Fluoroquinolone

Aka: Fluoroquinolone, Quinolone, Nalidixic Acid

1. Indications
   1. Cystic Fibrosis
   2. Complicated Urinary Tract Infection
   3. Enteric Fever
   4. Chronic Suppurative Otitis Media
   5. Multi-drug resistant Gram NegativeSepsis
   6. Multi-drug resistant Mycobacterium infection
   7. Skeletal infection caused by Gram Negatives
   8. Febrile neutropenic patients
   9. Bacterial Meningitis with resistant organisms
   10. Neisseria Meningitidis prophylaxis
2. Contraindications: Relative
   1. Not FDA approved for use under age 18 years
      1. Theoretical cartilage growth suppression
   2. Increasing use in pediatric patients
3. Precautions
   1. Tendinopathy and tendon rupture risk (especially over age 60 years) is an FDA Black Box Warning
4. Mechanism
   1. Gram Negative activity
      1. Inhibits DNA gyrase resulting in dsDNA fragmentation
   2. Gram Positive activity
      1. Inhibits DNA type IV topoisomerase
5. Pharmacokinetics
   1. Oral dosing equivalent to intravenous
   2. Tissue penetration
      1. High tissue concentrations
         1. Stool and bile
         2. Prostate
         3. Lung
         4. White Blood Cells: Neutrophils, Macrophages
         5. Kidney and urine
      2. Low tissue concentrations (poor penetration)
         1. Poor cerebrospinal fluid penetration
   3. Excretion
      1. Renal excretion: Most Fluoroquinolones
      2. Hepatic excretion
         1. Sparfloxacin (Zagam)
         2. Moxifloxacin (Avelox)
         3. Trovafloxacin (Trovan)
6. Pathophysiology: Bacterial Resistance Mechanisms
   1. Mutations of A Subunits of DNA gyrase
   2. Alterations of outer membrane porins
      1. Affects organism permeability
7. Mechanism: Fluoroquinolone classes
   1. First Generation Quinolones
      1. Good Gram Negative Rod efficacy
      2. Useful in Urinary Tract Infection
      3. Example: Nalidixic Acid (introduced in 1962)
   2. Second Generation Quinolones
      1. Most active on Aerobic Gram Negative Rods
      2. Some Gram Positive coverage
      3. Example: Ciprofloxacin (Cipro)
   3. Third Generation Quinolones
      1. Broad Spectrum
         1. Gram Negative Rod coverage as above
         2. Greater Gram Positive Cocci coverage
            1. Especially Pneumococcus coverage
      2. Example: Levofloxacin (Levaquin)
   4. Fourth Generation Quinolones
      1. Very Broad spectrum
         1. Gram Negative Rod coverage
         2. Gram Positive Cocci coverage
         3. Anaerobes
      2. Less resistance development
      3. Example: Trovafloxacin (Trovan)
8. Mechanism: Activity Spectrum
   1. Most Gram Negative Bacteria
      1. Best Fluoroquinolone Coverage
         1. Second Generation Fluoroquinolone
         2. Third Generation Fluoroquinolone
      2. Bacteria
         1. Enterobacteriaceae (Gram Negative Rods)
         2. Pseudomonas aeruginosa (especially Ciprofloxacin)
         3. HaemophilusInfluenzae
         4. Moraxella catarrhalis
   2. Gram Positive activity varies (4th generation is best)
      1. Best Fluoroquinolone coverage
         1. Moxifloxacin (strep activity 4-8 fold Levofloxacin)
         2. Trovafloxacin
         3. Levofloxacin (less active for Staph. and Strep.)
         4. Sparfloxacin (less active for Staph. and Strep.)
      2. Fluoroquinolones with minimal to no coverage
         1. First Generation Fluoroquinolones
         2. Second Generation Fluoroquinolones
      3. Bacteria
         1. Staphylococci
         2. Streptococci (Streptococcus Pneumoniae)
   3. Anaerobic Bacteria coverage
      1. Best Coverage
         1. Trovafloxacin
         2. Moxifloxacin (unlabeled use)
         3. Clinafloxacin (most potent against Anaerobes)
      2. Fluoroquinolones with no coverage
         1. First Generation Fluoroquinolones
         2. Second Generation Fluoroquinolones
   4. Atypical bacteria coverage
      1. Bacteria
         1. Legionella pneumophila
         2. Chlamydia pneumoniae
         3. Mycoplasma pneumoniae
         4. Ureaplasma
      2. Best Fluoroquinolone coverage
         1. Moxifloxacin
         2. Levofloxacin
         3. Gemifloxacin
9. Adverse Effects
   1. Interferes with cartilage growth in animals
      1. Avoid in children under age 18 years
   2. Nausea
   3. Taste disturbance
   4. Diarrhea
   5. Photosensitivity
   6. Pruritus or dermatitis
   7. Tendinopathy (black box warning)
      1. Onset at approximately day 13 of therapy
      2. Achilles Tendon Rupture increased risk (3.2 cases per 1000 patient treatment years)
      3. Higher risk patients
         1. Age over 60
         2. Concurrent Corticosteroid use
         3. Athletes
         4. Transplant recipients
      4. References
         1. (2005) Clin Infect Dis 41: 144
         2. (2002) BMJ 324:1306
   8. QTc Prolongation (risk of Torsades de Pointes)
      1. Grepafloxacin pulled from U.S. market in 1999
      2. Also may occur with Sparfloxacin and Moxifloxacin
   9. Neurologic effects
      1. Seizures (especially if concurrent NSAID use)
      2. Confusion
      3. Headache
      4. Dizziness
      5. Tremors
10. Drug Interactions
    1. Antiarrhythmics or Cisapride (risk QTc prolongation)
    2. NSAIDs (risk of Seizure)
    3. Increases level of other medications
       1. Increased Anticoagulation effect with Coumadin
       2. Increased Cyclosporine (also risks nephrotoxicity)
       3. Increased Caffeine level
       4. Increased Theophylline levels
       5. Increased Riluzole levels
    4. Chelates with cations (decreased Quinolone absorption)
       1. Avoid these agents within 2 hours of Quinolone
       2. Antacids containing Magnesium, Aluminum or Calcium
       3. Iron Sulfate
       4. Zinc
       5. Calcium
       6. Didanosine
       7. Sucralfate
    5. Decreases Norfloxacin activity
       1. Chloramphenicol
       2. Nitrofurantoin
       3. Rifampin
       4. Tetracycline
11. References
    1. Mandell (2000) Infectious Disease, Churchill, p. 576
    2. King (2000) Am Fam Physician 61(9):2741-8
    3. O'Donnell (2000) Infect Dis Clin North Am 14(2):489-513
    4. Oliphant (2002) Am Fam Physician 65(3):455-64
    5. Owens (2000) Med Clin North Am 84(6):1447-69