Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections (TDM-RCT)

Singapore Health Services (SingHealth)

Status: Enrolling

Conditions: Therapeutic Drug Monitoring; Hemodynamic Instability; Antimicrobial Resistance; Bacterial Infections; Sepsis

Treatments: Other: Therapeutic Drug Monitoring (TDM)

Study type: Interventional

Funder types: Other

Identifiers

NCT05942157

TDM RCT

Details and patient eligibility

About

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.

Full 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.

Enrollment: 810 estimated patients

Sex: All

Ages: 16 to 99 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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810 participants in 2 patient groups

Control

No Intervention group

Description:

The prescription of antibiotics will follow institution antibiotic prescribing guidelines or at the Infectious Disease (ID) clinician's discretion, based on culture and antibiotic susceptibilities results (whenever available). Empiric antibiotic treatment will be employed prior to the availability of culture or antibiotic susceptibilities results. Antibiotic level measurements, Minimum Inhibitory Concentrations (MIC) testing and Pharmacokinetics/Pharmacodynamics (PK/PD) target analysis will only be performed at Day 14 post enrolment, but the results will not be released to the ID clinician and the primary clinician.

Intervention

Experimental group

Description:

Once a positive GNB culture is known, antibiotic MIC testing will commence, and PK/PD target analysis will be performed using the antibiotic MIC. An every-other-day TDM-guided regimen will be chosen to rapidly adjust the antibiotic doses until the PK/PD target is achieved. In the event the antibiotic dose readjustment is unable to achieve the defined PK/PD target, blood sampling will continue every other day until Day 14 or the PK/PD target is achieved

Treatment:

Other: Therapeutic Drug Monitoring (TDM)