Fluoroquinolones

Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. A new fluoroquinolone, delafloxacin, covers both Pseudomonas aeruginosa and MRSA. Although fluoroquinolones have a wide spectrum of activity, the use is limited secondary to a number of risks associated with the fluoroquinolone class (i.e. permanent peripheral neuropathy and tendon rupture in children). Fluoroquinolones are indicated in complicated urinary, respiratory, intra-abdominal, bone, joint, and skin infections. Fluoroquinolones are 2nd-line agents used to treat tuberculosis and 1st-line agents in a number of less common infections (e.g., anthrax, plague, and tularemia).

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Classification and Chemistry

Classification

Fluoroquinolones are a class of broad-spectrum antibiotics. The common medications in the class include:

  • 1st generation: norfloxacin (no longer clinically used)
  • 2nd generation:
    • Ciprofloxacin (prototypical drug)
    • Ofloxacin
  • 3rd generation:
    • Levofloxacin
    • Moxifloxacin
    • Gemifloxacin
  • 4th generation: delafloxacin

Chemical structure

Fluoroquinolone structures:

  • Bicyclic core structure (all)
  • Ketone functional group (quinolones)
  • Fluorine atom (fluoroquinolones)

Mechanisms of Action and Resistance

Mechanism of action

  • Fluoroquinolones directly inhibit bacterial DNA synthesis by binding to:
    • Topoisomerase II (DNA gyrase) in gram-negative organisms
    • Topoisomerase IV in gram-positive organisms
  • Topoisomerase enzymes:
    • Unwind DNA prior to replication
    • Have both nuclease (DNA cleaving) and ligase (DNA repairing) activity
  • Fluoroquinolone binding to enzymes results in:
    • Inhibition of ligase activity only
    • DNA cleavage without the ability to repair the DNA
    • Cessation of DNA replication with broken DNA strands
    • Cell death → fluoroquinolones are bactericidal

Mechanisms of resistance

The dominant mechanisms of fluoroquinolone resistance:

  • ↓ Accumulation of the drug within bacterial cells:
    • ↓ Expression of porin channels → ↓ entry of the drug into cells
    • ↑ Expression of efflux pumps
  • ↓ Affinity of the drug to the target:
    • Chromosomal point mutations change the structure of the topoisomerase and affect the binding site.
    • The mutations are drug and bug specific (e.g., gyrA genes in Neisseria gonorrhoeae)
    • Plasmid-mediated resistance (typically a low-level resistance)

Clinically important resistance patterns

As resistance to fluoroquinolones becomes more common, fluoroquinolone use may be limited for the following indications:

  • Neisseria gonorrhoeae
  • Pseudomonas aeruginosa
  • Urinary tract infections (UTIs)
  • Typhoid

Pharmacokinetics

Absorption

  • Well absorbed in the upper GI tract
  • Good oral bioavailability
    • Levofloxacin (99%) > moxifloxacin (90%) > gemifloxacin/ciprofloxacin (70%) > delafloxacin (60%)
    • Ingestion with dairy, mineral supplements, and most antacids can significantly ↓ bioavailability
  • Peak concentrations: 1–3 hours after an oral dose

Distribution

  • Large volumes of distribution (VD): most exceed the total body water volume → the drug accumulates in the tissue
  • Drugs concentrate in:
    • Prostate tissue
    • Bile and stool
    • Lungs
    • Kidneys (except moxifloxacin)
    • Neutrophils and macrophages

Metabolism

  • < 15% of drug concentrations undergo hepatic metabolism (except moxifloxacin)
  • Moxifloxacin:
    • Approximately 50% of the drug is metabolized in the liver.
    • Metabolized via glucuronidation and sulfate conjugation rather than CYP450 mechanisms
  • Ciprofloxacin: 
    • Inhibits CYP1A2 → can ↑ the levels of drugs metabolized by CYP1A2
    • Some affected drugs include:
      • Clozapine
      • Theophylline
      • Tizanidine

Excretion

  • Elimination:
    • Primarily via renal tubular secretion (except moxifloxacin)
    • Some fecal excretion for ciprofloxacin, moxifloxacin, gemifloxacin, and delafloxacin
  • Moxifloxacin:
    • Hepatic clearance
    • May be used in renal failure
    • Should not be used for UTIs
  • Half-life: 3–9 hours (typically dosed twice daily)

Spectrum of Activity

Fluoroquinolones are considered broad-spectrum antibiotics: Ciprofloxacin covers gram-negative rods the best; Levofloxacin and moxifloxacin provide excellent coverage of most potential respiratory pathogens; Delafloxacin covers both P. aeruginosa and MRSA.

Aerobic gram-negative organisms

  • Drugs with activity:
    • Most fluoroquinolones are highly active against gram-negative rods.
    • Ciprofloxacin has the most activity.
  • Organisms covered by fluoroquinolones:
    • Enterobacteriaceae: 
      • Escherichia coli
      • Klebsiella spp.
      • Proteus spp.
    • Haemophilus spp.
    • Moraxella catarrhalis
    • P. aeruginosa (ciprofloxacin > levofloxacin and delafloxacin > moxifloxacin)
    • Neisseria meningitidis and N. gonorrhoeae

Aerobic gram-positive organisms

  • Drugs with activity: 
    • Primarily the later generation drugs: 
      • Levofloxacin
      • Moxifloxacin
      • Delafloxacin
    • Ciprofloxacin has limited-to-no activity against the organisms.
  • Organisms covered:
    • Staphylococcus aureus (MRSA by delafloxacin only)
    • Some Streptococcus spp. (including S. pneumoniae)

