Mariann D. Churchwell

Daptomycin clearance during modeled continuous renal replacement therapy

Background/Aims: Pharmacotherapy in critically ill patients receiving continuous renal replacement therapies (CRRT) is challenging due to the lack of published information to base dosing regimens. Methods: Daptomycin’s transmembrane clearance during continuous hemofiltration and hemodialysis was assessed using an in vitro model with AN69 and polysulfone hemodiafilters at varying ultrafiltrate and dialysate flow rates (1, 2, 3 and 6 l/h). Results: During continuous hemofiltration, mean daptomycin sieving coefficient ranged from 0.14 to 0.20. Transmembrane clearances were significantly different between filter types for ultrafiltration rates of 2, 3 and 6 l/h. For continuous hemodialysis, mean daptomycin saturation coefficient ranged from 0.05 to 0.15. AN69-based daptomycin clearances were significantly lower than polysulfone values at dialysate flow rates of 2, 3 and 6 l/h. Conclusion: The extent of daptomycin’s transmembrane clearance is dependent on hemodiafilter type, dialysate and ultrafiltration rates. CRRT with high ultrafiltrate or dialysate rates may result in substantial daptomycin clearances.

Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury

Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that nonrenal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of nonrenal clearance affected by AKI. Acute kidney injury may also impair the clearance of formed metabolites. The fact that AKI does not solely influence kidney function may have important implications for drug dosing, not only of renally eliminated drugs but also of those that are hepatically cleared. A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that changes in nonrenal clearance are highly complicated and poorly studied, but they may be quite common. At present, our understanding of how AKI affects drug metabolism and nonrenal clearance is limited. However, based on the available evidence, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect nonrenal clearance as well as drug metabolite clearance.

Drug dosing during continuous renal replacement therapy.

Continuous renal replacement therapy (CRRT) has given clinicians an important option in the care of critically ill patients. The slow and continuous dialysate and ultrafiltrate flow rates that are employed with CRRT can yield drug clearances similar to an analogous glomerular filtration rate of the native kidneys. Advantages such as superior volume control, excellent metabolic control, and hemodynamic tolerance by critically ill patients are well documented, but an understanding of drug dosing for CRRT is still a bit of a mystery. Although some pharmaceutical companies have dedicated postmarket research in this direction, many pharmaceutical companies have chosen not to pursue this information as it is not mandated and represents a relatively small part of their market. This lack of valuable information has created many challenges in the care of the critically ill patient as intermittent hemodialysis drug dosing recommendations cannot be extrapolated to CRRT. This drug dosing review will highlight factors that clinicians should consider when determining a pharmacotherapy regimen for a patient receiving CRRT.

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.

Intradialytic Administration of Daptomycin in End Stage Renal Disease Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Infusion of intravenous antibiotics after hemodialysis (HD) may delay initiation of treatment for the next HD shift. Intradialytic administration of drugs such as vancomycin during the final hour of HD obviates these delays. Daptomycin has potent activity against Gram-positive bacteria, but the manufacturer recommends that the dose be infused after HD ends. This study determined the pharmacokinetics of intradialytically dosed daptomycin in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective crossover study compared single-dose daptomycin (6 mg/kg, 30-min intravenous infusion) pharmacokinetics administered after HD versus during the last part of HD with high-permeability (HP) and low-permeability (LP) dialyzers to seven patients who had ESRD and were on thrice-weekly HD. Serial blood samples were collected to determine daptomycin serum concentrations and protein binding. Statistical analysis was done using linear mixed model analysis. RESULTS The maximum serum concentration observed with a 6 mg/kg post-HD dose was 61.1 +/- 7.6 microg/ml with a mean protein binding of 89.2%. Intradialytic daptomycin administration resulted in reduced maximum serum concentration and area under the curve values that were approximately 12 to 20% lower when administered during HD with LP dialyzers and approximately 35% lower with HP dialyzers. CONCLUSIONS Intradialytic daptomycin administration during the last 30 min of HD is feasible, provided that larger dosages are used to compensate for intradialytic drug loss. On the basis of our findings, intradialytic doses of approximately 7 mg/kg (LP) or approximately 9 mg/kg (HP) theoretically should be bioequivalent to 6 mg/kg infused after HD. The calculated dosages are mathematically driven and must be validated in prospective clinical trials.

Physical compatibility of 4% sodium citrate with selected antimicrobial agents.

PURPOSE The physical compatibility of 4% sodium citrate with vancomycin, gentamicin, tobramycin, daptomycin, and linezolid was evaluated. METHODS Admixtures were prepared by mixing 4% sodium citrate with clinically relevant concentrations of antimicrobial agents (vancomycin 5 mg/mL, vancomycin 10 mg/mL, vancomycin 20 mg/mL, daptomycin 5 mg/mL, gentamicin 2.4 mg/mL, tobramycin 2.4 mg/mL, and linezolid 1 mg/mL). Three samples of each admixture were incubated (1) at 22-23 degrees C and exposed to light, (2) in a water bath at 37 degrees C and exposed to light, (3) at 22-23 degrees C and protected from light, and (4) in a water bath at 37 degrees C and protected from light. Visual compatibility, spectrophotometric absorbance, and pH were evaluated immediately after mixing (baseline) and at 8, 24, and 48 hours. Physical compatibility was defined as the absence of visible precipitation, a pH value at 48 hours that did not vary by more than 10% from baseline, and an absorbance value of <0.015. RESULTS There was no visual evidence of precipitation and no clinically important changes in pH observed during the 48-hour study period in any admixture. However, turbidity, based on absorbance, was noted with vancomycin 20 mg/mL at each time point. CONCLUSION No evidence of incompatibility was observed when vancomycin 5 mg/ mL, vancomycin 10 mg/mL, daptomycin 5 mg/mL, gentamicin 2.4 mg/mL, tobramycin 2.4 mg/mL, or linezolid 1 mg/mL was mixed with 4% sodium citrate as might occur in an antimicrobial lock. Vancomycin 20 mg/mL mixed with 4% sodium citrate displayed spectrophotometric evidence of incompatibility.

