Fluoroquinolone

See Also

Indications

Cystic Fibrosis
Complicated Urinary Tract Infection
Enteric Fever
Chronic Suppurative Otitis Media
Multi-drug resistant Gram Negative Sepsis
Multi-drug resistant Mycobacterium infection
Skeletal infection caused by Gram Negatives
Febrile neutropenic patients
Bacterial Meningitis with resistant organisms
Neisseria Meningitidis prophylaxis
Otitis Media with patent Tympanostomy Tubes (drops)
Bacterial Conjunctivitis (drops)
Otitis Externa (drops)

Contraindications
Relative

Not FDA approved for use under age 18 years
1. Theoretical cartilage growth suppression
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]

Precautions
FDA Warnings

See adverse effects below
Informed Consent regarding black box warnings is recommended
1. Avoid high impact sports (e.g. bounding Exercises) while taking Fluoroquinolones
2. Onset typically within first 1-2 weeks of exposure, but may be delayed up to 90 days
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)
Peripheral Neuropathy (FDA warning in 2013)
1. Potentially long-lasting, disabling complication
Aortic Complications (FDA warning in 2019)
1. Increased risk of Aortic Dissection, aortic aneurysm and Aortic Rupture

Pharmacokinetics

Oral dosing equivalent to intravenous
Enterohepatic circulation (excreted in bile and reabsorbed by intestinal tract)
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
Excretion
1. Renal excretion
  1. Most Fluoroquinolones
2. Hepatic excretion
  1. Sparfloxacin (Zagam)
  2. Moxifloxacin (Avelox)
  3. Trovafloxacin (Trovan)

Types
Fluoroquinolone classes

First Generation Quinolones (Nalidixic Acid)
1. Nalidixic Acid (introduced in 1962 as NegGram), is the precursor to the Quinolone class
  1. Nalidixic Acid is a Quinolone (without fluorine)
  2. Subsequent agents added fluorine, resulting in Fluoroquinolones
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)
Second Generation Quinolones
1. Most active on Aerobic Gram Negative Rods (including Pseudomonas)
2. Some Gram Positive coverage
3. Example: Ciprofloxacin (Cipro)
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)
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)
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

Mechanism
Activity Spectrum

General
1. Disrupts DNA gyrase and DNA topoisomerase, preventing Bacterial DNA synthesis
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. Haemophilus Influenzae
  4. Moraxella catarrhalis
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)
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
Atypical Bacteria coverage
1. Bacteria
2. Best Fluoroquinolone coverage
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

Adverse Effects

Interferes with cartilage growth in animals
1. Avoid in children under age 18 years (however see caveat under contraindications as above)
Nausea
Taste disturbance
Diarrhea
Photosensitivity
Pruritus or dermatitis
Clostridium difficile (esp. Moxifloxacin)
Retinal Detachment
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
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
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]
QTc Prolongation (risk of Torsades de Pointes)
1. Grepafloxacin pulled from U.S. market in 1999
2. Also may occur with Sparfloxacin and Moxifloxacin
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
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

Safety

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

Drug Interactions

Antiarrhythmics or Cisapride (risk QTc Prolongation)
NSAIDs (risk of Seizure)
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
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
Decreases Norfloxacin activity

References

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