Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia

Objective: To compare the efficacy and toxicity of single daily dosing of amikacin and ceftriaxone with that of multiple daily dosing of amikacin and ceftazidime for febrile episodes in patients with cancer and granulocytopenia. Design: A prospective, randomized, unblinded, multicenter trial. Setting: Twenty-one tertiary care or university medical centers. Patients: Six hundred seventy-seven patients with cancer and granulocytopenia (858 febrile episodes). Interventions: Random assignment to empiric therapy with a single daily dose of amikacin (20 mg/kg) and ceftriaxone (adults, 30 mg/kg; children, 80 mg/kg) (24-hour group) or with multiple daily doses of amikacin (6.5 mg/kg every 8 hours) and ceftazidime (33 mg/kg every 8 hours) (8-hour group). Measurements: Percentage response to each regimen and occurrence of nephrotoxicity and ototoxicity. Results: Single daily dosing of amikacin and ceftriaxone was as effective as multiple daily dosing of amikacin and ceftazidime (71% compared with 74%; difference, -3%; 95% CI, - 10% to 3%; P > 0.2). Equivalent responses also were noted for each category of infection. Median peak (30 minutes after a 60-minute infusion) serum concentrations of amikacin were higher in the 24-hour group than in the 8- hour group (45.6 compared with 21 μg/mL, P < 0.001), whereas trough (preinfusion) levels were lower (0.9 compared with 2 μg/mL, P < 0.001). Nephrotoxicity was 3% in the 24-hour group and 2% in the 8-hour group (difference, 1%; CI, -1% to 4%). Increases in serum creatinine, however, were delayed (P = 0.048) and smaller (P = 0.06) in the 24-hour group than in the 8-hour group and occurred almost exclusively after other nephrotoxic drugs were added. Audiometry was only done in 144 patients (21%). Ototoxicity was 9% in the 24-hour group and 7% in the 8-hour group (difference, 2%; CI, -7% to 11%; P > 0.2). Further infections developed in 15% and 12% of patients, respectively (difference, 3%; CI, -2% to 9%). The overall mortality rate was 11% in both treatment groups (difference, 0%; CI, -5% to 5%). Conclusions: Single daily dosing of amikacin and ceftriaxone was as effective and no more toxic than multiple daily dosing of amikacin and ceftazidime for the empiric therapy of infection in patients with cancer and granulocytopenia.