Quinolones &UTI

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  • Nalidixic acid is not used for systemic infection because more (98.5%) protein bindingOxolinic acid – marginal better than Nalidixic acid
  • Bacillary these drug donotdistrub normal flore  useful in acute entric bacterial infection. Traveller’sdiahrroeacotrimoxazoleThphoid – 3rd generation cephalosporinsSTD- ceftiaxone for N.Gonorrheae
  • Quinolones &UTI

    1. 1. QUINOLONES
    2. 2. • Synthetic anti microbials • • • • • Bactericidal broad spectrum antimicrobial activity Nalidixic acid, 1962-Lasher G-ve 1970s – Oxolinic acid & cinoxacin Developed in 1980s Increasingly used because of their relative safety, their availability both orally and parenterally and their favorable pharmacokinetics • Comparatively slow rate of resistance to these agents
    3. 3. Structure-Activity Relationships 4-quinolone-3-carboxylic acid affect G(-ve) activity O F 5 COOH 4 N HN 1 N 8 R1 8-F- improve P.k 3 Cyclopropyl: inc. spectrum Piperazine ring :anti-pseudomonal activity
    4. 4. Generation Drug Names Clinical use Uncomplicated 1st Norfloxacin Ciproflaxcin Ofloxacin Pefloxacin Lomefloxacin 2nd Levofloxacin Fleroxacin Clindafloxacin Complicated UTI, GIT infection Prostatitis, STD 3rd Gatifloxacin Sparfloxacin same+ community acquried pneumonia Atrofloxacin Trovafloxacin Alatrofloxacin Major systems infection (abdominal infections) 4th UTI
    5. 5. M. O. A. :* ACT BY INHIBITING D. N. A. GYRASE IN BACTERIA (PROKARYOTIC CELLS). * * ENZYME TOPOISOMERASE IV IN GRAM POSITIVE BACTERIA. DO NOT AFFECT MAMMALS CELLS (TOPOISOMERASE II ENZYME). SPECTRUM : * BROAD SPECTRUM. * MORE ACTIVE AGAINST G -ve IN COMP. TO G+ BACTERIA.
    6. 6. MICROBIOLOGICAL FEATURES OF FQs: • • • • • Rapidly Bactericidal activity Long Post-Antibiotic Effect Low Frequency of Resistance High Tissue Penetrability Active against Beta-Lactum & Aminoglcoside Resistant Bacteria.
    7. 7. PHARMACOKINETICS : * ABSORBED P. O. * DISTRIBUTED TO ALL BODY COMPARTMENTS : PROSTATE, BONE , LUNG, SPUTUM, AQUEOUS HUMOR, NEUTROPHILLS BUT CONC. IN C. S. F. IS POOR * EXCRETION THROUGH KIDNEY (Conc. Higher than Plasma)
    8. 8. Anti microbial spectrum 1st generation: • Enterobacteriaceae (E. coli, Sallmonella, Shigella) • G –ve: H.influenzae, H.ducreyi, P.aeruginosa, V.cholerae • G-ve cocci :N. gonorrhoea, N. meningitidis • G+ve bacilli : Bacillus anthracis (Modest activity) • Other: M.tuberculosis, M. pneumoniae, Rickettsiae 2nd generation: • Better activity against G+ve cocci 3rd generation: • Enhanced activity against G –Ve cocci 4th generation: • Enhanced activity against G+Ve cocci+ greater activity against anaerobes
    9. 9. THERAPEUTIC USES : 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. R – RESP TRACT INF. Levofloxacin, sparfloxacin, ofloxacin T – TYPHOID. Cipro, oflo, F – FURUNCULOSIS T – TUBERCULOSIS O – OSTEOMYELITIS – ciproflo- long therapy 4-6week U – U. T. I. Norfloxacin 4-6 weeks C – CONJUNCTIVITIS. B – BACILLARY DYSENTRY. - Nor, cipro, trallver’s-cotrimoxaz O – OTITIS MEDIA. L – LEPROSY S – S. T. D. EXCEPT SYPHILLIS. 2nd line – Cipro, oflo, gati M – MENINGITIS. ( 2nd line drugs)
    10. 10. RESERVED THERAPY FOR TREATMENT OF UNTREATABLE CONDITION BY OTHER LONG STANDING MICROBICIDALS.
