Pharmacokinetic Factors Associated With Early Meropenem Target Attainment in Pediatric Severe Sepsis
Kelli Paice1,2, Sonya Tang Girdwood2,3,4, Tomoyuki Mizuno2,4
1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Insights
In pediatric severe sepsis, most children achieved early meropenem concentration targets. Higher drug clearance was linked to failing to reach therapeutic targets, suggesting a need for individualized dosing strategies in critically ill children.
Area of Science:
- Pediatric Critical Care Medicine
- Pharmacokinetics and Pharmacodynamics
- Infectious Diseases
Background:
- Severe sepsis in critically ill children requires effective antimicrobial therapy.
- Achieving therapeutic drug concentrations is crucial for optimal outcomes.
- Meropenem is a broad-spectrum antibiotic used for severe bacterial infections.
Purpose of the Study:
- To determine the frequency of early meropenem concentration target attainment (TA) in critically ill children with severe sepsis.
- To explore factors associated with TA, including clinical, therapeutic, and pharmacokinetic variables.
- To assess the relationship between fluid resuscitation, volume status, and early TA.
Main Methods:
- Retrospective analysis of a prospective observational cohort study.
- Inclusion of 29 critically ill children with severe sepsis receiving meropenem.
- Analysis of concentration-time profiles using population pharmacokinetic modeling and Bayesian estimation.
Main Results:
- Twenty-one of 29 patients (72%) achieved the target of 40% time above 4x minimum inhibitory concentration (MIC).
- Higher meropenem clearance was associated with failure to attain therapeutic targets.
- No significant association was found between TA and volume of distribution, age, weight, eGFR, or fluid administration.
Conclusions:
- A significant proportion of pediatric patients with severe sepsis did not achieve early meropenem therapeutic targets.
- Higher drug clearance is a key factor associated with failing to meet meropenem targets.
- Individualized meropenem dosing strategies may be necessary for critically ill children to optimize target attainment.
Objectives:
To determine the frequency of early meropenem concentration target attainment (TA) in critically ill children with severe sepsis; to explore clinical, therapeutic, and pharmacokinetic factors associated with TA; and to assess how fluid resuscitation and volume status relate to early TA.
Design:
Retrospective analysis of prospective observational cohort study.
Setting:
PICU in a single academic quaternary care children's hospital.
Patients:
Twenty-nine patients starting meropenem for severe sepsis (characterized as need for positive pressure ventilation, vasopressors, or ≥ 40 mL/kg bolused fluid), of which 17 were newly escalated to PICU level care.
Interventions:
None.
Measurements And Main Results:
Concentration-time profiles were analyzed using modeling software employing opportunistic sampling, Bayesian estimation, and a population pharmacokinetic model. Time above four times minimum inhibitory concentration (T > 4×MIC), using the susceptibility breakpoint of 1 µg/mL, was determined for each patient over the first 24 hours of meropenem therapy, as well as individual clearance and volume of distribution (Vd) estimates. Twenty-one of 29 patients met a target of 40%T > MIC 4 μg/mL. Reaching TA, vs. not, was associated with lower meropenem clearance. We failed to identify a difference in Vd or an association between the TA group and age, weight, creatinine-based estimated glomerular filtration rate (eGFR), or the amount of fluid administered. eGFR was, however, negatively correlated with overall T > MIC.
Conclusions:
Eight of 29 pediatric patients with early severe sepsis did not meet the selected TA threshold within the first 24 hours of meropenem therapy. Higher clearance was associated with failure to meet targets. Identifying patients likely to have higher meropenem clearance could help with dosing regimens.
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