Efficacy of Betalactam Antibiotics in Prolonged Infusion Compared to Intermittent in Pediatric Patients With Sepsis

Efficacy and Safety of the Administration of Betalactam Antibiotics in Continuous or Extended Infusion Compared to Intermittent Infusion in Patients With Sepsis in Two Pediatric Third-level Care Hospitals

This study evaluates the efficacy and safety of the administration of betalactam antibiotics in prolonged infusion compared to intermittent infusion in children with sepsis. Half of participants will receive piperacillin/tazobactam, imipenem or meropenem in continuous or extended infusion, while the other half will receive piperacillin/tazobactam, imipenem or meropenem in intermittent infusion.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Intermittent Piperacillin/tazobactam; Drug: Continuous Piperacillin/tazobactam; Drug: Intermittent Imipenem; Drug: Extended Imipenem; Drug: Intermittent Meropenem; Drug: Extended Meropenem

Detailed Description

Sepsis is the leading cause of morbidity and mortality in hospitalised patients globally. Betalactams are time-dependent antibiotics, and so, the duration of time for which the free drug plasma concentration remains above the minimum inhibitory concentration (fT > MIC) is the pharmacokinetic/pharmacodynamic index associated with bacterial killing and clinical improvement. Numerous studies have demonstrated that continuous infusion (infusion in 24 hours) and extended infusion (through prolonging the infusion time to greater than 3 hours) allows the maintenance of concentrations above the MIC for a longer period of time within the dosing interval (30 minute or 1 hour), and so, capitalises on the pharmacodynamic properties of betalactams and maximises bacterial killing, therefore potentially improving clinical outcomes. In adult patients, the several studies suggest that prolonged infusion may offer clinical benefits and significant reduction in mortality without increasing the risk of toxicity, however, there is limited information about these dosing strategies in pediatric patients.

• Study Type: Interventional
• Enrollment (Actual): 426
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Mexico
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 06720
      • Hospital Infantil de Mexico Federico Gomez
    • Mexico, Distrito Federal, Mexico, 06720
      • Instituto Mexicano del Seguro Social

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients diagnosed with sepsis, who have been evaluated by an infectious physician and are candidates to receive piperacillin/tazobactam, imipenem or meropenem as empiric treatment.

Exclusion Criteria:

• Patients with a history of allergy to one or more of the proposed antibiotics.
• Patients with chronic kidney disease or acute renal failure.
• Patients with acute liver failure of any cause.
• Patients in palliative or supportive care only.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intermittent Piperacillin/tazobactam; Piperacillin/tazobactam 300mg/kg/day, divided into 4 doses/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 30 minutes infusion every 6 hours.	Drug: Intermittent Piperacillin/tazobactam; Piperacillin/tazobactam administered in 30 minutes infusion.; Other Names: Intermittent Infusion of Piperacillin/tazobactam; PiSA
Experimental: Continuous Piperacillin/tazobactam; Piperacillin/tazobactam initial doses 75mg/kg in 30 minutes infusion, immediately thereafter continue 300mg/kg/day, diluted in 5% glucose solution, at a concentration of 50mg/ml, to be administered in 24 hours infusion every 24 hours, as determined by antibiotic stability at room temperature.	Drug: Continuous Piperacillin/tazobactam; Piperacillin/tazobactam administered in 24 hours infusion.; Other Names: PiSA; Continuous Infusion of Piperacillin/tazobactam
Active Comparator: Intermittent Imipenem; Imipenem 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes infusion every 6 hours.	Drug: Intermittent Imipenem; Imipenem administered in 60 minutes infusion.; Other Names: PiSA; Intermittent Infusion of Imipenem
Experimental: Extended Imipenem; Imipenem initial doses 20mg/kg in 60 minutes infusion, immediately thereafter continue 80mg/kg/day, divided into 4 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 6 hours, as determined by antibiotic stability at room temperature.	Drug: Extended Imipenem; Imipenem administered in 6 hours infusion.; Other Names: PiSA; Extended Infusion of Imipenem
Active Comparator: Intermittent Meropenem; Meropenem 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution, at a concentration of 7mg/ml, to be administered in 60 minutes every 8 hours.	Drug: Intermittent Meropenem; Meropenem administered in 60 minutes infusion.; Other Names: Intermittent Infusion of Meropenem; Kener; Merrem, AstraZeneca
Experimental: Extended Meropenem; Meropenem initial doses 35mg/kg in 60 minutes infusion, immediately thereafter continue 100mg/kg/day, divided into 3 doses/day, diluted in 0.9% saline solution at a concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours, as determined by antibiotic stability at room temperature.	Drug: Extended Meropenem; Meropenem administered in 8 hours infusion.; Other Names: Kener; Merrem, AstraZeneca; Extended Infusion of Meropenem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Response	Resolution. Disappearance of all signs and symptoms related to the infection. Failure. Insufficient lessening of the signs and symptoms of infection to qualify as improvement, including death or indeterminate (no evaluation possible, for any reason).	Number of participants with clinical response at 14 days after antibiotic cessation, up to an average of 28 days or the day of your discharge if this occurred before 14 days after antibiotic cessation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Any harmful, undesirable, potentially serious and life threatening effects occurring during or after administration of the antibiotics proposed in this study (piperacillin / tazobactam, imipenem or meropenem), was evaluated as: none or adverse event classified according to the intensity of the clinical manifestation (severity) as: mild, moderate or severe and for each antibiotic.	Number of participants with adverse events evaluated by an physician at the time of administration of antibiotics, up to an average to 24 hours after the study drug cessation.

Collaborators and Investigators

• Sponsor: Coordinación de Investigación en Salud, Mexico
• Collaborators: Instituto Mexicano del Seguro Social; Hospital Infantil de Mexico Federico Gomez; Hospital Regional de Alta Especialidad del Bajio
• Investigators: Principal Investigator: Yazmín del Carmen Fuentes, Instituto Mexicano del Seguro Social

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Actual): December 30, 2019
• Study Completion (Actual): January 30, 2020

Study Registration Dates

• First Submitted: December 26, 2016
• First Submitted That Met QC Criteria: January 11, 2017
• First Posted (Estimate): January 13, 2017

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 14, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Imipenem; Meropenem; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination
• Other Study ID Numbers: 2016-785-099

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Identified individual participant data for all primary and secondary outcome measures will be made available within six months of study completion

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No