Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity

Objective: To determine the incidence of nephrotoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of tobramycin in critically ill patients. Design: Randomized, prospective clinical trial. Setting: Adult intensive care units at two university hospitals. Patients: Fifty-eight critically ill patients with a suspected or documented aerobic Gram-negative infection. Interventions: Patients were randomized to receive tobramycin by ODD (7 mg/kg) or MDD. Baseline urine aliquots and 24-hr urine collections were collected on days 3, 7, and 11 during therapy and on days 3, 7, and 11 following discontinuation of therapy for measurement of alanine aminopeptidase (AAP), N-acetyl-β-D-glucosaminidase (NAG), and creatinine. Measurements and Main Results: Fifty-four patients were evaluable (ODD n = 25; MDD n = 29). The groups were similar with regard to demographic and clinical variables. The tobramycin dose was higher in the ODD group compared with the MDD group (425 ± 122.5 mg vs. 312.8 ± 116.6 mg, p <.001). Patients in the MDD group received a mean of 3.89 ± 1.14 mg.kg -1 .day -1 at intervals of 11.92 ± 3.12 hrs. In the ODD group, patients had a higher measured creatinine clearance at the end of therapy compared with MDD group (70 ± 18.6 vs. 64.8 ± 17.5 mUmin, p = .047). Fewer patients in the ODD group developed nephrotoxicity than the MDD group (5 vs. 12, p =.142). Although there were increases in urinary enzymes in both treatment groups (AAP, 8.7 ± 2.9 vs. 5.2 ± 2.1 units/24 hrs, p <.01 MDD vs. ODD; NAG, 14.7 ± 4.9 vs. 6.8 ± 3.1, p <.01 MDD vs. ODD), the increases in the ODD group were significantly lower than in the MDD group. Conclusions: The ODD tobramycin regimen appeared to be less nephrotoxic than the MDD regimen despite significantly higher doses. Tobramycin administered by ODD may be the preferred dosing method in selected critically ill medical patients to reduce the incidence and extent of renal damage.