Comparison of once-daily versus pharmacokinetic dosing of aminoglycosides in elderly patients

Abstract

Once-daily dosing has been suggested as an alternative method of dosing aminoglycosides that would reduce their toxicity while maintaining efficacy. There have been no studies published to date comparing once-daily dosing and pharmacokinetic dosing of aminoglycosides. We conducted a randomized controlled trial comparing the safety and effectiveness of 4 mg/kg IV once-daily dosing of gentamicin or tobramycin with a pharmacokinetic dosing method using an initial dose of 2 mg/kg IV every 12 hours. Ninety-six patients were randomly assigned to either the once-daily dosing group (4 mg/kg) or the pharmacokinetic dosing group (initial dose of 2 mg/kg every 12 hours). In the once-daily dosing group, the dosing interval was extended by 12 to 24 hours to maintain a serum trough concentration < 1.5 mg/L regardless of the peak concentration. Dosing in the other group was adjusted based on the individual pharmacokinetic data to achieve a serum peak concentration of 6 to 10 mg/L and a trough concentration below 1.5 mg/L. The patients studied were predominantly elderly males (mean age 69 years). All patients were assessed for treatment efficacy and nephrotoxicity. There was no significant difference between the two groups with regard to clinical and bacteriologic efficacy. Incidence of nephrotoxicity was 24% in the once-daily group and 14% in the pharmacokinetic dosing group but the difference was not statistically significant (P = 0.13). Unlike previous studies, we found a correlation between high serum peak concentration and incidence of nephrotoxicity in the once-daily dosing group. Nephrotoxicity developed in six out of 10 patients (60%) with an initial serum peak concentration greater than 12.0 mg/L compared to two out of 24 patients (8.3%) with an initial peak concentration less than 12.0 mg/L (P < 0.001) in the once-daily group. Serum peak concentrations in the pharmacokinetic dosing group were not correlated with nephrotoxicity. Once-daily dosing and pharmacokinetic dosing of aminoglycosides appear to have equal efficacy and toxicity. However, in the elderly population, high serum peak concentrations that occur with once-daily aminoglycoside dosing may increase the risk of nephrotoxicity.