Clinical trial NCT05942157: Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections
Official title: Evaluation of the Efficacy and Safety of Antibiotic Therapeutic Drug Monitoring (TDM) in Patients With Difficult-to-Treat Gram-Negative Bacterial (DT-GNB) Infections
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Sepsis
Hemodynamic Instability
Bacterial Infections
Therapeutic Drug Monitoring
Antimicrobial Resistance
Keywords: Sepsis
Hemodynamic Instability
Therapeutic Drug Monitoring
Gram-negative Bacteria
Beta-Lactams
Fosfomycin
Fluoroquinolone
Glycylcycline
Dialysis
Lead sponsor: Singapore General Hospital
Sponsor class: OTHER
First posted: 2023-07-12
Enrollment: 810
Sex: ALL
Minimum age (years): 16
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A prospective, open-label, randomized controlled trial will be conducted to evaluate a novel TDM-guided therapy in management of DT-GNB infections. We hypothesize that TDM-guided antibiotic therapy will reduce 14-day all-cause mortality by 6% (absolute risk reduction) in septic patients with DT-GNB infections, when compared to standard therapy. TDM for 11 antibiotics will be performed for all trial patients although test information will be withheld for the standard therapy arm. The primary aim is to compare the 14-day all-cause mortality rates of novel TDM-guided antibiotic dosing versus standard therapy.

Detailed description: Sepsis remains a major cause of morbidity and mortality worldwide in the face of antimicrobial resistance especially in patients with Gram-negative bacteria (GNB) infections. Limited new antibiotics for GNB infections pose a severe threat to clinical management of these patients and thus call for old antibiotics to be repurposed. Dosing regimens of old antibiotics often fail to achieve therapeutic drug concentrations in some septic patients. Septic patients commonly have significant hemodynamic changes and/or undergo extracorporeal interventions that may increase patients' susceptibility to treatment failure and increase the chance of more resistant bacteria emergence, or toxicity from the antibiotic. Hence, the "one size fits all" dosing principle for antimicrobial treatments of suspect sepsis due to infection by antibiotic-resistant- or less susceptible-GNB \[collectively known as "difficult-to-treat" (DT)-GNB infections\] is no longer viable. This will require therapeutic drug monitoring (TDM) to inform if the dosing is adequate to treat such infections.

This study seeks to provide evidence supporting the application of TDM-guided antibiotic therapy on reducing mortality and morbidity among septic patients with DT-GNB infections and significant hemodynamic changes, which can potentially shift current practice paradigms.

Eligibility criteria: Inclusion Criteria:

* 16 years or older
* Receive intravenous therapy of the study antibiotics
* Antibiotic treatment should be aimed for at least 3 days at time of inclusion

Exclusion Criteria:

* Pregnancy
* Antibiotics cessation before first blood sample collection
* Receiving antibiotics only as prophylaxis
* On palliative care or with less than 48 hours of life expectancy

Primary outcomes:
measure: 14-day All-Cause Mortality Rate
timeFrame: 14 Days
Secondary outcomes:
measure: Fever Resolution
timeFrame: 14 Days
measure: Microbiological Treatment Cure of Difficult to Treat Gram-Negative Bacteria (DT-GNB)
timeFrame: 14 Days
measure: Improved or Stabilized Sequential Organ Failure Assessment (SOFA)
timeFrame: 14 Days
measure: Incidences of Adverse Drug Reactions
timeFrame: Start to End of Antibiotic Therapy (Up to 90 days from randomization, discharge or demise, whichever comes earliest)
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: Singapore General Hospital
Study officials:
affiliation: Singapore General Hospital
name: Tze Peng Lim, PhD
role: PRINCIPAL_INVESTIGATOR
References: