In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill patients receiving prolonged intermittent renal replacement therapy
Abstract
BackgroundProlonged intermittent renal replacement therapy (PIRRT) is a growing option to treat acute kidney injury in critically ill patients, but absent pharmacokinetic data challenge optimal drug dosing. Inappropriate antibiotic dosing can cause widespread bacterial resistance and decreased antibiotic utility. The purpose of this study was to evaluate probability of target attainment (PTA) of various ciprofloxacin and levofloxacin regimens in critically ill patients receiving PIRRT, utilizing Monte Carlo simulation (MCS).MethodsThe models incorporated published body weights and pharmacokinetic parameters (volume of distribution, non-renal clearance, and extraction coefficients) and their associated variability and ranges. Four different PIRRT effluent/duration combinations (4 L/h × 10 h or 5 L/h × 8 h in hemodialysis or hemofiltration, respectively) occurring at the beginning or 14-16 h after drug administration were modeled. MCS predicted drug disposition during the first 72 h in 5000 virtual patients for each dosing regimen. Desired pharmacodynamic targets to calculate PTA were the 24-h area under the curve/minimum inhibitory concentration (AUC24h:MIC) of ≥125 and ≥50 for Gram-negative and Gram-positive infections, respectively. The “successful” doses were the ones with PTA of ~90 % in all PIRRT settings.ResultsNo conventional, FDA-approved regimens attained ~90 % of PTA for Gram-negative infection with Pseudomonas aeruginosa at the MIC of 1 and 2 mg/L for ciprofloxacin…
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