Sepsis
Conditions
Brief summary
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.
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.
Interventions
DRUGIntermittent Piperacillin/tazobactam
Piperacillin/tazobactam administered in 30 minutes infusion.
DRUGContinuous Piperacillin/tazobactam
Piperacillin/tazobactam administered in 24 hours infusion.
DRUGIntermittent Imipenem
Imipenem administered in 60 minutes infusion.
DRUGExtended Imipenem
Imipenem administered in 6 hours infusion.
DRUGIntermittent Meropenem
Meropenem administered in 60 minutes infusion.
DRUGExtended Meropenem
Meropenem administered in 8 hours infusion.
Sponsors
Instituto Mexicano del Seguro Social
Hospital Infantil de Mexico Federico Gomez
Hospital Regional de Alta Especialidad del Bajio
Coordinación de Investigación en Salud, Mexico
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Response | 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. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 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. | 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. |
Countries
Mexico
Participant flow
Pre-assignment details
the pre-specified intent was to only compare Intermittent and Prolonged Arm/Groups with the grouping of betalactam antibiotics (imipenem, meropenem and piperacillin/tazobactam)
Participants by arm
| Arm | Count |
|---|---|
| Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem 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.
Intermittent Piperacillin/tazobactam: Piperacillin/tazobactam administered in 30 minutes infusion.
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.
Intermittent Imipenem: Imipenem administered in 60 minutes infusion.
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.
Intermittent Meropenem: Meropenem administered in 60 minutes infusion. | 201 |
| Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem 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.
Continuous Piperacillin/tazobactam: Piperacillin/tazobactam administered in 24 hours infusion.
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.
Extended Imipenem: Imipenem administered in 6 hours infusion.
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.
Extended Meropenem: Meropenem administered in 8 hours infusion. | 202 |
| Total | 403 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | acute liver failure in the first 24 hours of randomization | 4 | 5 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | viral or fungal infection | 3 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem |
|---|---|---|---|
| Age, Categorical <=18 years | 403 Participants | 202 Participants | 201 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6 years | 6 years | 6 years |
| B-lactam antibiotic imipenem | 81 Participants | 42 Participants | 39 Participants |
| B-lactam antibiotic meropenem | 105 Participants | 52 Participants | 53 Participants |
| B-lactam antibiotic piperacillin/tazobactam | 217 Participants | 108 Participants | 109 Participants |
| Comorbid conditions Cardiovascular | 23 Participants | 8 Participants | 15 Participants |
| Comorbid conditions Gastrointestinal | 35 Participants | 15 Participants | 20 Participants |
| Comorbid conditions Genetic | 20 Participants | 9 Participants | 11 Participants |
| Comorbid conditions Hematologic/immunologic | 15 Participants | 4 Participants | 11 Participants |
| Comorbid conditions Metabolic | 2 Participants | 1 Participants | 1 Participants |
| Comorbid conditions Neonatal | 5 Participants | 3 Participants | 2 Participants |
| Comorbid conditions Neoplastic | 258 Participants | 133 Participants | 125 Participants |
| Comorbid conditions Neurological | 19 Participants | 11 Participants | 8 Participants |
| Comorbid conditions Renal | 1 Participants | 0 Participants | 1 Participants |
| Comorbid conditions Respiratory | 4 Participants | 2 Participants | 2 Participants |
| Comorbid conditions Stem cell transplant | 1 Participants | 1 Participants | 0 Participants |
| Comorbidity | 383 Participants | 187 Participants | 196 Participants |
| Hospital stay prior to enrollment to the study protocol | 235 Participants | 122 Participants | 113 Participants |
| Number of participants with organisms identified | 161 Participants | 86 Participants | 75 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment Mexico | 403 participants | 202 participants | 201 participants |
| septic shock at enrollment | 110 Participants | 61 Participants | 49 Participants |
| Sex: Female, Male Female | 182 Participants | 91 Participants | 91 Participants |
| Sex: Female, Male Male | 221 Participants | 111 Participants | 110 Participants |
| type of infection bacteremia | 65 Participants | 35 Participants | 30 Participants |
| type of infection febrile neutropenia | 124 Participants | 55 Participants | 69 Participants |
| type of infection intraabdominal | 95 Participants | 55 Participants | 40 Participants |
| type of infection respiratory tract | 61 Participants | 27 Participants | 34 Participants |
| type of infection skin and soft tissue | 21 Participants | 10 Participants | 11 Participants |
| type of infection unknown | 25 Participants | 14 Participants | 11 Participants |
| type of infection urinary tract | 12 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 201 | 19 / 202 |
| other Total, other adverse events | 1 / 201 | 3 / 202 |
| serious Total, serious adverse events | 0 / 201 | 0 / 202 |
Outcome results
Primary
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).
Time frame: 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.
Population: The efficacy of the maneuver was evaluated by frequency of clinical response and calculation of the absolute risk reduction and the number needed to treat.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem | Number of Participants With Clinical Response | 178 Participants |
| Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Number of Participants With Clinical Response | 169 Participants |
p-value: 0.15695% CI: [0.87, 1.02]Chi-squared
Secondary
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.
Time frame: 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.
Population: evaluation of the safety of the intervention with analysis of the frequency of adverse events by treatment group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intermittent. Piperacillin/Tazobactam, Imipenem, Meropenem | Number of Participants With Adverse Events | 1 Participants |
| Prolonged Infusion. Continuous Piperacillin/Tazobactam, Extended Imipenem, Extended Meropenem | Number of Participants With Adverse Events | 3 Participants |
p-value: 0.72295% CI: [0.31, 28.45]Chi-squared