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An update on vancomycin dosing and monitoring practices in hemodialysis patients.

OBJECTIVES

After reading this article, readers should be able to:

1. Describe common indications for vancomycin therapy in hemodialysis patients

2. Explain the importance of therapeutic drug monitoring using vancomycin serum concentrations

3. Identify target trough serum drug concentrations

4. Compare and contrast different vancomycin dosing protocols in hemodialysis patients

5. Describe the ability of different dosing protocols to achieve target trough serum concentrations

BACKGROUND

Infection is the second leading cause of death in hemodialysis (HD) patients (Lafrance, Rahme, Lelorier, & Iqbal, 2008; Vandecasteele, Boelaert, & De Vriese, 2009). In this population, infection accounts for 12% to 36% of mortality, with the main cause being vascular access-related septicemia (Lafrance et al., 2008; Vandecasteele et al., 2009). Gram-positive organisms cause 58% to 99% of tunnelled catheter-related bloodstream infections and 70% to 93% of arteriovenous fistula or graft-related bloodstream infections in HD patients (Lafrance et al., 2008).

According to the Canadian Antimicrobial Resistance Alliance (2011), Staphylococcus aureus and coagulase negative Staphylococci (CONS) cause approximately 15% and 12% of all bacteremias in Ontario, respectively. In hemodialysis patients, S. aureus is the single leading pathogen as it causes 27%-39% of all bacteremias, which are complicated in almost half of cases (Lafrance et al., 2008; Vandecasteele et al., 2009). Furthermore, HD patients have a 100-fold higher risk for invasive methicillin-resistant S. aureus (MRSA) infections than the general population (45.2/1,000 versus 0.2-0.4/1,000 in USA in 2005). In Canada, Williams and Simor (2012) found that the MRSA rate in hemodialysis outpatients is approximately 0.58/10,000 patient days.

Vancomycin is a glycopeptide antibiotic used for complicated and drug-resistant gram-positive infections (Launay-Vacher, Izzedine, Mercadal, & Deray, 2002). It works by inhibiting cell wall synthesis of gram-positive bacteria (Vandecasteele et al., 2009). Vancomycin is poorly metabolized and is mainly excreted unchanged in urine, thus there is decreased renal clearance in those with renal failure. Non-renal clearance of vancomycin may account for up to 30% of its total body clearance and also decreases in terminal renal insufficiency, possibly due to inhibition of vancomycin metabolism by uremic toxins (Launay-Vacher et al., 2002).

It is important to note that in hemodialysis patients vancomycin has a low volume of distribution, low protein-bound fraction, and low molecular weight, thus easily diffusing through dialysis membranes (Launay-Vacher et al., 2002). It is significantly dialyzable when hemodialysis is performed using a high-flux membrane such as polysulfone, polyacrylonitrile and poly-methlmethacrylate.

MONITORING SERUM VANCOMYCIN CONCENTRATIONS

Trough serum vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness, as it can be used as a surrogate marker for Area Under the Curve (AUC). It would be impractical to collect the multiple serum vancomycin concentrations required to determine the AUC, which is needed to determine overall vancomycin exposure (Rybak et al., 2009).

It is recommended to collect serum vancomycin concentrations just prior to dialysis. A rebound in vancomycin concentrations at the end of a dialysis session is frequently observed. This may be due to recirculation from plasma protein binding sites (Launay-Vacher et al., 2002). In Pollard et al.'s study (1994), serum vancomycin concentrations decreased to 67% of pre-HD concentrations during a high-flux hemodialysis session and eventually increased to 87% of pre-HD concentrations in the post-dialysis redistribution phase. This phase averaged six hours, but ranged from one to 12 hours. The clinical significance of this rebound phenomenon is yet to be determined. In addition, while it may be most accurate to measure serum vancomycin levels at least one to two hours after dialysis, this may not be practical.

The 2009 consensus review by the Infectious Diseases Society of America (IDSA) and the American Society of Health-System Pharmacists (ASHP) on therapeutic monitoring of vancomycin in adults recommends maintenance of minimum serum vancomycin trough concentrations above 10 mg/L to avoid the development of vancomycin-intermediate Staphylococcus Aureus (VISA) in the treatment of S. aureus infections. For complicated infections including bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia (HAP) caused by S. aureus, vancomycin serum trough concentrations of 15 mg/L-20 mg/L are recommended. These targets were selected to potentially improve penetration in the tissues, to increase the probability of obtaining optimal target serum concentrations, and to improve clinical outcomes (Rybak et al., 2009).

