days Ofloxacin 400mg BD x 10days skin and soft tissue infections by Pefloxacin 400mg BD x 7days gram negative organisms Lomefloxacin 400mg OD x 7days Prulifloxacin 600mg Ciprofloxacin + Clindamycin/Metronidazole  Diabetic Foot Ciprofloxacin 500-750mg BD x 6weeks  Malignant otitis externa THERAPEUTIC USES
• 39.
  RESPIRATORY INFECTIONS First generationFQ’s are used in Gram Negative sinusitis and bronchitis Not drugs of choice though. Ciprofloxacin 500mg BD x 7days Pefloxacin 400mg BD x 7days Ofloxacin 400mg BD x 10days Lomefloxacin 400mg OD x 10days Second generation FQ’s can be used in gram positive as well as gram negative infections – PRULIFLOXACIN 600mg OD • Acute exacerbation of chronic bronchitis. • Community acquired pneumonia • Nosocomial pmeumonia • Acute sinusitis Fourth generation FQ’s are used in anaerobic infections. • They have enhanced activity against penicillin/erythromycin resistant gram positive bacteria. MOXIFLOXACIN 400mg orally OD
• 40.
  THERAPEUTIC USES ANTHRAX Ciprofloxacin 500mgBD orally x 60days  Post exposure treatment; Inhalational/Cutaneous (Bioterrorism) If gastrointestinal/oropharyngeal involvement: Ciprofloxacin 400mg iv 12hrly + any 2 of : Rifampicin, Ampicillin, Imipenam, Clindamycin, Clarithromycin for 60 days
• 41.
  TUBERCULOSIS Ciprofloxacin/Ofloxacin are combinedwith anti TB drugs for Multidrug Resistance TB For H+R resistance – ZE + S/ Kanamycin/ Amikacin/ Capreomycin + Ciprofloxacin/ Ofloxacin ± Ethionamide MYCOBACTERIUM AVIUM COMPLEX IN AIDS PATEINTS Third generation FQ’s are used as adjuvant in treatment of MAC. Intensive Phase (4drugs) : Clarithromycin/ Azithromycin + Ethambutol + Rifabutin + FQ/ Clofazimine/ Ethionamide (2-6months) Maintenance Phase (2drugs) : Clarithromycin/ Azithromycin + Ethambutol/ FQ/ Rifabutin for 12 months – lifetime
• 42.
  MISCELLANEOUS MENINGITIS : Pefloxacinconcentrates more than due to gram negative organisms other FQ’s on CSF Chronic bacterial PROSTATITIS : ciprofloxacin 500mg BD x 28days pefloxacin 400mg BD x 28days ofloxacin 300mg BD x 42days *Good Accumulation In Prostatic Fluid Surgical Prophylaxis In Transurethral/Transrectal Procedures : Lomefloxacin Prophylaxis in neutropenia : Ciprofloxacin + Gentamicin (in neutropenic cancer patients) Cystic Fibrosis : Ciprofloxacin Bacterial conjuctivitis, corneal ulcer Topical eye drops/ointment : ~All FQ’s
• 43.
   Dose dependent,mild, discontinuation not required.  Nausea, vomiting, diarrhoea, headache, dizziness, photosensitivity M/C  Tendonitis, tendon rupture on prolonged use  Ciprofloxacin: ligament damage has been associated in anthrax treatment/prophylaxis cases. ADVERSE EFFECTS
• 44.
  ADVERSE EFFECTS  QTcprolongation : Moxifloxacin and Gatifloxacin Moxifloxacin : post marketing reports are suggestive of phototoxicity  Gatifloxacin : QTc prolongation; photosensitivity; Episodes of hypo- and hyperglycemia. Risky in diabetics. Recently withdrawn from market.  Lowering of seizure threshold : isolated clinical reports - Ciprofloxacin, Ofloxacin, Moxifloxacin, etc  Hepatotoxicity : Trovafloxacin/ Alatrofloxacin
• 45.
  ADVERSE EFFECTS PREGNANCY:  Increasedrisk of malformations  Spontaneous abortions  Birth defects
• 46.
  INTERACTIONS  Oral absorptionof FQ’s is decreased with: Al+++ , Mg ++ , Ca ++ , containing antacids Form chelation complexes Zn++ , Fe ++ salts Sucralfate  Theophylline metabolism is inhibited by FQ’s except lomefloxacin, levofloxacin and sparfloxacin  Warfarin metabolism is decreased by FQ’s  Enhanced effects exceptions – Levofloxacin, Sparfloxacin.  FQ’s prolonging QTc interval (caution/avoided) class IA (quinidine, procainamide) class III (amiodarone, sotalol, ibulitide) other drugs prolonging QTc interval (erythromycin, cisapride, TCA’s, etc)
• 47.
  S U M M A R Y
• 48.
  Q U E S T I O N
• 49.
  A N S W E R . .
• 50.
  THANK YOU…