fluoroquinolone

fluoroquinolone
Class identifier	Fluoroquinolone
Use	Antibacterial
ATC prefix	J01
Biological target	DNA gyrase, topoisomerase IV

fluoroquinolone. Fluoroquinolones are a class of synthetic broad-spectrum antibacterial agents derived from the foundational compound nalidixic acid. These agents function by inhibiting the essential bacterial enzymes DNA gyrase and topoisomerase IV, thereby disrupting DNA replication and transcription. Their development, spearheaded by researchers at Bayer and Kyorin Pharmaceutical, has produced numerous widely prescribed agents, though their use is now tempered by recognition of significant potential adverse effects and growing antimicrobial resistance.

Mechanism of action

The primary bactericidal action stems from the inhibition of two type II topoisomerase enzymes: DNA gyrase and topoisomerase IV. In Gram-negative bacteria, the principal target is typically DNA gyrase, which introduces negative supercoils into bacterial DNA to facilitate DNA replication. In Gram-positive bacteria, such as Staphylococcus aureus, the primary target is often topoisomerase IV, which decatenates daughter chromosomes following replication. By binding to the enzyme-DNA complex, these agents stabilize it, preventing DNA resealing and leading to double-strand breaks. This interference with DNA supercoiling and chromosome segregation triggers the SOS response and ultimately results in bacterial cell death.

Medical uses

Due to their broad spectrum and favorable pharmacokinetics, these agents have been employed against a wide array of infections. They are commonly prescribed for complicated urinary tract infections, community-acquired pneumonia, and certain sexually transmitted infections like gonorrhea. They also play a role in treating nosocomial infections, including those caused by Pseudomonas aeruginosa, and are used in prophylaxis for patients undergoing transrectal ultrasound-guided biopsy. However, following safety reviews by the U.S. Food and Drug Administration and the European Medicines Agency, their use is now restricted to situations where no alternative antibacterial therapy exists, particularly for uncomplicated infections.

Adverse effects

The use of these agents has been associated with a range of serious, sometimes disabling, adverse effects. These include tendinopathy and Achilles tendon rupture, peripheral neuropathy, and central nervous system effects such as insomnia, anxiety, and seizures. Perhaps most notably, they carry a risk of potentially permanent multi-system symptoms affecting the musculoskeletal system, peripheral nervous system, and central nervous system, sometimes referred to collectively as "fluoroquinolone-associated disability." Other concerns involve QT interval prolongation, phototoxicity, and disruption of glycemic control. These risks have prompted stringent regulatory actions from the U.S. Food and Drug Administration and other agencies worldwide.

Pharmacokinetics

Members of this class generally exhibit excellent oral bioavailability and extensive tissue penetration. They are primarily eliminated via the kidney through glomerular filtration and tubular secretion, though some newer agents also undergo significant hepatic metabolism via the cytochrome P450 system. Their volume of distribution often exceeds total body water, allowing effective concentrations in prostate tissue, lung, and bone. The presence of metal cations, such as those in antacids or dietary supplements, can significantly impair oral absorption through chelation, a key consideration for dosing.

History and development

The origin of this class traces back to the accidental discovery of nalidixic acid in 1962 during research on the antimalarial chloroquine at the George Washington University. The first true agents with systemic activity, such as norfloxacin, were developed in the late 1970s and early 1980s by scientists at Kyorin Pharmaceutical and Bayer. Subsequent "respiratory" agents with enhanced activity against Streptococcus pneumoniae, including levofloxacin and moxifloxacin, were introduced by Daiichi Sankyo and Bayer, respectively. The development pipeline has since slowed considerably due to the challenges of overcoming resistance and managing toxicity profiles.

Resistance

Resistance arises through several key mechanisms, primarily mutations in the quinolone resistance-determining regions of the genes encoding DNA gyrase and topoisomerase IV. Efflux pumps, such as the AcrAB-TolC system in Escherichia coli or the NorA pump in Staphylococcus aureus, can actively expel the drug from the bacterial cell. Plasmid-mediated resistance genes, like qnr, which produce proteins that protect the target enzymes, have also spread globally, facilitated by their location on mobile genetic elements. The widespread use of these agents in both human medicine and, historically, in veterinary medicine for livestock has significantly contributed to the selection and dissemination of resistant strains, including methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis.

Category:Antibiotics Category:Drug classes