Feasibility and fidelity of beta‐lactam antibiotic therapeutic drug monitoring in critically ill adults with sepsis: a pilot randomised controlled trial

Abstract Background Therapeutic drug monitoring (TDM) of beta‐lactam antibiotics may optimise dosing in critically ill patients with sepsis, but evidence on operational feasibility and workflow fidelity is limited. Prior trials introduced TDM later in therapy or applied constraints on dose escalation, potentially limiting the clinical impact of dose adaptation. Aim To evaluate the feasibility and fidelity of implementing early beta‐lactam TDM and TDM‐guided dose adaptation. Method This single‐centre, open‐label pilot randomised controlled trial enrolled adult intensive care unit patients with sepsis within 72 h of commencing meropenem, piperacillin‐tazobactam, or cefepime from June 2023–February 2024. Participants were randomised to standard of care (SOC) or early TDM‐guided dosing. Trough concentrations were measured daily for up to 5 days; dose adjustments were based on predefined algorithms without upper limits on dose escalation. Primary outcomes were feasibility (recruitment rate) and fidelity (proportion of TDM delivered as intended). Secondary outcomes included target attainment and clinical outcomes. Ethics approval was granted by the Alfred Hospital Human Research Ethics Committee (Reference no: 565/22) and the study conforms with the Australian National statement on ethical conduct in human research . Informed consent was obtained from all patients or their substitute medical treatment decision‐makers via direct approach with project information confirming their participation was voluntary and anonymous, and written consent was obtained. The study was registered with the Australian and New Zealand Clinical Trials Registry (Registration no: ACTRN12623000032651). Results Forty‐two patients (TDM n = 22; SOC n = 20) were enrolled. Recruitment occurred Monday–Wednesday each week during the study period. The weekly randomisation rate was two participants. Feasibility was demonstrated with 72% of eligible patients consenting and 85.7% completing ≥3 samples. Median time from antibiotic initiation to randomisation and to first TDM was 21 h and 12 h, respectively. All dosing recommendations were accepted. Target attainment was higher with TDM (53% versus 42%). No significant differences in clinical outcomes were observed. Conclusion Early randomisation and dose adaptation were feasible despite a weekday‐limited recruitment model. TDM‐guided dosing improved target attainment and was well accepted. This trial provides feasibility data to inform future multicentre trials.