Clinical trial NCT03019965
Conditions: Sepsis
Sponsor: Coordinación de Investigación en Salud, Mexico
Start date: 2017-02-01; Completion date: 2020-01-30
Enrollment: 426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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. arm 6: 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.
Interventions: intervention 1: Intermittent Piperacillin/tazobactam intervention 2: Continuous Piperacillin/tazobactam intervention 3: Intermittent Imipenem intervention 4: Extended Imipenem intervention 5: Intermittent Meropenem intervention 6: Extended Meropenem
Intervention descriptions: intervention 1: Piperacillin/tazobactam administered in 30 minutes infusion. intervention 2: Piperacillin/tazobactam administered in 24 hours infusion. intervention 3: Imipenem administered in 60 minutes infusion. intervention 4: Imipenem administered in 6 hours infusion. intervention 5: Meropenem administered in 60 minutes infusion. intervention 6: Meropenem administered in 8 hours infusion.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Official title: 
 
 
Efficacy of Betalactam Antibiotics in Prolonged Infusion 
Compared to Intermittent in Pediatric Patients With Sepsis 
 
 
NCT number: 
 
 
03019965 
 
Date: 
 
January 20, 2020 
 
 
 
 
 
 
 
 
 


Methods 
Study design 
This was a prospective, three-center, open label clinical trial of prolonged infusion 
versus intermittent infusion (II) of piperacillin/tazobactam, imipenem or meropenem 
in patients with sepsis from three Pediatric third-level care Hospitals: (1) Unidad 
Médica de Alta Especialidad, Hospital de Pediatría de Centro Médico Nacional Siglo 
XXI del Instituto Mexicano del Seguro Social, Cd. México (approved November 15, 
2016); (2) Hospital Infantil de México “Federico Gómez”, Cd. México (approved 
March 22, 2017); and (3) Hospital General Regional de Alta Especialidad del Bajío, 
León, Gto (approved July 13, 2017). Institutional ethics approval was obtained at 
each participating site, an annual reapproval in January 20, 2020. Written informed 
consent to participate in the study was obtained from each participant prior to study 
enrolment. The study was registered with the National Institutes of Health (NIH) trial 
registry (NCT03019965). All patients who were admitted between December 1, 
2016, and December 1, 2019, were screened. 
 
Participants and randomisation 
Patients were eligible for inclusion if they developed sepsis (defined according to 
criteria established in the International pediatric sepsis consensus conference: 
Definitions for sepsis and organ dysfunction in pediatrics), age > one month or < 17 
years old, candidates to receive piperacillin/tazobactam, imipenem or meropenem 
as treatment. Exclusion criteria were as follows: 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 and patients in 


palliative or supportive care only, morbid obesity, and received more than 48 hours 
of treatment with piperacillin/tazobactam, imipenem or meropenem before the 
inclusion. Prior to the start of the research project, the allocation sequence was 
generated by mode of administration, using a table of random numbers with an 
allocation ratio of 1:1, no restriction was made to the randomization scheme. They 
were indicated in sealed numbered envelopes as: continuous (CI)/extended infusion 
(EI) or intermittent infusion (II). Once the informed consent letter was signed, the 
Medical Coordinator of each Hospital Unit contacted the main researcher (YFP) to 
indicate consecutively the assignment in 2 intervention groups, such as: Group 1. 
II.- patients who received piperacillin/tazobactam, imipenem, or meropenem in 
regular 
intermittent 
infusion. 
Group 
2. 
CI/EI.- 
patients 
who 
received 
piperacillin/tazobactam in continuous infusion, imipenem or meropenem in extended 
infusion 
 
Intervention 
Group 1 received the antibiotic in II of piperacillin/tazobactam 300mg/kg/day based 
on piperacillin, 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), 
without exceeding a maximum dose of 16 g/day; 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), without exceeding a maximum 
dose of 4g/day; or meropenem 100mg/kg/day, divided into 3 doses (diluted in 0.9% 
saline solution at a concentration of 7mg/ml, to be administered in 60 minutes 
infusion, every 8 hours), without exceeding a maximum dose of 6g/day; and Group 


2 received the antibiotic in CI: to 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; imipenem initial doses 20mg/kg/doses in 60 minutes 
infusion, immediately thereafter continue 80mg/kg/day, diluted in 0.9% saline 
solution, at a concentration of 7mg/ml, to be administered in 6 hours infusion every 
6 hours; or meropenem initial doses 35mg/kg/doses in 60 minutes infusion, 
immediately thereafter continue 100mg/kg/day, diluted in 0.9% saline solution at a 
concentration of 7mg/ml, to be administered in 8 hours infusion every 8 hours. 
Nursing staff were trained in the preparation and administration of antibiotics by 
administration modality, as well as continuous supervision of the maneuver. The 
study antibiotic was administered until the treating phisician decided to cease the 
drug, or substituted with other antibiotics if clinically indicated or according to the 
culture and susceptibility result if prescribed empirically; discharge; or death. 
 
Outcomes and measurements 
The primary clinical outcome was clinical cure at 14 days after antibiotic cessation, 
it was evaluated clinical response at 72 hours and 7 days. Clinical outcome was 
rated as either resolution: disappearance of all signs and symptoms related to the 
infection or 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 endpoints included adverse events occurring during or 
after administration of the antibiotics proposed, was evaluated as: none or adverse 
event classified according to the intensity of the clinical manifestation (severity) as: 


mild, moderate or severe (2) and for each antibiotic (3). The evaluation was carried 
out in each hospital unit by 2 researchers 
 
Sample size 
It was calculated taking into account a difference between both groups of 15% 
superiority of continuous or extended infusion, starting from 50% for the intermittent 
infusion group and 65% for the intervention group, considering a confidence level of 
95%, statistical power of 80%, a sample size of 134 was calculated; an estimated 
loss of 20%, a minimum of 170 patients per group would be required. 
 
Statistical Analysis 
The analysis was performed by intention to treat including all randomized patients 
who received at least one dose of antibiotic, although they have not concluded in the 
mode of administration to which it was assigned, and per protocol analysis to 
evaluate only the patients who received the assigned maneuver during all your 
treatment. Descriptive statistics to evaluate the baseline characteristics of the 
patients: calculation of simple frequencies and percentages for the qualitative 
variables, and for the mean or median quantitative variables according to their 
distribution, bivariate analysis with Pearson's Chi-square, Fisher's exact test and U 
Mann's -Whitney. The efficacy of the maneuver was evaluated by calculating the 
absolute risk reduction and the number needed to treat; evaluation of the safety of 
the intervention with analysis of the frequency of adverse events by treatment group. 
Multivariate logistic regression analysis to identify predictive variables associated 


with clinical cure, adjusted for the main confounding variables found in the bivariate 
analysis, with a value of p £ 0.15 were considered to build the model.