Clinical trial NCT06049771: The Population Pharmacokinetics Study of Tigecycline and Pharmacokinetics- Pharmacodynamics Index in Patients With Carbapenem Resistant Enterobacteriaceae Bloodstream Infection
Official title: The Population Pharmacokinetics Study of Tigecycline and Pharmacokinetics- Pharmacodynamics Index in Patients With Carbapenem Resistant Enterobacteriaceae Bloodstream Infection
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Carbapenem-resistant Enterobacteriaceae
Keywords: Tigecycline
Population pharmacokinetics
pharmacokinetics-pharmacodynamics index
bloodstream infection
CRE
Carbapenem-resistant Enterobacteriaceae
Lead sponsor: Phramongkutklao College of Medicine and Hospital
Sponsor class: OTHER
Collaborators: name: Silpakorn University
First posted: 2023-09-22
Enrollment: 72
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: rate constant for tigecycline distribution from the central to the peripheral compartment
timeFrame: up to 6 months
measure: rate constant for tigecycline distribution from the peripheral to central the compartment
timeFrame: up to 6 months
measure: elimination rate constant
timeFrame: up to 6 months
measure: intercompartmental clearance
timeFrame: up to 6 months
measure: total clearance
timeFrame: up to 6 months
measure: volume of central compartment
timeFrame: up to 6 months
measure: volume distribution of peripheral compartment
timeFrame: up to 6 months
measure: steady state volume distribution
timeFrame: up to 6 months
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: up to 6 months
measure: Peak Plasma Concentration (Cmax)
timeFrame: up to 6 months
Secondary outcomes:
measure: PK/PD index for CRE bloodstream infection
timeFrame: up to 6 months
measure: Rate of mortality
timeFrame: 7,14 and 28 days
measure: Number of Participants with the clinical outcome
timeFrame: 14 days
measure: Number of Participants with the microbiological outcome
timeFrame: 7 days
measure: Genotype classification of carbapenemase producing CRE
timeFrame: up to 6 months
Other outcomes:
Locations:
city: Ratchathewi
country: Thailand
facility: Phramongkutklao Hospital
state: Bangkok
Study officials:
affiliation: Faculty of Pharmacy, Silpakorn University
name: Sirapat Somsirikarnjanakoon, PharmD.
role: STUDY_CHAIR
affiliation: Faculty of Pharmacy, Silpakorn University
name: Wichai Santimaleeworagun, PhD.
role: STUDY_DIRECTOR
affiliation: Phramongkutklao College of Medicine and Hospital
name: Worapong Nasomsong, MD.
role: STUDY_DIRECTOR
References: