Vancomycin and daptomycin dosing recommendations in patients receiving home hemodialysis using Monte Carlo simulation.

BACKGROUND: Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen. METHODS: Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses. RESULTS: HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets. CONCLUSIONS: Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.

Evaluation and Development of Vancomycin Dosing Schemes to Meet New AUC/MIC Targets in Intermittent Hemodialysis Using Monte Carlo Simulation Techniques.

Published vancomycin dosing recommendations for patients receiving maintenance hemodialysis were not designed to meet newly recommended 24-hour area under the curve/minimum inhibitory concentration (AUC24h /MIC) pharmacokinetic/pharmacodynamic targets. The aims of this study were to predict pharmacokinetic/pharmacodynamic target attainment rates with a commonly used vancomycin regimen and to design a new dosing scheme incorporating therapeutic drug monitoring (TDM) to maximize target attainment in patients receiving vancomycin and hemodialysis with high- or low-flux hemodialyzers. Vancomycin pharmacokinetic- and dialysis-specific parameters were incorporated into Monte Carlo simulations (MCS). A commonly used vancomycin regimen was modeled to determine its likelihood of attaining AUC24h /MIC targets for 1 week of thrice-weekly hemodialysis treatments. MCS was then used to develop optimal initial vancomycin dosing for patients receiving intradialytic or postdialytic vancomycin administration with either high- or low-flux hemodialyzers. Finally, a new MCS model incorporating TDM was built to further optimize the probability of pharmacokinetic/pharmacodynamic target attainment. Traditional vancomycin dosing methods are unlikely to meet AUC24h /MIC targets. Vancomycin doses necessary to attain AUC24h /MIC targets are significantly influenced by hemodialyzer permeability and whether vancomycin is administered intradialytically or after hemodialysis. Depending on dialyzer type and whether vancomycin is administered during or after hemodialysis, loading doses of 25 to 35 mg/kg followed by maintenance doses of 7.5 to 15 mg/kg are necessary to reach minimum AUC24h /MIC targets in 90% of virtual patients. For a 3-day interdialytic period, a 30% higher maintenance dose is required to maintain target attainment. Dosing based on a single vancomycin serum concentration obtained prior to the second dialysis session greatly enhances the probability of target attainment.

Therapeutic Monitoring of Vancomycin for Serious Methicillin-resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

BACKGROUND: Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring. METHODS AND RESULTS: This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. CONCLUSIONS: The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

OBJECTIVES: To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. DESIGN: The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. SETTING: Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. PATIENTS: Virtual critically ill patients requiring continuous renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. CONCLUSIONS: Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

Development of a vancomycin dosing approach for critically ill patients receiving hybrid hemodialysis using Monte Carlo simulation.

OBJECTIVES: Prolonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy. METHODS: Monte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC24h) of 400-700 mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy. RESULTS: An initial vancomycin dose of 15 or 20 mg/kg immediately followed by 15 mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC24h of ≥400 mg·h/L for ≥90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC24h of ≥700 mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC24h of 400-700 mg·h/L. CONCLUSION: An initial loading dose of 15-20 mg/kg followed by a maintenance regimen of 15 mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

Preparation times and costs for various solutions used for continuous renal replacement therapy.

PURPOSE: Results of a study to determine time and cost requirements for final preparation of continuous renal replacement therapy (CRRT) products are reported. METHODS: A 3-phase observational study was conducted at a tertiary care university hospital to evaluate costs associated with manual addition of phosphate and/or potassium to 3 commercial 5-L CRRT products. In the first phase of the study, pharmacy workflow processes for solution preparation were established; in the second phase, pharmacist and pharmacy technician time spent in the CRRT workflow and all materials used were observed and recorded. In the third phase, time and personnel requirements were analyzed in economic terms to estimate final preparation costs. RESULTS: Through direct observation over 35 days, the CRRT workflow was observed and work times recorded for 511 bag preparations. The main cost contributors were the base CRRT solution and electrolyte additive prices. Technician compounding time differed substantially by solution brand and the need for electrolyte addition. Pharmacist verification time did not differ meaningfully by product. CONCLUSION: Preparation and verification of premade CRRT solutions that contained physiological electrolyte concentrations required less technician and pharmacist time than solutions that needed addition of electrolytes in the pharmacy. Personnel costs, which were a small part of the total cost of dispensed CRRT bags, were higher for technicians than pharmacists. The baseline costs of the solutions and the electrolyte additives, if needed, were the main contributors to total cost.

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 (4 L/h × 10 hours or 5 L/h × 8 hours 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 48 hours 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 1 g every 6 hours following a 2 g loading dose, ceftazidime 2 g every 12 hours, and piperacillin/tazobactam 4.5 g every 6 hours 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 2 g pre-prolonged intermittent renal replacement therapy and 3 g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1 g every 6 hours or 3 g continuous infusion following a 2 g 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.

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

Use of Monte Carlo Simulations to Determine Optimal Carbapenem Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy.

