Defining Antibiotic Levels in Intensive care patients (DALI-2) protocol - A multi-national pharmacokinetic/pharmacodynamic cohort study to determine whether contemporary antibiotic dosing for critically ill patients achieves therapeutic exposures.

This multi-national pharmacokinetic/pharmacodynamic cohort study evaluates the achievement of therapeutic antibiotic exposures in critically ill patients with serious infections. The primary objective is to describe whether contemporary antibiotic dosing regimens attain target drug concentrations in the intensive care unit population. This is clinically relevant as altered pharmacokinetics in critical illness may result in suboptimal antibiotic levels, potentially compromising treatment efficacy and contributing to treatment failure or development of resistance.

The secondary objectives are:

• To describe the achievement of alternative target exposures for select antibiotics, including specific thresholds for beta-lactam antibiotics (50% fT>MIC, 50% fT>4xMIC, 100%fT>MIC and 100%fT>4xMIC), vancomycin trough concentrations (≥15 mg/L in adults, 15 to 25 mg/L for intermittent and continuous infusions; 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus and 10 to 15 mg/L for non-MRSA in children).

• To determine the relationship between achievement of target antibiotic exposures and patient-related outcomes, including positive and negative clinical outcomes, mortality at day 14 and day 30, ICU-free days at day 30, and emergence of antibiotic resistance.

• To determine the proportion of critically ill patients whose observed antibiotic concentrations surpass pre-defined values associated with toxicity.

• To determine the frequency of suspected adverse drug events and the relationship between antibiotic concentration and such events.

• To describe the pharmacokinetic variability of individual antibiotics in ICU patients.

This clinical trial enrolled a total of **1,050 participants** diagnosed with **serious infections** who were **critically ill patients** receiving **antibiotic** treatment. The study population included both **male** and **female** subjects across **pediatric** and **adult** age groups, with a minimum corrected gestational age of 1 month. Participants were selected from patients admitted to an **intensive care unit (ICU)** who were receiving specified **intravenous antibiotics** for the treatment of infection and had been administered the study antibiotic for at least 24 hours prior to enrollment. The trial included a **vulnerable population**. Eligible participants were required to have suitable intravenous or intra-arterial access to facilitate sample collection, and informed consent was obtained for participation in the study.

This clinical trial is designed as a prospective, multi-national pharmacokinetic/pharmacodynamic cohort study to evaluate whether contemporary antibiotic dosing regimens achieve therapeutic drug exposures in critically ill patients. The study will be conducted in intensive care units and involves patients receiving various intravenous antibiotics for the treatment of serious infections. The trial is classified as a low-intervention study in which all medicinal products are used in accordance with their marketing authorizations. The study employs a non-randomized, observational design without blinding procedures, as it focuses on describing antibiotic concentrations and their correlation with clinical outcomes rather than comparing different treatment interventions.

The maximum duration of participant involvement in the study is 21 days, which corresponds to the maximum treatment period with the study antibiotics. Recruitment is estimated to commence in December 2025, with the trial anticipated to conclude by December 2027. Participants must be admitted to an intensive care unit and receiving one of the specified intravenous antibiotics for at least 24 hours prior to enrollment. Eligible patients must have a corrected gestational age of at least one month and possess suitable intravenous or intra-arterial access for blood sample collection. Informed consent is required for participation in the study.

The study involves multiple antibiotics administered via intravenous use, including beta-lactam antibiotics such as benzylpenicillin, amoxicillin, ampicillin, piperacillin, ceftazidime, ceftriaxone, cefepime, cefotaxime, cefazolin, aztreonam, meropenem, imipenem, and ertapenem. Combinations with beta-lactamase inhibitors such as clavulanic acid, tazobactam, avibactam, sulbactam, and cilastatin are also included. Additional antibiotics comprise glycopeptides including vancomycin and teicoplanin, aminoglycosides such as gentamicin, tobramycin, and amikacin, fluoroquinolones including ciprofloxacin and levofloxacin, as well as linezolid, daptomycin, tigecycline, colistin, fosfomycin, metronidazole, and the combination of sulfamethoxazole and trimethoprim. The maximum daily doses and total doses vary according to the specific antibiotic administered, with treatment periods not exceeding 21 days.

The primary endpoint of the trial is the achievement of predefined pharmacokinetic/pharmacodynamic plasma targets for each study drug, determined through measurement of antibiotic plasma concentrations. Secondary endpoints include the evaluation of alternative pharmacokinetic/pharmacodynamic targets, such as the percentage of time that free drug concentrations remain above the minimum inhibitory concentration for beta-lactam antibiotics, and specific trough concentration ranges for vancomycin in both adult and pediatric populations. The study will also assess correlations between targeted antibiotic plasma concentrations and clinical outcomes, including clinical success, clinical failure, mortality at day 14 and day 30 after initiation of the study antibiotic, the number of intensive care unit-free days at day 30, and the identification of resistant organisms in subsequent microbiological samples within 14 days. Additional secondary endpoints involve determining the proportion of patients whose observed antibiotic concentrations exceed predefined values associated with toxicity, examining correlations between antibiotic plasma concentrations and the occurrence of adverse events, and providing a comprehensive description of observed antibiotic plasma concentrations.

