Fluoroquinolone

Aka: Fluoroquinolone, Quinolone, Nalidixic Acid

advertisement

II. 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
  11. Otitis Media with patent Tympanostomy Tubes (drops)
  12. Bacterial Conjunctivitis (drops)
  13. Otitis Externa (drops)

III. Contraindications: Relative

  1. Not FDA approved for use under age 18 years
    1. Theoretical cartilage growth suppression
  2. Increasing use in pediatric patients
    1. Quinolones have a long track record of use in children with Cystic Fibrosis
    2. Despite cartilage effects in study young dogs, no strong evidence of similar effects in children
    3. Consider for specific infections (Pseudomonas aeruginosa) or resistant infections (e.g. Pneumonia, Sinusitis)
    4. Transient myalgias and Arthralgias may occur (however Quinolone induced Tendinopathy is rare in children)
    5. Bradley (2014) Pediatrics 134(1):e146-53 [PubMed]

IV. Precautions: FDA Warnings

  1. See adverse effects below
  2. Informed Consent regarding risk is recommended
    1. Avoid high impact while taking Fluoroquinolones
    2. Onset typically within first 1-2 weeks of exposure, but may be delayed up to 90 days
  3. Tendinopathy and tendon rupture risk (FDA Black Box Warning)
    1. Highest risk in age >60 years, males, Chronic Kidney Disease, and especially Corticosteroid use (RR:46)
  4. Peripheral Neuropathy (FDA warning in 2013)
    1. Potentially long-lasting, disabling complication
  5. Aortic Complications (FDA warning in 2019)
    1. Increased risk of Aortic Dissection, aortic aneurysm and Aortic Rupture

V. 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)

VI. Types: Fluoroquinolone classes

  1. First Generation Quinolones (Nalidixic Acid)
    1. Nalidixic Acid (introduced in 1962 as NegGram), is the precursor to the Fluoroquinolone class
    2. Nalidixic Acid is a prodrug, hydroxylated to an active bactericidal agent that concentrates in the urine (but not Prostate)
    3. Nalidixic Acid inhibits a subunit of DNA gyrase, preventing supercoiling, and Bacterial DNA synthesis
    4. Nalidixic Acid has good Gram Negative Rod efficacy (no Pseudomonas coverage), and is useful in Urinary Tract Infections
    5. Nalidixic Acid shares many of the same adverse effects of Fluoroquinolones (e.g. Growth Plate arrest)
  2. Second Generation Quinolones
    1. Most active on Aerobic Gram Negative Rods (including Pseudomonas)
    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 (esp. 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. Examples: Trovafloxacin (Trovan), Delafloxacin (Baxdela)
  5. Other Quinolones
    1. Delafloxacin (Baxdela)
      1. Broad spectrum Antibiotic FDA approved in 2017 for acute Bacterial Skin Infections
      2. Increased Gram Positive coverage (including MRSA) over other Quinolones
      3. However, should be reserved for resistant infections refractory to other agents
      4. (2017) Presc Lett 24(11): 66

VII. Mechanism: Activity Spectrum

  1. General
    1. Disrupts DNA gyrase and DNA topoisomerase, preventing Bacterial DNA synthesis
  2. Most Gram Negative Bacteria
    1. Inhibits DNA gyrase resulting in dsDNA fragmentation
    2. Best Fluoroquinolone Coverage
      1. Second Generation Fluoroquinolone
      2. Third Generation Fluoroquinolone
    3. Bacteria
      1. Enterobacteriaceae (Gram Negative Rods)
      2. Pseudomonas aeruginosa (especially Ciprofloxacin)
      3. HaemophilusInfluenzae
      4. Moraxella catarrhalis
  3. Gram Positive activity varies (4th generation is best)
    1. Inhibits DNA type IV topoisomerase
    2. 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.)
    3. Fluoroquinolones with minimal to no coverage
      1. First Generation Fluoroquinolones
      2. Second Generation Fluoroquinolones
    4. Bacteria
      1. Staphylococci
      2. Streptococci (Streptococcus Pneumoniae)
  4. 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
  5. 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
  6. Fluoroquinolone Bacterial Resistance Mechanisms
    1. Mutations of A Subunits of DNA gyrase
    2. Alterations of outer membrane porins
      1. Affects organism permeability
    3. Antibiotic Resistance has increased due to overuse
      1. Staphylococcus aureus
      2. Escherichia coli
      3. Neisseria gonorrhoeae
      4. Pseudomonas aeruginosa
      5. More virulent strains of Clostridium difficile

