InfectionPhase 4PEBBLENCT07484633

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

A Phase 4 study testing Extended infusion time of the following beta-lactam: meropenem, Short-term infusion time of the following beta-lactam: meropenem and Extended infusion time of the following beta-lactam: piperacillin/tazobactam in people with Infection and Sepsis, run by Semmelweis University at 2 sites in Hungary.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 0 hours to 17 years
Conditions the study is for: Infection, Sepsis, NICU
What is being tested?: Extended infusion time of the following beta-lactam: meropenem, Short-term infusion time of the following beta-lactam: meropenem and Extended infusion time of the following beta-lactam: piperacillin/tazobactam
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 110 participants
Where: 2 sitesHungary
Study dates: 1 Sep 2026to 31 Aug 2028
Phase: Phase 4
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 0 hours to 17 years
All sexes
No healthy volunteers
Child

Who may be able to join

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.

Who cannot join

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.

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Kinga Anna Budai contact

+36206632915

budai.kinga@semmelweis.hu

Hungary2 sites, 2 recruiting

Pediatric Center (Bókay Street Department), Semmelweis University
Budapest, 1083
Kinga Anna Budai, +36206632915, budai.kinga@semmelweis.hu
Recruiting
Pediatric Center (Tűzoltó Street Department), Semmelweis University
Budapest, 1094
Kinga Anna Budai, +36206632915, budai.kinga@semmelweis.hu
Recruiting

Other trials in Hungary

About this study

Official title: 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 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.

Read the 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.

Conditions: Infection, Sepsis, NICU, PICU, Beta Lactams
Being tested: Extended infusion time of the following beta-lactam: meropenem, Short-term infusion time of the following beta-lactam: meropenem, Extended infusion time of the following beta-lactam: piperacillin/tazobactam, Extended infusion time of the following beta-lactam: cefepime, Extended infusion time of the following beta-lactam: ceftriaxone
Medical subject headings: Infections, Sepsis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Extended infusion time of the following beta-lactam: meropenemDrug
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.
Short-term infusion time of the following beta-lactam: meropenemDrug
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.
Extended infusion time of the following beta-lactam: piperacillin/tazobactamDrug
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.
Extended infusion time of the following beta-lactam: cefepimeDrug
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.
Extended infusion time of the following beta-lactam: ceftriaxoneDrug
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.
Short-term infusion time of the following beta-lactam: piperacillin/tazobactamDrug
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.
Short-term infusion time of the following beta-lactam: cefepimeDrug
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.
Short-term infusion time of the following beta-lactam: ceftriaxoneDrug
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.

Study groups in NCT07484633
Study group	Role	What they receive
pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)	Active comparator	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 Receives: 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
pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)	Experimental	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 Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

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).
Measured: two times >48 hours after initiation of antibiotic treatment according to the treatment allocation

Secondary outcomes (13)

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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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
Measured: 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.
Measured: From enrollment to the end of treatment (maximum 30 days).
All-cause mortality
The total number of deaths from any cause.
Measured: 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).
Measured: Each day from enrollment to the end of treatment (maximum 30 days).

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Sep 202631 Aug 2028

First posted20 Mar 2026
Study start1 Sep 2026
Primary completion31 Aug 2028 (estimated)
Study completion31 Aug 2028 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (10)Papers the sponsor has linked to this study.
Other trials for InfectionStudies of the same condition, open and under way.
More trials run by Semmelweis UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Single blind
Who is masked: Outcomes assessor
Enrolment: 110 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT07484633
Sponsor's protocol ID: 2024-518115-19-02
Acronym: PEBBLE
Status last verified: Sep 2026
First submitted: 3 Mar 2026
Last updated: 6 Nov 2026
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: After publication, the IPD that underlie the results will be available upon request in encrypted form, subject to approval by the corresponding author.

Publications

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.
PubMed 35083184
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.
PubMed 35426861
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.
PubMed 41454710
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.
PubMed 39097265
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.
PubMed 24429437
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.
PubMed 34572670
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.
PubMed 31432468
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.
PubMed 29112080
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.
PubMed 35350159
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.
PubMed 38021371

Interested in taking part?

Kinga Anna Budai

+36206632915

budai.kinga@semmelweis.hu

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 6 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT07484633
Acronym / sponsor ID: PEBBLE / 2024-518115-19-02
Conditions: Infection, Sepsis, NICU, PICU, Beta Lactams
Phase: Phase 4
Study type: Interventional
Recruitment status: Recruiting
Enrolment: 110 participants (estimated)
Lead sponsor: Semmelweis UniversityUniversity, hospital or other
Study start: 1 Sep 2026 (actual)
Primary completion: 31 Aug 2028 (estimated)
Study completion: 31 Aug 2028 (estimated)
First posted: 20 Mar 2026 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The main question it aims to answer is:

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.