Longitudinal Hemodiafilter Performance in Modeled Continuous Renal Replacement Therapy

Background/Aims: With advanced anticoagulation, many institutions operate continuous renal replacement therapy (CRRT) circuits longer than manufacturers’ recommendations. This extended use may change hemodiafilter performance and clearance properties. However, hemodiafilter performance over time has not been assessed. We investigated solute clearance over time in modeled CRRT. Methods: In vitro continuous hemofiltration (CH) and continuous hemodialysis (CD) were operated for 48 h using AN69 polyacrylonitrile, cellulose triacetate, F70 polysulfone, and Optiflux F160NR polysulfone hemodiafilters with citrated bovine blood. Urea, creatinine, gentamicin, vancomycin, and albumin clearances were assessed in CH (ultrafiltration rates = 1 and 3 l/h). Clearances of urea, creatinine, gentamicin, and albumin, were assessed in CD with dialysate flow rate of 2 l/h. Results: Solute CH clearances were significantly higher at 3 l/h. Only creatinine and gentamicin clearances were affected by time. Creatinine CD clearance significantly declined at 48 h for all hemodiafilters, especially polysulfone hemodiafilters. Conclusions: CRRT duration affects solute transmembrane clearance. Clinicians should consider hemodiafilter age when assessing hemodialysis dose or drug clearance.

Modeled Dalbavancin Transmembrane Clearance during Intermittent and Continuous Renal Replacement Therapies

Background/Aims: Knowledge of dalbavancin renal replacement therapy (RRT) disposition is vital to ensure appropriate dosing. In vitro models of continuous RRT and intermittent hemodialysis (IHD) were used to determine dalbavancin transmembrane clearance (CLtm). Methods: Dalbavancin saturation and sieving coefficients (SCs) were determined for hemodialysis and hemofiltration therapies, respectively, using various hemodiafilter and effluent rate combinations. Dalbavancin CLtm estimates were calculated from observed saturation and SCs. Results: Saturation and SCs for both modalities of continuous dialysis and hemofiltration and IHD with high permeability hemodiafilters were small. Nonetheless, during continuous RRT with high dialysate and ultrafiltration rates, dalbavancin CLtm (0.20–1.26 ml/min) matched and often exceeded literature-derived dalbavancin renal clearances. Dalbavancin CLtm was undetectable during IHD with low-permeability hemodialyzers, but with high-permeability hemodialyzers, substantial CLtm (1.90–2.43 ml/min) was noted. Conclusion: Dalbavancin CLtm is dependent on RRT modality, hemodiafilter, and effluent flow. Dalbavancin doses may need to be adjusted depending on RRT parameters.

Telavancin and hydroxy propyl-β-cyclodextrin clearance during continuous renal replacement therapy: An in vitro study

Background/Aims Telavancin is a lipoglycopeptide antimicrobial agent which has been approved in Europe and has been recently FDA approved in the United States. Telavancins parenteral solution contains hydroxy propyl-β-cyclodextrin (HP-β-CD) to enhance its solubility. The disposition of telavancin and HP-β-CD during continuous renal replacement therapies (CRRT) has not been previously reported. Methods The transmembrane clearances (CLtm) of telavancin and HP-β-CD during continuous hemofiltration and hemodialysis were assessed using an in vitro bovine blood model with AN69 and polysulfone hemodiafilters at varying ultrafiltrate and dialysate flow rates (1, 2, 3, & 6 l/hr). Results The mean telavancin sieving coefficient ranged from 0.25 to 0.31 during continuous hemofiltration. At all ultrafiltration rates, no differences were observed in telavancin CLtm between the two hemodiafilter types. For continuous hemodialysis, mean telavancin saturation coefficients ranged from 0.10 to 0.43 and CLtm tended to be higher for the polysulfone hemodiafilter than the AN69 hemodiafilter, especially at higher flow rates. Mean HP-β-CD sieving coefficients ranged from 0.63 to 1.03 and saturation coefficients from 0.63 to 1.38, resulting in a CLtm that was similar to ultrafiltrate and dialysate flow rates. Conclusion Telavancin CLtm is dependent on hemodiafilter type, dialysate and ultrafiltration rates. CRRT with high ultrafiltrate or dialysate rates may result in sufficient telavancin clearance to alter telavancin dosing. HP-β-CD clearance by continuous hemodialysis or continuous hemofiltration is substantial and may be sufficient to prevent HP-β-CD accumulation in subjects receiving CRRT. Pharmacokinetic studies conducted in patients receiving CRRT and telavancin are needed to confirm these in vitro findings.

Selected Pharmacokinetic Issues in Patients with Chronic Kidney Disease

Pharmacotherapy plays an important role in the care of a chronic kidney disease (CKD) patient but delivering this therapy can be challenging. Besides alterations in the pharmacokinetic parameters of absorption, distribution, metabolism and elimination, the average CKD patient must take multiple medications each day. The likelihood of an adverse drug reaction increases with each medication added to these patients’ daily regimen. In this article we discuss selected pharmacokinetic issues unique to CKD patients.