Potential impact of quantitative susceptibility tests on the design of aminoglycoside dosing regimens

Abstract

Therapeutic drug monitoring of aminoglycosides currently applies pharmacokinetic principles to maintain peak concentrations between 4 and 10 micrograms/ml and troughs less than 2 micrograms/ml. These predetermined concentrations are based on statistical rates of cure and incidences of adverse effects. At present, recommended serum concentration ranges for aminoglycosides (as with other antibiotics) do not specifically target the susceptibility of the individual organism, but compensate only for altered clearance due to diseases. The design of antibiotic regimens based on both pharmacokinetics and pharmacodynamics is called dual individualization. Logically, the pharmacodynamic parameters, the minimum inhibitory concentration (MIC) of the organism and the postantibiotic effect (PAE), should also play a significant role in design of the dosing regimen. Simulations were performed to examine the consequences of designing aminoglycoside regimens considering both disease effects on excretion and bacterial susceptibility (MIC and PAE). The application of dual individualization concepts to aminoglycosides argues for a wider range of dosage requirements than observed with regimens that maintain desired peaks and troughs. If these concepts are accepted, some patients will clearly require more aminoglycoside than is currently used, and others can be managed with substantially less. The aminoglycoside therapeutic window, as it is now conceived, could be markedly different in the future.