Aminoglycoside adaptive resistance - Importance for effective dosage regimens

There are various pharmacodynamic features of the aminoglycosides that are thought to contribute to the benefits of once-daily administration, of whic h the ability to induce adaptive resistance is the least understood and dis cussed. However, this may be the most important characteristic conferring i ncreased efficacy with extended interval dose administration. Adaptive resi stance describes a reversible refractoriness to the bactericidal effect of an antibacterial agent. It is well documented for the aminoglycosides but h as also been seen with the quinolones. It does not appear to be caused by a genetic mutational change but rather by a protective phenotypic alteration in bacterial characteristics. This includes reversible down-regulation of the active transport of aminoglycosides into Gram-negative bacteria. In vitro, animal and clinical studies have shown that marked adaptive resis tance of Gram-negative bacteria to aminoglycosides occurs within 1-2 hours of the first dose. The duration of adaptive resistance relates directly to the half-lift: of elimination of the aminoglycoside. With normal human amin oglycoside pharmacokinetics, the resistance may be maximal for up to 16 hou rs after a single dose of aminoglycoside, followed by partial return of bac terial susceptibility at 24 hours and complete recovery at around 40 hours. With conventional dosage regimens, second and subsequent doses of aminogly coside are given at the time of maximal resistance and this practice is als o likely to reinforce the resistance. Dose administration at 24 hour interv als, or longer, may increase efficacy by allowing time for adaptive resista nce to reverse.