    11. 11. Ciprofloxacin • Administration [Usual Dosage]: IV, PO [500 – 750 mg] • Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor activity against Strep. pneumoniae. • Indications: -- Nosocomial pneumonia -- Intra-abdominal infections – Uncomplicated/complicated UTI – Anthrax exposure and prophylaxis • Unique Qualities: – Binds divalent cations (i.e. Ca & Mg) which decreases absorption -- Increased effects of warfarin • ADRs – QTC prolongation, arrhythmias – Nausea, GI upset – Interstitial nephritis
    12. 12. Levofloxacin • Administration [Usual Dosage]: IV, PO and ophthalmic [500-750 mg ] • Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens, Mycobacterium tuberculosis • Indications: – Chronic bronchitis – Nosocomial pneumonia – Intra-abdominal infections • Unique Qualities: – Binds divalent cations (i.e. Ca & Mg) which decreases absorption ADRs – Blood glucose disturbances in DM patients – QTC prolongation, arrhythmias – Nausea, GI upset – Interstitial nephritis
    13. 13. Moxifloxacin • • Administration [Usual Dosage]: IV, PO and ophthalmic [400mg ] • Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) & atypicals (L. pneumophila, C pneumonia & M. pneumoniae), Mycobacterium tuberculosis, gram-negative anaerobes • Indications: – Chronic bronchitis – Bacterial conjuctivitis – Sinusitis • Unique Qualities: – Binds divalent cations (i.e. Ca & Mg) which decreases absorption – Safety and efficacy not established in patients <18 • ADRs – – – – Blood glucose disturbances in DM patients QTC prolongation, arrhythmias Nausea, GI upset Interstitial nephritis
    14. 14. Fluoroquinolones Adverse Effects • Gastrointestinal – 5 %  Nausea, vomiting, diarrhea, dyspepsia • Central Nervous System   Headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures (elderly) • Hepatotoxicity  LFT elevation (withdrawal of trovafloxacin) • Phototoxicity  levofloxacin, pefloxacin • Cardiac   Variable prolongation in QTc interval withdrawal of grepafloxacin, sparfloxacin
    15. 15. Fluoroquinolones Adverse Effects • Articular Damage  Arthropathy, Growing cartilage damage, arthralgias, and joint swelling  Led to contraindication in pediatric patients and pregnant or breast feeding women  Risk versus benefit • Other adverse reactions: tendon rupture, hypersensitivity
    16. 16. Fluoroquinolones Drug Interactions • Divalent and trivalent cations – ALL FQs    Zinc, Iron, Calcium, Aluminum, Magnesium Antacids, Sucralfate, enteral feedings Impair oral absorption of orally-administered FQs – may lead to CLINICAL FAILURE • Theophylline and Cyclosporine - cipro  inhibition of metabolism, levels, • Warfarin – idiosyncratic, all FQs toxicity
    17. 17. Dose of commonly used quinolones Drug Norfloxacin Ciproflaxcin Ofloxacin Pefloxacin Lomefloxacin Sparfloxacin Gatifloxacin Moxifloxacin Gemifloxacin Dosage per day 400mg twice 500-750mg twice 200-400mg twice 400mg twice 400mg once 200-400mg 400mg once 400mg once 320mg once
    18. 18. Introduction • UTIs are defined by the presence of micro organisms within the urinary tract that may be difficult to distinguish between contamination, colonisation or infection
    19. 19. ● UTIs mainly contain gram negative aerobic organisms originating from the gut flora ● Proteus, other Enterobactericiae, S. saprophyticus, enterococci, group B Strep and Chlamydiae cause ~ 20% of uncomplicated UTIs
