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 which the ability to induce adaptive resistance is the least understood and discussed. However, this may be the most important characteristic conferring increased efficacy with extended interval dose administration. Adaptive resistance describes a reversible refractoriness to the bactericidal effect of an antibacterial agent. It is well documented for the aminoglycosides but has 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 resistance 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-life of elimination of the aminoglycoside. With normal human aminoglycoside pharmacokinetics, the resistance may be maximal for up to 16 hours after a single dose of aminoglycoside, followed by partial return of bacterial susceptibility at 24 hours and complete recovery at around 40 hours. With conventional dosage regimens, second and subsequent doses of aminoglycoside are given at the time of maximal resistance and this practice is also likely to reinforce the resistance. Dose administration at 24 hour intervals, or longer, may increase efficacy by allowing time for adaptive resistance to reverse.