Fluoroquinolones Pharmacology
Fluoroquinolones inhibit bacterial DNA gyrase and topoisomerase IV, providing broad-spectrum bactericidal activity with concentration-dependent killing.
Overview
Fluoroquinolones are synthetic broad-spectrum antibiotics that target bacterial DNA topoisomerases, enzymes essential for DNA replication and transcription. They display concentration-dependent bactericidal activity with a prolonged post-antibiotic effect, excellent oral bioavailability, and broad tissue distribution.
Mechanism of Action
DNA gyrase (topoisomerase II) introduces negative supercoils ahead of replication forks in gram-negative bacteria. Topoisomerase IV decatenates daughter chromosomes after replication in gram-positive bacteria. Fluoroquinolones stabilize the drug-enzyme-DNA cleavage complex (similar to eukaryotic topoisomerase inhibitors), converting transient strand breaks into permanent double-strand breaks that cause bacterial cell death. Gram-negatives: gyrase is primary target; gram-positives: topoisomerase IV is primary target.
Spectrum and Classification
- Older agents (ciprofloxacin, ofloxacin): Primarily gram-negative, including Pseudomonas; limited gram-positive (S. pneumoniae)
- Respiratory fluoroquinolones (levofloxacin, moxifloxacin): Extended gram-positive coverage (S. pneumoniae, MSSA), atypicals (Legionella, Mycoplasma, Chlamydia), gram-negatives. Moxifloxacin adds anaerobic coverage but lacks Pseudomonas activity. First-line for CAP in patients with comorbidities.
- Delafloxacin: Active against MRSA (both oral and IV formulations)
Pharmacokinetics
Excellent oral bioavailability (>80% for most agents). Chelation with divalent cations (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺, Zn²⁺) reduces absorption by 50-75% — separate from antacids, multivitamins, and dairy by 2+ hours. Wide tissue distribution; high concentrations in prostate, lung, urine, and intracellularly. Primarily renal elimination (ciprofloxacin, levofloxacin — dose-adjust in renal impairment); moxifloxacin is hepatically metabolized.
Resistance
Mutations in gyrase (gyrA, gyrB) or topoisomerase IV (parC, parE) reduce drug binding. Efflux pump overexpression (MexAB-OprM in Pseudomonas) and reduced outer membrane permeability (OprD porin loss) also contribute. PMQR (plasmid-mediated quinolone resistance) — low-level but facilitates further resistance development.
Adverse Effects
- Tendinopathy/tendon rupture: Achilles tendon rupture is a class effect (risk increases with corticosteroid use, age >60, renal failure). Black box warning.
- CNS toxicity: Seizures, confusion, psychosis (especially in elderly); lowers seizure threshold.
- QTc prolongation: Moxifloxacin > levofloxacin; avoid with other QT-prolonging drugs.
- Peripheral neuropathy: Permanent in some cases; black box warning.
- Dysglycemia: Hypo- and hyperglycemia, especially with sulfonylureas.
- Phototoxicity: Sparfloxacin (no longer used); mild with current agents.
Key Takeaways
- Fluoroquinolones inhibit DNA gyrase (gram-negatives) and topoisomerase IV (gram-positives)
- Concentration-dependent killing; AUC/MIC drives efficacy
- Chelation with divalent cations reduces absorption; separate administration by 2 hours
- Tendinopathy, QTc prolongation, CNS effects, and peripheral neuropathy are significant class toxicities