Individualising beta-lactam antibiotic dosing in septic intensive care unit patients based on plasma concentration measurements using therapeutic drug monitoring

Dose adaptation of beta-lactam antibiotics (meropenem, piperacillin/tazobactam, cefepime) based on plasma concentrations obtained using therapeutic drug monitoring (TDM) in sepsis/septic shock. Aim: To pilot and implement beta-lactam antibiotic (beta-lactam) TDM to individualise doses in critically ill patients with suspected or proven sepsis Participants will be randomly allocated to TDM guided dosing or standard dosing (as per site ICU guidelines). The choice of beta-lactam will not be mandated by the study and will be directed by the treating team. The initial dose will be determined by the treating clinician or based on ICU guidelines. Once randomised to the intervention group, the dose will be adapted based on target plasma concentrations. Participants in the TDM arm will receive the study beta-lactam guided by daily TDM. The initial dose will be per Alfred ICU guidelines. After four doses (steady state) the first plasma sampling will be performed. Subsequent doses will be adjusted based on the concentrations obtained in the TDM arm. Sampling will be performed once daily (Monday to Friday) with result notification and dose adjustment as necessary on the same day. The time commitment for sample collection is estimated to be approximately ten minutes. The subsequent samples will be timed 24-hourly from the first sampling. The dose adjustments will be performed based on algorithm adapted from previously published literature (Reference 1), while taking into account any clinical parameters such as renal function, initiation of renal replacement therapy or recovery from acute renal impairment. The duration of intervention will depend on the duration of therapy. Doses will be adjusted either by increasing or decreasing the strength, increasing or decreasing the frequency of dosing or increasing or decreasing the duration of infusion depending on the plasma target concentration aimed for (see below). The dose adaptation algorithm used in this study will be compared with doses adjustments predicted based on plasma concentrations by an open access web based Bayesian dose adjustment software platform, TDMx. TDMx will not be used in actual dose modification and will be used to compare the dose adaptation recommendation only. Acceptance of dose adaptation recommendation by treating teams will be audited at the end of the study. The duration of antibiotic therapy will be determined by the treating physician. All eligible consenting patients with suspected or proven bacterial sepsis receiving study beta-lactams over a period of six months will be included in the control arm of the study. The pharmacodynamic target for Piperacillin/Cefepime/ Meropenem will be the epidemiological cut-off (ECOFF) value of Pseudomonas aeruginosa for empiric therapy. The pharmacokinetic/pharmacodynamic (PK/PD) target aimed for in this study is 100% time (fT) > minimum inhibitory concentration (MIC) and concentrations aimed for will be 2-4xMIC. The ECOFF values (mg/L) for piperacillin, meropenem and cefepime are 16, 2, and 8, respectively. Below are the minimum and maximum target concentrations (mg/L). The infusion rate will be determined based on initial dosing regimen, target concentrations and patient parameters (renal function, need for organ support) and infection characteristics (focus of infection). Antibiotic, Min target concentration, Max target concentration (range), Dose range g/24 h: Piperacillin, 32, 64 - 96, 12 - 24 Meropenem, 4 - 8, 16, 3 - 8 Cefepime, 8 - 16, 20, 3 - 8 Reference: 1 De Waele JJ, Carrette S, Carlier M, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam and meropenem: a randomised controlled trial. Intensive Care Med 2014; 40: 380–387.