What is the optimal loading dose of broad-spectrum β-lactam antibiotics in septic patients? Results from pharmacokinetic simulation modelling.

Optimal loading doses of β-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum β-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration. Pharmacodynamic (PD) targets were considered as drug concentrations exceeding at least 50% of time above four times the minimum inhibitory concentration (T) of Pseudomonas aeruginosa, according to EUCAST criteria, for PIP, 70%T for CAZ and FEP and 40%T for MEM. The probability of target attainment (PTA) was derived by calculating the percentage of patients who attained the PK/PD target at each MIC. The optimal loading dose was defined as the one associated with a ≥90% probability to achieve the PD targets. Our simulation model identified an optimal loading dose for PIP of 8 g given as a 3-h infusion (PTA of 96.2%), for CAZ and FEP of 4 g given as a 3-h infusion (PTA of 96.5% and 98.4%, respectively), and for MEM of 2 g given as a 30-min infusion (PTA of 93.4%), with the following antibiotic dose administered 6 h thereafter regardless of the drug. A higher first dose of broad-spectrum β-lactams should be given to adequately treat less-susceptible pathogens in septic patients. These findings need to be validated in a prospective study.