A Monte Carlo Simulation Approach for Beta-Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Cefepime, ceftazidime, and piperacillin/tazobactam are commonly used beta-lactam antibiotics in the critical care setting. For critically ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic data are available to inform clinicians on the dosing of these agents. Monte Carlo simulations (MCS) can be used to guide drug dosing when pharmacokinetic trials are not feasible. For each antibiotic, MCS using previously published pharmacokinetic data derived from critically ill patients was used to evaluate multiple dosing regimens in 4 different prolonged intermittent renal replacement therapy effluent rates and prolonged intermittent renal replacement therapy duration combinations (4L/hx10hours or 5 L/hx8hours in hemodialysis and hemofiltration modes). Antibiotic regimens were also modeled depending on whether drugs were administered during or well before prolonged intermittent renal replacement therapy therapy commenced. The probability of target attainment (PTA) was calculated using each antibiotic's pharmacodynamic target during the first 48hours of therapy. Optimal doses were defined as the smallest daily dose achieving 90% probability of target attainment in all prolonged intermittent renal replacement therapy effluent and duration combinations. Cefepime 1g every 6hours following a 2g loading dose, ceftazidime 2g every 12hours, and piperacillin/tazobactam 4.5g every 6hours attained the desired pharmacodynamic target in 90% of modeled prolonged intermittent renal replacement therapy patients. Alternatively, if an every 6-hours cefepime regimen is not desired, the cefepime 2g pre-prolonged intermittent renal replacement therapy and 3g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1g every 6hours or 3g continuous infusion following a 2g loading dose also met targets. These recommended doses provide simple regimens that are likely to achieve the pharmacodynamics target while yielding the least overall drug exposure, which should result in lower toxicity rates. These findings should be validated in the clinical setting.