Fluoroquinolones (DNA Gyrase Inhibitors) PDF

FLUOROQUINOLONES (DNA GYRASE INHIBITORS) Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  2 Fluoroquinolones 1st gen Nalidixic acid - Cover only g...

FLUOROQUINOLONES (DNA GYRASE INHIBITORS) Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  2 Fluoroquinolones 1st gen Nalidixic acid - Cover only gram-negative - Inadequate tissue levels for systemic infections 2nd gen Ciprofloxacin, - Against some gram positive, aerobic gram-negative and atypical Norfloxacin, bacteria Ofloxacin - Significant intracellular penetration 3rd gen Levofloxacin - Cover gram-positive bacteria (greater), gram-negative (lesser) and atypical bacteria 4th gen Moxifloxacin - Cover gram-negative and enhanced activities against anaerobic and gram-positive Moxifloxacin  Mechanism ofaction Inhibition of Topoisomerase II (DNA gyrase) prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication 1st and 2nd gen are more selective on this target  Mechanism ofaction Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. 3rd and 4th gen are more selective on this target  9 Antimicrobial spectrum Alternative for patients with severe B-lactam allergy Bactericidal. Effective against gram-positive (streptococci), gram-negative (Escherichia coli, P. aeruginosa, Haemophilus influenzae), atypical organisms (Legionellaceae, Chlamydiaceae), and some mycobacteria (Mycobacterium tuberculosis). Levofloxacin, moxifloxacin (respiratory fluoroquinolones)----excellent against S. pneumoniae, community-acquired pneumonia (CAP).  13 Antimicrobial spectrum Quinolones = most commonly used to treat serious infections caused by Klebsiella pneumoniae (Nosocomial pathogen) and other members of the genus Enterobacteriaceae.  11 Resistance 1.Altered target: Mutations in the bacterial DNA gyrase and Topoisomerase IV (decreased affinity) 2. Decreased accumulation: ↓ porin proteins in the outer membrane. ↓ Energy-dependent efflux system in the cell membrane.  15 Clinical Uses Ciprofloxacin: - treat systemic infections caused by gram-negative Bacilli. - Against Pseudomonas aeruginosa and is commonly used in cystic fibrosis patients for this indication. - Treat traveler’s diarrhoea caused by E. coli and typhoid fever caused by Salmonella typhi Levofloxacin (active aginst streptococci): Respiratory - Treat prostatitis, skin infections, CAP and nosocomial fluoroquinolones!! pneumonia (broad spectrum). - Excellent activity against pneumococcus. Moxifloxacin: - Enhanced activity against gram-positive organisms (for example, S. pneumoniae) but also has excellent activity against many ANAEROBES. - Does not concentrate in urine and is not indicated for the treatment of UTIs.  18 Adversereactions 1.Gastrointestinal: Nausea, vomiting, and diarrhea 2. Central nervous system problems: headache, dizziness/light- headedness. 3. Phototoxicity 4. Peripheral neuropathy and glucose dysregulation (hypoglycaemia) 5. Tendonitis and tendon rupture: Avoid to use these drugs in pregnancy, lactation and < 18 years old  12 Pharmacokinetics Absorption Well oral absorption excepts for Norfloxacin (25-70%) ↓ fluoroquinolones absorption if taken with sucralfate (antacids containing aluminum or magnesium), dietary supplements containing iron/zinc and calcium products. Distribution Binding to plasma proteins ranges from 10% to 40%. Well distributed to all tissues and body fluids excepts CSF (But ofloxacin can cross BBB well) Levels are high in bone, urine (except moxifloxacin), kidney, and prostatic tissue (but not prostatic fluid), and concentrations in the lungs > serum. Accumulate in macrophages and polymorphonuclear leukocytes (against intracellular organisms such as Legionella pneumophila and Mycoplasma pneumoniae). Elimination Fluoroquinolones are excreted renally excepts for moxifloxacin.  31 T H A N K O U ;)