The study does not specify principal exclusion criteria beyond the inclusion requirements. Conditions that may lead to early termination from the study are not explicitly detailed in the available data. Blood samples for pharmacokinetic analysis will be collected at specified time points during the treatment period to measure antibiotic concentrations and evaluate whether therapeutic exposures are achieved. The observational nature of the study allows for the collection of real-world data on antibiotic dosing practices and their pharmacokinetic/pharmacodynamic outcomes in the critically ill patient population without altering standard clinical care.

This clinical trial investigates multiple antibiotic treatments administered to critically ill patients to evaluate therapeutic drug exposures. All medications are administered via intravenous route over a maximum treatment period of 21 days. The study employs various antibiotic agents representing multiple pharmacological classes, each with specific dosing regimens tailored to achieve optimal pharmacokinetic and pharmacodynamic targets in the intensive care setting.

Benzylpenicillin is administered as a combination product containing benzylpenicillin procaine, benzathine benzylpenicillin, and benzylpenicillin potassium. The maximum daily dose is 6 million international units, with a total maximum dose of 126 million international units over the treatment period. The medication is provided for intravenous use.

Linezolid is administered in two pharmaceutical forms. The solution for infusion formulation has a maximum daily dose of 1.8 grams, with a total maximum dose of 37.8 grams. An alternative powder formulation containing linezolid has a maximum daily dose of 6 grams and a total maximum dose of 126 grams over the treatment period. Both formulations are administered intravenously.

Cefiderocol powder for solution for infusion is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams over the treatment period.

Imipenem and cilastatin combination product contains cilastatin sodium and imipenem. The powder for solution for infusion is administered intravenously with a maximum daily dose of 4 grams and a total maximum dose of 84 grams.

Levofloxacin powder for solution for infusion is administered intravenously with a maximum daily dose of 1 gram and a total maximum dose of 21 grams over the treatment period.

Aztreonam and avibactam combination contains aztreonam and avibactam as a beta-lactamase inhibitor. The powder for solution for infusion is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams.

Ceftazidime is available in two formulations. The powder for solution for injection/infusion containing ceftazidime pentahydrate has a maximum daily dose of 8 grams and a total maximum dose of 168 grams. Both formulations are administered intravenously.

Aztreonam powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams over the treatment period.

Colistin powder for solution is administered intravenously with a maximum daily dose of 12 million international units and a total maximum dose of 252 million international units.

Cloxacillin powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 12 grams and a total maximum dose of 252 grams over the treatment period.

Amoxicillin powder for solution for injection/infusion containing amoxicillin sodium is administered intravenously with a maximum daily dose of 300 milligrams per kilogram body weight and a total maximum dose of 6300 milligrams per kilogram.

Vancomycin powder for solution for infusion is administered intravenously with a maximum daily dose of 30 milligrams per kilogram body weight and a total maximum dose of 630 milligrams per kilogram over the treatment period.

Amoxicillin and clavulanic acid combination contains amoxicillin sodium and clavulanic acid as a beta-lactamase inhibitor. The powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams.

Ceftazidime and avibactam combination contains ceftazidime and avibactam as a beta-lactamase inhibitor. The powder for solution for infusion is administered intravenously with a maximum daily dose of 6 grams and a total maximum dose of 126 grams.

Ertapenem powder for solution for infusion containing ertapenem sodium is administered intravenously with a maximum daily dose of 1 gram and a total maximum dose of 21 grams over the treatment period.

Tigecycline powder for solution for injection is administered intravenously with a maximum daily dose of 200 milligrams and a total maximum dose of 4200 milligrams over the treatment period.

Ampicillin and sulbactam combination contains ampicillin sodium, sulbactam sodium, and lidocaine hydrochloride. The powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams.

Imipenem, cilastatin and relebactam combination contains cilastatin and imipenem. The powder for solution for infusion is administered intravenously with a maximum daily dose of 2 grams and a total maximum dose of 41 grams.

Fosfomycin powder for concentrate for solution for infusion containing fosfomycin calcium is administered intravenously with a maximum daily dose of 16 grams and a total maximum dose of 336 grams over the treatment period.

Teicoplanin powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 12 milligrams per kilogram body weight and a total maximum dose of 252 milligrams per kilogram.

Ampicillin powder for solution for injection containing ampicillin sodium is administered intravenously with a maximum daily dose of 12 grams and a total maximum dose of 252 grams over the treatment period.

