Beta-Lactams in Critically Ill Children: Time to Step Up Our Game?*

Abstract

Evidence on optimal drug dosing in children is lacking, especially in critically ill children. This vulnerable population is particularly susceptible to overdosing and underdosing due to illness-associated changes in drug pharmacokinetics and important gaps in drug dosing guidance. Beta-lactams are commonly used for empiric treatment of pediatric sepsis due to their broad-spectrum activity and low toxicity. Their efficacy relies on the fraction of time that the free concentrations (ƒt-unbound to plasma proteins) are above the minimal inhibitory concentration (MIC) (ƒt > MIC), which represents the minimal antibiotic concentration able to inhibit bacteria growth. Given that efficacy is time-dependent, one way to optimize this pharmacokinetic/pharmacodynamic parameter is through extended or continuous infusions. The need for such prolonged infusions in children has not yet been demonstrated. Are standard beta-lactam dosing regimens adequate in critically ill children? Would prolonged infusions be beneficial in a subgroup of our patients? Identifying the exact population who may benefit the most from prolonged infusions is of critical importance in pediatrics, probably more so than in adults, given the limited venous access in children.In this issue of Pediatric Critical Care Medicine, Van Der Heggen et al ( 1) attempt to answer this question. They report a post hoc analysis of a prospective single-center observational pharmacokinetic study on IV amoxicillin-clavulanic acid (60 children), piperacillin-tazobactam (48 children), and meropenem (49 children) in a total of 157 critically ill children. Based on plasma trough concentrations, they report that only 25.5% of children attained the established pharmacokinetic/pharmacodynamic target of ƒt greater than MIC = 100% when using MIC corresponding to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for Escherichia coli (amoxicillin-clavulanic acid), Pseudomonas aeruginosa (piperacillin-tazobactam), and Enterobacteriaceae species (meropenem). Only 10% of the children treated with piperacillin-tazobactam reached this efficacy target.The authors found that augmented renal clearance (ARC) and the absence of vasopressors were the two main risk factors for subtherapeutic concentrations. The presence of ARC among the risk factors was expected. ARC affects 8% to 78% of critically ill children depending on the used definition, and its association with subtherapeutic concentrations is well recognized in adults and increasingly reported in pediatrics (2, 3). The association between low beta-lactam exposure and the absence of vasopressors is somewhat reassuring, suggesting that severity of illness is correlated with higher exposure. Our sickest patients are therefore more likely to have higher beta-lactam exposure. This finding is consistent with the fact that shock is often associated with acute kidney injury