    20. 20. TYPES ACUTE • Infection localized to urethra and bladder. • frequency,urgency,dysuria, pain in perineum. • No fever chills leucocytosis • Pus cells (+++) • Urine culture (+)– “significant bactertiuria” CHRONIC • General loss of health anaemia,hypertension. • Chronic PylonephritisChronic hypertension &renal failure. • Pus cells (+) • Significant bacteriuria
    21. 21. BACTERIOLOGY • 95% of UTI are due to gram –ve bacilli. -80% E.coli (commonest) -15% Proteus Klebsiella Pseudomonas • 5% of UTI are due to gram +ve cocci Enterococci Staphylococci Streptococci • Mixed infections are likely to be present in chronic cases, in diabetics, obstructive uropathies,indwelling catheters
    22. 22. DRUG THERAPY • BACTERIOSTATIC AGENT Sulfonamides Tetracycline Nitrofurantoin • URINARY ANTISEPTICS Nalidixic acid Methenamine mandelate Nitrofurantoin • BACTERICIDAL AGENTS Cotrimoxazole Ampicillin Extended spect. Penicillin Aminoglycosides Fluroquinolones Cephalosporins
    23. 23. SULFONAMIDES • • • • • Effective against E.coli effective only un complicated UTIs Cheap, easily available,and effective orally Bacterial resistance major problem. DOC: Sulfisoxazole 2g initially 1g for 7-10 days • Prerequisite-Alkaline urine, liberal fluid intake.
    24. 24. NITROFURANTOIN • • • • • • Sybthetic agent, active G-& +ve . proteus, P.aureginosa resistence Rapid g.i. absorption, high urinary concentration. Bacteriostatic against common pathogens. Pseudomonas, proteus resistant. For ‘Chronic suppressive therapy’— 50-100 mg /day for several wks. • Mainly useful for resistant infections, mixed infections, infections associated with obstructive uropathy.
    25. 25. METHENAMINE MANDELATE • Mandelic acid +methenamine Formaldehyde (acid PH 5.5) Active against g-ve pathogens • Not effective in acute ,upper UTI,aginst proteus & pseudomonas • Dose:1 g qid
    26. 26. NALIDIXIC ACID • Used as reserved drug for occasional cases (esp. proteus resistant to other drugs) • Dose: 1gm qid x 7-10 days
    27. 27. COTRIMOXAZOLE • Highly potent and cost effective bactericidal combination used aginst E.coli & proteus. • Dose: acute UTI-2 tab bd x 7-10 days chronic UTI-1 tab twice a wk. • Contraindicated in pregnancy. • Successful in recurrent UTI in men (prostatic focus) • Ineffective in renal insufficiency.
    28. 28. AMPICILLIN • Effective bactericidal to E.coli ,aerobacter. • Proteus,pseudomonas resistant. • Ineffective against penicillinase producing staph. aureus. • Safe in pregnancy • Dose:.0.5 g qid x 7-10 days. • Resistant strains of E.coli esp..hospital acquired has been found.
    29. 29. AMINOGLYCOSIDES • Gentamicin is the only aminoglycoside used in UTI. • Effective against E.coli,proteus,pseudo. • Disadv.- parental use renal toxicity ototoxicity • Reserved for complicated UTI
    30. 30. FLUROQUINOLONES • Ideal agents and drug of choice. • Useful in nosocomial pylonephritis, complicated UTI. • Present status: first line drug for all UTI.
    31. 31. CEPHALOSPORINS • Valuable in infections resistant to other antibiotics (E.coli, Proteus ,Pseudomonas) • Doc. –Klebsiella infections. • Indicated in septicemic UTI.
    32. 32. UPPER UTI 1.Acute uncomplicated pylonephritis: Drug regimen : Cotrimoxazole /Gentamicin with/ without Ampicillin / Cephalosporins 2.Complicated UTI : Minimal symptoms- Cipro. 500mg bd Severe illness : (Inj. Cefotaxime 2g qid iv & Inj.Genta 5 mg/kg od iv) x7-14 days 3.Chronic Pylonephritis ; cause to be searched.

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