Once-daily versus multiple-daily dosing of aminoglycosides

The pharmacodynamic characteristics of isepamicin and other aminoglycosides, both in terms of efficacy and toxicity, explain why once-daily administration of these agents should be the optimal dosing regimen. Isepamicin, as with other aminoglycosides, exhibits concentration-dependent bactericidal activity and produces prolonged post-antibiotic effects against susceptible organisms. High concentrations of these drugs would be expected to produce more rapid and extensive bacterial killing than lower levels. Furthermore, the post-antibiotic effect would protect against bacterial regrowth when serum and tissue concentrations fall below inhibitory levels. In animal models, the magnitude of the peak serum concentration or the area under the concentration-time curve, are the important determinants of efficacy for isepamicin and the other aminoglycosides. Isepamicin also exhibits the "first-exposure effect", i.e. initial exposure of bacteria to isepamicin down-regulates subsequent uptake of the drug. During this period of down-regulation, bacteria exhibit decreased killing and shorter post-antibiotic effects. Since the first-exposure effect lasts for several hours, once-daily administration of the aminoglycosides allows for this effect to dissipate completely between doses. High peak concentrations, greater than 8-10 times the minimum inhibitory concentration (MIC), will also decrease the emergence of resistant strains. With regard to toxicity, one of the first steps in the uptake of aminoglycosides into sites of toxicity is their binding to the brush borders of renal cells and to the cochlea and vestibular membranes. Binding to these membranes demonstrates saturable kinetics. As a result, uptake of the aminoglycosides is more efficient with low sustained concentrations than with high intermittent levels. Once-daily dosing of aminoglycosides has consistently been less toxic than more frequent dosing in animals. In clinical studies, once-daily dosing of aminoglycosides compared to two-or three-times daily administration has generally exhibited similar efficacy and toxicity. However, a few studies has shown greater efficacy or lower toxicity with once-daily dosing of aminoglycosides. Once-daily dosing of the aminoglycosides has the potential to enhance efficacy, reduce toxicity, and lower administration costs for this drug class.