"Getting Serious About Vancomycin Selection and Dosing" by Steven P. LaRosa, M.D.

Introduction

As an Infectious Disease physician and Antimicrobial Stewardship Director I encounter a large number of patients who have been empirically started on Vancomycin due to a concern for MRSA infections or Gram positive infection with a reported penicillin allergy. I often see patients being given 1gm IV q 12hours without any attention to seriousness of illness, body weight, kidney function or susceptibility of the infecting organism. This blog will address how to optimize the use and dosing of Vancomycin.

Is Vancomycin even necessary?

Vancomycin is quite often given as part of empiric therapy for pneumonia and skin and soft tissue infections without much thought as to if it is necessary. A good starting point in the evaluation of the need for Vancomycin is to a "chart biopsy" on the patient. In the evaluation of the EMR I look for past cultures or MRSA screen results. This exercise may reveal that the patient has had in fact MSSA and not MRSA colonization/infections (see next section). In pneumonia, data now exists that Vancomycin can safely be discontinued if a patient is not colonized with MRSA. In a patient with pneumonia I will typically order MRSA screens of both the nares and pharynx. If both of these results are negative I will stop Vancomycin unless there is a sputum or BAL that grows MRSA. In skin and soft tissue infections, IDSA guidelines do not recommend the empiric use of Vancomycin in non-purulent cellulitis. For purulent infections I use microbiology results to guide further use of vancomycin. An MRSA screen of the groin will also yield evidence of MRSA colonization is cases where the nares MRSA screen is negative.

MSSA infections and "Penicillin allergies"

Vancomycin is often given as a substitute for Cefazolin and Oxacillin in patients with reported penicillin allergies. The literature however is quite clear that for serious Methicillin sensitive Staph aureus (MSSA) infections that Vancomycin is inferior in efficacy to Beta -lactams. Additionally, of the 10% of patients who have a stated penicillin allergy only 10% of those or 1% overall will have a true penicillin allergy. Data from the University of Washington has shown a very rare incidence of allergic reactions to Cefazolin even in patients with listed penicillin allergies. In MSSA infections we should really be following their advice that Cefazolin can be given unless the patient has a history of anaphylaxis or Steven-Johnson syndrome from penicillin.

Loading Dose

It is quite common for patients to be initiated on a standing every 12 hour dose of vancomycin without a loading dose even in serious infections. The absence of a loading dose can lead to a 3 day delay in achieving adequate drug exposure. A loading dose of 25mg/kg actual body weight can significantly shorten the time to adequate drug exposures. Concerns for nephrotoxicity with high loading doses of Vancomycin (up to 3 gms) have not been found in clinical studies.

Vancomycin Dosing and Exposure

The Infectious Disease Society of America (IDSA) guidelines recommend that in serious MRSA infections one should target a Vancomycin trough of 15-20. In a review of the literature there is very little data to support vancomycin troughs as a biomarker for drug efficacy. Vancomycin 's efficacy is determined by drug exposure over time. It is both concentration dependent and time dependent. In animal studies and human studies efficacy is best seen with a Vancomycin AUC to MIC ratio that exceeds 400. A very poor correlation exists between Vancomycin troughs and AUC: MIC ratio. In fact in many patients with MRSA infection (MIC < or =1) an AUC: MIC ratio> 400 can be achieved with a Vancomycin trough < 15. What we then see is patients being exposed to excessively high Vancomycin levels in an effort to chase a Vancomycin trough of 15-20. This practice only results in unwanted nephrotoxicity.

So how does a busy clinician practically target an AUC: MIC ratio of 400? The denominator MRSA MIC can be ascertained from the microbiology report or can be assumed to be 1 for empiric therapy provided your institution does not have a large number of MRSA isolates with MICs > 1. A quick and dirty way to estimate the required daily dose to achieve an AUC: MIC ratio is to multiply 400 X estimated Vancomycin clearance. Estimated Vancomycin clearance is calculated as follows: Creatinine clearance X 0.79 + 15.4 X 0.06. Estimated doses can also be calculated using many available apps.  I use the Vancomycin Calculator by Sean Kane, PharmD on my Iphone. The only data I need to load to get my initial dosing guidance are age, gender, height, weight and serum creatinine. In terms of checking to see that the exposure is adequate on a given regimen it is best to get 2 Vancomycin levels during a dosing interval. I typically will obtain a Vancomycin peak 1 hour after the third dose and a Vancomycin trough thirty minutes before the fourth dose. These values are then entered into the calculator to yield information as to if the dose and infusion duration needs to be altered to achieve a Vancomycin AUC: MIC ratio > 400.

Vancomycin MICs >1

The discussion above implies the significance of the MRSA MIC to Vancomycin dosing. One can easily see that despite having a "sensitive" MRSA isolate with a Vancomycin of 2 that you would have to double the daily dose of vancomycin to achieve an AUC: MIC of > 400. For a healthy person with normal or augmented renal function this could entail daily doses far in excess of 4 gms/ day. The incidence of Vancomycin-induced nephrotoxicity rises precipitously as you go to > 3-4 grams per day. Additionally clinical studies have demonstrated increased mortality when with Vancomycin when the MIC is > 1. For this reason I immediately go to an alternative agent such as Daptomycin if the patient has had a previous or current MRSA isolate with a Vancomycin MIC > 1.

Concluding Remarks

As can be gleaned from above, the choice of vancomycin and appropriate dosing is quite complicated business. I have become of the mind that Vancomycin use and dosing should become subject to a 100% prospective Antimicrobial Stewardship audit. Many hospitals have already gone to a pharmacy directed Vancomycin dosing service. I would envision also looking at past records, colonization status, allergy review, indication and microbiology data in addition to dosing.