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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

The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.
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Requests for Reprints: Thierry Calandra, MD, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. Acknowledgments: The authors thank Philippe Moreillon, MD, for critical review of the manuscript and Leslie Leonard, PhD, for helpful suggestions. Grant Support: In part by Hoffmann-La Roche AG (Basel, Switzerland) and Bristol-Myers Squibb (Princeton, New Jersey). (The funding agencies did not participate in the collection of or in the analysis of the data. They were not involved in the writing of this article.)

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(7_Part_1):584-593. doi:10.7326/0003-4819-119-7_Part_1-199310010-00006
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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 empirical 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 g/mL, P < 0.001), whereas trough (preinfusion) levels were lower (0.9 compared with 2 g/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 empirical therapy of infection in patients with cancer and granulocytopenia.





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