Piperacillin-tazobactam dosing in anuric acute kidney injury patients receiving continuous renal replacement therapy.

INTRODUCTION: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of "piperacillin-tazobactam," "CRRT," and "pharmacokinetics" or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. RESULTS: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25-35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. CONCLUSION: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.

Optimal Meropenem Dosing Regimens in Patients Undergoing Continuous Renal Replacement Therapy: Systematic Review and Monte Carlo Simulations.

INTRODUCTION: The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic (PD) concepts are not well established. This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving CRRT and (2) to define the optimal meropenem dosing regimens in these populations via Monte Carlo simulations. METHODS: We used Medical Subject Headings "meropenem," "continuous renal replacement therapy," and "pharmacokinetics" or related terms to identify studies for systematic review. A one-compartment pharmacokinetic model was conducted to predict meropenem levels for the initial 48 h of therapy. The PD targets were 40% of free drug above a threshold of 1 times the minimum inhibitory concentration (MIC) (40% fT > MIC), 4 times the MIC (40% fT > 4MIC), and an additional target of free drug level above 1 times MIC 100% of the time (fT > MIC). The dose that achieved at least 90% of the probability of target attainment (PTA) was defined as an optimal dose. RESULTS: Twenty-one articles were included for our systematic review. The necessary pharmacokinetic parameters such as volume of distribution and CRRT clearance were cited in 90.5 and 71.4% of articles, respectively. None of the published studies reported completed necessary parameters. A regimen of 750 mg q 8 h was found to be the optimal dose for pre-dilution continuous venovenous hemofiltration and continuous venovenous hemodialysis modality using two effluent rates (25 and 35 mL/kg/h) which achieved the PD target of 40% fT > 4MIC. CONCLUSION: None of the published studies showed the necessary pharmacokinetic parameters. PD target significantly contributed to meropenem dosage regimens in these patients. Differing effluent rates and types of CRRT shared similar dosing regimens. Clinical validation of the recommendation is suggested.

Levetiracetam dosing in patients receiving continuous renal replacement therapy.

OBJECTIVE: The study was aimed to define appropriate levetiracetam dosing regimens from available published pharmacokinetics (PK) studies in critically ill patients with and without cirrhosis receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulation (MCS). METHODS: Mathematical pharmacokinetic models were developed using published demographic and PK data in adult critically ill patients with known variability and correlations between PK parameters. CRRT modalities (continuous venovenous hemofiltration and continuous venovenous hemodialysis) with different effluent rates were modeled. Levetiracetam regimens from available clinical resources were evaluated on the probability of target attainment (PTA) using pharmacodynamics (PD) target of the trough concentrations and area under the time-concentration curve within a range of 6-20 mg/L and 222-666 mg × hour/L for the initial 72 hours of therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results showed the optimal levetiracetam dosing regimen of 750-1000 mg every 12 hours is recommended for adult patients receiving both CRRT modalities with two different effluent rates of 25 and 35 mL/kg/h. Child-Pugh class C cirrhotic patients undergoing CRRT required lower dosing regimens of 500-750 mg every 12 ours due to smaller non-renal clearance. Of interest, some of literature-based dosing regimens were not able to attain the PK and PD targets. SIGNIFICANCE: Volume of distribution, non-renal clearance, CRRT clearance, and body weight were significantly correlated with the PTA targets. Dosing adaptation in this vulnerable population should be concerned. Clinical validation of our finding is absolutely needed.

Recommendations of Gentamicin Dose Based on Different Pharmacokinetic/Pharmacodynamic Targets for Intensive Care Adult Patients: A Redefining Approach.

Background: In addition to the maximum plasma concentration (Cmax) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC24h) to MIC has recently been suggested as pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy and safety in once-daily dosing of gentamicin (ODDG) in critically ill patients. Purpose: This study aimed to predict the optimal effective dose and risk of nephrotoxicity for gentamicin in critically ill patients for two different PK/PD targets within the first 3 days of infection. Methods: The gathered pharmacokinetic and demographic data in critically ill patients from 21 previously published studies were used to build a one-compartment pharmacokinetic model. The Monte Carlo Simulation (MCS) method was conducted with the use of gentamicin once-daily dosing ranging from 5-10 mg/kg. The percentage target attainment (PTA) for efficacy, Cmax/MIC ~8-10 and AUC24h/MIC ≥110 targets, were studied. The AUC24h >700 mg⋅h/L and Cmin >2 mg/L were used to predict the risk of nephrotoxicity. Results: Gentamicin 7 mg/kg/day could achieve both efficacy targets for more than 90% when the MIC was <0.5 mg/L. When the MIC increased to 1 mg/L, gentamicin 8 mg/kg/day could reach the PK/PD and safety targets. However, for pathogens with MIC ≥2 mg/L, no studied gentamicin doses were sufficient to reach the efficacy target. The risk of nephrotoxicity using AUC24h >700 mg⋅h/L was small, but the risk was greater when applying a Cmin target >2 mg/L. Conclusion: Considering both targets of Cmax/MIC ~8-10 and AUC24h/MIC ≥110, an initial gentamicin dose of 8 mg/kg/day should be recommended in critically ill patients for pathogens with MIC of ≤1 mg/L. Clinical validation of our results is essential.

What is the right gentamicin dose for multiple trauma patients? A Monte Carlo simulation exploration study.

Background: The appropriate dose of gentamicin is important to prevent and treat infections. The study aimed to determine the optimal dose of gentamicin to achieve the probability of pharmacokinetic/pharmacodynamic (PK) targets for efficacy and safety in multiple trauma patients. Methods: PK parameters of gentamicin in multiple trauma patients were gathered to develop a one-compartment PK model for prediction. The Monte Carlo simulation method was performed. The 24-h area under the concentration time curve to the minimum inhibitory concentration ratio (AUC24h/MIC) ≥50 was defined for the infection prevention target. AUC24h/MIC ≥110 or the maximum serum concentration to MIC ratio ≥8-10 was for the treatment of serious Gram-negative infection target. The risk of nephrotoxicity was the minimum serum concentration ≥2 mg/L. The optimal dose of gentamicin was determined when the efficacy target was >90% and the risk of nephrotoxicity was lowest. Results: The optimal gentamicin dose to prevent infection when the MIC was <1 mg/L was 6-7 mg/kg/day. A higher dose of gentamicin up to 10 mg/kg/day could not reach the target for treating serious Gram-negative infection when the expected MIC was ≥1 mg/L. The probability of nephrotoxicity was minimal at 0.2-4% with gentamicin doses of 5-10 mg/kg/day for 3 days. Conclusions: Once daily gentamicin doses of 6-7 mg/kg are recommended to prevent infections in patients with multiple trauma. Gentamicin monotherapy could not be recommended for serious infections. Further clinical studies are required to confirm our results.

Lacosamide dosing in patients receiving continuous renal replacement therapy.

BACKGROUND: Lacosamide is one of the anticonvulsants used in critically ill patients. This study aimed to suggest appropriate lacosamide dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulations. METHODS: Mathematical models were created using published demographic and pharmacokinetics in adult critically ill patients. CRRT modalities with different effluent rates were added into the models. Lacosamide regimens were evaluated on the probability of target attainment (PTA) using pharmacodynamic targets of trough concentrations and area under the curve within a range of 5-10 mg/L and 80.25-143 and 143-231 mg*h/L for the initial 72 h-therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each dosing regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results revealed the optimal lacosamide dosing regimen of 300-450 mg/day is recommended for adult patients receiving both CRRT modalities with 20-25 effluent rates. The dose of 600 mg/day was suggested in higher effluent rate of 35 mL/kg/h. Moreover, a patient with body weight > 100 kg was less likely to attain the targets. CONCLUSIONS: Volume of distribution, total clearance, CRRT clearance and body weight were significantly contributed to lacosamide dosing. Clinical validation of the finding is strongly indicated.

Efficacy and Safety of Enteral Erythromycin Estolate in Combination With Intravenous Metoclopramide vs Intravenous Metoclopramide Monotherapy in Mechanically Ventilated Patients With Enteral Feeding Intolerance: A Randomized, Double-Blind, Controlled Pilot Study.

BACKGROUND: In this pilot study, we aimed to determine the efficacy and safety of enteral erythromycin estolate in combination with intravenous metoclopramide compared to intravenous metoclopramide monotherapy in mechanically ventilated patients with enteral feeding intolerance. METHODS: This randomized, double-blind, controlled pilot study included 35 mechanically ventilated patients with feeding intolerance who were randomly assigned to receive 10-mg metoclopramide intravenously every 6-8 hours in combination with 250-mg enteral erythromycin estolate (study group) or placebo every 6 hours for 7 days. The primary outcome was an administered-to-target energy ratio of ≥80% at 48 hours, indicating a successful feeding. Secondary, prespecified outcomes were daily average gastric residual volume (GRV), total energy intake, administered-to-target energy ratio, hospital length of stay, in-hospital mortality, and 28-day mortality. RESULTS: The rate of successful feeding was not significantly different between the study and placebo groups (47.1% and 61.1%, respectively; P = .51). The average daily GRV was significantly lower in the study group than in the placebo group (ß = 91.58 [95% Wald CI, -164.35 to -18.8]), determined by generalized estimating equation. Other secondary outcomes were comparable, and the incidence of adverse events was not significantly different between the 2 groups. One common complication was cardiac arrhythmia, which was mostly self-terminated. CONCLUSION: Although the combination therapy of enteral erythromycin estolate and intravenous metoclopramide reduced GRV, the successful feeding rate and other patient-specific outcomes did not improve in mechanically ventilated patients with feeding intolerance.

Optimal levofloxacin dosing regimens in critically ill patients with acute kidney injury receiving continuous renal replacement therapy.

