Efficacy and Safety Comparison of Extended vs. Intermittent Infusion of Beta-Lactams in Critically Ill Pediatric Patients with Suspected or Proven Infection

The primary objective of this study is to investigate the probability of target attainment of **beta-lactams** (100% fT>MIC) when administered as extended versus short-term intermittent infusion in critically ill pediatric patients. This is clinically relevant as achieving optimal pharmacokinetic/pharmacodynamic targets is crucial for effective treatment of infections, particularly in critically ill populations where drug distribution and clearance can be significantly altered.

Secondary objectives include evaluating: - Achieving a higher target (100% fT>4xMIC) - All-cause mortality - Adverse events - Clinical response - Clinical success - Duration of the antibiotic - Length of stay in the Pediatric Intensive Care Unit or Neonatal Intensive Care Unit (PICU or NICU) - Length of hospital stay (LOS) - C-reactive protein (CRP) normalization - Procalcitonin (PCT) normalization - White blood cells (WBC) normalization - Microbiological eradication rate - Treatment failure

The clinical trial involves **paediatric patients** aged 0-17 years with suspected or proven bacterial infection, specifically those diagnosed with sepsis and treated in a PICU or NICU. The study population includes both male and female subjects, with no specific mention of vulnerable populations being selected. Participants are required to be receiving **β-lactams** such as meropenem, piperacillin/tazobactam, cefepime, ceftazidime, or ceftriaxone, with therapy initiated within the previous 24 hours or due to clinical deterioration. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have a normal or decreased estimated glomerular filtration rate (eGFR) that does not necessitate dosage adjustment, and ongoing infection must be likely, with or without culture positivity. Written informed consent by a parent or guardian is required for participation. No specific lifestyle considerations such as diet or physical activity are mentioned in the trial details.

The clinical trial is designed as a **randomized**, partially blind, parallel-group study with two arms, aimed at comparing the efficacy and safety of extended (3-hour) versus intermittent (0.5-hour) infusion of **beta-lactams** in critically ill pediatric patients. The trial will involve **paediatric patients** aged 0-17 years with suspected or proven bacterial infections, treated in a Pediatric Intensive Care Unit (PICU) or Neonatal Intensive Care Unit (NICU), and diagnosed with sepsis. The study will assess the probability of target attainment of beta-lactams, with the primary outcome being the proportion of patients achieving therapeutic and optimal exposure when plasma concentrations are above the minimum inhibitory concentration (MIC) for 100% of the dosing interval.

The trial is expected to commence recruitment on September 1, 2025, and conclude by September 1, 2027. Participants will be involved in the study for a maximum treatment period of 30 days. The study visits will include an initial screening visit to confirm eligibility based on inclusion criteria such as age, infection status, and renal function. Follow-up visits will be scheduled to monitor therapeutic outcomes, adverse events, and pharmacokinetic/pharmacodynamic indices. The end-of-study visit will evaluate the overall clinical response and microbiological eradication rates.

Participants may be withdrawn from the study if they experience clinical deterioration requiring a change in antibiotic therapy, develop antibiotic resistance, or if any adverse events necessitate discontinuation of the study drug. The trial will ensure that all procedures adhere to ethical standards, with informed consent obtained from parents or guardians. The study aims to provide valuable insights into the optimal administration of beta-lactams in a vulnerable pediatric population, potentially influencing future treatment protocols for critically ill children with infections.

The clinical trial involves the administration of several **beta-lactam** antibiotics, each with specific pharmaceutical forms, dosages, and administration routes. **Meropenem** is utilized in various formulations, including Meropenem Qilu, Meropenem Kalceks, Meropenem Steriscience, and Meropenem Kabi. These formulations are available as solutions for injection or infusion, with dosages of 500 mg or 1 g. The maximum daily dose for Meropenem is 120 mg/kg, with a total maximum dose of 6 g. The administration route is via intravenous infusion, and the treatment period can extend up to 30 days.

**Piperacillin/Tazobactam** is administered in formulations such as Piperacillin/Tazobactam Kabi and Piperacillin/Tazobactam Sandoz. These are provided as solutions for infusion, with a dosage of 4 g/0.5 g. The maximum daily dose is 400 mg/kg, with a total maximum dose of 16 g. The administration is through intravenous infusion, and the treatment duration is up to 30 days.

**Ceftriaxone** is available in formulations like Ceftriaxon MIP, Ceftriaxone Qilu, and Ceftriaxone Kalceks. These are provided as solutions for injection or infusion, with dosages of 1 g or 2 g. The maximum daily dose is 100 mg/kg, with a total maximum dose of 2 g. The administration route is via intravenous bolus injection or infusion, with a treatment period of up to 30 days.

**Cefepime** is administered in formulations such as Cefepim AptaPharma, available as solutions for injection or infusion, with dosages of 1 g or 2 g. The maximum daily dose is 150 mg/kg, with a total maximum dose of 2 g. The administration is through intravenous bolus injection or infusion, and the treatment duration is up to 30 days.

Participant compliance is monitored through adherence to the dosing schedules and administration routes as specified. The trial aims to compare the efficacy and safety of extended (3-hour) versus intermittent (0.5-hour) infusion of these **beta-lactam** antibiotics in critically ill pediatric patients, focusing on the probability of target attainment (100% fT>MIC) as the primary outcome.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the proportion of patients achieving therapeutic and optimal exposure, defined as plasma concentrations above the minimum inhibitory concentration (MIC) for 100% of the dosing interval. Trough plasma concentration levels will be measured to determine this endpoint.

Secondary endpoints include several parameters:

• The proportion of patients achieving a pharmacokinetic/pharmacodynamic (PK/PD) index of 100% fT>4xMIC (Ctrough >4xMIC).
• Normalisation of C-reactive protein (CRP) levels to less than 10 mg/L and procalcitonin (PCT) levels to less than 0.5, measured in days.
• Normalisation of white blood cell (WBC) count to less than 10,000/µl, also measured in days.
• All-cause mortality within 30 days or until hospital discharge.
• Adverse events recorded daily.
• Microbiological eradication rate at different time points: 1st day, 2nd day, 3rd day, and 5th day.
• Clinical response, defined as resolution, improvement, or failure.
• Clinical success, measured as the time in days when clinical success or resolution is achieved.
• Treatment failure, indicated by the number of patients for whom the **β-lactam** antibiotic had to be stopped due to clinical deterioration and/or antibiotic resistance.
• Duration of antibiotic treatment in days.
• Length of stay in the Pediatric Intensive Care Unit (PICU) or Neonatal Intensive Care Unit (NICU) in days.
• Overall length of hospital stay (LOS) in days.