title: Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial.
abstract: OBJECTIVE
  The objectives of this study were to describe piperacillin exposure in febrile neutropenia patients and determine whether therapeutic drug monitoring (TDM) can be used to increase the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets.
  
  
  METHODS
  In a prospective randomized controlled study (Australian New Zealand Registry, ACTRN12615000086561), patients were subjected to TDM for 3 consecutive days. Dose was adjusted in the intervention group to achieve a free drug concentration above the MIC for 100% of the dose interval (100% fT>MIC), which was also the primary outcome measure. The secondary PK/PD target was 50% fT>MIC. Duration of fever and days to recovery from neutropenia were recorded.
  
  
  RESULTS
  Thirty-two patients were enrolled. Initially, patients received 4.5 g of piperacillin/tazobactam every 8 h or every 6 h along with gentamicin co-therapy in 30/32 (94%) patients. At the first TDM, 7/32 (22%) patients achieved 100% fT>MIC and 12/32 (38%) patients achieved 50% fT>MIC. Following dose adjustment, 11/16 (69%) of intervention patients versus 3/16 (19%) of control patients (P = 0.012) attained 100% fT>MIC, and 15/16 (94%) of intervention patients versus 5/16 (31%) of control patients (P = 0.001) achieved 50% fT>MIC. After the third TDM, the proportion of patients attaining 100% fT>MIC improved from a baseline 3/16 (19%) to 11/15 (73%) in the intervention group, while it declined from 4/16 (25%) to 1/15 (7%) in the control group. No difference was noted in the duration of fever and days to recovery from neutropenia.
  
  
  CONCLUSIONS
  Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia fekade.sime@mymail.unisa.edu.au.
authors.forename: Fekade Bruck
authors.initials: FB
authors.lastname: Sime
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia Therapeutics Research Centre, School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Department of Haematology/Oncology, The Queen Elizabeth Hospital, Adelaide, Australia SA Pathology and the University of Adelaide, Adelaide, Australia.
authors.forename: Ing Soo
authors.initials: IS
authors.lastname: Tiong
authors.affiliation: Department of Haematology/Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Julia H
authors.initials: JH
authors.lastname: Gardner
authors.affiliation: Department of Haematology/Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Sheila
authors.initials: S
authors.lastname: Lehman
authors.affiliation: Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Peake
authors.affiliation: Department of Haematology/Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hahn
authors.affiliation: SA Pathology and the University of Adelaide, Adelaide, Australia.
authors.forename: Morgyn S
authors.initials: MS
authors.lastname: Warner
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia Royal Brisbane and Women's Hospital, Herston, Brisbane, Queensland, Australia Burns, Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane, Queensland, Australia Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016903:Drug Monitoring; D005260:Female; D005335:Fever of Unknown Origin / Q000188:drug therapy*; D019337:Hematologic Neoplasms / Q000150:complications*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009503:Neutropenia / Q000150:complications*; D009520:New Zealand; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: pharmacodynamics; pharmacokinetics; β-lactams