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

November 23, 2025 updated by: Manuel Ángel Gómez-Ríos, Complexo Hospitalario Universitario de A Coruña

Therapeutic Monitoring of Beta-lactams in Critically Ill Patients With Sepsis: OPTIBETA Clinical Trial Protocol

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Sepsis is a global health problem of enormous magnitude, responsible for more than 48 million cases and 11 million deaths annually, accounting for around 20% of global mortality. Its prevalence is particularly high in critically ill patients, occurring in up to 40% of ICU admissions. In Spain, it causes more than 17,000 deaths per year, exceeding the mortality rate of some types of cancer. In addition to its clinical impact, sepsis entails a considerable economic burden, with direct costs estimated at between €20,000 and €30,000 per patient admitted to the ICU, to which must be added indirect costs arising from functional sequelae and loss of productivity. Early and appropriate antibiotic treatment is essential to improve prognosis, with beta-lactam antibiotics being the most widely used group due to their broad spectrum of action and safety profile. These drugs have time-dependent pharmacodynamics and high pharmacokinetic variability in septic patients, conditioned by factors such as multiple organ dysfunction, increased distribution volume, and renal hyperfiltration. These alterations make it difficult to achieve adequate therapeutic concentrations and can lead to both underdosing-associated with therapeutic failure and the development of resistance-and overdosing, with an increased risk of toxicity, especially neurological toxicity. These alterations make it difficult to achieve adequate therapeutic concentrations and can lead to both underdosing-associated with therapeutic failure and the development of resistance-and overdosing, with an increased risk of toxicity, especially neurological toxicity.

Therapeutic drug monitoring (TDM) applied to beta-lactam antibiotics allows for individualized dosage adjustment based on pharmacokinetic/pharmacodynamic (PK/PD) targets. Despite strong observational evidence supporting this strategy, its clinical implementation remains limited due to technical, organizational, and economic barriers, and the absence of pragmatic randomized clinical trials makes it difficult to establish its true impact on healthcare practice.

In this context, the OPTIBETA project hypothesizes that personalized dosing of beta-lactam antibiotics guided by MDT improves time to clinical cure compared to standard dosing in critically ill patients with sepsis. The primary objective of this trial is to evaluate the efficacy of individualized dosing based on MDT versus the conventional regimen in terms of reducing the time to complete clinical cure.

Hypothesis:

The administration of beta-lactam antibiotics adjusted to PK/PD targets in critically ill patients with sepsis based on plasma level determination improves clinical and microbiological cure compared to standard dosing.

Objectives:

The overall objective is to evaluate the efficacy and safety of personalized dosing of beta-lactam antibiotics based on TDM, compared to standard dosing, in critically ill patients with sepsis.

  • Primary objective Evaluate whether individualized dosing of beta-lactam antibiotics based on pharmacokinetic monitoring and achievement of PK/PD targets is superior to standard dosing in terms of reducing the time to complete clinical cure (resolution of signs and symptoms of infection, functional recovery, baseline or improved SOFA score (≤2 points), and absence of need for new antibiotics).

  • Secondary objectives

    • To evaluate the overall clinical efficacy of personalized dosing versus conventional dosing using variables such as: survival rate, clinical and microbiological cure rate, total length of hospital stay, number of days free of life-support therapies (vasopressors, renal replacement therapies, extracorporeal membrane oxygenation (ECMO)).
    • Analyze the emergence of antimicrobial resistance in both groups.
    • Compare the incidence of adverse effects (nephrotoxicity, hepatotoxicity, and neurotoxicity) between the personalized dosing group and the control group.
    • Determine the percentage of patients who achieve the established PK/PD targets: ≥100% fT > MIC or ≥100% fT > 4×MIC.
    • Study the influence of clinical variables (type of infection, microorganism involved, severity of clinical symptoms, etc.) on the probability of achieving PK/PD targets.
    • Evaluate the relationship between the total concentration and the free fraction of the antibiotic, and its impact on achieving the desired PK/PD parameters.

Study Type

Interventional

Enrollment (Estimated)

198

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Manuel A Gómez-Rios, Anesthesiologist

Study Locations

  • Spain
    • A Coruña
      • Santiago de Compostela, A Coruña, Spain, 15705
        • Clinical Hospital of Santiago de Compostela
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥18 years.
  • Diagnosis of sepsis according to Sepsis-3 (SOFA ≥2).
  • Initiation of treatment with beta-lactam antibiotics.
  • Informed consent signed by the patient or their legal representative within the first 48 hours after the start of antibiotic therapy.

