What are fluoroquinolones (antibiotics)?

Fluoroquinolones: A Broad-Spectrum Antibiotic Class

Fluoroquinolones are a synthetic class of broad-spectrum antibiotics that inhibit bacterial DNA replication by targeting DNA gyrase and topoisomerase IV enzymes, making them effective against a wide range of infections but carrying significant risks of musculoskeletal complications. 1

Mechanism of Action and Development

• Fluoroquinolones inhibit bacterial topoisomerase IV and DNA gyrase (type II topoisomerases), which are enzymes required for DNA replication, transcription, repair, and recombination 2
• First introduced in the 1980s to treat gram-negative bacterial infections, they evolved from nalidixic acid (the first quinolone, approved in 1964) 1
• They are entirely man-made antibiotics, with subsequent generations developed through chemical modifications to improve spectrum and pharmacokinetics 3

Classification and Spectrum of Activity

Generations of Fluoroquinolones:

• First generation: Nalidixic acid (limited gram-negative coverage) 1
• Second generation: Ciprofloxacin, levofloxacin, norfloxacin, ofloxacin (improved gram-negative coverage including Pseudomonas) 1
• Third generation: Gemifloxacin (increased activity against Streptococcus pneumoniae while maintaining gram-negative coverage) 1
• Fourth generation: Moxifloxacin (maintained gram-positive/negative activity with improved anaerobic coverage) 1

Antimicrobial Spectrum:

• Highly active against: Enterobacteriaceae, Haemophilus influenzae, Neisseria species, and Pseudomonas aeruginosa 4, 5
• Good activity against: Staphylococcus aureus (methicillin-susceptible) and other staphylococci 2
• Variable activity against: Streptococci (generally less susceptible) 5
• Poor activity against: Most anaerobes 5
• Specific pathogens covered: Mycobacteria (including M. tuberculosis), Legionella, Mycoplasma, and Chlamydophila 1, 2

Clinical Uses

Fluoroquinolones are used to treat various infections, including:

• Urinary tract infections: Particularly effective against gram-negative pathogens like E. coli 1
• Respiratory tract infections: Especially with newer agents like levofloxacin for community-acquired pneumonia 1, 2
• Gastrointestinal infections: Effective for Salmonella and Shigella infections, though resistance is increasing 1
• Skin and soft tissue infections: Particularly those caused by gram-negative organisms 6
• Bone and joint infections: Though caution is needed due to cartilage effects 1
• Multidrug-resistant tuberculosis: As part of combination therapy 1

Pharmacokinetic Properties

• Absorption: Well absorbed orally, though absorption may be delayed when taken with food 4
• Distribution: Widely distributed throughout the body with good tissue penetration, including lungs, bone, and prostate 5
• Metabolism: Limited metabolism for most fluoroquinolones 2
• Elimination: Primarily renal excretion, with dose adjustments needed in renal impairment 4, 2
• Half-life: Long half-lives allowing for once or twice daily dosing 7

Adverse Effects and Safety Concerns

Musculoskeletal Complications:

• FDA black box warning: Increased risk of tendinitis and tendon rupture, particularly affecting the Achilles tendon 1
• Cartilage damage: Shown in juvenile animal models, limiting use in children 1
• Other musculoskeletal effects: Arthralgia, myalgia, and potential impairment of fracture healing 1

Other Adverse Effects:

• Gastrointestinal: Nausea, vomiting, diarrhea 7
• Neurological: Dizziness, headache, rarely seizures 7, 8
• Cardiac: QT interval prolongation (particularly with certain agents) 3
• Dermatologic: Photosensitivity reactions 3
• Drug interactions: Decreased clearance of theophylline, caffeine, and warfarin; reduced absorption with magnesium/aluminum-containing antacids 4

Risk Factors for Adverse Events

• Age: Increasing age significantly increases risk of tendinopathy 1
• Corticosteroid use: Concomitant systemic corticosteroids substantially increase risk of tendon complications 1
• Renal impairment: Requires dose adjustment to avoid toxicity 4, 2

Resistance Concerns

• Resistance develops through chromosomal mutations altering DNA gyrase and decreasing drug permeation 5
• Resistance is particularly problematic with Pseudomonas aeruginosa and Staphylococcus aureus 5
• Cross-resistance occurs between different fluoroquinolones but rarely with other antibiotic classes 7
• Increasing fluoroquinolone use has led to rising resistance rates, particularly in certain geographic regions 1

Clinical Considerations

• Due to safety concerns and resistance issues, fluoroquinolones should be reserved for infections where no safe and effective alternative exists 1
• Higher dosages may be required for serious nosocomial infections to achieve optimal clinical outcomes 8
• For skin and soft tissue infections, fluoroquinolones are generally equivalent to beta-lactam antibiotics 6