A Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients

A Protocol of a Randomised, Two-arm Superiority Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients

The goal of this clinical trial is to examine the success and safety of administering certain antibiotics (beta-lactams) given in a longer 3-hour infusion to children (0-17 years) who are critically ill and have severe infection.

The main question it aims to answer is:

Is the longer infusion more effective than the conventional short-term (0.5-hour-long) infusion? Researchers will compare the 3-hour-long infusion group to the 0.5-hour-long infusion group to determine whether the longer infusion can cure the infection earlier and whether it is equally safe. The doses are the same in the two groups. Only the duration differs until the patient receives the antibiotic.

Participants will:

• be given the required antibiotic drug in a 3-hour-long or in a 0.5 hour-long infusion.
• be examined to make sure their blood drug levels are correct. This will require two blood tests.
• be treated according to routine care and have examinations and blood tests performed.

Treatment begins with a short, intermittent infusion of antibiotics. If the patient meets study criteria, randomisation must occur within 24 hours. Prior to enrolment, written informed consent or a declaration of contribution must be signed by the legal guardian and, where age-appropriate, the patient.

Plans for the collection and laboratory evaluation of biological samples:

Per protocol:

This study involves collecting blood samples (200 µl per sample) to monitor drug levels, with each sample identified by the patient's assigned PIN (Personal Identification Number). To ensure measurements reflect steady-state conditions, samples must be collected at least 48 hours after the first post-allocation dose and immediately prior to the next scheduled dose (trough or minimum level). Analysis of free (unbound) drug concentrations is performed via High-Performance Liquid Chromatography (HPLC) with specific absorbance detection for meropenem (290 nm), piperacillin (252 nm), tazobactam (210 nm), and cefepime (263 nm); ceftriaxone is measured using Liquid Chromatography-Mass Spectrometry (LC-MS).

For evaluating the drug levels:

Pathogen minimal inhibitory concentration (MIC) values will be sourced directly from the microbiology laboratory when available; otherwise, values will be retrieved from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database. In place of a measured MIC, the epidemiological cut-off value (ECOFF)-representing the upper MIC limit for wild-type, non-resistant bacteria-may be used. For empirical dosing where no specific pathogen is identified, the highest MIC for antibiotic-susceptible bacteria will be applied to account for a worst-case scenario.

Standard care:

Routine laboratory assessments-including a complete blood count (CBC) and blood chemistry tests-will be conducted at enrolment and daily thereafter. To ensure accuracy, samples must be analysed within 1-2 hours of collection. Baseline data will include inflammatory markers (C-reactive protein [CRP], procalcitonin [PCT]), hematological parameters (white blood cell count [WBC], platelet count), liver function (liver enzymes and total/direct bilirubin), and serum creatinine. Additionally, clinical severity will be assessed using Paediatric Index of Mortality 3 (PIM-3), Paediatric Risk of Mortality III (PRISM III), and Paediatric Logistic Organ Dysfunction 2 (PELOD 2) scores. While all patients require a pre-antibiotic blood culture, those with negative cultures will be excluded from the microbiological eradication analysis.

In cases where microbiological cultures are negative, the clinician will diagnose infection based on clinical signs and symptoms. These signs and symptoms will also be examined when assessing the clinical response outcome.

Signs of infection may include elevated acute phase proteins (CRP > 10 mg/L or PCT > 0.5 µg/L or WBC > 10,000 /µL), or infection/inflammation confirmed by imaging and any clinical signs (fever > 37.5 °C core temperature or haemodynamic instability - need for inotropic or vasopressor therapy or abnormal blood gas values (normal arterial blood gas values: pH=7.35-7.45, PaO2=80-100 mmHg, PCO2=35-45 mmHg, [HCO3-]=22-28 mEq/L and lactate<3 mmol/L; normal venous blood gas values: pH=7.31-7.41, PvO2=35-45 mmHg, PCO2=41-51 mmHg, [HCO3-]=22-28 mEq/L and lactate<3 mmol/L; normal capillary blood gas values: pH=7.35-7.45, PCO2=35-45 mmHg, [HCO3-]=22-28 mEq/L) or respiratory failure or neurological signs or enteral feeding intolerance.

Criteria for discontinuation or modification of designated interventions:

If blood samples reveal sub-therapeutic antibiotic levels (underexposure), dosing must be adjusted by increasing the dose or the frequency of administration. All adjustments must be documented. Patients requiring these changes will remain in their originally assigned study arm for analysis under the modified intention-to-treat (mITT) population; crossover between study arms is strictly prohibited. In the event of clinician-reported adverse events, the Steering Committee (SC) will determine whether the antibiotic should be discontinued.

If β-lactam therapy must be changed due to clinical deterioration or antibiotic resistance, and the new antibiotic is also a study β-lactam (meropenem, piperacillin/tazobactam, cefepime, or ceftriaxone), the patient remains in the assigned arm (extended infusion [EI] or short-term infusion [SI]) and is not excluded.

All patients are followed for 30 days post-allocation or until discharge or death. For patients discharged before the 30-day mark, a telephone follow-up will be conducted on day 30 to evaluate their clinical status.

Inclusion Criteria:

• paediatric patients (0-17 years of age) with suspected or confirmed bacterial infection who are treated in a PICU or NICU and diagnosed with sepsis with a total Phoenix Sepsis Score ≥2 points, and the infection is clinically probable or confirmed by microbiological culture (e.g. from a blood culture, cerebrospinal fluid, urine, trachea, wound, etc.), excluding contamination;
• who are receiving β-lactams including meropenem, piperacillin/tazobactam, cefepime and ceftriaxone;
• who received the same β-lactam therapy within 24 hours prior to inclusion or started new β-lactam therapy due to clinical deterioration;
• written consent of the parent or guardian is obtained.

Exclusion Criteria:

• palliative care patients;
• patients participating in other drug trials;
• patients with impaired renal function if dosing modification is required (estimated Glomerular Filtration Rate [eGFR]<50 mL/min/1.73m2 for meropenem, cefepime, and piperacillin/tazobactam; eGFR<10 mL/min/1.73m2 for ceftriaxone);
• patients undergoing plasmapheresis (TPE);
• patients undergoing extracorporeal therapy (continuous kidney replacement therapy [CKRT] or extracorporeal membrane oxygenation [ECMO]);
• β-lactam allergy;
• patients admitted from another institution or department who have been on the same β-lactam treatment for more than 24 hours;
• pregnancy.