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.

Background: In addition to the maximum plasma concentration (C_max) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC_24h) 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, C_max/MIC ~8– 10 and AUC_24h/MIC ≥ 110 targets, were studied. The AUC_24h > 700 mg⋅h/L and C_min > 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 AUC_24h > 700 mg⋅h/L was small, but the risk was greater when applying a C_min target > 2 mg/L. Conclusion: Considering both targets of Cmax/MIC ~8– 10 and AUC_24h/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.

Background: Uremic pruritus is one of the most debilitating complications among patients with end-stage kidney disease (ESKD) receiving hemodialysis. For patients who are refractory to traditional therapies (topical analgesics, antihistamines, or gabapentinoids), the use of low-dose naltrexone can be an option where difelikefalin is not available. Case report: In our case report, we present a case of a female patient who developed intractable uremic pruritus despite the adequate trials of traditional therapies. The patient was initiated with low-dose naltrexone of 5 mg daily. Uremic symptoms improved within 3 days of naltrexone initiation. The side effects were tolerated. Conclusion: Low-dose naltrexone provided symptomatic improvement in individuals with severe uremic pruritus when difelikefalin was inaccessible. While limited to a single case, this report highlights the potential role of naltrexone and underscores the need for further research to establish its safety and efficacy.

Background: In 2021, the National Kidney Foundation–American Society of Nephrology (NKF-ASN) recommended the use of the 2021 refit equation without race; however, the effect of the removal is unclear. Our research aimed to examine the implications of antidiabetic dosing and eligibility on the new 2021 equation among Black patients. Methods: This is a retrospective analysis of patients receiving care at the diabetes treatment center (DTC) of an academic medical center. Estimated glomerular filtration rates (eGFRs) based on serum creatinine were calculated using the 2009 and 2021 CKD-EPI equations. A Monte Carlo simulation was performed to create 10,000 virtual patients. Dosing simulations based on each estimate of kidney function were performed for antidiabetics based on product labeling. The proportion and percentage of patients who were eligible based on the estimates were calculated. Results: The percentages of patients ineligible for metformin based on the estimates from the 2009 and 2021 CKD-EPI equations at the DTC were comparable (8.02% and 8.36%, respectively). In our 10,000 simulated virtual patients, the percentage of ineligibility increased only by 1%. For the GFR cut points of 20 mL/min and 25 mL/min, the rates of ineligibility were similar in our cohort and simulated patients. Conclusions: The exclusion of race from the 2021 CKD-EPI equation may slightly reduce medication eligibility among Black patients.

Background: The appropriate dosing of imipenem for critically ill AKI patients undergoing CRRT remains scarce. Purpose: This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving continuous renal replacement therapy (CRRT) and (2) to define the optimal imipenem dosing regimens in these populations via Monte Carlo simulations. Methods: The databases of PubMed, Embase, and ScienceDirect were searched from inception to May 2020. We used the Medical Subject Headings of “Imipenem,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for systematic reviews. A one-compartment pharmacokinetic model was conducted to predict imipenem levels for the initial 48 h of therapy. The pharmacodynamic target was 40% of free drug level above 4 times of the MIC (40% fT > 4 MIC). The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Results: Eleven articles were identified and included for our systematic review. The necessary pharmacokinetic parameters such as the volume of distribution and the CRRT clearance were mentioned in 100 and 90.9%, respectively. None of the current studies reported the complete necessary parameters. A regimen of 750 mg q 6 h was the optimal dose for the predilution-CVVH and CVVHD modality with two effluent rates (25 and 35 mL/kg/h) for the pharmacodynamic target of 40% fT > 4MIC. Conclusions: None of the current studies showed the complete necessary pharmacokinetic parameters for drug dosing. Pharmacodynamic target significantly contributed to imipenem dosing regimens in these patients. Different effluent rates and types of CRRT had minimal impact on dosing regimens. Clinical validation of the recommendation is necessary.