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QUINOLONES
• 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
Structure-Activity Relationships
O
COOH F
Cyclopropyl-
: inc. spectrum
affect G(-ve) activity
NNR1
HN
Piperazine ring
:anti-pseudomonal activity
1
4
5
8
3
8-F- improve P.k
4-quinolone-3-carboxylic acid
Generation Drug Names Clinical use
1st
Norfloxacin CiproflaxcinOfloxacinPefloxacinLomefloxacin
Uncomplicated UTI
2nd
LevofloxacinFleroxacin Clindafloxacin
Complicated UTI, GIT infectionProstatitis, STD
3rdGatifloxacin Sparfloxacin
same+ community acquried pneumonia
4th
AtrofloxacinTrovafloxacin Alatrofloxacin
Major systems infection (abdominal infections)
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
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.
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)
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 cocci3rd generation:• Enhanced activity against G –Ve cocci4th generation:• Enhanced activity against G+Ve cocci+ greater activity
against anaerobes
THERAPEUTIC USES :1. R – RESP TRACT INF. Levofloxacin, sparfloxacin, ofloxacin 2. T – TYPHOID. Cipro, oflo, 3. F – FURUNCULOSIS 4. T – TUBERCULOSIS 5. O – OSTEOMYELITIS – ciproflo- long therapy 4-6week 6. U – U. T. I. Norfloxacin 4-6 weeks7. C – CONJUNCTIVITIS.8. B – BACILLARY DYSENTRY. - Nor, cipro, trallver’s-cotrimoxaz9. O – OTITIS MEDIA. 10. L – LEPROSY 11. S – S. T. D. EXCEPT SYPHILLIS. 2nd line – Cipro, oflo, gati12. M – MENINGITIS. ( 2nd line drugs)
RESERVED THERAPY FOR TREATMENT OF
UNTREATABLE CONDITION BY OTHER
LONG STANDING MICROBICIDALS.
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
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
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
FluoroquinolonesAdverse 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
FluoroquinolonesAdverse 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
FluoroquinolonesDrug 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
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
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
● 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
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
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
DRUG THERAPY
• BACTERIOSTATIC AGENT
SulfonamidesTetracyclineNitrofurantoin
• URINARY ANTISEPTICS
Nalidixic acidMethenamine mandelateNitrofurantoin
• BACTERICIDAL AGENTS
CotrimoxazoleAmpicillinExtended spect. Penicillin
AminoglycosidesFluroquinolonesCephalosporins
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.
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.
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
NALIDIXIC ACID
• Used as reserved drug for occasional cases (esp. proteus resistant to other drugs)
• Dose: 1gm qid x 7-10 days
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.
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.
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
FLUROQUINOLONES
• Ideal agents and drug of choice.
• Useful in nosocomial pylonephritis, complicated UTI.
• Present status: first line drug for all UTI.
CEPHALOSPORINS
• Valuable in infections resistant to other antibiotics (E.coli, Proteus ,Pseudomonas)
• Doc. –Klebsiella infections.• Indicated in septicemic UTI.
UPPER UTI1.Acute uncomplicated pylonephritis:Drug regimen :Cotrimoxazole /Gentamicin with/ without Ampicillin /Cephalosporins
2.Complicated UTI :Minimal symptoms- Cipro. 500mg bdSevere illness :(Inj. Cefotaxime 2g qid iv & Inj.Genta 5 mg/kg od iv) x7-14 days
3.Chronic Pylonephritis ; cause to be searched.