Special Feature
Appropriate Dosage of Vancomycin in End-Stage Renal Disease Patients Requiring Intermittent Hemodialysis
By Kevin Singh; Sherman Lau, Pharm.D.,
Jessica C. Song, M.A., Pharm.D, Clinical Supervisor of Pharmacy and Therapeutics, Ambulatory Care, and Mental Health at Santa Clara Valley Medical Center, San Jose, CA, is Associate Editor for Infectious Disease Alert.
Kevin Singh, Sherman Lau and Jessica C. Song report no financial relationships relevant to this field of study.
Infection is the second leading cause of death in hemodialysis patients, with mortality rates ranging from 12-36% in this vulnerable population.1 Vascular-access related septicemia accounts for approximately 75% of deaths associated with infections, with Staphylococcus aureus causing up to 39% of all bacteremias.1 Moreover, hemodialysis patients have a 100-fold greater risk for experiencing invasive methicillin-resistant S. aureus (MRSA) infections than the general population.1
At present, the current standard of practice is to use vancomycin, a bactericidal glycopeptide antibiotic for the treatment of hemodialysis patients with catheter-related bloodstream infections caused by MRSA.1 Vancomycin has a complex pharmacokinetic profile in end-stage renal disease (ESRD) patients requiring intermittent hemodialysis. This agent undergoes three phases of elimination during intermittent hemodialysis: (1) a rapid extraction phase during the intradialytic phase (serum extraction rate of 30-46% with high-flux membranes); (2) administration and redistribution (lasts ~2 hours); and (3) prolonged, linear clearance during the interdialytic interval.2 Since the half life of vancomycin in anuric patients may range from 100 to 200 hours, a very gradual reduction in concentrations occur during the interdialytic interval (typically 44-68 hours).
A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists recommended a target of a 24-hour area under the concentration curve over the minimal inhibitory concentration (AUC/MIC) of at least 400 in order to achieve clinical success in patients infected by staphylococcal species.3 However, since multiple vancomycin levels must be drawn from patients in order to calculate AUC/MIC's, a more practical monitoring tool would be to check vancomycin trough levels, given the positive correlation between drug exposure yielded by both parameters. There has been a steady rise in the fraction of S. aureus strains with an MIC between 1 and 2 mg/L over the past decade. An estimated 16.2% of S. aureus strains in the United States exhibited MICs between 1 and 2 mg/L in 2005.4 In addition, the emergence of vancomycin-intermediary and vancomycin resistant strains of S. aureus has further increased the risk of treatment failure in patients requiring vancomycin therapy.
These changing patterns in epidemiology and susceptibility to vancomycin in S. aureus have resulted in substantial changes in the dosing guidelines for this drug, with suggested target trough levels of 15 to 20 mg/L in patients with complicated infections caused by S. aureus.3 To date, underdosing appears to be the main problem in the majority of patients undergoing dialysis.4 The purpose of this review is to discuss newer clinical prescribing practices regarding vancomycin in patients requiring intermittent hemodialysis.
Vancomycin Dosing
To date, earlier studies of vancomycin dosing in patients undergoing intermittent hemodialysis used inappropriate therapeutic ranges, thereby providing limited guidance for contemporary clinical practice.5-7 Two investigators studied similar algorithms using a weight-based loading dose of 20 mg/kg (dry body weight), followed by fixed doses of 500 mg (timed with each dialysis session).5,6 The only difference between the regimens involved the timing of administering vancomycin; one investigator gave the loading and maintenance doses after dialysis,5 whereas the other investigator had patients receive vancomycin during the final hour of dialysis.6 Twenty-eight percent of patients who received vancomycin post-dialysis achieved troughs of 15-20 mg/L and 12% of patients achieved similar levels when they received vancomycin during the last hour of dialysis. Pai and associates used a 1000 mg loading dose, with the following maintenance doses: (1) 1000 mg if trough levels fell below 8 mg/L; (2) 500 mg if trough levels ranged from 9 to 15.9 mg/L; and (3) no supplemental dose with trough levels of 16 mg/L and higher. Approximately 20% of patients achieved trough levels of 15.1-20 mg/L.7
Taylor et al. recently reported on the outcomes of using their vancomycin dosing protocol in 34 hospitalized hemodialysis patients (weight range, 50-118 kg).8 Patients received a 20 mg/kg (actual body weight, dose in multiples of 250 mg) loading dose scheduled to end with the dialysis session. Patients received maintenance doses of 1000 mg during the last hour of subsequent dialysis sessions and trough vancomycin concentrations were measured immediately prior to the fourth dialysis session. Thirty-five percent of patients achieved trough vancomycin concentrations between 15 to 20 mg/L and 15% of patients displayed trough concentrations in excess of 25 mg/L. Only 6% of patients had trough concentrations below 10 mg/L.
