Vancomycin dosing and monitoring in hemodialysis

Let's start with a patient case.  A patient on hemodialysis (M/W/F) is admitted to the hospital with cellulitis who also meets sepsis criteria.  He has a history of an MRSA infection during a previous admission so you want to initiate vancomycin at this time.  The patient is 76 kg and still makes some urine.  What dosing strategy should you choose and when/should vancomycin concentrations be monitored?

What do we monitor and why?

Vancomycin is one of the most commonly used medications for treating infections due to MRSA.  To see, its antibacterial mechanism, see the discussion here.  It is associated with a number of toxicities such as nephrotoxicity, ototoxicity, and infusion-related reactions.  Targeting a narrow therapeutic range can minimize these toxicities while ensuring therapeutic efficacy and reducing the development of resistance from inadequate dosing.  Several different pharmacokinetic strategies have been used to predict therapeutic outcomes [checking peaks versus troughs, percent of time over the minimum inhibitory concentration (T>MIC), area under the curve over minimum inhibitory concentration (AUC:MIC)] and the AUC:MIC ratio was shown to be the predictive parameter.  In practice, the trough concentration is used as a surrogate for the AUC for practical reasons.

Vancomycin pharmacokinetics in a person without CKD

Vancomycin exhibits a multicompartment model and is eliminated unchanged almost entirely by glomerular filtration (and therefore correlates with creatinine clearance).  The half-life ranges from as little as 4-6 hours in a healthy adult to more than a week in anephric individuals.  So as creatinine clearance decreases, vancomycin dosing needs to be adjusted in order to avoid accumulation and increased risk of toxicity.

Effects of hemodialysis on vancomycin concentration

Vancomycin has been shown to be eliminated by hemodialysis depending on the type of dialysis performed.  Low flux dialysis does not significantly remove vancomycin but high flux (like those used at North Shore University Hospital) will remove vancomycin.  Studies have also shown that vancomycin concentrations will rebound following a session using a high flux membrane as vancomycin redistributes from a peripheral compartment or protein binding sites as you can see in this graph below.

This rebound may be clinically significant so it is recommended that vancomycin trough concentrations be drawn prior to dialysis in those undergoing chronic hemodialysis. 

Dosing vancomycin in hemodialysis patients

Specific dosing strategies for loading and maintenance dosing of vancomycin are not described in the current guidelines.  Several studies have been performed that attempt to determine the optimal loading dose to achieve a therapeutic vancomycin concentration of 15-20 mg/L*.  One study found that a loading dose of 15-20 mg/kg is likely to yield an optimal prehemodialysis concentration.  The other found that a loading dose of 15 mg/kg yields a prehemodialysis concentration of 19 mg/L.  Authors also recommend that maintenance dosing should be administered according to the value of the trough level.  A suggested strategy is to administer 500 mg to 1 g when prehemodialysis trough concentrations fall below 15 mg/L.

Back to the patient case

So according to our patient vignette, this patient should be started on vancomycin with the target of quickly achieving a prehemodialysis vancomycin of 15-20 mg/L.  Since he weighs 76 kg, the loading dose at 15 mg/kg calculates to be 1140 mg.  For practical purposes, this should be rounded to 1000 mg or 1250 mg.  After administered, the vancomycin concentration should be drawn prior to his first dialysis session.  If it is reported <15 mg/L, the patient should be given a maintenance dose of 500 mg or if very low 1 g.  If the concentration is >15 mg/L, the patient should not receive a maintenance dose and should have another concentration drawn prior to the next hemodialysis session. 

About the target range

*The current target concentration for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, hospital-acquired pneumonia is 15-20 mg/L.  This goal is higher than previous goals in the past decades as MIC breakpoints are revised due to the development of resistance to vancomycin.  Currently, even isolates of S. aureus with MICs of 1-2 mg/L have increased treatment failure (versus lower MICs) even though MICs ≤2 will report as ‘S’ on the microbiology report.

Take home points:

• Trough concentrations should be monitored to minimize toxicity, ensure efficacy, and reduce development of resistance
• Target a prehemodialysis concentration of 15-20 mg/L
• A reasonable initial dose is 15-20 mg/kg rounded to the nearest 250 mg (for practical purposes)
• Be mindful of an MIC ‘S’ of 1.5-2 mg/L for S. aureus as this is associated with poor outcomes – a different antibiotic may necessary

References:

1. Rybak MJ, Lomaestro BM, Rotschafer JC, et al.  Therapeutic monitoring of vancomycin in adults. Pharmacotherapy 2009;29(11):1275-9.
2. Barth RH, DeVincenzo N. Use of vancomycin in high-flux hemodialysis: experience with 130 courses of therapy.  Kidney International 1996;50:929-36.
3. Launay-Vacher V, Izzedine H, Mercadal L, et al.  Clinical review: Use of vancomycin in haemodialysis patients.  Critical Care2002;6(4):313-6.
4. Nekidy WS, El-Masri MM, Umstead GS, et al.  Factors influencing vancomycin loading dose for hospitalized hemodialysis patients: prospective observational cohort study. Can J Hosp Pharm 2012;65(6):436-42.
5. Brown M, Polisetty R, Gracely EJ, et al.  Weight-based loading of vancomycin in patients on hemodialysis.  Clin Infect Dis 2011;53(2):164-6.

photo by becre8tv