PURPOSES: To determine appropriate dosing of levofloxacin in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: All necessary pharmacokinetic and pharmacodynamic parameters from critically ill patients were obtained to develop mathematical models with first order elimination. Levofloxacin concentration-time profiles were calculated to determine the efficacy based on the probability of target attainment (PTA) of AUC24h/MIC ≥50 for Gram-positive and AUC24h/MIC ≥125 for Gram-negative infections. A group of 5000 virtual patients was simulated and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the dose achieved target PTA at least 90% of the virtual patients. RESULTS: No conventional, FDA approved regimens achieved at least 90% of PTA for Gram-negative infection with Pseudomonas aeruginosa at MIC of 2 mg/L. The successful dose (1750 mg on day 1, then 1500 mg q 24 h) was far exceeded the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg q 24 h was sufficient to attain PTA target of ~90% at the MIC of 2 mg/L for Streptococcus pneumoniae. CONCLUSIONS: Levofloxacin cannot be recommended as an empiric monotherapy for serious Gram-negative infections in patients receiving CRRT due to suboptimal efficacy.

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

PURPOSES: To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. METHODS: All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. RESULTS: The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. CONCLUSIONS: A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

Antiviral Dosing Modification for Coronavirus Disease 2019-Infected Patients Receiving Extracorporeal Therapy.

Previous literature regarding coronavirus disease 2019 outlined a presence of organ dysfunction including acute respiratory distress syndrome and acute kidney injury that are linked to mortality. Several patients require extracorporeal therapy. This review aims to gather available published resources including physicochemical and pharmacokinetic properties and suggests antiviral drug dosing adaptation for coronavirus disease 2019-infected critically ill patients receiving extracorporeal therapy. A literature search was performed using PubMed, clinical trial registries, and bibliographic review of textbooks and review articles. Unfortunately, no standard of pharmacologic management and recommendations of drug dosing for coronavirus disease 2019 infection for critically ill patients receiving extracorporeal therapy exist due to the limited data on pharmacokinetic and clinical studies. All available extracted data were analyzed to suggest the appropriate drug dosing adjustment. Antiviral drug dosing adjustments for critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy are presented in this review. Considering pathophysiologic changes, drug properties, and extracorporeal modalities, applying our suggestions is recommended.

Optimal vancomycin dosing regimens for critically ill patients with acute kidney injury during continuous renal replacement therapy: A Monte Carlo simulation study.

PURPOSE: This study aims to determine the optimal vancomycin dosing in critically ill patients with acute kidney injury receiving continuous renal replacement therapy (CRRT) using Monte Carlo simulation. METHODS: A one compartment pharmacokinetic model was conducted to define vancomycin deposition for the initial 48hours of therapy. Pharmacokinetic parameters were gathered from previously published studies. The AUC24/MIC ratio of at least 400 and an average of AUC0-24 at > 700mgh/L were utilized to evaluate efficacy and nephrotoxicity, respectively. The doses achieved at least 90% of the probability of target attainment (PTA) with the lowest risk of nephrotoxicity defined as the optimal dose. RESULTS: The regimens of 1.75grams every 24hours and 1.5grams loading followed by 500mg every 8hours were recommended for empirical therapy of an MRSA infection with expected MIC ≤1mg/L, and definite therapy with actual MIC of 1mg/L. The probabilities of nephrotoxic results from these regimens were 35%. CONCLUSIONS: A higher dose of vancomycin than the current literature-based recommendation was needed in CRRT patients.

Cefepime dosing regimens in critically ill patients receiving continuous renal replacement therapy: a Monte Carlo simulation study.

BACKGROUND: Cefepime can be removed by continuous renal replacement therapy (CRRT) due to its pharmacokinetics. The purpose of this study is to define the optimal cefepime dosing regimens for critically ill patients receiving CRRT using Monte Carlo simulations (MCS). METHODS: The CRRT models of cefepime disposition during 48 h with different effluent rates were developed using published pharmacokinetic parameters, patient demographic data, and CRRT settings. Pharmacodynamic target was the cumulative percentage of a 48-h period of at least 70% that free cefepime concentration exceeds the four times susceptible breakpoint of Pseudomonas aeruginosa (minimum inhibitory concentration, MIC of 8). All recommended dosing regimens from available clinical resources were evaluated for the probability of target attainment (PTA) using MCS to generate drug disposition in a group of 5000 virtual patients for each dose. The optimal doses were defined as achieving the PTA at least 90% of virtual patients with lowest daily doses and the acceptable risk of neurotoxicity. RESULTS: Optimal cefepime doses in critically ill patients receiving CRRT with Kidney Disease: Improving Global Outcomes (KDIGO) recommended effluent rates were a regimen of 2 g loading dose followed by 1.5-1.75 g every 8 h for Gram-negative infections with a neurotoxicity risk of < 17%. Cefepime dosing regimens from this study were considerably higher than the recommended doses from clinical resources. CONCLUSION: All recommended dosing regimens for patients receiving CRRT from available clinical resources failed to achieve the PTA target. The optimal dosing regimens were suggested based on CRRT modalities, MIC values, and different effluent rates. Clinical validation is warranted.