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J Antimicrob Chemother. 2019 Jun 20. pii: dkz248. doi: 10.1093/jac/dkz248. [Epub ahead of print]

Parameters influencing the pharmacokinetics/pharmacodynamics of piperacillin/tazobactam in patients with febrile neutropenia and haematological malignancy: a prospective study.

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Service des Maladies infectieuses et tropicales, Hospices Civils de Lyon, Lyon, France.
Institut des Agents Infectieux, Laboratoire de bactériologie, Hospices Civils de Lyon, Lyon, France.
Centre International de Recherche en Infectiologie (CIRI), Inserm 1111, Universite´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, Lyon, France.
Département d'Hématologie, Hospices Civils de Lyon, Pierre-Bénite, France.
INSERM1052, CNRS 5286, Université Claude Bernard, Faculté de Médecine Lyon-Sud Charles Mérieux Lyon-1, Pierre-Bénite, France.
Laboratoire de Biochimie et biologie moléculaire, Unité de pharmaco-toxicologie, Hospices Civils de Lyon, Pierre-Bénite, France.
Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
Univ Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie de Lyon, Lyon, France.
Service Pharmaceutique, Hospices Civils de Lyon, Lyon, France.



To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs).


We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of β-lactams was documented for Gram-negative bacteria involved in BSIs.


Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam.


In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.


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