SepsisNCT02569086
Piperacillin PK Analysis in Severe Sepsis Patients
An observational study of Sepsis and Severe Sepsis, run by University of Aarhus at 1 site in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Severe Sepsis
- What is being tested?
- Blood draw
- How many people
- 22 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Nov 2015to 30 Jun 2016
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with severe sepsis treated empirically with Piperacillin/Tazobactam
Who may be able to join
- Treatment with Piperacillin/Tazobactam 4g/0.5g every 8 hour for less than 48 hours
Who cannot join
- renal replacement therapy
- Age under 18
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Department of Infectious Diseases, Aarhus University Hospital, Denmark
Aarhus, Danmark, 8200
About this study
Official title: Population Pharmacokinetics of Piperacillin in the Early Phase of Severe Sepsis - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
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.
Read the 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.
- Conditions
- Sepsis, Severe Sepsis
- Being tested
- Blood draw
- Keywords
- Sepsis, Therapeutic Drug Monitoring, Beta-lactams, Pharmacokinetics
- Medical subject headings
- Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood drawOther
What is being measured
The primary outcome is the main question the study is designed to answer.
100% f T>MIC: Free Piperacillin Concentration Maintained Above the MIC Throughout the Dosing Interval.
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.
Measured: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment.
50% f T>MIC: Free Piperacillin Concentration Maintained at a Level Four Times Above the MIC 50% of the Dosing Interval.
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.
Measured: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2015 (estimated)
- Study start1 Nov 2015
- Primary completion30 Jun 2016
- Study completion30 Jun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by University of AarhusThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kristina Öbrink-Hansen, University of Aarhus
- Investigators
- Merete Storgaars, MD, PhD, Study director, Department of Infectious Diseases, Aarhus University Hospital, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02569086
- Sponsor's protocol ID
- PIP/TAZO-INTERMEDIATE
- Status last verified
- Oct 2015
- First submitted
- 30 Sep 2015
- Last updated
- 13 Nov 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Andersen MG, Thorsted A, Storgaard M, Kristoffersson AN, Friberg LE, Obrink-Hansen K. Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered? Antimicrob Agents Chemother. 2018 Apr 26;62(5):e02306-17. doi: 10.1128/AAC.02306-17. Print 2018 May.
PubMed 29507062
Study at a glance
From the registry record, last updated by the sponsor on 13 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Population Pharmacokinetics of Piperacillin in the Early Phase of Severe Sepsis - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
- ClinicalTrials.gov ID
- NCT02569086
- Acronym / sponsor ID
- PIP/TAZO-INTERMEDIATE
- Conditions
- Sepsis, Severe Sepsis
- Keywords
- Sepsis, Therapeutic Drug Monitoring, Beta-lactams, Pharmacokinetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Study start
- 1 Nov 2015 (actual)
- Primary completion
- 30 Jun 2016 (actual)
- Study completion
- 30 Jun 2016 (actual)
- First posted
- 6 Oct 2015 (estimated)
- Results
- Posted 13 Nov 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with severe sepsis treated empirically with Piperacillin/Tazobactam
Key inclusion criteria (1 listed)
- Treatment with Piperacillin/Tazobactam 4g/0.5g every 8 hour for less than 48 hours
Key exclusion criteria (2 listed)
- renal replacement therapy
- Age under 18
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood draw | Other | – |
Primary outcome
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.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Nov 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29507062Andersen MG, Thorsted A, Storgaard M, Kristoffersson AN, Friberg LE, Obrink-Hansen K. Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered? Antimicrob Agents Chemother. 2018 Apr 26;62(5):e02306-17. doi: 10.1128/AAC.02306-17. Print 2018 May.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Merete Storgaars, MD, PhD study director
Department of Infectious Diseases, Aarhus University Hospital, Denmark
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Sepsis and Severe Sepsis, run by University of Aarhus at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Nov 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02569086, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Nov 2017.