QUINOLONES

Dr.Rahul Asso. Prof. pharmacology

RMC, PIMS (DU)

Quinolones

Bactericidal broad spectrum drugs Increasingly used because of their relative

safety, their availability both orally and par-enterally and their favorable pharamacokinet-ics

There is increasing concern about the emer-gence of resistance to these agents

Parent drug: nalidixic acid

Classification

Quinolones (1st generation)Highly protein boundMostly used in UTIs

Fluoroquinolones (2nd, 3rd and 4th genera-tion)Modified 1st generation quinolonesNot highly protein boundWide distribution to urine and other tissues; lim-ited CSF penetration.

Genera-tion

Drug Names Spectrum

1stNalidixic acid Cinoxacin

Gram- but not Pseu-domonas

2nd

NorfloxacinCiprofloxacin Ofloxacin

Gram-(including Pseu-domonas) some Gram+ (S. aureus)some atypicals

3rd

Levofloxacin Sparfloxacin MoxifloxacinGemifloxacin

Same as 2nd generation: extended Gram+ and atyp-ical coverage

4th*Trovafloxacin Same as 3rd generation:

broad anaerobic coverage *withdrawn from the market in

1999

FQs Spectrum of Activity

Gram-positive

Older agents with poor activity; newer FQs with enhanced potency

• Methicillin-susceptible Staphylococcus au-reus

• Streptococcus pneumoniae (including PRSP)• Group and viridans streptococci – limited activ-

ity• Enterococcus sp. – limited activity

Gram-Negative all FQs have excellent activity

(cipro=levo>gati>moxi)

• E. coli, Klebsiella sp,• Enterobacter sp, Proteus sp• Salmonella Shigella,• Serratia marcescens, H. influenzae, • M. catarrhalis, Neisseria sp.

• Pseudomonas aeruginosa significant resistance has emerged; ciprofloxacin and levofloxacin with best activ-ity

FQs Spectrum of ActivityAtypical Bacteria

– All FQs have excellent activity against atypi-cal bacteria including:

Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum

Mechanism of action:

Enzymes required for DNA replication

1.Topoisomerase II (DNA gyrase): GyrA and GyrB2.Topoisomerase IV: ParC and ParE

Mechanism of DNA gyrase

Mechanism of action:

Inhibit bacterial DNA synthesis by in-hibiting DNA gyrase and topoiso-merase IV rapid cell death

Mostly Topo II inhibition in G- bacterias Topo IV inhibition more in G+ bacterias Post antibiotic effect: lasts 1 to 2

hours, increases with increasing con-centration

PK and PD profile

Absorption - good oral availability, but food will inhibit, as well as Al, Ca, Mag, Fe.

Distribution - good tissue penetra-tion, including prostate, bile, lung. Poor CNS coverage

Elimination – renal (for 1st genera-tion)

PD: Concentration dependent killing

USES

UTI Bacterial gastroen-

teritis Intra abdominal in-

fections Typoid fever Gonorrehea MDR- tuberculosis Leprosy Osteomyelitis

Invasive otitis media Nosocomial pneumo-

nia Septicemia Bacterial conjuctivitis Chronic bronchitis Sinusitis Anthrax

UTI

Most commonly used antimicrobials Very effective against E.coli, proteus, Enter-

obacteriace Higher urine conc. than serum conc.good

for complicated renal cysts & recurrent UTI from prostatitis

Ciprofloxacin 750mg bd X 3 wks

Bacterial diarrheoas

Very effective against shigella, salmo-nella,, E.coli.

Norfloxacin, ciprofloxacin , ofloxacin are effecive

Intraabdominal or Gi Infec-tions

(Comparative studies) 1) ciprofloxacin + metronidazole 2) Imipenem 3) Trovafloxacin

4) amoxicillin/clavulanate similar activity

Typhoid

Ciprofloxacin 750mg BD X 10 days Pefloxacin, Ofloxacin can also be used

Gonnococcal infection

Cervicitis Urethritis PID Single dose :Cipro..500mg, Oflox. 400mg Problem : resistance So Ceftriaxone first drug of choice

Mycobacterial infections

MDR tuberculosis MAC infections Leprosy (ROM theraphy)

Skin and soft tissue infections

Trovafloxacin approved by the FDA for treatment of soft-tissue infections, including DM foot

Levofloxacin Superior to ciprofloxacin in SSTI caused by S. aureus

Clinical uses of New Fluoroquinolones (Levofloxacin & Next G FQs)

Community-acquired Pneumonia

Outpatients : new fluoroquinolones Hospitalized General wards : new FQs monotherapy

ICU : -lactam + new FQs

Upper respiratory infections : acute sinusitis, chronic bronchitis

Other uses

Prophylaxis and treatment of infections in neutropenic patients

Conjunctivitis due to G-ve bacteria Invasive otitis media Prophylaxis and exposure Anthrax Respiratory infection : (Levofloxacin)

Chronic bronchitis Nosocomial pneumonia Sinusitis

FluoroquinolonesAdverse Effects

Gastrointestinal – 5 % Nausea, vomiting, diarrhea, dyspepsia

Central Nervous System Headache, agitation, insomnia, dizziness, rarely, hallucinations and seizures (elderly)

Hepatotoxicity LFT elevation (led to withdrawal of trovafloxacin)

Phototoxicity (uncommon with current FQs) More common with older FQs (halogen at position 8)

Cardiac Variable prolongation in QTc interval Led to withdrawal of grepafloxacin, sparfloxacin

FluoroquinolonesAdverse Effects

Articular Damage Arthopathy including articular cartilage damage,

arthralgias, and joint swelling contraindication in pediatric patients and pregnant

or breast feeding women Risk versus benefit

Other adverse reactions: Tendon rupture, Dysglycemias, Hypersensitivity

Fluroquinolone

Doses Preferred Uses

Norloxacin 400mg OD/BD UTIBacterial Diarrheoas

Ciprofloxacin 250-750mg BD

UTITyphoidBacterial diarrheoasGonorrhea…etc

Ofloxacin 200-400mg BD

Tuberculosis LeprosyAtypical PneumoniaChlamydial infections

Levofloxacin 500mg OD Community aquired pnumoniaBronchitis, UTISkin & soft tissue infections

Gatifloxacin Community aquired pnumoniaBronchitis, UTIGonnococcal infections

Moxifloxacin Community aquired pnumoniaBronchitis, Sinusitis, otitis media