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Saturday 15 April 2006

Fluoroquinolones

By: David C Hooper, MD

The fluoroquinolones have become an increasingly popular class of antibiotics for use in a variety of infections.

Newer drugs in this class have been developed with a broader spectrum of activity including better coverage of gram-positive organisms and in one case even anaerobes. However, toxicities have been associated with some of these newer agents.

Grepafloxacin has been withdrawn from the market by the manufacturer because of adverse cardiac events.Sparfloxacin was withdrawn in February, 2001, primarily due to lack of sales.Trovafloxacin was withdrawn because of risks of hepatic toxicity. Gemifloxacin has been approved for the treatment of mild to moderate community-acquired pneumonia and acute exacerbation of chronic bronchitis, but almost 14 percent of women under age 40 develop rash when taking the drug for longer than seven days. This adverse effect is largely avoided by use of a five day course of treatment.

The spectrum of activity, mechanisms of action and resistance, pharmacokinetics, interactions with other drugs, and adverse effects of the fluoroquinolones will be reviewed here. The use of these drugs in a variety of specific infections is discussed separately. (See "Use of fluoroquinolones in the treatment of respiratory tract infections" and see "Use of fluoroquinolones in the treatment of bone and joint infections" and see "Use of fluoroquinolones in the treatment of gastrointestinal and abdominal infections").

Mechanisms of action - Fluoroquinolones are the only class of antimicrobial agents in clinical use that are direct inhibitors of bacterial DNA synthesis. Fluoroquinolones inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV, which have essential and distinct roles in DNA replication. The quinolones bind to the complex of each of these enzymes with DNA; the resulting complexes, including the drug, block progress of the DNA replication enzyme complex. Ultimately, this action results in damage to bacterial DNA and bacterial cell death. Thus, fluoroquinolones are bactericidal agents.

Encode the subunits of DNA gyrase and topoisomerase IV (altered target mechanism)

Regulate the expression of cytoplasmic membrane efflux pumps or proteins that constitute outer membrane diffusion channels (altered permeation mechanism)

Plasmid-mediated resistance has been reported in some clinical strains of Klebsiella pneumoniae, Escherichia coli, Enterobacter, and other enteric bacteria due to expression of a plasmid-encoded protein, Qnr, which appears to protect DNA gyrase from quinolone action. Plasmids encoding Qnr produce low-level quinolone resistance, but they also usually encode other antibiotic resistances and have been found in strains with additional chromosomal mutations resulting in high-level quinolone resistance along with multidrug resistance. Accumulation of mutations can result in highly resistant strains.

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