Pharmacokinetic/pharmacodynamic analyses with Monte Carlo simulations (MCSs) can be used to integrate prior information on model parameters into a new renal replacement therapy (RRT) to develop optimal drug dosing when pharmacokinetic trials are not feasible. This study used MCSs to determine initial doripenem, imipenem, meropenem, and ertapenem dosing regimens for critically ill patients receiving prolonged intermittent RRT (PIRRT). Published body weights and pharmacokinetic parameter estimates (nonrenal clearance, free fraction, volume of distribution, extraction coefficients) with variability were used to develop a pharmacokinetic model. MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration) occurring at the beginning or 14-16 hours after drug infusion. The probability of target attainment (PTA) was calculated using ≥40% free serum concentrations above 4 times the minimum inhibitory concentration (MIC) for the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all PIRRT combinations. At the MIC of 2 mg/L for Pseudomonas aeruginosa, optimal doses were doripenem 750 mg every 8 hours, imipenem 1 g every 8 hours or 750 mg every 6 hours, and meropenem 1 g every 12 hours or 1 g pre- and post-PIRRT. Ertapenem 500 mg followed by 500 mg post-PIRRT was optimal at the MIC of 1 mg/L for Streptococcus pneumoniae. Incorporating data from critically ill patients receiving RRT into MCS resulted in markedly different carbapenem dosing regimens in PIRRT from those recommended for conventional RRTs because of the unique drug clearance characteristics of PIRRT. These results warrant clinical validation.

Reenvisioning assessment for the Academy and the Accreditation Council for Pharmacy Education's standards revision process.

Assessment has become a major aspect of accreditation processes across all of higher education. As the Accreditation Council for Pharmacy Education (ACPE) plans a major revision to the standards for doctor of pharmacy (PharmD) education, an in-depth, scholarly review of the approaches and strategies for assessment in the PharmD program accreditation process is warranted. This paper provides 3 goals and 7 recommendations to strengthen assessment in accreditation standards. The goals include: (1) simplified standards with a focus on accountability and improvement, (2) institutionalization of assessment efforts; and (3) innovation in assessment. Evolving and shaping assessment practices is not the sole responsibility of the accreditation standards. Assessment requires commitment and dedication from individual faculty members, colleges and schools, and organizations supporting the college and schools, such as the American Association of Colleges of Pharmacy. Therefore, this paper also challenges the academy and its members to optimize assessment practices.

Daptomycin pharmacokinetics and pharmacodynamics in a pooled sample of patients receiving thrice-weekly hemodialysis.

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥ 24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC(48-72)) that were <50% of the SAB-IE AUC(48-72) values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC(48-72) values, while maintaining acceptable trough concentration (C(min)) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C(min) reaching ≥ 24.3 mg/liter were observed in one of the three studies. Given the high probability of C(min) being ≥ 24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.

Optimizing anemia management in hospitalized patients with end-stage renal disease.

OBJECTIVE: To review available literature on the use of erythropoiesis-stimulating agents (ESAs) in patients with end-stage renal disease (ESRD) who require hospitalization and to provide recommendations for ESA use in this setting. DATA SOURCES: Primary articles were identified by English-language MEDLINE search (1966-October 2008) using the MeSH headings: kidney failure (chronic), anemia, erythropoietin, darbepoetin, hospitalization, and hematinics. Relevant data presented at recent nephrology scientific meetings (2004-October 2008) were also identified. STUDY SELECTION AND DATA EXTRACTION: Identified studies were reviewed and information regarding hospitalization, ESA use, and patient outcomes was evaluated. DATA SYNTHESIS: Studies demonstrate that hospitalized patients with ESRD usually experience a decline in hemoglobin values. Contributing factors include infection, inflammation, and untreated iron deficiency. ESAs are used inconsistently during hospitalization, with less than 50% of hospitalized patients with ESRD receiving ESA therapy in some reports. Some controversy exists regarding optimal hemoglobin targets for ESA therapy in nonhospitalized patients with ESRD, and no targets are defined for hospitalized patients. Clinical trials examining in-hospital ESA use have primarily involved the intensive care population and excluded ESRD patients. Following the patient's hospitalization, lower hemoglobin values may persist for 6 months, despite increased ESA dosing. Variability exists in frequency of hemoglobin monitoring and ESA dose changes. To date, no clinical trials have evaluated different approaches to anemia management in hospitalized patients with ESRD, and there are no published guidelines in this area. Based on published observations and clinical experience, we offer recommendations for anemia management around the time of hospitalization in an attempt to define a more rational approach to ESA therapy in this population. CONCLUSIONS: Trials are needed to define optimal ESA dosing strategies and hemoglobin targets in hospitalized patients with ESRD.

Drug dosing considerations in alternative hemodialysis.

The provision of renal replacement therapy for patients with chronic kidney disease has been reasonably standardized for decades, with thrice-weekly hemodialysis being the standard. Short-daily and nocturnal hemodialysis are 2 new hemodialysis techniques, each are administered 6 to 7 days a week but differ primarily in the duration of the treatment and blood-flow rate. The emergence of these hemodialysis regimens has shown promise in attenuating some of the complications associated with chronic kidney disease. The benefits of these daily regimens are postulated to be a result of enhanced solute clearance and improved extracellular volume management. The improved solute clearance associated with daily hemodialysis is likely to lead to altered dialytic clearance of drugs given to patients receiving these therapies. The purpose of this paper is to review the concepts pertinent to drug removal by hemodialysis and discuss the issues related to these new dialysis techniques and how they may have a impact on drug removal and the design of dosing regimens.