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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis; Infection; NICU; Beta Lactams; PICU
• Intervention / Treatment: Drug: Short-term infusion time of the following beta-lactam: meropenem; Drug: Short-term infusion time of the following beta-lactam: piperacillin/tazobactam; Drug: Short-term infusion time of the following beta-lactam: cefepime; Drug: Short-term infusion time of the following beta-lactam: ceftriaxone; Drug: Extended infusion time of the following beta-lactam: meropenem; Drug: Extended infusion time of the following beta-lactam: piperacillin/tazobactam; Drug: Extended infusion time of the following beta-lactam: cefepime; Drug: Extended infusion time of the following beta-lactam: ceftriaxone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kinga Anna Budai; Phone Number: +36206632915; Email: budai.kinga@semmelweis.hu

Study Locations

• Hungary
  • Budapest, Hungary, 1083
    • Pediatric Center (Bókay Street Department), Semmelweis University
    • Contact: Kinga Anna Budai; Phone Number: +36206632915; Email: budai.kinga@semmelweis.hu
  • Budapest, Hungary, 1094
    • Pediatric Center (Tűzoltó Street Department), Semmelweis University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI); subset P: 28 days - 17 years subset N: term or pre-term infants < 28 days of post-natal age, or PMA* < 44 weeks *postmenstrual age	Drug: Short-term infusion time of the following beta-lactam: meropenem; Group short-term infusion (SI): Duration of infusion is 0.5 hour (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - meropenem (MPM): 30 mg/kg or 40 mg/kg for meningitis q8h (max. 2 g q8h) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Short-term infusion time of the following beta-lactam: piperacillin/tazobactam; Group short-term infusion (SI): Duration of infusion is 0.5 hour (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - piperacillin/tazobactam (TZP): 90 mg/kg piperacillin q6h for non-immunosuppressed patients and 100 mg/kg piperacillin q6h for immunosuppressed patients (max. 4.5 g piperacillin/tazobactam per dose) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Short-term infusion time of the following beta-lactam: cefepime; Group short-term infusion (SI): Duration of infusion is 0.5 hour (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - cefepime (CFP): 30-50 mg/kg q8h or q12h (>1 month: 30 mg/kg every 8-12 hours, 2 months-17 years (bodyweight up to 41 kg): 50 mg/kg every 8-12 hours (max. 2 g per dose; increased dose [q8h] used for severe infection and febrile neutropenia) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Short-term infusion time of the following beta-lactam: ceftriaxone; Group short-term infusion (SI): Duration of infusion is 0.5 hour (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - ceftriaxone (CTX): 50 mg/kg q12h (max. 4 g per day) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.
Experimental: pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI); subset P: 28 days - 17 years subset N: term or pre-term infants < 28 days of post-natal age, or PMA* < 44 weeks *postmenstrual age	Drug: Extended infusion time of the following beta-lactam: meropenem; Group extended infusion (EI): Duration of infusion is 3 hours (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - meropenem (MPM): 30 mg/kg or 40 mg/kg for meningitis q8h (max. 2 g q8h) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Extended infusion time of the following beta-lactam: piperacillin/tazobactam; Group extended infusion (EI): Duration of infusion is 3 hours (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - piperacillin/tazobactam (TZP): 90 mg/kg piperacillin q6h for non-immunosuppressed patients and 100 mg/kg piperacillin q6h for immunosuppressed patients (max. 4.5 g piperacillin/tazobactam per dose) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Extended infusion time of the following beta-lactam: cefepime; Group extended infusion (EI): Duration of infusion is 3 hours (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - cefepime (CFP): 30-50 mg/kg q8h or q12h (>1 month: 30 mg/kg every 8-12 hours, 2 months-17 years (bodyweight up to 41 kg): 50 mg/kg every 8-12 hours (max. 2 g per dose; increased dose [q8h] used for severe infection and febrile neutropenia) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.; Drug: Extended infusion time of the following beta-lactam: ceftriaxone; Group extended infusion (EI): Duration of infusion is 3 hours (h) Subset paediatric (P): The doses of beta-lactams are (q…h= every…hours): - ceftriaxone (CTX): 50 mg/kg q12h (max. 4 g per day) Subset neonatal (N): The doses of beta-lactams are as recommended by NeoFax® (MerativeTM Micromedex® database), based on postmenstrual age (PMA) and postnatal age.