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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.

Author information

1
Service des Maladies infectieuses et tropicales, Hospices Civils de Lyon, Lyon, France.
2
Institut des Agents Infectieux, Laboratoire de bactériologie, Hospices Civils de Lyon, Lyon, France.
3
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.
4
Département d'Hématologie, Hospices Civils de Lyon, Pierre-Bénite, France.
5
INSERM1052, CNRS 5286, Université Claude Bernard, Faculté de Médecine Lyon-Sud Charles Mérieux Lyon-1, Pierre-Bénite, France.
6
Laboratoire de Biochimie et biologie moléculaire, Unité de pharmaco-toxicologie, Hospices Civils de Lyon, Pierre-Bénite, France.
7
Univ Lyon, Université Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
8
Univ Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie de Lyon, Lyon, France.
9
Service Pharmaceutique, Hospices Civils de Lyon, Lyon, France.

Abstract

OBJECTIVES:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
31219562
DOI:
10.1093/jac/dkz248

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