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

Carbapenem-resistant Enterobacteriaceae Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06049771
• Other study ID #: PMK0009
• Status: Recruiting
• Phase: N/A
• Start date: September 17, 2023
• Est. completion date: June 30, 2025

Study information

• Verified date: September 2023
• Source: Phramongkutklao College of Medicine and Hospital
• Contact: Sirapat Somsirikarnjanakoon, PharmD.
• Phone: 0982511524
• Email: sirapat.rx[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: June 30, 2025
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carbapenem-resistant Enterobacteriaceae
• Infections
• Sepsis

Intervention

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

Locations

Country	Name	City	State
Thailand	Phramongkutklao Hospital	Ratchathewi	Bangkok

Sponsors (2)

Lead Sponsor	Collaborator
Phramongkutklao College of Medicine and Hospital	Silpakorn University

Country where clinical trial is conducted

Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	rate constant for tigecycline distribution from the central to the peripheral compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	rate constant for tigecycline distribution from the peripheral to central the compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	elimination rate constant	Population pharmacokinetic parameter of tigecycline	up to 6 months
Primary	intercompartmental clearance	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	total clearance	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	volume of central compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	volume distribution of peripheral compartment	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	steady state volume distribution	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	Area under the plasma concentration versus time curve (AUC)	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Primary	Peak Plasma Concentration (Cmax)	Population pharmacokinetic parameter outcome of tigecycline	up to 6 months
Secondary	PK/PD index for CRE bloodstream infection	pharmacokinetics-pharmacodynamics parameter of tigecycline for CRE bloodstream infection	up to 6 months
Secondary	Rate of mortality	Alive or death	7,14 and 28 days
Secondary	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
Secondary	Number of Participants with the microbiological outcome	Eradicated or persistent evaluated by culture of bloodstream	7 days
Secondary	Genotype classification of carbapenemase producing CRE		up to 6 months