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:        

1^st generation:

• Narrow spectrum; mainly gram-negative.
• Norfloxacin, lomefloxacin.

2^nd generation:

• Ciprofloxacin & ofloxacin.

3^rd generation:

• More active against gram-positive.
• Levofloxacin, gatifloxacin, pefloxacin, sparfloxacin.

4^th 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 1^st generation drugs:

• Norfloxacin – Useful in UTI.
• Urinary concentration is bactericidal; Ineffective for systemic use.

Uses of 2^nd 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.

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