VIII. Adverse Effects

  1. Interferes with cartilage growth in animals
    1. Avoid in children under age 18 years (however see caveat under contraindications as above)
  2. Nausea
  3. Taste disturbance
  4. Diarrhea
  5. Photosensitivity
  6. Pruritus or dermatitis
  7. Clostridium difficile (esp. Moxifloxacin)
  8. Retinal Detachment
  9. Glucose effects in Diabetes Mellitus
    1. May result in Hypoglycemia (esp. with sulonylurea) and Hyperglycemia
      1. Kabbara (2015) Ther Clin Risk Manag 11: 639–647 [PubMed]
    2. Increased Hypoglycemia risk in elderly, Renal Insufficiency, especially if on Insulin or Sulfonylurea
      1. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM612834.pdf
  10. Aortic Complications (FDA warning in 2019)
    1. Increased risk of Aortic Dissection, aortic aneurysm and Aortic Rupture (1 in 11,000)
    2. May occur with short Quinolone course, but risk increases with duration, and risk may persist for months
    3. Highest risk (1 in 300) in patients already at risk for aortic complications (Quinolones may double risk)
      1. Elderly
      2. History of aortic aneurysm
      3. Tobacco Abuse
      4. Vascular disease or risk factors (e.g. Hypertension)
      5. Marfan Syndrome
      6. Ehlers-Danlos Syndrome
    4. References
      1. (2019) Presc Lett 26(2): 7
      2. FDA alert
        1. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm
  11. Tendinopathy (black box warning)
    1. Tendinopathy risk with Fluoroquinolones is 4 fold higher than other Antibiotics
    2. Informed Consent regarding risk (and avoiding high impact activities) is recommended
    3. Onset typically within first 1-2 weeks of exposure, but may be delayed up to 90 days
    4. Achilles Tendon Rupture increased risk (3.2 cases per 1000 patient treatment years)
    5. Higher risk patients
      1. Age over 60 years
      2. Chronic Kidney Disease
      3. Concurrent Corticosteroid use (RR 46)
      4. Athletes
      5. Transplant recipients
    6. References
      1. Delaney in Herbert (2015) EM:Rap 15(9):11-2
      2. (2005) Clin Infect Dis 41: 144 [PubMed]
      3. (2002) BMJ 324:1306 [PubMed]
  12. QTc Prolongation (risk of Torsades de Pointes)
    1. Grepafloxacin pulled from U.S. market in 1999
    2. Also may occur with Sparfloxacin and Moxifloxacin
  13. Peripheral Neuropathy
    1. Potentially long-lasting complication with serious Disability (led to FDA warning in 2013)
    2. http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm
  14. Other neurologic effects (3% of patients)
    1. Confusion, Delirium, impaired memory or other mental status changes
      1. Most common in the elderly or those with decreased Renal Function
    2. Seizures (especially if concurrent NSAID use)
    3. Myasthenia Gravis exacerbation
    4. Insomnia
    5. Hallucinations
    6. Headache
    7. Dizziness
    8. Tremors

IX. Safety

  1. Avoided in pregnancy (despite most Fluoroquinolones pregnancy Category C)
    1. Cartilage damage risk
    2. Moxifloxacin is Pregnancy Category X
  2. Considered safe in Lactation
    1. However, risk of pediatric Arthropathy

X. 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
    6. Sulfonylurea associated-Hypoglycemia
  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

XI. References

  1. Mandell (2000) Infectious Disease, Churchill, p. 576
  2. King (2000) Am Fam Physician 61(9):2741-8 [PubMed]
  3. O'Donnell (2000) Infect Dis Clin North Am 14(2):489-513 [PubMed]
  4. Oliphant (2002) Am Fam Physician 65(3):455-64 [PubMed]
  5. Owens (2000) Med Clin North Am 84(6):1447-69 [PubMed]

Images: Related links to external sites (from Bing)

These images are a random sampling from a Bing search on the term "Fluoroquinolone." Click on the image (or right click) to open the source website in a new browser window. Search Bing for all related images

Related Studies

Related Topics in Pharmacology

advertisement