Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

Abstract

To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes. Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT>MIC) and (ii) 5×MIC at 100% of dosing interval (100%fT>5×MIC). Correlation to clinical outcomes was evaluated using Cox regression. Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5±16.8mg/L and 101.6±81.1mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT>MIC and 44% for 100%fT>5×MIC. Failure to achieve 40-50%fT>MIC within 48h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT>5×MIC within 48h was significantly associated with shorter length of hospital stay. Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.