Fluoroquinolones

FLUOROQUINOLONES


FLUOROQUINOLONES

  • Oral agents.
  • Have long post-antibiotic effect (PAE).

MOA:

  • Acts by inhibiting DNA gyrase (topoisomerase II) & topoisomerase IV –> DNA replication inhibition.

Classification of fluoroquinolones:

  • Based on spectrum of antibacterial activity:        
  • 1st generation:
    • Narrow spectrum; mainly gram-negative.
    • Norfloxacin, lomefloxacin.
  • 2nd generation:
    • Ciprofloxacin & ofloxacin.
  • 3rd generation:
    • More active against gram-positive.
    • Levofloxacin, gatifloxacin, pefloxacin, sparfloxacin.
  • 4th generation:
    • Broadest spectrum.
    • Moxifloxacin, fleroxacin, garenoxacin, gemifloxacin & trovafloxacin.

Pharmacokinetics:

  • Good oral bioavailability (except norfloxacin).
    • Levofloxacin – 100% bioavailability.
  • Multivalent cations interfere with absorption (like tetracycline).               

Metabolism & excretion:

  • Hepatic metabolism & biliary excretion
    • Moxifloxacin & trovafloxacin.
  • Excreted by both renal & hepatic route – 
    • Sparfloxacin & pefloxacin.
  • Excreted by tubular secretion – 
    • All other drugs (ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin & ofloxacin).
    • Probenecid inhibits tubular secretion.

Half-lives:

  • Sparfloxacin, moxifloxacin & trovafloxacin – Long half-lives.
  • Sparfloxacin – Longest half-life among fluoroquinolones.
  • Hence, administered once daily orally.

Dose adjustment:

  • Required in renal disease for all fluoroquinolones, except pefloxacin, moxifloxacin & trovafloxacin (mnemonic: PMT).

Individual drug description:

  • Levofloxacin:
    • L-isomer of ofloxacin.
  • Sparfloxacin:
    • Greater activity against gram-positive organisms; Ineffective against Pseudomonas.

Clinical Uses:

  • Greatest activity against Pseudomonas (maximum with ciprofloxacin).
  • Uses of 1st generation drugs:
    • Norfloxacin – Useful in UTI.
    • Urinary concentration is bactericidal; Ineffective for systemic use.
  • Uses of 2nd generation drugs:
    • Ciprofloxacin – DOC for prophylaxis & treatment of anthrax & for prophylaxis of meningococcal meningitis.

Combination drugs:

  • Ciprofloxacin & ofloxacin – Effective against gonorrhea & other gram-negative organisms including Pseudomonas.
  • Ciprofloxacin & levofloxacin – Only fluoroquinolones effective against Pseudomonas.
  • Levofloxacin -Effective against atypical microorganism (mycoplasma) infection.
  • “Respiratory fluoroquinolones”: 
    • Levofloxacin, gatifloxacin, gemifloxacin & moxifloxacin.
    • Due to their enhanced activity against gram-positive & atypical organisms (chlamydia, mycoplasma & legionella).
  • Moxifloxacin & trovafloxacin: 
    • Widest spectrum including gram (-ve) & gram (+ve) micro-organisms, including anaerobes.
  • Ciprofloxacin, levofloxacin &moxifloxacin:
    • Effective in tuberculosis.
    • For prophylaxis of neutropenic patients.
  • Finafloxacin – 
    • Recently approved for topical treatment of acute otitis externa caused by Pseudomonas & Staphylococcus.
    • Used for adolescent cystic fibrosis with pulmonary exacerbations.

Contraindications:

  • Epilepsy.
  • In children less than 18 yrs old & in pregnancy – Due to cartilage problems.

Adverse effects:

  • GI distress (most common).
  • CNS side effects (headache & dizziness; rarely seizures).
  • Tendinitis resulting in tendon rupture (rarely in adults).
  • Phototoxicity (maximum incidence with lomefloxacin & sparfloxacin).
  • Sparfloxacin & gatifloxacin prolong QTc interval.

