Harrold Fluoroquinolones

What is the significance of naldixic acid and cinoxacin?

Older quinolone agents that are no longer available, but served as prototype drugs for better agents

Active against gram-negative, but mjuch less active against gram-positive

Reached high urine concentrations, but low systemic concentrations

• Useful for UTIs, but not for systemic infections

What two modifications were made to quinolone agents to create fluoroquinolones?

Addition of a 6-fluoro group

• Greatly improved antimicrobial activity by increasing lipophilicity → increased penetration into the bacterial cell

Addition of the basic piperazine ring (or analog)

• Greatly enhanced spectrum of action

What advantages do fluoroquinolones have compared to initial quinolone agents?

Improved spectrum

Decreased ability of bacteria to develop resistance

Improved PK parameters

• Increased systemic concentrations

• Increased oral absorption

• Increased half life → many are used BID

Mechanism of fluoroquinolones

Inhibit DNA Gyrase and topoisomerase IV, which dictate the conformation of DNA

• Similar to human topoisomerase enzymes, but with structural differences that allow for selectivity

• Causes the bacteral cell to be unable to properly access its DNA and inhibits DNA synthesis

General function of topoisomerase enzymes

Unwind and rewind DNA to allow for replication and transcription

Are fluoroquinolones bacteriostatic or bacteriocidal?

Bacteriocidal

Mechanism of resistance to fluoroquinolones

Gene mutations of gyrA and/or gyrB enzymes hinder the binding of these drugs to their binding sites

• Does NOT affect normal enzyme function

Notable adverse effects of fluoroquinolones

Increased risk of tendonitis and tendon rupture

QT prolongation

• Least likely with ciprofloxacin

Phototoxicity

May exacerbate muscle weakness in patients with myasthenia gravis

Increased risk of CNS reactions

Hypoglycemia

Peripheral neuropathy

_____ was the first fluoroquinolone to receive an indication for use in children ≥1 year of age

Ciprofloxacin

How do the fluoroquinolones compare in tendency to cause phototoxicity?

Ciprofloxacin > levofloxacin > moxifloxacin

How do fluoroquinolones cause hypoglycemia?

Stimulate insulin release from the pancreas → decreases glucose concentration in the blood

• Worst offender was gatifloxacin → now only used ophthalmically

Significance of fluoroquinolone induced peripheral neuropathy

Can potentially cause serious nerve damage and may occur soon after these drugs are taken and may be permanent

• Does NOT occur with ophthalmic administration

Due to the chelating ability of the fluoroquinolones, this class of drugs has a drug interaction withh _____

Polyvalent cations found in antacids and other preparations

• Chelates decrease water solubility and oral absorption

• Administer 1-2 hours before or 4 hours after dairy products, antacids, iron preps, multivitamins, etc.

Interaction between ciprofloxacin and xanthines (theophylline and caffeine)

Ciprofloxacin can form a metabolite where the piperazine ring is oxidized → this oxoquinolone metabolite inhibits CYP1A2, which is required for normal xanthine metabolism → theophylline-induced toxicity

• Only occurs with ciprofloxacin because other drugs have steric hindrance or a different ring