DOSING RECOMMENDATIONS

Usual dosing practices of vancomycin in patients undergoing high-flux hemodialysis are similar to administering a loading dose (LD) of 1,000 mg followed by maintenance doses of (MD) 500 mg during or after the last hour of each hemodialysis session. Recent literature has consistently shown that vancomycin trough concentration targets of 15 mg/L-20 mg/L are not obtained in the majority of hemodialysis patients with the current dosing practices (Vandecasteele & De Vriese, 2010).

In Barth and DeVincenzo's dose comparison report (1996), an LD of 1,000 mg followed by an MD of 500 mg after each HD session resulted in 42.7% of patients who did not achieve the target of 15 mg/L. However, 60.6% of patients did have trough concentrations between 10 mg/L-20 mg/L. With the same dosing regimen, but given intradialytically during the last hour of dialysis, Ariano, Fine, Sitar, Rexrode, and Zelenitsky (2005) showed that approximately 60% of patients achieved vancomycin trough concentrations between 10 mg/L-20 mg/L, but only 12% reached 15 mg/L or above.

In Crawford, Largen, Walton, and Doran's prospective, 20-week study (2008), a single dose of vancomycin 35 mg/kg was administered to nine patients receiving out-patient dialysis three times per week through a high-flux synthetic dialyzer. The dose was administered either pre or post dialyzer. The group proposed that once-weekly dosing protocols might minimize medication errors and burden on patients and staff while eliminating the need to monitor for serum vancomycin concentrations. However, with this regimen, no patient achieved the primary outcome of achieving a pre-dialysis serum concentration of 10 mg/L or more on study day eight. Mean day eight pre-dialysis serum vancomycin concentrations (ranges) were 3.7 mg/L (3.5 mg/L-5 mg/L) after pre-dialyzer administration and 6.4 mg/L (3.5 mg/L-8.2 mg/L) after post-dialyzer administration of vancomycin. Therefore, this type of dosing may not achieve ideal vancomycin concentrations to treat infections in HD patients.

Emerging evidence suggests that weight-related loading doses, with fixed or weight-related maintenance doses, are more efficacious at achieving target serum trough concentrations. In Zelenitsky, Ariano, McCrae, and Vercaigne's study (2012), using kinetic modelling, a new initial vancomycin dosing protocol (Table 1 (page 27)) was developed and then prospectively validated. Specifically, they evaluated the ability for this protocol to achieve pre-hemodialysis trough concentrations of 10 mg/L-20mg/L, with an optimal target of 15 mg/L-20mg/L in hemodialysis patients. Two pre-hemodialysis blood samples were requested for 29 patients. One was collected prior to session #2 (post-load trough) and another after two maintenance doses or prior to hemodialysis session #4, 5 or 6 (maintenance trough). Of the post-load troughs, 76.9% were collected after 48 hours. All of the maintenance troughs were collected after 48-hour inter-dialytic periods with 41.4% being collected after 72-hour inter-dialytic periods. The group found that 65.5% of patients were able to achieve maintenance trough concentrations of 10 mg/L-20 mg/L including 37.9% who achieved 15 mg/L-20 mg/L.
Table 1: Threshold weight based nomogram (Zelenitsky et al., 2012)

Actual Body Weight     LD        MD

< 70 kg             1,000 mg    500 mg
70 kg-100 kg        1,250 mg    750 mg
> 100 kg            1,500 mg  1,000 mg


The group had other findings of note: (1) pharmacokinetic simulations showed no improvement in target attainment with weight-based (mg/kg) dosing, as compared to a dosing algorithm using body weight thresholds; (2) vancomycin therapeutic drug monitoring is valuable in guiding the need for subsequent dose modifications to achieve targets; and (3) conventional vancomycin therapy is no longer sufficient for treating serious S. aureus infections, as the trough concentrations obtained are suboptimal.

Similar results were found in a study done by Taylor and Allon (2010), where 34 hospitalized hemodialysis patients received LD of 20 mg/kg followed by MD of 1,000 mg during the last hour of treatment. The trough vancomycin concentration was measured after the third dose of vancomycin and immediately before the fourth dialysis session. Mean trough serum concentrations were 19.0mg/L (95% CI: 16.7-21.3). Twelve patients (35%) had trough vancomycin concentrations of 15 mg/L-20 mg/L and 27 (79%) had concentrations of 10 mg/L-25 mg/L. Two patients had trough vancomycin concentra-tions of <10 mg/L and five patients had concentrations > 25 mg/L.

