Fluoroquinolones Overview

Fluoroquinolones

• First-generation: primarily covers gram-negative bacteria (e.g., Nalidixic acid).
• Second-generation: covers some gram-positive bacteria, aerobic gram-negative bacteria, and atypical bacteria (e.g., Ciprofloxacin, Norfloxacin, Ofloxacin). They have significant intracellular penetration.
• Third-generation: covers a broader range of gram-positive bacteria, gram-negative bacteria, and atypical bacteria (e.g., Levofloxacin).
• Fourth-generation: covers gram-negative bacteria and has enhanced activity against anaerobic and gram-positive bacteria (e.g., Moxifloxacin).

Mechanism of Action

• Inhibition of topoisomerase II (DNA gyrase):
  • Prevents relaxation of positively supercoiled DNA
  • Required for normal transcription and replication
  • First and second-generation fluoroquinolones are more selective for this target.
• Inhibition of topoisomerase IV:
  • Interferes with chromosomal DNA separation during cell division
  • Third and fourth-generation fluoroquinolones are more selective for this target.

Antimicrobial Spectrum

• Alternative for patients with severe β-lactam allergy
• Bactericidal
• Effective against:
  • Gram-positive bacteria: Streptococci
  • Gram-negative bacteria: E. coli, P. aeruginosa, H. influenzae
  • Atypical organisms: Legionellaceae, Chlamydiaceae
  • Mycobacteria: M. tuberculosis
• Respiratory fluoroquinolones:
  • Levofloxacin and Moxifloxacin
  • Excellent activity against S. pneumoniae, used for community-acquired pneumonia (CAP)
• Commonly used to treat serious infections caused by:
  • Klebsiella pneumoniae (Nosocomial pathogen)
  • Other members of the Enterobacteriaceae family

Resistance

• Altered target:
  • Mutations in bacterial DNA gyrase and topoisomerase IV
  • Decreased affinity for the target
• Decreased Accumulation:
  • Reduced porin proteins in the outer membrane
  • Decreased energy-dependent efflux system in the cell membrane

Clinical Uses

• Ciprofloxacin:
  • Treats systemic infections caused by gram-negative bacilli
  • Effective against P. aeruginosa, used in cystic fibrosis patients
  • Treats traveler's diarrhea caused by E. coli and typhoid fever caused by S. typhi
• Levofloxacin:
  • Active against Streptococci
  • Treats prostatitis, skin infections, CAP, and nosocomial pneumonia
  • Excellent activity against pneumococcus
• Moxifloxacin:
  • Enhanced activity against gram-positive organisms (e.g., S. pneumoniae)
  • Excellent activity against many anaerobes
  • Does not concentrate in urine, not indicated for UTIs

Adverse Reactions

• Gastrointestinal: nausea, vomiting, diarrhea
• Central nervous system: headache, dizziness/lightheadedness
• Phototoxicity
• Peripheral neuropathy and glucose dysregulation (hypoglycemia)
• Tendonitis and tendon rupture: avoid use in pregnancy, lactation, and < 18 years old

Pharmacokinetics

• Absorption:
  • Well-absorbed orally, except for Norfloxacin (25-70% absorption)
  • Reduced absorption if taken with sucralfate, antacids containing aluminum or magnesium, dietary supplements containing iron/zinc, and calcium products
• Distribution:
  • Plasma protein binding ranges from 10% to 40%
  • Well distributed to all tissues and body fluids, except for CSF (Ofloxacin can cross the BBB well)
  • High levels in bone, urine (except Moxifloxacin), kidney, prostatic tissue (but not prostatic fluid), and lungs
  • Accumulate in macrophages and polymorphonuclear leukocytes (effective against intracellular organisms like Legionella pneumophila and Mycoplasma pneumoniae)
• Elimination:
  • Fluoroquinolones are excreted renally, except for Moxifloxacin.

Explore the different generations of fluoroquinolones and their mechanisms of action. This quiz will test your knowledge about their specific uses against various bacteria and how they inhibit DNA processes. Perfect for pharmacy students or those interested in antimicrobial agents.