BETARGET: Randomized Trial of Individualized Beta‑lactam Dosing (TDM, MIC‑guided, Model‑Based) vs Standard Care in ICU Patients with Sepsis due to Gram‑negative Bacilli

The primary objective is to evaluate the impact of an individualized beta‑lactam dosing strategy—incorporating minimal inhibitory concentration, therapeutic drug monitoring, and model‑based dose adjustment—on ICU free days at day 28 in intensive‑care patients with gram‑negative bacilli infection and sepsis. Secondary objectives are to assess the strategy’s effect on organ failure at day 1 and day 7 (or at the last assessment before death or readiness for ICU discharge), use of therapeutic support during the ICU stay and up to day 28, 28‑day mortality, emergence of multidrug‑resistant or third‑generation cephalosporin‑resistant Enterobacterales (carriage or infection) during the ICU stay and up to day 28, clinical cure at day 14 (or earlier if ready for discharge), relapse or superinfection between the end of initial antibiotic therapy and readiness for discharge (or up to day 28), microbiological cure at day 3, encephalopathy until day 7, number and type of beta‑lactam dosage adjustments during the first 7 days, antibiotic‑free days at day 28, and beta‑lactam exposure during the first 7 days.

The trial enrolled adult patients (≥18 years) of both sexes who were hospitalized in an ICU and diagnosed with sepsis caused by Enterobacterales or non‑fermenting Gram‑negative bacilli. All participants required treatment with a beta‑lactam antibiotic (e.g., cefotaxime, ceftazidime, cefepime, piperacillin, piperacillin‑tazobactam, meropenem, amoxicillin, or ceftazidime‑avibactam). The study population was defined as vulnerable patients, reflecting the critical‑ill nature of the cohort. The sponsor did not provide the total number of participants. Selection was based on the principal inclusion criteria, and patients with contraindications to the specified beta‑lactam agents or lacking informed consent were excluded.

The BETTARGET study is a prospective, randomized, controlled trial evaluating an individualized beta‑lactam dosing strategy that integrates minimum inhibitory concentration, therapeutic drug monitoring, and model‑based dose adjustment in intensive care unit patients with documented gram‑negative bacilli infection and sepsis. Eligible participants (≥18 years, ICU admission, microbiologically confirmed Enterobacterales or non‑fermenting gram‑negative bacilli, receiving one of the specified beta‑lactam agents) are enrolled after a screening visit that confirms inclusion criteria and obtains baseline laboratory data. Randomization occurs at the baseline visit (day 0) to either the BETTARGET individualized dosing arm or standard care. Subsequent study visits are scheduled on days 1, 3, 7, 14, and 28 to collect therapeutic drug concentrations, assess clinical and microbiological outcomes, record organ support measures, and adjust dosing according to the study algorithm during the first 7 days. The end‑of‑study visit on day 28 captures the primary endpoint (ICU‑free days), mortality, and safety assessments. Participant involvement extends up to 28 days post‑randomization, with the possibility of earlier discontinuation for death, withdrawal of consent, severe adverse events, or inability to receive the study drug. The overall trial recruitment period spans from September 2026 to February 2029, and the protocol defines the primary and secondary efficacy and safety endpoints to be analyzed at study completion.

The study investigates an individualized beta-lactam therapeutic strategy that incorporates minimum inhibitory concentration data, therapeutic drug monitoring, and model‑based dose adjustment for intensive care unit patients with gram‑negative bacilli infection.

Piperacillin is administered intravenously as an infusion of 12 g per dosing interval. The infusion is prepared in a sterile solution and delivered according to the protocol‑defined schedule.

The combination of tazobactam and piperacillin is given by intravenous infusion, containing 1.5 g/l of tazobactam and 12 g of piperacillin per dosing interval. Both agents are mixed in a compatible diluent and infused as specified in the study protocol.

Amoxicillin is provided as an intravenous infusion of 12 g per dosing interval. The preparation is administered through a dedicated line following the assigned dosing schedule.

Cefotaxime is supplied for intravenous infusion at a dose of 12 g per dosing interval. The drug is reconstituted in an appropriate carrier solution and infused according to the protocol.

Ceftazidime is administered intravenously as an infusion of 6 g per dosing interval. In the subgroup receiving the beta‑lactamase inhibitor, avibactam is co‑infused at 1.5 g per dosing interval alongside ceftazidime.

Cefepime dihydrochloride monohydrate is given by intravenous infusion at a dose of 6 g per dosing interval, prepared in a sterile diluent and administered as directed.

Meropenem trihydrate is delivered as an intravenous infusion of 6 g per dosing interval, with preparation and administration following the study‑specified guidelines.

Non‑experimental treatments may include standard‑of‑care antimicrobial therapy selected according to local institutional guidelines, as well as placebo or comparator agents when applicable. These concomitant therapies are administered in accordance with routine clinical practice and documented in the case report form.

Dosing schedules are defined in the trial protocol and may be adjusted based on therapeutic drug monitoring results. Blood samples for drug concentration measurements are obtained at predetermined time points to assess compliance and to guide model‑based dose modifications throughout the treatment period.

The primary efficacy parameter is the number of ICU‑free days at day 28 after inclusion, a composite measure that integrates survival status at 28 days and the cumulative duration of ICU stay. This endpoint is determined by recording the total days each participant spends in the ICU up to day 28 and subtracting that value from 28; patients who die before day 28 are assigned zero ICU‑free days.

Secondary efficacy assessments include: the change in sepsis severity as measured by the SOFA score between day 1 and day 7 (or the last assessment before death); time to readiness for ICU discharge; the count of treatment‑support days (catecholamine use, invasive mechanical ventilation, renal replacement therapy) within the ICU stay up to day 28; all‑cause mortality up to day 28; emergence of multidrug‑resistant or C3G‑resistant Enterobacterales detected in weekly screening or clinical isolates during the ICU stay; clinical cure status evaluated at day 14 or earlier if discharge readiness is achieved; use of alternative antibiotic therapy for documented relapse or superinfection from the end of initial therapy to discharge or day 28; microbiological cure defined by a negative tracheal aspiration culture on day 3; presence of encephalopathy before day 7 or at the last pre‑death assessment using the daily ICDSC; number and type of beta‑lactam dosage adjustments during the first 7 days; total days without antibiotic therapy at day 28 (calculated as 28 minus days of antibiotic exposure); and the beta‑lactam concentration‑to‑MIC ratio over the first 7 days, obtained through therapeutic drug monitoring. Each parameter is collected at the specified timepoints using validated clinical scales (SOFA, ICDSC), microbiological cultures, and pharmacokinetic assays, with data analyzed according to the predefined statistical plan for the trial.