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

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.

• 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]
• Overall survival (OS) [Time frame: 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 free of life support [Time frame: 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.]
• 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.]
• 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.]
• 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.]
• 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.]