title: Randomized controlled trial of once- versus thrice-daily tobramycin in febrile neutropenic children undergoing stem cell transplantation.
abstract: BACKGROUND
  The benefits of aminoglycoside antibiotics, such as tobramycin, administered as a once-daily dose to manage febrile neutropenia, have been demonstrated in many patient populations. However, toxicity and safety data are lacking for pediatric stem cell transplant recipients, who are at especially high risk for aminoglycoside-related toxicity and infectious morbidity. In particular, the relative nephrotoxicity and efficacy of tobramycin administered as a single daily dose or as three daily doses among this patient population is not known.
  
  
  METHODS
  We conducted a randomized, double-blind controlled study of tobramycin dosing among children 18 years or younger who had fever and neutropenia while undergoing stem cell transplantation. From October 2000 through November 2002, 60 children were randomly assigned to receive intravenous tobramycin, as either a single daily dose (n = 29) or every 8 hours (n = 31), in combination with either piperacillin or ceftazidime (intravenous). Tobramycin doses were adjusted to achieve pharmacokinetic targets. The primary outcome was nephrotoxicity, as represented by the maximal percent increase in serum creatinine concentration throughout the episode of febrile neutropenia relative to the baseline serum creatinine concentration. Efficacy was a secondary outcome and was defined as survival of the episode without modification of the antibacterial regimen. All statistical tests were two-sided.
  
  
  RESULTS
  In a modified intent-to-treat analysis, the mean maximal percent increase in serum creatinine concentration was 32% (N = 26) in the once daily dose group and 51% (N = 28) in the every 8 hours dose group (difference = 19%, 95% confidence interval [CI] = 0% to 38%; P =.054). Among patients evaluable for efficacy, 12 (46%) of 26 patients in the once daily dose group and five (19%) of 27 patients in the every 8 hours dose group survived the episode of febrile neutropenia without requiring antibacterial treatment modification (difference = 27%, 95% CI = 4% to 52%; P =.03). There was one death in each group.
  
  
  CONCLUSIONS
  In febrile neutropenic children undergoing stem cell transplantation, tobramycin may be less nephrotoxic and more efficacious when administered as a once daily dose than when administered every 8 hours.
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. lillian.sung@sickkids.ca
authors.forename: Lillian
authors.initials: L
authors.lastname: Sung
authors.forename: L Lee
authors.initials: LL
authors.lastname: Dupuis
authors.forename: Bonnie
authors.initials: B
authors.lastname: Bliss
authors.forename: Anna
authors.initials: A
authors.lastname: Taddio
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdolell
authors.forename: Upton
authors.initials: U
authors.lastname: Allen
authors.forename: Martha
authors.initials: M
authors.lastname: Rolland
authors.forename: Agnes
authors.initials: A
authors.lastname: Tong
authors.forename: Tracey
authors.initials: T
authors.lastname: Taylor
authors.forename: John
authors.initials: J
authors.lastname: Doyle
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002648:Child; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000209:etiology*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009503:Neutropenia / Q000150:complications*; D033581:Stem Cell Transplantation; D014031:Tobramycin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; D014031:Tobramycin