The ROAD Study - Resistant Optimised Antimicrobial Dosing in Critically Ill Patients

This is a prospective, open-labeled, single-centre phase IIa clinical study, which aims to evaluate the safety and tolerability, as well as the clinical efficacy of meropenem and piperacillin/tazobactam dosing regimens that are optimised (via PK/PD approach) to prevent the emergence of bacterial resistance in critically ill patients. The initial meropenem and piperacillin/tazobactam dosing regimens (dose, dosing interval and method of administration) will be determined by treating clinician in accordance to standard prescribing practices, which will be based on patient’s clinical status, body weight and renal function. Once enrolled in the study the subsequent meropenem and piperacillin/tazobactam dosing regimens will be optimised to achieve exposures likely leading to maximal suppression of bacterial resistance. Based on our hollow-fibre infection model data, which are further corroborated by other studies, these exposures are likely to be: (a) Cmin >/=8 mg/L for meropenem (defined as Cmin exposures that are 4 x EUCAST MIC breakpoint for P. aeruginosa i.e., 2 mg/L); and (b) Cmin >/=64 mg/L for piperacillin (defined as Cmin exposures that are 4 x EUCAST MIC breakpoint for P. aeruginosa i.e., 16 mg/L). However, dosing optimisation will consider previously published toxicity thresholds for meropenem and piperacillin, and will not aim to achieve such concentrations. Therefore, once informed consent is obtained, subsequent dosing regimens will be optimised to achieve these concentrations: Cmin >/=8 mg/L (but not greater than 45 mg/L) for meropenem and Cmin >/=64 mg/L (but not greater than 360 mg/L for piperacillin). This step to dosing optimisation will be performed by a Consultant Clinical Pharmacist at the RBWH ICU with the aid of Bayesian dose-optimising software, ID-ODS™. ID-ODS™ uses drug concentrations (via TDM) and causative organism’s MIC, combined with patient clinical data (age, height, weight, gender, serum creatinine and previous dosing details), to provide a patient-specific dosing recommendation to reach a concentration target. This approach to dosing optimisation (i.e., combining TDM results with ID-ODS™ to predict dosing requirements) has been routinely used for the last six years by pharmacists at the RBWH ICU. Patients will be continuously monitored whilst in the ICU as per standard ICU care. Doses will be administered by intensive care nurses or intensive care research nurses. The possible dosage ranges are as follows: Mode of administration will be intravenous infusion (1) Meropenem 1 – 2 g every 8-hourly as determined by treating clinician (2) Piperacillin/tazobactam 4.5 g every 6 – 8-hourly as determined by treating clinician The PK/PD-optimised dosing regimens will continue to be administered until either: (a) the study antibiotic is ceased by treating clinician; (b) beta-lactam concentrations via TDM are deemed to be toxic at any time-point during the study (concentrations of >/=45 mg/L for meropenem and >/=360 mg/L for piperacillin); (c) patient manifests signs and symptoms of beta-lactam toxicity; (d) patient completes 5-days of PK/PD-optimised meropenem and piperacillin/tazobactam dosing; or (e) the patient is discharged from the ICU, whichever is sooner. As this is a single site study, protocol adherence will be easily monitored. The study will be conducted in accordance with ethical principles consistent with the Declaration of Helsinki, and all relevant national and local guidelines on the ethical conduct of research. The research team will include experienced research coordinators, intensive care specialists and senior pharmacists all with GCP training and they will have oversight of all study required interventions and protocol adherence. Although potentially more frequent than standard care all the study procedures are routinely performed within the intensive care environment and will be performed by experienced medical and nursing staff. These procedures are necessary to ensure the safety and effectiveness of the optimised dosing regimens.