CONCLUSION

In summary, current vancomycin dosing protocols involving fixed doses of 1,000 mg LD followed by 500 mg MD with each dialysis session are unable to consistently meet target trough concentrations of 10 mg/L to 20 mg/L. Emerging evidence for weight-related dosing protocols (either based on mg/kg or by thresholds) demonstrates that these are more likely to achieve target vancomycin serum trough concentrations.

Copyright [c] 2013 Canadian Association of Nephrology Nurses and Technologists

REFERENCES

Ariano, R.E., Fine, A., Sitar, D.S., Rexrode, S., & Zelenitsky, S.A. (2005). Adequacy of a vancomycin dosing regimen in patients receiving high-flux hemodialysis. American Journal of Kidney Diseases, 46, 681-687.

Barth, R.H., & DeVincenzo, N. (1996). Use of vancomycin in high-flux hemodialysis: Experience with 130 courses of therapy. Kidney International, 50, 929-936.

Canadian Antimicrobial Resistance Alliance. (2011). CANWARD 2011 Pathogens: Ontario data from blood specimens. Retrieved from http://www.can-r.com/study.php?study=canw201

Crawford, B.S., Largen, R.F., Walton, T., & Doran, J.J. (2008). Once-weekly vancomycin for patients receiving high-flux hemodialysis. American Journal of Health-System Pharmacy, 65(13), 1248-1253.

Lafrance, J.P., Rahme, E., Lelorier, J., & Iqbal, S. (2008). Vascular access-related infections: Definitions, incidence rates, and risk factors. American Journal of Kidney Diseases, 52, 982-993.

Launay-Vacher, V., Izzedine, H., Mercadal, L., & Deray, G. (2002) Clinical review: Use of vancomycin in haemodialysis patients. Critical Care, 6(4), 313-316.

Pollard, T.A., Lampasona, V., Akkerman, S., Tom, K., Hooks, M.A., Mullins, R.E., & Maroni, B.J. (1994). Vancomycin redistribution: Dosing recommendations following high-flux hemodialysis. Kidney International, 45, 232-237.

Rybak, M., Lomaestro, B., Rotschafer, J.C. Moellering, R., Craig, W., Billeter, M., ... Levine, D.P. (2009). 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. American Journal of Health-System Pharmacy, 66, 82-98.

Taylor, M.E., & Allon, M. (2010). Practical vancomycin dosing in hemodialysis patients in the era of emerging resistance: A single-centre experience. American Journal of Kidney Diseases, 55(6), 1163-5.

Vandecasteele, S.J., & De Vriese, S. (2010). Recent changes in vancomycin use in renal failure. Kidney International, 77, 760-764.

Vandecasteele, S.J., Boelaert, J.R., & De Vriese, A.S. (2009). Staphylococcus aureus infections in hemodialysis: What a nephrologist should know. Clinical Journal of the American Society of Nephrology, 4, 1388-1400.

Williams, V., & Simor, A.E. (2012). Colonization and infection with methicillin-resistant staphylococcus aureus (MRSA) in patients at a Canadian outpatient hemodialysis centre. Poster session presented at ID Week 2012, San Francisco, CA.

Zelenitsky, S.A., Ariano, R.E., McCrae, M.L., & Vercaigne, L.M. (2012). An INITIAL vancomycin dosing protocol to achieve therapeutic serum concentrations in hemodialysis patients. Clinical Infectious Diseases, 55(4), 527-33.

Maria Y. Zhang, PharmD, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON

Linda Dresser, PharmD, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto ON Clinical Pharmacist--University Health Network, Toronto, ON

Marisa Battistella, BScPhm, PharmD, ACPR Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto ON Clinical Pharmacist--Nephrology, University Health Network, Toronto, ON

Address correspondence to: Marisa Battistella, BScPhm, PharmD, ACPR, Clinical Pharmacist--Nephrology, University Health Network, 200 Elizabeth Street, EB 214 Toronto, ON, M5G 2C4

Email: marisa.battistella@uhn.ca
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Title Annotation:CONTINUING EDUCATION SERIES
Author:Zhang, Maria; Dresser, Linda; Battistella, Marisa
Publication:CANNT Journal
Date:Oct 1, 2013
Words:1971
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