Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of β‐Lactam Antibiotics in Critically Ill Children

Abstract

There has been increasing interest in incorporating β‐lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration‐versus‐time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single‐center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2‐week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

“…Our previous work has shown that there is high variability in plasma protein binding of other b-lactam antibiotics in the critically ill pediatric population (10), which is not unexpected given the high prevalence of hypoalbuminemia in critical illness (11). Since ceftriaxone is more highly bound to protein than many other b-lactam antibiotics, we sought to measure both total and free concentrations and develop separate concentrations but not free, unbound concentrations.…”

“…Opportunistic sampling. Blood samples were obtained using scavenged opportunistic sampling as described previously (10,20). Briefly, all patients in the PICU who were administered at least one dose of ceftriaxone were screened to determine if the clinical team had ordered laboratory tests (e.g., complete blood counts and metabolic panels) after a ceftriaxone dose was given.…”

“…Blood samples were requested within 7 days of blood draws from the clinical laboratory, which stores the residual sample at 4°C after test completion. We conducted stability studies, as described previously (10), and showed that total ceftriaxone did not degrade more than 15% over a period of 7 days at 4°C (see Table S4 in the supplemental material). Samples that were obtained within 30 min of the start of ceftriaxone administration or more than 30 h after a dose were excluded.…”

Review of Scavenged Sampling for Sustainable Therapeutic Drug Monitoring: Do More With Less

“…Eventually, 19 of the 23 studies were included; 4 studies that did not meet the inclusion criteria were used to support the concept of scavenged sampling. 8,9,11–31 Table 1 presents the characteristics of the 19 included studies. Table 2 presents the outcomes and limitations of included studies as described by the authors.…”

“…In addition, Tang-Girdwood et al demonstrated a broad distribution of antibiotic-free concentrations, particularly toward the end of the dosing intervals. 29 However, the authors indicate that there are possibly multiple factors contributing to the wide variability in free concentrations, including pathophysiological changes because of critical illness and variable protein binding, as well as patient factors.…”