Gentamicin cream containing betamethasone valerate and gentamicin sulfate is administered intravenously with a maximum daily dose of 10 milligrams per kilogram body weight and a total maximum dose of 210 milligrams per kilogram.

Daptomycin powder for solution for injection or infusion is administered intravenously with a maximum daily dose of 12 milligrams per kilogram body weight and a total maximum dose of 252 milligrams per kilogram over the treatment period.

Piperacillin and tazobactam combination contains piperacillin sodium and tazobactam sodium as a beta-lactamase inhibitor. The powder for solution for infusion is administered intravenously with a maximum daily dose of 20 milligrams and a total maximum dose of 420 milligrams.

Sulfamethoxazole and trimethoprim combination contains bromhexine hydrochloride, sulfamethoxazole, and trimethoprim. The powder for concentrate for solution for infusion is administered intravenously with a maximum daily dose of 2.4 grams and a total maximum dose of 50.4 grams.

Cefepime powder for solution for injection or infusion containing cefepime hydrochloride is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams over the treatment period.

Cefotaxime powder for solution for injection/infusion containing cefotaxime and lidocaine is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams.

Ceftolozane and tazobactam combination contains tazobactam and ceftolozane. The powder for solution for infusion is administered intravenously with a maximum daily dose of 6 grams and a total maximum dose of 126 grams over the treatment period.

Meropenem and vaborbactam combination contains meropenem. The powder for solution for infusion is administered intravenously with a maximum daily dose of 6 grams and a total maximum dose of 126 grams.

Ceftriaxone powder for solution for injection/infusion containing ceftriaxone sodium and lidocaine hydrochloride is administered intravenously with a maximum daily dose of 2 grams and a total maximum dose of 42 grams over the treatment period.

Tobramycin powder for solution for injection/infusion is administered intravenously with a maximum daily dose of 10 milligrams per kilogram body weight and a total maximum dose of 210 milligrams per kilogram.

Ciprofloxacin solution for infusion containing ciprofloxacin hydrochloride and ciprofloxacin is administered intravenously with a maximum daily dose of 1.5 grams and a total maximum dose of 31.5 grams over the treatment period.

Metronidazole powder for solution for infusion containing metronidazole and glucose is administered intravenously with a maximum daily dose of 1.5 grams and a total maximum dose of 31.5 grams.

Amikacin powder for solution for injection/infusion containing amikacin sulfate is administered intravenously with a maximum daily dose of 30 milligrams per kilogram body weight and a total maximum dose of 630 milligrams per kilogram over the treatment period.

Piperacillin powder for solution for injection/infusion containing piperacillin sodium and lidocaine hydrochloride is administered intravenously with a maximum daily dose of 12 grams and a total maximum dose of 252 grams.

Flucloxacillin powder for solution for injection containing flucloxacillin sodium is administered intravenously with a maximum daily dose of 12 grams and a total maximum dose of 252 grams over the treatment period.

Cefazolin powder for solution for injection/infusion containing cefazolin sodium is administered intravenously with a maximum daily dose of 8 grams and a total maximum dose of 168 grams.

All antibiotic treatments in this study are classified as experimental medications and represent standard-of-care therapy for critically ill patients with suspected or confirmed bacterial infections. Participant compliance monitoring includes pharmacokinetic sampling at specified time points to measure antibiotic concentrations and assess achievement of therapeutic targets. The study does not employ placebo or comparator treatments, as all participants receive active antibiotic therapy according to clinical indication and local prescribing practices.

Efficacy will be assessed through evaluation of antibiotic pharmacokinetic/pharmacodynamic plasma targets and clinical outcomes. The primary endpoint is the achievement of antibiotic pharmacokinetic/pharmacodynamic plasma targets specific to each study drug, with antibiotic plasma concentrations measured throughout the study period. Secondary endpoints include assessment of alternative pharmacokinetic/pharmacodynamic targets, such as 50% fT>MIC, 50% fT>4xMIC, 100% fT>MIC, and 100% fT>4xMIC for **beta-lactam antibiotics**, and specific trough concentration ranges for **vancomycin** administered via intermittent or continuous infusions. For adults, vancomycin trough concentrations of ≥15 mg/L and 15 to 25 mg/L will be evaluated, while for children, target ranges of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus and 10 to 15 mg/L for non-methicillin-resistant Staphylococcus aureus infections will be assessed. Additional secondary endpoints include correlation between targeted antibiotic plasma concentrations and clinical success, clinical failure, mortality at day 14 and day 30 after initiation of the study antibiotic, the number of intensive care unit free days at day 30, and identification of resistant organisms in subsequent microbiological samples within 14 days of study antibiotic initiation. The proportion of patients whose observed antibiotic concentrations surpass pre-defined values associated with toxicity will be determined. Correlation between antibiotic plasma concentrations and the occurrence of adverse events will be evaluated, and observed antibiotic plasma concentrations will be described.