Withdrawn fluoroquinolones: 

  • Temafloxacin – Immune hemolytic anemia.
  • Gatifloxacin – Dysglycemic effects.
  • Trovafloxacin – Hepatotoxicity.
  • Grepafloxacin – Cardiotoxicity, arrhythmias due to increasing QT interval.
  • Clinafloxacin – Phototoxicity.
  • Recent FDA warning on peripheral neuropathy by fluoroquinolones.

Drug interactions:

  • With methylxanthines (theophylline):
    • Fluoroquinolones (particularly ciprofloxacin or pefloxacin) increase plasma methylxanthines concentration (Theophylline).
    • Enhances theophylline toxicity.
  • With NSAID’s:
    • NSAIDs increase CNS toxicity (seizures) of these drugs.
    • Hence, contra-indicated in epilepsy.

Exam Important

  • Fluoroquinolones have long post-antibiotic effect (PAE).
  • Fluoroquinolones act by inhibiting DNA gyrase (topoisomerase II) & topoisomerase IV –> DNA replication inhibition.
  • 1st generation fluoroquinolones (Norfloxacin lomefloxacin) are narrow spectrum, mainly gram-negative.
  • Ciprofloxacin & ofloxacin are 2nd generation fluoroquinolones.
  • 3rd generation fluoroquinolones are more active against gram-positive.
  • Levofloxacin, gatifloxacin, pefloxacin, sparfloxacin belong with 3rd generation fluoroquinolones.
  • Broadest spectrum fluoroquinolones are 4th generation flouroquinolones.
  • Moxifloxacin & trovafloxacin is hepatic metabolism & biliary excretion.
  • Sparfloxacin & pefloxacin is excreted by both renal & hepatic route.
  • All other drugs (ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin & ofloxacin) excreted by tubular secretion.
  • Sparfloxacin, moxifloxacin & trovafloxacin exhibit long half-lives, administered once daily orally.
  • Sparfloxacin is longest half-life among fluoroquinolones.
  • Dose adjustment required in renal disease for all fluoroquinolones, except pefloxacin, moxifloxacin & trovafloxacin (mnemonic: PMT).
  • Norfloxacin is useful in UTI, urinary concentration is bactericidal.
  • Ciprofloxacin is DOC for prophylaxis & treatment of anthrax & meningococcal meningitis prophylaxis.
  • Ciprofloxacin & ofloxacin is effective against gonorrhea.
  • Ciprofloxacin & levofloxacin is only fluoroquinolones effective against Pseudomonas.
  • “Respiratory fluoroquinolones” include Levofloxacin, gatifloxacin, gemifloxacin & moxifloxacin, due to their enhanced activity against gram-positive & atypical organisms (chlamydia, mycoplasma & legionella).
  • Moxifloxacin & trovafloxacin is widest spectrum including gram (-ve) & gram (+ve) micro-organisms, including anaerobes.
  • Ciprofloxacin, levofloxacin & moxifloxacin are effective in tuberculosis.
  • Finafloxacin is approved for topical treatment of acute otitis externa, caused by Pseudomonas & Staphylococcus.
  • Fluoroquinolones are contraindicated in epilepsy.
  • Maximum incidence of phototoxicity is with lomefloxacin & sparfloxacin.
  • Sparfloxacin & gatifloxacin prolong QTc interval.
  • Grepafloxacin is cardiotoxicity, arrhythmias increasing QT interval.
  • Recent FDA warning on peripheral neuropathy by fluoroquinolones.
  • Fluoroquinolones (particularly ciprofloxacin or pefloxacin) increase plasma methylxanthines concentration (Theophylline), enhances theophylline toxicity.
  • NSAID’s with fluoroquinolones, NSAIDs increase CNS toxicity (seizures) of these drugs, hence contra-indicated in epilepsy.

 

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