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

Study Overview
=================
Brief 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.

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.

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

Conditions
-----------------
Carbapenem-resistant Enterobacteriaceae

Intervention / Treatment
-----------------
* Other: Collect blood sample


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 20 years and older who were admitted at Phramongkutklao Hospital Patients who were diagnosed bloodstream infection with CRE and who were sepsis or septic shock 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: Pregnancy or Breastfeeding Patients who cannot tolerant to the toxicity of tigecycline for example hypersensitivity to tigecycline or any component of the formulation Patients who were infected with more than one isolated in blood culture at the same time

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Patients who were infected caused by CRE bloodstream infection and were treated with tigecycline. Blood samples were collected. | Other: Collect blood sample<br>* 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<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tigecycline, Population pharmacokinetics, pharmacokinetics-pharmacodynamics index, bloodstream infection, CRE, Carbapenem-resistant Enterobacteriaceae