Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections

NCT ID: NCT05942157

Last Updated: 2023-07-19

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 810 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-29
• Study Completion Date: 2025-12-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Intervention

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

Group Type: EXPERIMENTAL

Therapeutic Drug Monitoring (TDM)

Intervention Type: OTHER

Upon randomization and before the bacterial culture results are known, blood sampling will be obtained from the patient during the morning round of initial empiric antibiotic administration. PK/PD target analysis based on the clinical susceptibility breakpoints of Enterobacterales (the most prevalent organism family of DT-GNB infections in our setting) will be performed and a dosage recommendation will be communicated to the primary ID clinician. Antibiotic dosing adjustments (if any) will be made within 8 - 24 hours of the blood sampling by the Primary / Infectious Diseases clinician. In case of inappropriate dosing, where the PK/PD target is not achieved or exceeded with antibiotic side effects observed, the dosage will be increased or decreased, respectively.

Interventions

Therapeutic Drug Monitoring (TDM)

Upon randomization and before the bacterial culture results are known, blood sampling will be obtained from the patient during the morning round of initial empiric antibiotic administration. PK/PD target analysis based on the clinical susceptibility breakpoints of Enterobacterales (the most prevalent organism family of DT-GNB infections in our setting) will be performed and a dosage recommendation will be communicated to the primary ID clinician. Antibiotic dosing adjustments (if any) will be made within 8 - 24 hours of the blood sampling by the Primary / Infectious Diseases clinician. In case of inappropriate dosing, where the PK/PD target is not achieved or exceeded with antibiotic side effects observed, the dosage will be increased or decreased, respectively.

Intervention Type: OTHER

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

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Singapore General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tze Peng Lim, PhD

Role: PRINCIPAL_INVESTIGATOR

Singapore General Hospital

Locations

Singapore General Hospital

Singapore, , Singapore

Site Status: RECRUITING

Countries

Singapore

Central Contacts

Tze Peng Lim, PhD

Role: CONTACT

lim.tze.peng@sgh.com.sg

+65 6326 6959

Facility Contacts

Lim Tze Peng, PhD

Role: primary

lim.tze.peng@sgh.com.sg

Other Identifiers

TDM RCT

Identifier Type: -

Identifier Source: org_study_id