Fluoroquinolones and pyoderma: Using the best drug at the right dosage (Sponsored by Pfizer)
Aug 01, 2005
Fluoroquinolone antibiotics represent one of the greatest developments in antibiotic therapy in the last fifty years. However, with their tremendous benefit comes great risk.1,2
Fluoroquinolones are one of the most effective groups of antibiotics developed to date because of their unique and potent mechanism of action. They specifically target DNA gyrase molecules in bacterial cells, making it impossible for those cells to reproduce.3,5 This targeted effect makes fluoroquinolones highly effective against susceptible bacteria when used at appropriate doses for the proper duration of therapy.
Fluoroquinolones are widely used based on their extended-spectrum of activity, ease of administration, and low toxicity.6 These drugs are well-absorbed upon oral administration and are widely distributed into most tissues.6,7 Fluoroquinolones accumulate within white blood cells, increasing in concentration at the target tissue as long as active inflammation is present.6,7 Because of the extended half-life of these drugs and the way they persistently suppress bacterial growth after dosing (the postantibiotic effect), fluoroquinolones can be administered once daily, which improves compliance.Fluoroquinolone antibiotics kill bacteria rapidly if used at appropriate concentrations in the target tissue based on the organism's minimum inhibitory concentration (MIC).6-8 This class of antibiotics is concentration-dependent, so the peak drug concentration after administration in the target tissue (skin, kidney, urine) is the most important dosing factor. To achieve high bactericidal concentrations, it is extremely important to select an appropriate dose or resistance may develop.
Studies have shown that the inhibitory quotient and the area under the inhibition curve (AUIC) are the most important factors in predicting fluoroquinolone efficacy while minimizing the development of resistant bacteria. These parameters are calculated as:
Inhibitory quotient = Cmax ÷ MIC90
AUIC = AUC ÷ MIC90
Ideally these calculations should include the Cmax at the target tissue and the MIC for the pathogen being treated. Often the Cmax at the target tissue is not known, and the plasma Cmax, where drug concentrations are lower than many target tissues, is used. For the fluoroquinolone to be effective, the inhibitory quotient should be greater than or equal to eight, the AUIC should be greater than or equal to 125, and the dose should be adjusted to achieve these levels. These values were derived from in vitro studies or studies involving neutropenic rats or critically ill humans and do not take into account the effect of a functioning immune system.
The mutant selection window is a new theory on dose selection to minimize the development of resistance. It proposes that a drug concentration range (selection window) exists for which mutation of the pathogen is promoted. Current dosing practices for fluoroquinolones tend to place drug concentrations in some target tissues inside this window. By identifying and avoiding this window, the amplification of selecting for resistant pathogens can be slowed. The mutant prevention concentration (MPC) is the concentration of an antibiotic that inhibits the growth of the least susceptible subpopulation of a pathogen when more than 1010 cells are tested. Above this concentration, a bacteria must acquire two concurrent resistance mutations for growth, which rarely occurs. The lower boundary of the appropriate selection window is approximated by the MIC90 and the upper boundary by the MPC. The selection window hypothesis has not been extensively tested in human or veterinary medicine, and data are still lacking.