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.
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.
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);
Parallel
Extended infusion time of the following beta-lactam: meropenem
DrugGroup 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: meropenem
DrugGroup 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/tazobactam
DrugGroup 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: cefepime
DrugGroup 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: ceftriaxone
DrugGroup 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/tazobactam
DrugGroup 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: cefepime
DrugGroup 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: ceftriaxone
DrugGroup 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.
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).
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).
Time to normalisation of C-reactive protein (CRP)
It shows how many days it takes for CRP to return to normal (\<10 mg/L).
Time to normalisation of procalcitonin (PCT)
It shows how many days it takes for PCT to return to normal (\<0.5 µg/L).
Time to normalisation of white blood cells (WBC)
It shows how many days it takes for WBC to return to normal (\<10,000 /µl).
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