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving PK/PD index: 100% fT>MIC (Ctrough >MIC)	In critically ill patients, it is recommended to maintain plasma levels 1-4 times higher than the minimal inhibitory concentration (MIC) of the bacterium isolated throughout the dosing interval (100% fT>1-4×MIC). The primary outcome for the study will be the proportion of patients achieving therapeutic and optimal drug exposure, defined as plasma concentrations above the MIC for 100% of the dosing interval. Trough plasma concentration levels should be measured. The pharmacokinetic-pharmacodynamic (PK/PD) index used is 100% fT>MIC (Ctrough >MIC).	two times >48 hours after initiation of antibiotic treatment according to the treatment allocation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving PK/PD index: 100% fT>4xMIC (Ctrough >4xMIC)	In critically ill patients, it is recommended to maintain plasma levels 1-4 times higher than the MIC (minimal inhibitory concentration) of the bacterium isolated throughout the dosing interval (100% fT>1-4×MIC). Trough plasma concentration levels should be measured. The pharmacokinetic-pharmacodynamic (PK/PD) index used is 100% fT>4xMIC (Ctrough >4xMIC).	two times >48 hours after initiation of antibiotic treatment according to the treatment allocation
Time to normalisation of C-reactive protein (CRP)	It shows how many days it takes for CRP to return to normal (<10 mg/L).	From enrollment to the end of treatment (maximum 30 days).
Time to normalisation of procalcitonin (PCT)	It shows how many days it takes for PCT to return to normal (<0.5 µg/L).	From enrollment to the end of treatment (maximum 30 days).
Time to normalisation of white blood cells (WBC)	It shows how many days it takes for WBC to return to normal (<10,000 /µl).	From enrollment to the end of treatment (maximum 30 days).
Microbiological eradication rate	Blood culture must be taken from each patient before starting antibiotic treatment. Additional samples should be taken according to the regimen mentioned below.	On day 0 before initiation of antibiotic treatment and on days 2, 3 and 5 after initiation of antibiotic treatment
Clinical response	Resolution (or clinical success): disappearance of all signs and symptoms related to the infection.; Improvement: a marked or moderate reduction in the severity and/or number of signs and symptoms of infection.; Failure: reduction in signs and symptoms of infection is not sufficient to meet the criteria for improvement, which encompasses outcomes such as death or cases where evaluation was not feasible for any reason.	Each day from enrollment to the end of treatment (maximum 30 days).
Time to clinical success or resolution	It shows how many days it takes to achieve clinical success or resolution.	From enrollment to the end of treatment (maximum 30 days).
Treatment failure	Number of patients for whom the β-lactam antibiotic therapy had to be discontinued due to clinical deterioration and/or antibiotic resistance. If the newly initiated β-lactam is also among the study β-lactams (meropenem, piperacillin/ tazobactam, cefepime, and ceftriaxone), the patient remains in the originally assigned treatment arm (EI or SI).	From enrollment to the end of treatment (maximum 30 days).
Duration of the antibiotic therapy	It shows how many days the antibiotic had to be administered.	From enrollment to the end of treatment (maximum 30 days).
Length of hospital stay (LOS) in days	It shows how many days passed from admission to discharge.	From enrollment to the end of treatment (maximum 30 days).
All-cause mortality	The total number of deaths from any cause.	From enrollment to the end of treatment (maximum 30 days).
Adverse events (AEs)	Definition of adverse event: any harmful, undesirable, potentially severe, or life-threatening effects occurring during or after the administration of the antibiotics proposed in this study. They will be collected in a form where all AEs are listed according to the Summary of Product Characteristics (SmPCs).	Each day from enrollment to the end of treatment (maximum 30 days).
Length of PICU/NICU stay in hours	It shows how many hours passed from admission to discharge. PICU=Pediatric Intensive Care Unit NICU=Neonatal Intensive Care Unit	From enrollment to the end of treatment (maximum 30 days).

