Pharmacokinetic Factors Associated With Early Meropenem Target Attainment in Pediatric Severe Sepsis.

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.