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.
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