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.

Prevention of hypophosphatemia during continuous renal replacement therapy-An overlooked problem.

Hypophosphatemia is a common and potentially serious complication occurring during continuous renal replacement therapy (CRRT). Phosphate supplementation is required in the vast majority of patients undergoing CRRT, particularly beyond the first 48 hours. Supplementation can be provided either as a standalone oral or parenteral treatment or as an additive to CRRT solutions. Each approach has advantages and disadvantages, and clinicians must weigh the individual factors most relevant in their practice setting. Currently there are no consensus protocols for phosphate replacement in CRRT, and many centers replete phosphate in response to hypophosphatemia as opposed to pre-emptively. Repletion protocols have also been challenged in recent years by shortages in injectable phosphate solutions. More recently a commercially available phosphate-containing CRRT solution was approved in the United States, but there has been limited clinical experience with this product. In this review, we present recommendations for phosphate repletion in CRRT to prevent hypophosphatemia, and describe our experience using phosphate-containing CRRT solutions.

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.

Continuous venovenous hemodiafiltration trace element clearance in pediatric patients: a case series.

Continuous renal replacement therapy (CRRT) is used to treat critically ill children with acute kidney injury. The effect of CRRT on trace element clearance is poorly characterized. The purpose of this study was to quantify the transmembrane clearance of chromium, copper, manganese, selenium and zinc during continuous venovenous hemodiafiltration (CVVHDF). The transmembrane clearance of trace elements was assessed prospectively in five critically ill children receiving CVVHDF at the pediatric intensive care unit of a tertiary care university hospital. Pre-filter blood and effluent samples were measured for trace element concentrations. Transmembrane clearance of trace elements was calculated, and daily loss of each trace element was determined. Daily trace element loss via CVVHDF was compared with daily standard supplementation of trace elements in pediatric parenteral nutrition. Five patients (age range 23 months to 15 years) with a body weight range of 10.5-53 kg completed the study. The median transmembrane clearance of chromium, copper, manganese, selenium and zinc during CVVHDF was calculated as 0 ml, 0.59 ml, 2.48 ml, 1.22 ml, and 1.90 ml, respectively, per 1.73 m(2) body surface area per minute. The calculated CVVHDF losses were substantially smaller than the daily parenteral supplementation for all trace elements.

Enhanced clearance of highly protein-bound drugs by albumin-supplemented dialysate during modeled continuous hemodialysis.

BACKGROUND: In 2006, there were 16 796 toxic exposures attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) reported to the US Toxic Exposure Surveillance System. Of these, 30% (5046) were treated in a health care facility with 12 cases resulting in death. These drugs are highly protein bound and poorly dialyzable; however, it has been suggested that albumin-supplemented dialysate may enhance dialytic clearance. We investigated whether the addition of albumin to dialysate affects dialytic clearance of VPA, CBZ and PHT. METHODS: VPA, CBZ and PHT were added to a bovine blood-based in vitro continuous hemodialysis circuit, which included a polysulfone or an AN69 hemodialyzer. VPA, CBZ and PHT clearances were calculated from spent dialysate and pre-dialyzer plasma concentrations. VPA, CBZ and PHT clearances with control (albumin-free) dialysate were compared to clearances achieved with 2.5% or 5% human albumin-containing dialysate. The influences of blood flow (180 and 270 mL/min) and dialysate flow (1, 2 and 4 L/h) on dialysis clearance were also assessed. RESULTS: The addition of 2.5% albumin to dialysate significantly enhanced dialytic clearance of VPA and CBZ, but not PHT. Use of 5% albumin dialysate further increased VPA and CBZ clearance. Overall, drug clearance was related directly to dialysate flow but independent of blood flow. CONCLUSION: Continuous hemodialysis with albumin-supplemented dialysate significantly enhanced VPA and CBZ, but not PHT, clearance compared to control dialysate. Continuous hemodialysis with albumin-supplemented dialysate may be a promising therapy to enhance dialytic clearance of selected highly protein-bound drugs.

Trace element removal during in vitro and in vivo continuous haemodialysis.

BACKGROUND: Continuous renal replacement therapy (CRRT) increasingly is being used to treat critically ill patients with renal disease. CRRT removes waste products but also nutrients. Our understanding of trace element CRRT clearance has been limited by poor assay sensitivity. The development of inductively coupled plasma mass spectrometry (ICP-MS) allows for the measurement of CRRT trace element removal. METHODS: Continuous venovenous haemodialysis (CVVHD) transmembrane clearances of trace elements and urea were assessed using a bovine blood-based in vitro model using two different haemodialyser types. These findings were validated in 10 critically ill adult patients receiving continuous venovenous haemodiafiltration (CVVHDF). Calculated daily trace element loss was compared with a typical dose of daily trace element supplementation. RESULTS: The mean +/- SD in vitro CVVHD transmembrane clearances (ml/min) for the polysulfone haemodialyser were chromium 0.97 +/- 0.23, copper 0.47 +/- 0.18, manganese 4.6 +/- 3.6, selenium 1.2 +/- 0.63 and zinc 2.3 +/- 0.32 and for the cellulose diacetate haemodialyser chromium 1.54 +/- 0.91, copper 0.21 +/- 0.07, manganese 7.8 +/- 4.1, selenium 0.76 +/- 0.39 and zinc 2.7 +/- 0.37. The in vivo CVVHDF transmembrane clearances (ml/min) were chromium 5.4 +/- 2.4, copper 0.45 +/- 0.33, manganese 1.9 +/- 4.6, selenium 1.6 +/- 1.2, and zinc 4.0 +/- 1.3. CONCLUSION: ICP-MS assays detected the five trace elements in the effluent of CVVHDF patients. Trace element CVVHD transmembrane clearance estimates for our in vitro model were supported by the in vivo CVVHDF findings. Calculated daily trace element loss attributed to CVVHD and CVVHDF with dialysate flow rates of 33.3 ml/min is less than what is provided in a daily dose of a trace element supplementation product.

In vitro clearance of trace elements via continuous renal replacement therapy.

OBJECTIVE: Trace element loss during continuous renal replacement therapy in patients with acute renal failure has not been quantified sufficiently. DESIGN: Trace element loss was quantified using an in vitro model of continuous venovenous hemofiltration. Bovine blood was used for the experiment, and the plasma was analyzed for its chromium, copper, selenium, manganese, and zinc content. Two different polysulfone hemodiafilters, a low-flux F8 and high-flux F70 were used, and tested at two different ultrafiltrate flow rates of 1 L/hr and 2 L/hr, respectively. Trace element concentrations in the plasma and ultrafiltrate were analyzed using inductively coupled plasma mass spectrometry. The sieving coefficient and clearance of each trace element were calculated and compared between the two hemodiafilters. SETTING: In vitro bovine model of continuous venovenous hemofiltration. PATIENTS OR OTHER PARTICIPANTS: Not applicable. RESULTS: Mean sieving coefficients of both F8 and F70 hemodiafilters were similar for each trace element. Copper, chromium, manganese, selenium, and zinc all were detected in the ultrafiltrate. Estimated trace element loss using typical trace element blood concentrations and study-derived sieving coefficients suggest that daily losses of selenium are greater than what is replenished with a standard daily trace element supplement in total parenteral nutrition. CONCLUSION: These data suggest that the degree of continuous venovenous hemofiltration clearance chromium, copper, selenium, manganese, and zinc differ between elements and that selenium and copper might need to be replaced with doses that exceed typical supplementation guidelines.