Exclusion Criteria:

  • Pregnancy or breastfeeding.
  • Known hypersensitivity to beta-lactams.
  • Discontinuation of antibiotic treatment before the first TDM determination.
  • Simultaneous participation in another clinical trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention group (individualized dosing based on therapeutic monitoring)

Patients will receive individualized dosing of beta-lactam antibiotics based on therapeutic monitoring. Total and free plasma concentrations will be determined 48 hours after the start of antibiotic therapy and subsequently every 4-5 days, or sooner if there is a significant clinical change. Dosage adjustments will be made to achieve the defined PK/PD targets:

  • Standard: ≥100% fT > MIC.
  • Infections caused by multidrug-resistant pathogens, increased renal clearance, or immunosuppression: ≥100% fT > 4×MIC.

Concentrations will be interpreted in relation to the actual MIC of the identified pathogen or, failing that, to the ECOFF values defined by EUCAST.
Other: 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.
No Intervention: Control group (usual dosage):
Patients will receive the usual dosage of beta-lactam antibiotics following the recommendations of clinical guidelines and hospital protocols, without individualized adjustment based on MDT. Plasma samples will also be collected, but will be stored for deferred analysis at the end of the study, with no impact on clinical management.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to complete clinical cure
Time Frame: 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.
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.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to microbiological cure (negative cultures).
Time Frame: From the date of randomization to the date of microbiological cure, assessed every 7 days and until the end of the study, an average of 3 years
Time until microbiological cultures become negative
From the date of randomization to the date of microbiological cure, assessed every 7 days and until the end of the study, an average of 3 years
Overall survival (OS)
Time Frame: From the start date of treatment until the end of the study, an average of 3 years.
Length of time that patients remain alive after start of treatment.
From the start date of treatment until the end of the study, an average of 3 years.
Length of hospital stay
Time Frame: From the date of randomization until the end of the study, an average of 3 years.
Number of days the patient remains hospitalized
From the date of randomization until the end of the study, an average of 3 years.
Number of days free of life support
Time Frame: From the date of randomization until the end of the study, an average of 3 years.
Number of days free of life support (vasopressors, renal replacement therapy, extracorporeal membrane oxygenation).
From the date of randomization until the end of the study, an average of 3 years.
Security
Time Frame: From the start date of treatment until the end of the study, an average of 3 years.
Incidence of adverse effects related to beta-lactam antibiotics (nephrotoxicity, hepatotoxicity, and neurotoxicity).
From the start date of treatment until the end of the study, an average of 3 years.
Percentage of patients reaching established pharmacokinetics/pharmacodynamic (PK/PD) targets
Time Frame: From the date of randomization to the date of clinical cure, assessed every 4-5 days and until the end of the study, an average of 3 years.
Percentage of patients out of the total number of patients included in the study who achieve the PK/PD objective in any of the measurements taken throughout the study, with this PK/PD objective being set at 100% fT > MIC or ≥100% fT > 4×MIC, depending on clinical profile.
From the date of randomization to the date of clinical cure, assessed every 4-5 days and until the end of the study, an average of 3 years.
Ratio between total and free concentrations of beta-lactam antibiotics.
Time Frame: From the date of randomization to the date of clinical cure, assessed every 4-5 days and until the end of the study, an average of 3 years.
The ratio between the free beta-lactam concentration in the blood and the total concentration in each patient will be related, allowing relationships to be established between this ratio and the scope of the proposed PK/PD objective for that patient.
From the date of randomization to the date of clinical cure, assessed every 4-5 days and until the end of the study, an average of 3 years.
Identification of causative pathogens and their minimum inhibitory concentrations (MIC).
Time Frame: From the date of randomization until the end of the study, an average of 3 years.
From the date of randomization until the end of the study, an average of 3 years.
Determination of the mechanism of antimicrobial resistance developed by the causative microorganism during treatment.
Time Frame: From the start date of treatment until the end of the study, an average of 3 years.
From the start date of treatment until the end of the study, an average of 3 years.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Complexo Hospitalario Universitario de A Coruña

Collaborators

Hospital Clínico Universitario de Santiago de Compostela

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

January 1, 2026

Primary Completion (Estimated)

September 1, 2028

Study Completion (Estimated)

January 1, 2029

Study Registration Dates

First Submitted

November 14, 2025

First Submitted That Met QC Criteria

November 23, 2025

First Posted (Actual)

December 8, 2025

Study Record Updates

Last Update Posted (Actual)

December 8, 2025

Last Update Submitted That Met QC Criteria

November 23, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OPTIBETA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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