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Piperacillin PK Analysis in Severe Sepsis Patients

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ClinicalTrials.gov Identifier: NCT02569086
Recruitment Status : Completed
First Posted : October 6, 2015
Results First Posted : November 13, 2017
Last Update Posted : November 13, 2017
Sponsor:
Information provided by (Responsible Party):
Kristina Öbrink-Hansen, University of Aarhus

Brief Summary:

Antibiotic dosing in septic patients poses a challenge for clinicians due to the pharmacokinetic changes seen in this population. Piperacillin/tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality.

The investigators aim was to determined the pharmacokinetic profile of piperacillin 4g every 8 hour in 22 patients treated empirically for sepsis and severe sepsis. A PK population model was be established with the dual purpose to assess current standard treatment and to simulate alternative dosing regimens and modes of administration. Time above the minimal inhibitory concentration (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas Aeruginosa (16 mg/L). Pharmacokinetic-pharmacodynamic (PK-PD) targets evaluated were 100% f T>MIC and 50% fT>MIC.


Condition or disease Intervention/treatment
Sepsis Severe Sepsis Other: Blood draw

Detailed Description:

Appropriate empiric antibiotic therapy is crucial for reducing mortality in septic patients. Pathophysiological changes associated with the septic process, i.e. changes in volume of distribution (Vd), protein binding and drug clearance (Cl), lead to pharmacokinetic (PK) alterations that may influence the efficacy of the drug. As a consequence, antibiotic plasma concentrations are variable and hard to predict in this patient population. Optimal dosing and exposure can therefore be a challenge and standard antibiotic dosing regimens may result in subtherapeutic concentrations and therapeutic failure. Appropriate dosing is also essential in order to maximize bacterial killing and minimize development of antimicrobial resistance.

Piperacillin/tazobactam is a β-lactam-β-lactamase inhibitor combination with extended-spectrum antibacterial activity, which is often used for empirical treatment of severe infections. The antibacterial activity is time-depentent, i.e. the activity is related to the time for which the free unbound drug concentration is maintained above the minimum inhibitory concentration (MIC) (fT>MIC). By maximizing T>MIC, therapeutic impact increases and the risk of drug resistance development is reduced (7). For β-lactams, a fT>MIC of at least 50% is associated with clinical efficacy. However, higher targets may be needed for maximal bactericidal effect in critically ill patients. Piperacillin/tazobactam is by standard practice administered as intermittent bolus infusion (IB). However, prolonged infusion, both extended infusion (IE) and continuous infusion (CI) is believed to optimize drug exposure and has a PK advantage compared to IB.

Patients with known or suspected sepsis or severe sepsis, treated empirically with piperacillin/tazobactam 4g/0,5g (Tazocin®) every eight hour (q8h) were eligible for the study. Piperacillin/tazobactam (4g/0,5g) was administered intravenously (i.v.) as a 3-minute bolus infusion . Serial blood samples were collected over one dosing interval for up to three consecutive days if piperacillin/tazobactam treatment was maintained.

The free concentrations of piperacillin in sera were assessed using ultra high performance liquid chromatography (UHPLC).

Clinical MIC breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Pseudomonas aeruginosa were used to evaluate the following PK/PD targets: 100% f T>MIC and 50% fT>MIC.

There was no intervention in the study.

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Study Type : Observational
Actual Enrollment : 22 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Population Pharmacokinetics of Piperacillin in the Early Phase of Severe Sepsis - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
Actual Study Start Date : November 1, 2015
Actual Primary Completion Date : June 30, 2016
Actual Study Completion Date : June 30, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis




Primary Outcome Measures :
  1. 100% f T>MIC: Free Piperacillin Concentration Maintained Above the MIC Throughout the Dosing Interval. [ Time Frame: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment. ]
    The piperacillin plasma concentration-time profiles were best described by a two-compartment model. Each individual model predicted T>MIC was compared to clinical breakpoint MIC for P.aeruginosa (16 mg/L). The number of patients who achieved the pre-defined PK/PD target were reported.

  2. 50% f T>MIC: Free Piperacillin Concentration Maintained at a Level Four Times Above the MIC 50% of the Dosing Interval. [ Time Frame: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment. ]
    The piperacillin plasma concentration-time profiles were best described by a two-compartment model. Each individual model predicted T>MIC was compared to clinical breakpoint MIC for P.aeruginosa (16 mg/L). The number of patients who achieved the pre-defined PK/PD target were reported.


Biospecimen Retention:   Samples Without DNA
Whole blood


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with severe sepsis treated empirically with Piperacillin/Tazobactam
Criteria

Inclusion Criteria:

  • Treatment with Piperacillin/Tazobactam 4g/0.5g every 8 hour for less than 48 hours

Exclusion Criteria:

  • renal replacement therapy
  • Age under 18

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02569086


Locations
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Denmark
Department of Infectious Diseases, Aarhus University Hospital, Denmark
Aarhus, Danmark, Denmark, 8200
Sponsors and Collaborators
University of Aarhus
Investigators
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Study Director: Merete Storgaars, MD, PhD Department of Infectious Diseases, Aarhus University Hospital, Denmark
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Kristina Öbrink-Hansen, MD, University of Aarhus
ClinicalTrials.gov Identifier: NCT02569086    
Other Study ID Numbers: PIP/TAZO-INTERMEDIATE
First Posted: October 6, 2015    Key Record Dates
Results First Posted: November 13, 2017
Last Update Posted: November 13, 2017
Last Verified: October 2015
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Kristina Öbrink-Hansen, University of Aarhus:
Sepsis
Therapeutic Drug Monitoring
Beta-lactams
Pharmacokinetics
Additional relevant MeSH terms:
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Sepsis
Toxemia
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes