Clinical trial NCT02569086: Piperacillin PK Analysis in Severe Sepsis Patients
Official title: Population Pharmacokinetics of Piperacillin in the Early Phase of Severe Sepsis - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sepsis
Severe Sepsis
Keywords: Sepsis
Therapeutic Drug Monitoring
Beta-lactams
Pharmacokinetics
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2015-10-06
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with severe sepsis treated empirically with Piperacillin/Tazobactam

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.

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.

Eligibility 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

Primary outcomes:
measure: 100% f T>MIC: Free Piperacillin Concentration Maintained Above the MIC Throughout the Dosing Interval.
timeFrame: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment.
measure: 50% f T>MIC: Free Piperacillin Concentration Maintained at a Level Four Times Above the MIC 50% of the Dosing Interval.
timeFrame: Participants will be followed to day five (120 hours) after initiation of piperacillin/tazobactam treatment.
Secondary outcomes:
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Department of Infectious Diseases, Aarhus University Hospital, Denmark
state: Danmark
Study officials:
affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark
name: Merete Storgaars, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.