Quinolones &UTI

1. QUINOLONES

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. Structure-Activity Relationships O COOH F Cyclopropyl - : inc. spectrum affect G(- ve ) activity N N R 1 HN Piperazine ring :anti- pseudomonal activity 1 4 5 8 3 8-F- improve P.k 4-quinolone-3-carboxylic acid

4. Generation Drug Names Clinical use 1st Norfloxacin Ciproflaxcin Ofloxacin Pefloxacin Lomefloxacin Uncomplicated UTI 2nd Levofloxacin Fleroxacin Clindafloxacin Complicated UTI, GIT infection Prostatitis , STD 3rd Gatifloxacin Sparfloxacin same+ community acquried pneumonia 4th Atrofloxacin Trovafloxacin Alatrofloxacin Major systems infection (abdominal infections)

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 IN COMP. TO G + BACTERIA . - ve

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. 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. Anti microbial spectrum 1 st 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 2 nd generation : Better activity against G+ve cocci 3 rd generation : Enhanced activity against G – Ve cocci 4 th generation : Enhanced activity against G+Ve cocci + greater activity against anaerobes

9. THERAPEUTIC USES : 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. 2 nd line – Cipro , oflo , gati M – MENINGITIS. ( 2 nd line drugs)

10. R ESERVED T HERAPY F OR T REATMENT O F U NTREATABLE C ONDITION B Y O THER L ONG S TANDING M ICROBICIDALS .

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. 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. 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. 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. 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. 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,  toxicity Warfarin – idiosyncratic, all FQs

17. Dose of commonly used quinolones Drug Dosage per day Norfloxacin 400mg twice Ciproflaxcin 500-750mg twice Ofloxacin 200-400mg twice Pefloxacin 400mg twice Lomefloxacin 400mg once Sparfloxacin 200-400mg Gatifloxacin 400mg once Moxifloxacin 400mg once Gemifloxacin 320mg once

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. 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. 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 Pylonephritis-Chronic hypertension &renal failure. Pus cells (+) Significant bacteriuria

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. 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. 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. 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. 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. NALIDIXIC ACID Used as reserved drug for occasional cases (esp. proteus resistant to other drugs) Dose: 1gm qid x 7-10 days

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. 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. 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. FLUROQUINOLONES Ideal agents and drug of choice. Useful in nosocomial pylonephritis, complicated UTI. Present status: first line drug for all UTI.

31. CEPHALOSPORINS Valuable in infections resistant to other antibiotics (E.coli, Proteus ,Pseudomonas) Doc. –Klebsiella infections. Indicated in septicemic UTI.

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.