PK Analysis of Piperacillin in Septic Shock Patients

Septic Shock Clinical Trial

Official title:

Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock - Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02306928
• Other study ID #: PIP/TAZO-ICU
• Status: Completed
• Phase: N/A
• First received: December 1, 2014
• Last updated: February 9, 2016
• Start date: September 2014
• Est. completion date: January 2015

Study information

• Verified date: February 2016
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Dataprotection Agency
• Study type: Observational

Clinical 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.

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

Renal replacement therapy. Age under 18.

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Other:
• Blood draw

Locations

Country	Name	City	State
Denmark	Department of anesthesiology and intensive care, Aarhus University Hospital	Aarhus N

Sponsors (1)

Lead Sponsor	Collaborator
University of Aarhus

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.	No
Primary	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.	Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.	No
Secondary	The Maximum Concentration of Piperacillin (Cmax)	Maximum plasma concentration was predicted for each individual based on the final model fit.	Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.	No
Secondary	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.	Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.	No
Secondary	Trough Piperacillin Plasma Concentration (Cmin)	Trough plasma concentration (Cmin) was predicted for each individual based on the final model fit.	Participants were followed up to the third dosing interval after initiation of piperacillin/tazobactam. An average of 24 hours.	No