Detailed description

Plans for the collection and laboratory evaluation of biological samples:

Per protocol:

For evaluating the drug levels:

Standard care:

Criteria for discontinuation or modification of designated interventions:

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Single blind (outcomes assessor)
Number of arms: 2

Arm	Type	Receives
pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)	Active comparator	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: ceftriaxonesubset P: 28 days - 17 years subset N: term or pre-term infants < 28 days of post-natal age, or PMA* < 44 weeks *postmenstrual age
pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)	Experimental	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: ceftriaxonesubset P: 28 days - 17 years subset N: term or pre-term infants < 28 days of post-natal age, or PMA* < 44 weeks *postmenstrual age

Who may qualify

Ages: 0 hours to 17 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (4 listed)

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.

Key exclusion criteria (8 listed)

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]);

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Extended infusion time of the following beta-lactam: meropenemGroup 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	pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)
Short-term infusion time of the following beta-lactam: meropenemGroup 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	pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)
Extended infusion time of the following beta-lactam: piperacillin/tazobactamGroup 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	pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)
Extended infusion time of the following beta-lactam: cefepimeGroup 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	pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)
Extended infusion time of the following beta-lactam: ceftriaxoneGroup 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.	Drug	pediatric patients, extended infusion (P, EI) and neonatal patients, extended infusion (N, EI)
Short-term infusion time of the following beta-lactam: piperacillin/tazobactamGroup 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	pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)
Short-term infusion time of the following beta-lactam: cefepimeGroup 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	pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)
Short-term infusion time of the following beta-lactam: ceftriaxoneGroup 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.	Drug	pediatric patients, short-term infusion (P, SI) and neonatal patients, short-term infusion (N, SI)

Primary outcome

Proportion of patients achieving PK/PD index: 100% fT>MIC (Ctrough >MIC)
Time frame: two times >48 hours after initiation of antibiotic treatment according to the treatment allocation
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).

13 secondary outcomes

Proportion of patients achieving PK/PD index: 100% fT>4xMIC (Ctrough >4xMIC)
Time frame: two times >48 hours after initiation of antibiotic treatment according to the treatment allocation
Time to normalisation of C-reactive protein (CRP)
Time frame: From enrollment to the end of treatment (maximum 30 days).
Time to normalisation of procalcitonin (PCT)
Time frame: From enrollment to the end of treatment (maximum 30 days).
Time to normalisation of white blood cells (WBC)
Time frame: From enrollment to the end of treatment (maximum 30 days).
Microbiological eradication rate
Time frame: On day 0 before initiation of antibiotic treatment and on days 2, 3 and 5 after initiation of antibiotic treatment
Clinical response
Time frame: Each day from enrollment to the end of treatment (maximum 30 days).
Time to clinical success or resolution
Time frame: From enrollment to the end of treatment (maximum 30 days).
Treatment failure
Time frame: From enrollment to the end of treatment (maximum 30 days).
Duration of the antibiotic therapy
Time frame: From enrollment to the end of treatment (maximum 30 days).
Length of PICU/NICU stay in hours
Time frame: From enrollment to the end of treatment (maximum 30 days).
Length of hospital stay (LOS) in days
Time frame: From enrollment to the end of treatment (maximum 30 days).
All-cause mortality
Time frame: From enrollment to the end of treatment (maximum 30 days).
Adverse events (AEs)
Time frame: Each day from enrollment to the end of treatment (maximum 30 days).

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2026.
Background: PubMed 35083184Andre 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.
Background: PubMed 35426861Van 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.
Background: PubMed 41454710O'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.
Background: PubMed 39097265Briand 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.
Background: PubMed 24429437Roberts 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.
Background: PubMed 34572670Zhou 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.
Background: PubMed 31432468Hartman 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.
Background: PubMed 29112080Cies 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.
Background: PubMed 35350159Imburgia 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.
Background: PubMed 38021371Budai 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.
Individual participant dataSharing planned: Yes. After publication, the IPD that underlie the results will be available upon request in encrypted form, subject to approval by the corresponding author.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.

Kinga Anna Budai contact

+36206632915

budai.kinga@semmelweis.hu

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 6 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Hungary. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Kinga Anna Budai (+36206632915, budai.kinga@semmelweis.hu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of patients achieving PK/PD index: 100% fT>MIC (Ctrough >MIC) (time frame: two times >48 hours after initiation of antibiotic treatment according to the treatment allocation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07484633, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2026.