Collaborators and Investigators

• Sponsor: Semmelweis University

Publications and helpful links

General Publications

• Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J; DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014 Apr;58(8):1072-83. doi: 10.1093/cid/ciu027. Epub 2014 Jan 14.
• Andre P, Diezi L, Dao K, Crisinel PA, Rothuizen LE, Chtioui H, Decosterd LA, Diezi M, Asner S, Buclin T. Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance! Front Pediatr. 2022 Jan 5;9:768438. doi: 10.3389/fped.2021.768438. eCollection 2021.
• Van Der Heggen T, Dhont E, Willems J, Herck I, Delanghe JR, Stove V, Verstraete AG, Vanhaesebrouck S, De Paepe P, De Cock PAJG. Suboptimal Beta-Lactam Therapy in Critically Ill Children: Risk Factors and Outcome. Pediatr Crit Care Med. 2022 Jul 1;23(7):e309-e318. doi: 10.1097/PCC.0000000000002951. Epub 2022 Apr 15.
• O'Keefe K, Denny KJ, Le Marsney R, McCullough J, Gilholm P, Budai KA, Beranger A, Lodi C, Obeidat M, Ragonnet G, Wacharachaisurapol N, Roberts JA, Gibbons KS, Raman S. Prolonged Versus Intermittent Beta-Lactam Antibiotic Infusions in Paediatric Critical Care: A Systematic Review and Meta-Analysis. J Paediatr Child Health. 2026 Feb;62(2):160-170. doi: 10.1111/jpc.70275. Epub 2025 Dec 27.
• Briand A, Bernier L, Pincivy A, Roumeliotis N, Autmizguine J, Marsot A, Metras ME, Thibault C. Prolonged Beta-Lactam Infusions in Children: A Systematic Review and Meta-Analysis. J Pediatr. 2024 Dec;275:114220. doi: 10.1016/j.jpeds.2024.114220. Epub 2024 Aug 2.
• Zhou P, Zhang Y, Wang Z, Ying Y, Xing Y, Tong X, Zhai S. Extended or Continuous Infusion of Carbapenems in Children with Severe Infections: A Systematic Review and Narrative Synthesis. Antibiotics (Basel). 2021 Sep 9;10(9):1088. doi: 10.3390/antibiotics10091088.
• Hartman SJF, Bruggemann RJ, Orriens L, Dia N, Schreuder MF, de Wildt SN. Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature. Clin Pharmacokinet. 2020 Feb;59(2):173-205. doi: 10.1007/s40262-019-00813-w.
• Cies JJ, Moore WS 2nd, Enache A, Chopra A. beta-lactam Therapeutic Drug Management in the PICU. Crit Care Med. 2018 Feb;46(2):272-279. doi: 10.1097/CCM.0000000000002817.
• Imburgia TA, Kussin ML. A Review of Extended and Continuous Infusion Beta-Lactams in Pediatric Patients. J Pediatr Pharmacol Ther. 2022;27(3):214-227. doi: 10.5863/1551-6776-27.3.214. Epub 2022 Mar 21.
• Budai KA, Timar AE, Obeidat M, Mate V, Nagy R, Harnos A, Kiss-Dala S, Hegyi P, Garami M, Hanko B, Lodi C. Extended infusion of beta-lactams significantly reduces mortality and enhances microbiological eradication in paediatric patients: a systematic review and meta-analysis. EClinicalMedicine. 2023 Nov 2;65:102293. doi: 10.1016/j.eclinm.2023.102293. eCollection 2023 Nov.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: March 3, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; Infections; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; beta-Lactams; Lactams; Sulfones; Penicillanic Acid; Penicillins; Tazobactam
• Other Study ID Numbers: 2024-518115-19-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication, the IPD that underlie the results will be available upon request in encrypted form, subject to approval by the corresponding author.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No