Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Appropriate antibiotic dosing in critically ill, infected, patients receiving continuous renal replacement therapy (CRRT) is crucial to improve patient outcomes. Severe sepsis and septic shock result in changes in pharmacokinetic parameters, including increased volume of distribution, hypoalbuminemia, and changes in renal and nonrenal clearances. The lack of CRRT standardization, nonrecognition of how CRRT variability affects antibiotic removal, fear of antibiotic toxicity, and limited drug dosing resources all contribute to suboptimal antibiotic therapy. Even when antibiotic CRRT pharmacokinetic studies are available, they are often based on old CRRT methodologies that do not exist in contemporary CRRT practice, resulting in unhelpful/inaccurate dosing recommendations. Application of these older doses in Monte Carlo simulation studies reveals that many of the recommended dosing regimens will never attain pharmacodynamic targets. In this review, using cefepime as an example, we illustrate whether clinicians are likely to achieve pharmacokinetic/pharmacodynamic targets when the recommended dosing regimens are prescribed in this patient population. We encourage clinicians to aggressively dose antibiotics with large loading dose and higher maintenance doses to reach the targets.

Background/Aims: To determine ceftolozane/tazobactam transmembrane clearances (CL_TM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). Method: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CL_TM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CL_TM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. Results: CHF and CHD CL_TM did not differ at equivalent effluent rates. CL_TM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. Conclusion: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

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Background: Prolonged 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).