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.

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.

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.

The randomization sequence will be generated using independent software (randomization.com). Concealment will be ensured using opaque, sequentially numbered envelopes and an electronic case report form (eCRF) that is locked until assignment. Outcome assessors will remain blinded.