Fluroquinolones 2

DR.VIJAY NAGDEV H.O. MEDICAL UNIT-

ICHANDKA MEDICAL COLLEGE LARKANA

BackgroundIn 1962 nalidixic acid was discovered by

George lesher during synthesis of chloroquine and was named as quinolone

Fluoroquinolones were derived by adding flourine atom in nalidixic acid.

Earlier quinolones were useful only for treatment of UTI.

Fluorinated derivatives achieve bactericidal levels in blood and tissues so they have improved antibacterial spectrum.

MECHANISM OF ACTIONFluroquinolones are bactericidal agents

They block bacterial DNA synthesis by inhibiting bacterial DNA gyrase and topoisomerase IV.

Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication

Cont….Inhibition of topoisomeraseIV interferes with

separation of replicated chromosomal DNA into the respective daughter cells during cell division.

They can enter cells easily via porins and are

used to treat intracellular pathogens (Legionella, pneumophila and Mycoplasma)

RESISTANCEResistance is due to • one or more point mutations in the

quinolone binding region of the target enzyme

OR to a change in the permeability of the organism

Resistance to one FQL confers cross resistance to all members of the class.

CLASSIFICATION

Generations Drugs Spectrum

1st

(Quinolone)

Nalidixic acid

Cinoxacin

Gram-ve but not Pseudomonas species

2nd

Norfloxacin

Ciprofloxacin

Enoxacin

Ofloxacin

Gram- ve(including Pseudomonas species), some Gram+ (S. aureus) and some atypicals

3rd

Levofloxacin

Sparfloxacin

Moxifloxacin

Gemifloxacin

Same as 2nd generation with extended Gram+ve and atypical coverage

4th*Trovafloxacin Same as 3rd generation

with broad anaerobic coverage

PharmacokinecticsWell absorbed orally with bioavailability 80-

95% almost equal to i.v.Half life 3-10 hoursOral absorption impaired by divalent

cations(Antacids containg Mg, Ca,or AL ).Most of fluoroquinolones eleminated by renal

mechanism so adjustment required in patients with creatinine clearance <50 ml/min.

Limited CSF penetration.

Distribution [Conc] > serum:

Prostate tissueStoolBileLungKidneys NeutrophilsMacrophages

[Conc] < serum: Prostatic fluidBoneCSF

Drug interactions Drugs increasing levels of FQL

FQL increasing the levels of :

Theophyline Antidepressants

NSAIDS Imipramine

corticosteroids Caffene

Theophyline

Warfarin (INR –monitored)

Adverse effects.Generally safe antibioticsG.I.T-nausea,vomiting,diarrhea and antibiotic

associated colitis have been reported.CNS-confusion,insomnia,dizziness,anxiety,and

seizures(displacement of GABA from its receptors).

CVS-torsade de pointes,prolonged QTc interval.May damage growing cartilage resulting in

arthropathy(but that’s reversible so may b used in psudomonal infections in C.F where benefit outweighs the risk.)

Cont.Tendonitis and tendon rupture is rare but

very serious.Phototoxicity-avoid excesive sun exposure.Leukopenia,eosinophilia (rare)Mild elevation in transaminases (rare)

Contraindication Childrens (not absolute)PregnancyLactationEpilepsyQTc prolongation

Commonly used Fluoroquinolones

Ciprofloxacin 2nd generation fluoroquinoloneMainly effective against G –ve bacteria :Enterobacteriacae H. influenzae M. catarrhalisCampylobacter Pseudomonas N. gonorrheaeIntracellular pathogensM. Tuberculosis Mycoplasma ChlamydiaLegionella BrucellaNot effective against G+ and anaerobes

Clinical uses1.Urinary tract infections (G- bacteria)2. Osteomyelitis due to P. aeruginosa 3. Gonorrhea4. Travellers’ diarrhea- ciprofloxacin

commonly used5. Tuberculosis6. Prostatitis7. Community- acquired pneumoniae 8. Diabetic foot infections ( P. aeruginosa )9.Anthrax

Usual duration is 7-14 days Available forms

Brand name : ciproxin(bayer),cycin.

Oral Parentral Opthalmic

100 mg 200 mg iv 3mg/ml solution

250 mg 400 mg iv 3.3mg/mg ointment

500 mg

Levofloxacin 3rd generation fluoroquinolone

Spectrum: Gram-ve, Gram+ve (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens,

Mycobacterium tuberculosis

Indications:Chronic bronchitis and CAP• Nosocomial pneumoniaIntra-abdominal infections

Cont. Adverse reaction.Blood glucose disturbances in DM patientsQTC prolongation, torsades de pointes, arrhythmiasNausea, GI upsetInterstitial nephritis

Usual duration same 7-14 daysAvailable forms

Brand name:leflox,l-cyn,qumic

Oral Parentral Opthalmic

100 mg 5 mg/ml iv 5mg/ml solution

250 mg 25 mg/ml iv

500mg