In this episode, I’ll discuss vancomycin dosing by AUC:MIC instead of trough level.
The consensus vancomycin guidelines from 2009 are being revised. One prediction that many are making is that the new guidelines will recommend a big change to how we adjust vancomycin doses. Instead of dosing by trough level, the new guidelines are expected to recommend dosing by the area under the curve to MIC ratio (AUC:MIC).
The vancomycin trough goal in the 2009 guidelines of 15-20 mg/L in serious infection was controversial when it came out and remains so today.
The trough goal was proposed as a way to ensure that patients achieve the ideal 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC) of at least 400 mg-hr/L. However, analyses have demonstrated that patients with adequate renal function can typically achieve the AUC:MIC goal with a more conservative trough concentration. In addition, measures of cure with vancomycin are correlated to the AUC:MIC ratio achieved, not the trough level.
As the target vancomycin trough recommendation increased, so did vancomycin doses. Unfortunately, this also led to more reported instances of vancomycin-associated nephrotoxicity. Even troughs within the recommended target range of 15–20 mg/L are associated with increased odds of nephrotoxicity relative to troughs less than 15 mg/L.
Dosing by AUC:MIC should help keep vancomycin doses at levels that are associated with clinical response but below levels associated with increased risk of nephrotoxicity.
The AUC:MIC ratio associated with a clinical response is 400 mg-hr/L. The AUC that is associated with an increased risk of nephrotoxicity is above 600 mg-hr/L. This means that a dose of vancomycin with an effective clinical response and no increased risk of nephrotoxicity should be attainable for MRSA with a MIC up to and including 1.5 since an AUC of 600 with a MIC of 1.5 still gives an AUC:MIC ratio of 400.
Unfortunately, there is only reliable AUC:MIC efficacy data for vancomycin against staph aureus. As staph aureus is the most invasive of the organisms vancomycin is used to treat, it is hoped that other pathogens will be adequately covered by a vancomycin AUC in the 400 to 600 range.
To make this practice change, calculator support will be necessary.
Separate calculators will be needed for empiric dosing and subsequent adjustment based on levels.
The empiric AUC:MIC ratio for a vancomycin dosing regimen can be predicted in advance by a simple formula:
First, divide the total daily dose of vancomycin by the estimated clearance of vancomycin. Then divide this number by the MIC. The formula can be expressed as this: ((daily vancomycin dose)/(ClCr*0.75*0.06))/(MIC). Clearance of vancomycin is about 75% of creatinine clearance and this is multiplied by 0.06 to convert to L/hour.
I’ve created a calculator to do this estimation here.
To make patient-specific adjustments to the empiric vancomycin dose, two vancomycin levels within the same dosing interval are needed. The first level should be obtained after the distribution is complete, about 1–2 hours after the end of the infusion. The second level should be obtained after 1 half-life has passed, about 4-6 hours in patients with normal renal function and longer in patients with renal impairment. These two levels will then be used to calculate a patient-specific elimination rate constant and volume of distribution. With this information, a calculation can be done to adjust the empiric dose of vancomycin.
Despite needing two levels instead of a single trough to make adjustments, there are some significant benefits to dosing vancomycin this way including:
1. Being able to accurately adjust vancomycin dosing before the 2nd dose is given
2. Not having to repeat levels more often than weekly for patients that have stable renal function
3. Not having to worry about a precisely timed trough level
There is also an option to use Bayesian dosing software to predict the AUC based off of a single random vancomycin level. In this scenario, the timing of the level is even less important so long as the calculator knows the exact timing of the level in relation to the last vancomycin dose.
I expect that implementation of AUC-based dosing will follow the update to the vancomycin guidelines and improve the safety of vancomycin use, most notably with a reduction in vancomycin-associated AKI.
To get a free pdf of my visual critical care antibiotic guide to help you easily remember spectrum of activity, go to pharmacyjoe.com/abx.
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