The Population Pharmacokinetics Study of Tigecycline and Pharmacokinetics- Pharmacodynamics Index in Patients With Carbapenem Resistant Enterobacteriaceae Bloodstream Infection

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent global public health problem. Patients who were infected caused by CRE bloodstream infection were high mortality up to 40%. The National Antimicrobial Resistance Surveillance Center, Thailand (NARST) reported CRE increased from 1.1% to 17.9%. For carbapenemase producing CRE in Thailand was reported blaNDM 47.33%, blaOXA-48 43.33% and blaNDM+blaOXA-48 6.67%.

Tigecycline (TGC) was a glycylcyclines antibiotics. High dose tigecycline (HD-TGC) loading dose 200 mg then TGC 100 mg q 12 h via intravenous improve clinical cure in critically ill patients and reduce mortality in carbapenem resistance Klebsiella pneumoniae bloodstream infection compared with standard dose therapy. TGC has susceptibility to CR-KP 79.6% and has an activity to blaNDM, blaKPC and blaOXA-48 carbapenemase producing CRE. However, TGC has clearance (CL) 0.2-0.3 L/h/kg, and high volume of distribution (vd) 2.8-13 L/kg resulted in low levels of TGC in plasma. Moreover, the pharmacokinetics of TGC in critically ill was limited and inconsistent with the previous study. Now pharmacokinetics-pharmacodynamics index (PK/PD index) of TGC for CRE bloodstream infection was not reported. This study aims to study the population pharmacokinetic and PK-PD index of TGC in patients who were CRE bloodstream infection to increase the success rate of treatment.

Study Overview

• Status: Recruiting
• Conditions: Carbapenem-resistant Enterobacteriaceae
• Intervention / Treatment: Other: Collect blood sample

Detailed Description

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent global public health problem. Patients who were infected caused by CRE bloodstream infection were high mortality up to 40%. The National Antimicrobial Resistance Surveillance Center, Thailand (NARST) reported the carbapenem resistance Klebsiella pneumoniae (CR-KP) prevalence increased from 1.1% in 2000 to 17.9% in 2021 and the carbapenem resistance Escherichia coli was increased from 0.6% in 2000 to 5% in 2021. For carbapenemase producing CRE in Thailand was reported blaNDM 47.33%, blaOXA-48 43.33%, and blaNDM+blaOXA-48 6.67%. Ceftazidime-avibactam was first-line of treatment for CRE bloodstream infection recommended by Infectious Disease Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections but ceftazidime-avibactam was limited activity to blaNDM carbapenemase producing CRE.

Tigecycline (TGC) was a glycylcyclines antibiotics. TGC was approved for U.S.FDA for complicated intra-abdominal infection, complicated skin and skin structure infection and community acquired pneumonia with loading dose TGC 100 mg then TGC 50 mg q 12 h via intravenous. High dose tigecycline (HD-TGC) loading dose 200 mg then TGC 100 mg q 12 h improve clinical cure in critically ill patients and reduce mortality in CR-KP bloodstream infection compared with standard dose therapy. TGC has susceptibility to CR-KP 79.6% and has an activity to blaNDM, blaKPC and blaOXA-48 carbapenemase producing CRE. However, TGC has clearance (CL) 0.2-0.3 L/h/kg, and high volume of distribution (vd) 2.8-13 L/kg resulted in low levels of TGC in plasma. Moreover, the pharmacokinetics of TGC in critically ill was limited and inconsistent with the previous study. Now pharmacokinetics-pharmacodynamics index (PK/PD index) of TGC for CRE bloodstream infection was not reported. This study aims to study the population pharmacokinetic and PK-PD index of TGC in patients who were CRE bloodstream infection to increase the success rate of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sirapat Somsirikarnjanakoon, PharmD.; Phone Number: 0982511524; Email: sirapat.rx@gmail.com
• Study Contact Backup: Name: Wichai Santimaleeworagun, PhD.; Phone Number: 0814426713; Email: swichai1234@gmail.com

Study Locations

• Thailand
  • Bangkok
    • Ratchathewi, Bangkok, Thailand, 10400
      • Recruiting
      • Phramongkutklao Hospital
      • Sub-Investigator: Worapong Nasomsong, MD
      • Contact: Sirapat Somsirikarnjanakoon, PharmD.; Phone Number: 0982511524; Email: sirapat.rx@gmail.com
      • Contact: Wichai Santimaleeworagun, PhD; Phone Number: 0814426713; Email: swichai1234@gmail.com
      • Principal Investigator: Sirapat Somsirikarnjanakoon, PharmD
      • Principal Investigator: Wichai Santimaleeworagun, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 20 years and older who were admitted at Phramongkutklao Hospital
2. Patients who were diagnosed bloodstream infection with CRE and who were sepsis or septic shock
3. Patients who received tigecycline loading dose 200 mg infusion for 1 hour and following maintenance dose 100 mg every 12 h infusion for 1 hour at least 48 hours and grant for blood collection

Exclusion Criteria:

1. Pregnancy or Breastfeeding
2. Patients who cannot tolerant to the toxicity of tigecycline for example hypersensitivity to tigecycline or any component of the formulation
3. Patients who were infected with more than one isolated in blood culture at the same time

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Patients who were infected caused by CRE bloodstream infection and were treated with tigecycline. Blood samples were collected.	Other: Collect blood sample; Collect blood samples at different time points: after tigecycline administration 1 h, 2-4 h, 4-6 h, 6-11.5 h and 30 minutes before next dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate constant for tigecycline distribution from the central to the peripheral compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
rate constant for tigecycline distribution from the peripheral to central the compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
elimination rate constant	Population pharmacokinetic parameter of tigecycline	up to 6 months
intercompartmental clearance	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
total clearance	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
volume of central compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
volume distribution of peripheral compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
steady state volume distribution	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Area under the plasma concentration versus time curve (AUC)	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Peak Plasma Concentration (Cmax)	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK/PD index for CRE bloodstream infection	pharmacokinetics-pharmacodynamics parameter of tigecycline for CRE bloodstream infection	up to 6 months
Rate of mortality	Alive or death	7,14 and 28 days
Number of Participants with the clinical outcome	Clinical cure or clinical failure Clinical cure was defined as the resolution or improvement of all signs and symptoms present at study entry Clinical failure was defined as any one or more following circumstances: persistent or worsened signs and symptoms, a new clinical findings consistent with the progression of infection.	14 days
Number of Participants with the microbiological outcome	Eradicated or persistent evaluated by culture of bloodstream	7 days
Genotype classification of carbapenemase producing CRE		up to 6 months

Collaborators and Investigators

• Sponsor: Phramongkutklao College of Medicine and Hospital
• Collaborators: Silpakorn University
• Investigators: Study Chair: Sirapat Somsirikarnjanakoon, PharmD., Faculty of Pharmacy, Silpakorn University; Study Director: Wichai Santimaleeworagun, PhD., Faculty of Pharmacy, Silpakorn University; Study Director: Worapong Nasomsong, MD., Phramongkutklao College of Medicine and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 17, 2023
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: July 31, 2023
• First Submitted That Met QC Criteria: September 17, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 17, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: CRE; Tigecycline; bloodstream infection; Population pharmacokinetics; Carbapenem-resistant Enterobacteriaceae; pharmacokinetics-pharmacodynamics index
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Infections
• Other Study ID Numbers: PMK0009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No