DNA Gyrase Inhibitors

• Mechanism of Action

  • Fluoroquinones represent an important class of antimicrobial which work through inhibition of DNA gyrase.

  • Bacterial DNA gyrase (topoisomerase II) and topoisomerase IV are required for DNA synthesis.

  • Inhibition of DNA gyrase blocks relaxation of supercoiled DNA, relaxation being a requirement for transcription and replication.

  • Inhibition of topoisomerase IV is thought to interfere with sepation of replicated chromosomal DNA

• .Fluoroquinones: Spectrum of Action

  •  Norfloxacin (Noroxin)-least active of the fluoroquinolones

  •  Enoxacin (Penetrex)

  •  Pefloxacin

  •  Ciprofloxacin (Cipro)

  •  Ofloxacin (Floxin)

  •  Lomefloxacin (Maxaquin)

  •  Sparfloxacin (Zagam) {new agent (1998) several times more potent than other currently available fluoroquinolones}

*Ciprofloxacin (Cipro) & Ofloxacin (Floxin):inhibit gram negative cocci and bacilli: Enterobacteriaceae, Pseudomonas, Neisseria, Haemophilus Campylobacter; Staphylococci and streptococci are inhibited; Legionella, Chlamydia, M. tuberculosis, M avium are inhibited;Anaerobes: generally resistant

• Pharmacokinetics

  • After oral administration, bioavailability is good, 80% - 95%.

  • Half-lives range from 3 h (norfloxacin (Noroxin) and ciprofloxacin (Cipro)) to 10 (perfloxacin and fleroxacin)and 20 hours (sparfloxacin (Zagam)).

  • Long half-lives of sparfloxacin (Zagam) and levofloxacin (Levaquin)sparfloxacin and levofloxacin allow once daily dosing.

  • Most flouroquinolones are excreted by the kidney (tubular secretion, may be blocked by probenecid (Benemid)). Sparfloxacin (Zagam) is glucuronidated by the liver then renally cleared

•  Clinical Applications

  • Effective in urinary tract infections (UTI) caused by multidrug resistant strains.

  • Effective for diarrhea caused by Shigella, Salmonella, toxigenic E. coli or Campylobacter infections.

  • Most fluorquinolones that achieve adequate tissue concentrations are effective in treating soft-tissue, bone, and joint infections by multidrug resistant strains of Pseudomonas and Enterobacter.

  • Ciprofloxacin (Cipro): second-line agent for leginellosis.

  • Ciprofloxacin (Cipro)/ofloxacin (Floxin): gonococcal infection.

• Adverse Effects

  • Generally well tolerated

  • Most common side effects are nausea vomiting diarrhea

  • Concurrent administration of theophylline and ciprofloxacin may lead to theophylline toxicity.

  • Fluoroquinolones: damage to growing cartilage (not recommend for use in patients under 18 years old); however, since such damage appears reversible, these drugs may be used in children in some special cases--pseudomonal infections in cystic fibrosis patients.

  •  Contraindicated in nursing mothers--drug excreted in breast milk.

Chambers, H.F. and Jawetz, E.Sulfonamides,Trimethoprim, and Quinolones,in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 765-767.