Vandecasteele and associates proposed the following dosing guidelines for hemodialysis patients requiring vancomcyin therapy: (1) administer a loading dose of 20-25 mg/kg using actual dry body weight (dose not to exceed 4 grams); (2) infuse vancomycin at a rate of 15 mg/minute such that the infusion ends with the dialysis session; (3) check trough concentrations before each dialysis session; (4) aim for a target trough concentration of 15 to 20 mg/L; and (5) maintenance doses should be based on trough levels, interdialytic elapse, residual renal function, and body weight.1
Recently, a novel approach for dosing vancomycin in patients undergoing intermittent hemodialysis was highlighted in a report by Vandecasteele et al.2 A vancomycin dose calculator was developed and assessed for its accuracy in achieving trough concentrations of 15-20 mg/L in 18 patients requiring intermittent hemodialysis. This multivariate model showed that predialysis vancomycin trough concentration, dry body weight, and interdialytic elapse accounted for nearly 95% of the variance observed. Patients received a fixed loading dose infusion of 20 mg/kg timed to end with the dialysis session. The median vancomycin maintenance dose was 8.05 mg/kg (given during subsequent dialysis sessions); approximately 78% of patients achieved trough target concentrations ranging from 15 to 20 mg/L.
Resistance, Weight-Based Dosing
Since vancomycin is frequently used in patients undergoing intermittent hemodialysis, healthcare professionals need to monitor trough concentrations of this agent in order to prevent the occurrence of adverse events and sub-therapeutic levels. The emergence of resistance to vancomycin has resulted in a new emphasis on achieving target trough concentrations of 15-20 mg/L in patients with complicated infections caused by S. aureus.
Given the poor success rate of achieving trough concentrations of 15-20 mg/L with the use of fixed dosing regimens (1000 mg loading dose, followed by supplemental doses of 500 or 1000 mg), it would be prudent to use weight-based dosing regimens of vancomycin in patients undergoing intermittent hemodialysis. Areas of uncertainty in the dosing of vancomycin in this special population include selection of appropriate doses based on interdialytic elapse and the patients' residual renal function.2,9 Some experts in the fields of nephrology and infectious disease have proposed using loading doses of 15 mg/kg, 25 mg/kg, and 35 mg/kg, respectively, for 1-day, 2-day, and 3-day interdialytic elapses.2 Future studies are needed to determine optimal maintenance doses of vancomycin, since patient-specific factors such as weight and the extent of residual renal function may influence dosing.9
References
- Vandecasteele SJ, et al. Vancomycin dosing in patients on intermittent hemodialysis. Semin Dial 2011; 24: 50-5.
- Vandecasteele SJ, et al. Implementation of a dose calculator for vancomycin to achieve target trough levels of 15-20 µg/mL in persons undergoing hemodialysis. Clin Infect Dis 2011; 53: 124-9.
- Rybak M, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2009; 66: 82-98.
- Vandecasteele SJ, et al. Recent changes in vancomycin use in renal failure. Kidney Int 2010; 77: 760-4.
- Barth RH, et al. Use of vancomycin in high-flux hemodialysis: experience with 130 courses of therapy. Kidney Int 1996; 50: 929-36.
- Ariano RE, et al. Adequacy of a vancomycin dosing regimen in patients receiving high-flux hemodialysis. Am J Kidney Dis 2005; 46: 681-7.
- Pai AB, et al. Vancomycin dosing in high flux hemodialysis: a limited sampling algorithm. Am J Health Syst Pharm 2004; 61: 1812-6.
- Taylor ME, et al. Practical vancomycin dosing in hemodialysis patients in the era of emerging vancomycin resistance: a single-center experience. Am J Kidney Dis 2010; 55: 1163-5.
- Pallotta KE, et al. Vancomycin use in patients requiring hemodialysis: a literature review. Semin Dial 2008; 21: 63-70.
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