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
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.
For Staphylococcus intermedius commonly associated with canine pyoderma, MIC90s for fluoroquinolones are relatively low. However, the skin is one of the most difficult tissues in which to achieve drug
concentrations, and a higher dosage should be considered in treating pyodermas. In general, the higher end of the dose range
(approximately the MPC) is used in treating pyodermas in a referral dermatology practice to compensate for the decreasing
tissue concentrations as the pyoderma resolves and inflammation diminishes (Table 1).9
Table 1: Fluoroquinolone Dosages for Treating Recurrent Pyoderma