Septic ShockNCT02306928
PK Analysis of Piperacillin in Septic Shock Patients
An observational study of Septic Shock, run by University of Aarhus at 1 site in Denmark.
Trial summary
Antibiotic dosing in septic shock 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
- Septic Shock
- What is being tested?
- Blood draw
- How many people
- 15 participants
- Where
- 1 siteDenmark
- Study dates
- Sep 2014to Jan 2015
- 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: Critically ill patients with known or suspected septic shock admitted to the ICU, treated with piperacillin/tazobactam.
Who may be able to join
- Treatment with piperacillin/tazobactam for less than 24 hours. Treatment with noradrenaline. -
Who cannot join
- Renal replacement therapy. Age under 18.
- -
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Department of anesthesiology and intensive care, Aarhus University Hospital
Aarhus N, 8200
About this study
Official title: Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
Antibiotic dosing in septic shock 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.
We determined the pharmacokinetic profile of piperacillin 4g every 8 hour in 15 patients treated empirically for septic shock. A PK population model was 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 were 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>4xMIC.
Read the detailed description
Early appropriate antimicrobial therapy is of utmost importance for reducing mortality in critically ill patients with sepsis and septic shock. Patophysiological changes associated with the septic process, such as changes in volume of distribution (Vd), drug clearance (CL), decrease in plasma-protein concentration and organ dysfunction, lead to pharmacokinetic (PK) changes that may alter the efficacy of the antimicrobial given. As a consequence, antibiotic plasma concentrations are variable and hard to predict in these patients, which makes optimal antibiotic exposure a challenge, especially in the early phase of treatment. In sepctic shock patients, appropriate dosing is even more important, as effective antimicrobial therapy within the first hour of documented hypotension is associated with increased survival to hospital discharge.
Piperacillin/tazobactam is a β-lactam - β-lactamase inhibitor combination frequently used for empirical treatment in the critically ill. It is a time-dependent antibiotic where antibacterial activity is related to the time for which the free, unbound concentation of the drug is maintained above the minimal inhibitory concentration (f T>MIC). Maximizing f T>MIC both increases the therapeutic impact and reduces the risk of drug resistance development. Because of the PK changes seen in the critically ill, standard dosing of antimicrobials may result in subtherapeutic plasma-concentrations (17) and it has been suggested that current empiric dosing recommendations for ICU patients are inadequate and needs to be reconsidered (18). Patients with septic shock are especially vulnerable (7) and optimal dosing in these patients is crucial for reducing mortality.
Piperacillin/tazobactam 4g/0.5g every 8 hour (h) is the empiric standard dosing for sepsis and septic shock. The aim of this study was to determine if this dosing results in therapeutic plasma concentrations in septic shock patients, within the initial 24 hours of therapy. A PK population model was established with the dual purpose to assess current standard treatment and to simulate alternative dosing regimens and modes of administration.
Critically ill patients with known or suspected septic shock who required noradrenaline infusion and who were prescribed piperaillin/tazobactam 4g/0.5g (Tazocin®) by the treating physician were eligible for the study. Patients on renal replacement therapy and patients under the age of 18 were not included.
Piperacillin/tazobactam 4g/0.5g was administered intravenously (i.v.) over 3 minutes every 8 h. Blood samples (4 mL) were collected by trained staff from an arterial catheter around the time of administration of the third consecutive infusion. Each patient had a total of eight blood samples drawn; before administration of the drug (time 0), at 10, 20, 30 minutes and 1, 2, 4 and 8 h after administration of the drug.
The unbound piperacillin plasma concentrations were determined using ultra high performance liquid chromatography. If a bacteria was isolated from a patient, a MIC to piperacillin was obtained using E-tests on Mueller-Hinton agar plates. These MICs as well as 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>4xMIC.
There was no intervention in the study.
- Conditions
- Septic Shock
- Being tested
- Blood draw
- Keywords
- Septic shock, Intensive care unit, Therapeutic drug monitoring, Pharmacokinetics, Critically ill
- Medical subject headings
- Shock, Septic, Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood drawOther
| Study group | Role | What they receive |
|---|---|---|
| Piperacillin pharmacokinetics | Patients with suspected septic shock who are treated with piperacillin/tazobactam. Receives: Other: Blood draw |
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 were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
50% fT>4xMIC: Free Piperacillin Concentration Maintained at a Level Fourfold the MIC for at Least 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 were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Secondary outcomes (3)
The Maximum Concentration of Piperacillin (Cmax)
Maximum plasma concentration was predicted for each individual based on the final model fit.
Measured: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
The Area Under the Plasma-concentration Time Curve Concentration-time Curve From 0-8 Hours After the Studied Dose (AUC 0-8)
Area under the free plasma concentration-time curve (fAUC0-8) was predicted for each individual based on the final model fit.
Measured: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Trough Piperacillin Plasma Concentration (Cmin)
Trough plasma concentration (Cmin) was predicted for each individual based on the final model fit.
Measured: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2014 (estimated)
- Study startSep 2014
- Primary completionJan 2015
- Study completionJan 2015
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 Septic ShockStudies 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
- 15 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 Storgaard, MD, Study director, Department of Infectious Diseases, Aarhus University Hospital, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02306928
- Sponsor's protocol ID
- PIP/TAZO-ICU
- Status last verified
- Feb 2016
- First submitted
- 1 Dec 2014
- Last updated
- 11 Feb 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Obrink-Hansen K, Juul RV, Storgaard M, Thomsen MK, Hardlei TF, Brock B, Kreilgaard M, Gjedsted J. Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations? Antimicrob Agents Chemother. 2015 Nov;59(11):7018-26. doi: 10.1128/AAC.01347-15. Epub 2015 Sep 8.
