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Brain Exposure to Piperacillin in Acute Hemorrhagic Stroke Patients Assessed by Cerebral Microdialysis and Population Pharmacokinetics
- Source :
- Neurocritical Care
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Background The broad antibacterial spectrum of piperacillin/tazobactam makes the combination suitable for the treatment of nosocomial bacterial central nervous system (CNS) infections. As limited data are available regarding piperacillin CNS exposure in patients without or with low-grade inflammation, a clinical study was conducted (1) to quantify CNS exposure of piperacillin by cerebral microdialysis and (2) to evaluate different dosing regimens in order to improve probability of target attainment (PTA) in brain. Methods Ten acute hemorrhagic stroke patients (subarachnoid hemorrhage, n = 6; intracerebral hemorrhage, n = 4) undergoing multimodality neuromonitoring received 4 g piperacillin/0.5 g tazobactam every 8 h by 30-min infusions for the management of healthcare-associated pneumonia. Cerebral microdialysis was performed as part of the clinical neuromonitoring routine, and brain interstitial fluid samples were retrospectively analyzed for piperacillin concentrations after the first and after multiple doses for at least 5 days and quantified by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations with various doses and types of infusions were performed to predict exposure. A T>MIC of 50% was selected as pharmacokinetic/pharmacodynamic target parameter. Results Median peak concentrations of unbound piperacillin in brain interstitial space fluid were 1.16 (range 0.08–3.59) and 2.78 (range 0.47–7.53) mg/L after the first dose and multiple doses, respectively. A one-compartment model with a transit compartment and a lag time (for the first dose) between systemic and brain exposure was appropriate to describe the brain concentrations. Bootstrap median estimates of the parameters were: transfer rate from plasma to brain (0.32 h−1), transfer rate from brain to plasma (7.31 h−1), and lag time [2.70 h (coefficient of variation 19.7%)]. The simulations suggested that PTA would exceed 90% for minimum inhibitory concentrations (MICs) up to 0.5 mg/L and 1 mg/L at a dose of 12–16 and 24 g/day, respectively, regardless of type of infusion. For higher MICs, PTA dropped significantly. Conclusion Limited CNS exposure of piperacillin might be an obstacle in treating patients without general meningeal inflammation except for infections with highly susceptible pathogens. Brain exposure of piperacillin did not improve significantly with a prolongation of infusions. Electronic supplementary material The online version of this article (10.1007/s12028-020-00947-x) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Cerebral microdialysis
Subarachnoid hemorrhage
Microdialysis
Population
610 Medizin
Penicillanic Acid
Piperacillin, Cerebral microdialysis, Acute hemorrhagic stroke, Population pharmacokinetics, Probability of target attainment
Critical Care and Intensive Care Medicine
Tazobactam
03 medical and health sciences
0302 clinical medicine
615 Pharmazie
Pharmacokinetics
Interstitial fluid
medicine
Humans
Population pharmacokinetics
Probability of target attainment
education
Retrospective Studies
Piperacillin
Intracerebral hemorrhage
Cross Infection
ddc:610
education.field_of_study
Acute hemorrhagic stroke
business.industry
Brain
030208 emergency & critical care medicine
medicine.disease
ddc:615
Anti-Bacterial Agents
Hemorrhagic Stroke
Anesthesia
Pharmacodynamics
Female
Neurology (clinical)
business
Original Work
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15560961 and 15416933
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Neurocritical Care
- Accession number :
- edsair.doi.dedup.....641ce17d7be063b6b23f2a549679b2ae