Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

Abstract

Background Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. Methods Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. Results 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. Conclusion The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

A new HPLC–DAD method for contemporary quantification of 10 antibiotics for therapeutic drug monitoring of critically ill pediatric patients

“…Actually, in fact, available PK studies are based on drugs for which TDM is already applied with adequate information about several frequently used antibiotics, such as ceftriaxone, ceftazidime and penicillin, missing (Hartman et al, 2019). Therefore, an analytical method to simultaneously quantify circulating levels of antibiotics could be useful for daily clinical practice.…”

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

“…As proof of concept, we focused on the dosing regimens of antibiotics in critically ill children, as concentration targets are available, to enable concentration-based simulations (Tsai et al, 2015). Moreover, these drugs are relatively well studied in children with published pharmacokinetic data ranging from well-validated population PK (pop-PK) studies including dose simulations, to more basic studies simply reporting drug concentrations (Hartman et al, 2019).…”

Optimizing the Use of Antibiotic Agents in the Pediatric Intensive Care Unit: A Narrative Review

“…Many frequently used agents (e.g., ceftriaxone, ceftazidime, penicillin, flucloxacillin, metronidazole) even completely lack PK data in critically ill children. The PK studies that have been published report that conventional dosing strategies consistently fail to achieve the proper PK/PD targets [ 95 , 96 ]. Specifically for β-lactam antibiotics, 95% of a PICU study population had sub-therapeutic concentrations [ 97 ].…”

“…Monte Carlo simulations showed the need for more frequent, extended or continuous infusions to attain the target of T>MIC of 50%. Extended and continuous infusions of other β-lactam antibiotics (e.g., meropenem, cefotaxime) in a PICU setting have been observed to maximize the PK/PD target attainment as well [ 96 ]. In the case of vancomycin, an AUC/MIC dependent antibiotic, a recent RCT in young infants comparing continuous and intermittent infusions demonstrated continuous infusions to be associated with earlier and improved target attainment [ 133 ].…”