Atypical and anaerobic respiratory pathogens

Atypical organisms 

  • Drugs with activity:
    • Levofloxacin
    • Moxifloxacin
  • Organisms covered: 
    • Mycoplasma spp. (M. tuberculosis):
      • 2nd-line agents to treat tuberculosis
      • Used in cases of resistance and/or intolerance to 1st-line agents
    • Legionella spp.
    • Chlamydia pneumoniae

Anaerobic organisms

  • Moxifloxacin only
  • Covers anaerobic respiratory infections:
    • Aspiration pneumonia
    • Lung abscess
  • Generally not effective against Bacteroides (limited use for intra-abdominal infections)

Other organisms

Fluoroquinolones are also considered 1st-line options against susceptible infections caused by:

  • Bacillus anthracis
  • Francisella tularensis
  • Salmonella typhi
  • Yersinia pestis

Indications

Compared to other antibiotics, fluoroquinolones are associated with a higher risk of potentially permanent and disabling adverse events. Therefore, fluoroquinolones are generally not used for uncomplicated infections and should only be used against susceptible bacteria.

Complicated infections

  • Genitourinary infections:
    • Complicated UTIs and pyelonephritis
    • Prostatitis (acute and chronic)
    • Pelvic inflammatory disease
    • May be used in uncomplicated cystitis when no alternative options exist
  • Respiratory infections:
    • Hospital-acquired pneumonia
    • Pneumonia caused by multidrug-resistant (MDR) S. pneumoniae
    • Atypical pneumonia
    • Tuberculosis (levofloxacin and moxifloxacin (2nd-line agents))
    • May be used in uncomplicated infections when no alternative options exist:
      • Bacterial sinusitis
      • Chronic obstructive pulmonary disease (COPD) exacerbations
  • Abdominal infections:
    • Complicated intra-abdominal infections (in combination with metronidazole for anaerobic coverage)
    • Peritonitis and infection related to a peritoneal dialysis catheter
  • Skin, soft tissue, and musculoskeletal infections:
    • Bone and joint infections (including prosthetic joint infections)
    • Diabetic foot infections
    • Skin infections
    • Surgical prophylaxis in patients allergic to 1st-line agents (e.g., cephalosporins)
    • Infections from bite wounds
  • Nervous system infections: bacterial meningitis

Infections caused by single organisms

  • Travelers diarrhea (E. coli, Shigella, or Campylobacter)
  • Typhoid fever (Salmonella typhi)
  • Anthrax (Bacillus anthracis)
  • Tularemia (Francisella tularensis)
  • Plague (Yersinia pestis)
  • Cat scratch disease (Bartonella henselae)
  • Cholera (Vibrio cholerae)
  • Chancroid (Haemophilus ducreyi)

Adverse Effects and Contraindications

Adverse effects

Fluoroquinolones carry higher risks than many other antibiotics, which limits the use. Although adverse effects are uncommon, some may be permanent or severe.

  • Neurologic effects:
    • Common mild effects: 
      • Headache
      • Dizziness
      • Insomnia (transient)
    • Less common, more serious effects:
      • Peripheral neuropathy (may be permanent)
      • Delirium, psychosis, and/or hallucinations
      • Seizures
    • Exacerbation of myasthenia gravis
  • Musculoskeletal effects (especially in growing children and teenagers):
    • Tendinopathy, including tendon rupture:
      • Most often the Achilles tendon
      • Advise individuals to stop taking fluoroquinolone if pain and/or swelling develop.
    • Arthropathy:
      • Cartilage erosions
      • Noninflammatory effusions
  • GI effects:
    • Nausea, vomiting, and/or abdominal discomfort
    • Diarrhea (less common)
    • Clostridioides difficile infection
    • Hepatotoxicity (several drugs have been removed from the market due to hepatotoxicity)
  • Cardiovascular effects:
    • QT prolongation
    • Aortic aneurysm and dissection
  • Other effects:
    • Skin rashes
    • Phototoxicity
    • Dysglycemia (highest risk is with moxifloxacin in diabetic individuals)

Contraindications

  • Hypersensitivity to fluoroquinolones
  • Pregnancy
  • Growing children and teenagers
  • Concurrent use with other medications prolonging the QT interval
  • Myasthenia gravis
  • Use with caution with:
    • Diabetes
    • Rheumatoid arthritis (risk of tendon rupture)
    • Aortic aneurysm/dissection
    • Renal impairment (ciprofloxacin, levofloxacin, and delafloxacin)
    • Hepatic impairment (moxifloxacin)

Comparison of Medications

Comparison based on mechanisms of action

Antibiotics can be classified in several ways. One way is to classify antibiotics by mechanism of action:

Table: Antibiotics classified by primary mechanism of action
MechanismClasses of antibiotics
Bacterial cell wall synthesis inhibitors
  • Penicillins
  • Cephalosporins
  • Penems
  • Miscellaneous
Bacterial protein synthesis inhibitors
  • Tetracyclines
  • Macrolides
  • Ketolides
  • Lincosamides
  • Streptogramins
  • Linezolid
Agents acting against DNA and/or folate
  • Sulfonamides
  • Trimethoprim
  • Fluoroquinolones
Antimycobacterial agents
  • Anti-TB agents
  • Antileprosy agents
  • Atypical mycobacterial agents

Comparison based on coverage

Different antibiotics have varying degrees of activity against different bacteria. The table below outlines the antibiotics with activity against 3 important classes of bacteria: gram-positive cocci, gram-negative bacilli, and anaerobes.

Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Deck, D.H., Winston, L.G. (2013). Sulfonamides, Trimethoprim, and Quinolones. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology (12th Ed., pp. 831‒834). 
  2. Hooper, D.C. (2021). Fluoroquinolones. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 20, 2021, from https://www.uptodate.com/contents/fluoroquinolones 
  3. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 20, 2021, from:

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