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.