Therapeutic Monitoring of Beta-lactams in Critically Ill Patients With Sepsis

Condition(s) studied

Investigational drug(s) / intervention(s)

Individualized dosing of beta-lactam antibiotics based on therapeutic monitoring: In the intervention group, plasma levels will be determined 48 hours after the start of antibiotic treatment and subsequently every 4-5 days, with a pharmacotherapeutic report and dosage adjustment within \<24 hours. In the control group, samples will be stored at -80 °C and analyzed at the end of the study, with no impact on clinical practice. Plasma concentrations of beta-lactam antibiotics will be determined by high-performance liquid chromatography (HPLC) using validated commercial kits, which allow simultaneous quantification of several drugs in this group with reduced processing times and feasible implementation in hospital routine. Patients will be evaluated weekly until hospital discharge, death, or completion of antibiotic treatment. Clinical progression, inflammatory markers, emergence of resistance, adverse effects, and clinical and microbiological outcomes will be recorded.

Study summary

Background: Sepsis is a leading cause of morbidity and mortality among critically ill patients and is associated with intensive use of β-lactam antibiotics. These drugs show time-dependent pharmacodynamics and high pharmacokinetic variability in this population, making it difficult to achieve therapeutic levels. Therapeutic drug monitoring (TDM) may optimize dosing, but its routine clinical implementation remains limited.

Objective: To evaluate whether individualized β-lactam dosing guided by TDM reduces time to full clinical recovery compared with standard dosing in critically ill patients with sepsis.

Methods: OPTIBETA is a pragmatic, randomized, controlled, open-label clinical trial to be conducted at a tertiary hospital in Spain. Adult patients (≥18 years) admitted to the intensive care unit or infectious diseases ward with sepsis will be included. Participants will be randomized 1:1 to either a TDM-guided dosing arm (dose adjustments according to PK/PD targets) or a standard dosing arm. Clinical, microbiological, and pharmacological outcomes will be collected. The primary endpoint is time to complete clinical cure. Secondary outcomes include overall survival, microbiological cure, ICU and hospital length of stay, adverse events, and achievement of PK/PD targets. The estimated sample size is 198 patients.

Expected results: We hypothesize that TDM-guided dosing will reduce time to clinical cure, improve overall outcomes, and decrease adverse events compared with standard dosing.

Conclusions: OPTIBETA will provide high-quality evidence on the role of β-lactam TDM in critically ill septic patients and may support its inclusion in antimicrobial stewardship programs.

Eligibility

Primary outcome measure(s)

• Time to complete clinical cure — From the date of randomization to the date of clinical cure, assessed every 7 days and until the end of the study, an average of 3 years.
  The primary endpoint will be the time to complete clinical cure, defined as resolution of signs and symptoms of infection, functional recovery, baseline or improved SOFA score (≥2 points from baseline), and no need to initiate new antibiotic treatment.

Trial sites (1)