PubMed 26349823
Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
- ClinicalTrials.gov ID
- NCT02306928
- Acronym / sponsor ID
- PIP/TAZO-ICU
- Conditions
- Septic Shock
- Keywords
- Septic shock, Intensive care unit, Therapeutic drug monitoring, Pharmacokinetics, Critically ill
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Study start
- Sep 2014
- Primary completion
- Jan 2015 (actual)
- Study completion
- Jan 2015 (actual)
- First posted
- 3 Dec 2014 (estimated)
- Results
- Posted 11 Jun 2015
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 shock 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.
We determined the pharmacokinetic profile of piperacillin 4g every 8 hour in 15 patients treated empirically for septic shock. A PK population model was 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 were 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>4xMIC.
Detailed description
Early appropriate antimicrobial therapy is of utmost importance for reducing mortality in critically ill patients with sepsis and septic shock. Patophysiological changes associated with the septic process, such as changes in volume of distribution (Vd), drug clearance (CL), decrease in plasma-protein concentration and organ dysfunction, lead to pharmacokinetic (PK) changes that may alter the efficacy of the antimicrobial given. As a consequence, antibiotic plasma concentrations are variable and hard to predict in these patients, which makes optimal antibiotic exposure a challenge, especially in the early phase of treatment. In sepctic shock patients, appropriate dosing is even more important, as effective antimicrobial therapy within the first hour of documented hypotension is associated with increased survival to hospital discharge.
Piperacillin/tazobactam is a β-lactam - β-lactamase inhibitor combination frequently used for empirical treatment in the critically ill. It is a time-dependent antibiotic where antibacterial activity is related to the time for which the free, unbound concentation of the drug is maintained above the minimal inhibitory concentration (f T>MIC). Maximizing f T>MIC both increases the therapeutic impact and reduces the risk of drug resistance development. Because of the PK changes seen in the critically ill, standard dosing of antimicrobials may result in subtherapeutic plasma-concentrations (17) and it has been suggested that current empiric dosing recommendations for ICU patients are inadequate and needs to be reconsidered (18). Patients with septic shock are especially vulnerable (7) and optimal dosing in these patients is crucial for reducing mortality.
Piperacillin/tazobactam 4g/0.5g every 8 hour (h) is the empiric standard dosing for sepsis and septic shock. The aim of this study was to determine if this dosing results in therapeutic plasma concentrations in septic shock patients, within the initial 24 hours of therapy. A PK population model was established with the dual purpose to assess current standard treatment and to simulate alternative dosing regimens and modes of administration.
Critically ill patients with known or suspected septic shock who required noradrenaline infusion and who were prescribed piperaillin/tazobactam 4g/0.5g (Tazocin®) by the treating physician were eligible for the study. Patients on renal replacement therapy and patients under the age of 18 were not included.
Piperacillin/tazobactam 4g/0.5g was administered intravenously (i.v.) over 3 minutes every 8 h. Blood samples (4 mL) were collected by trained staff from an arterial catheter around the time of administration of the third consecutive infusion. Each patient had a total of eight blood samples drawn; before administration of the drug (time 0), at 10, 20, 30 minutes and 1, 2, 4 and 8 h after administration of the drug.
The unbound piperacillin plasma concentrations were determined using ultra high performance liquid chromatography. If a bacteria was isolated from a patient, a MIC to piperacillin was obtained using E-tests on Mueller-Hinton agar plates. These MICs as well as 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>4xMIC.
There was no intervention in the study.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Piperacillin pharmacokinetics | – | Other: Blood drawPatients with suspected septic shock who are treated with piperacillin/tazobactam. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Critically ill patients with known or suspected septic shock admitted to the ICU, treated with piperacillin/tazobactam.
Key inclusion criteria (1 listed)
- Treatment with piperacillin/tazobactam for less than 24 hours. Treatment with noradrenaline. -
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 | Piperacillin pharmacokinetics |
Primary outcome
100% f T>MIC: Free Piperacillin Concentration Maintained Above the MIC Throughout the Dosing Interval.
Time frame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
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% fT>4xMIC: Free Piperacillin Concentration Maintained at a Level Fourfold the MIC for at Least 50% of the Dosing Interval.
Time frame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
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.
3 secondary outcomes
The Maximum Concentration of Piperacillin (Cmax)
Time frame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
The Area Under the Plasma-concentration Time Curve Concentration-time Curve From 0-8 Hours After the Studied Dose (AUC 0-8)
Time frame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Trough Piperacillin Plasma Concentration (Cmin)
Time frame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 26349823Obrink-Hansen K, Juul RV, Storgaard M, Thomsen MK, Hardlei TF, Brock B, Kreilgaard M, Gjedsted J. Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations? Antimicrob Agents Chemother. 2015 Nov;59(11):7018-26. doi: 10.1128/AAC.01347-15. Epub 2015 Sep 8.
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Sepsis
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 Storgaard, MD 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 Septic Shock, 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 11 Feb 2016. 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 11 Jun 2015). 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 were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.). 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 NCT02306928, 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 11 Feb 2016.