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

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.