Clinical trial NCT02306928: PK Analysis of Piperacillin in Septic Shock Patients
Official title: Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock - Does Standard Dosing Result in Therapeutic Plasma Concentrations?
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Septic Shock
Keywords: Septic shock
Intensive care unit
Therapeutic drug monitoring
Pharmacokinetics
Critically ill
Lead sponsor: University of Aarhus
Sponsor class: OTHER
First posted: 2014-12-03
Enrollment: 15
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: Critically ill patients with known or suspected septic shock admitted to the ICU, treated with piperacillin/tazobactam.

Brief 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.

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.

Eligibility criteria: Inclusion Criteria:

Treatment with piperacillin/tazobactam for less than 24 hours. Treatment with noradrenaline. -

Exclusion Criteria:

Renal replacement therapy. Age under 18.

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Primary outcomes:
measure: 100% f T>MIC: Free Piperacillin Concentration Maintained Above the MIC Throughout the Dosing Interval.
timeFrame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
measure: 50% fT>4xMIC: Free Piperacillin Concentration Maintained at a Level Fourfold the MIC for at Least 50% of the Dosing Interval.
timeFrame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Secondary outcomes:
measure: The Maximum Concentration of Piperacillin (Cmax)
timeFrame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
measure: The Area Under the Plasma-concentration Time Curve Concentration-time Curve From 0-8 Hours After the Studied Dose (AUC 0-8)
timeFrame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
measure: Trough Piperacillin Plasma Concentration (Cmin)
timeFrame: Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.
Other outcomes:
Locations:
city: Aarhus N
country: Denmark
facility: Department of anesthesiology and intensive care, Aarhus University Hospital
Study officials:
affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark
name: Merete Storgaard, MD
role: STUDY_DIRECTOR
References:
citation: 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.