Evidence suggests AUC-guided vancomycin dosing is a safer method than traditional trough-guided dosing.
Few topics in infectious diseases pharmacotherapy provoke such strong emotions and opinions in so broad an audience as vancomycin dosing and monitoring. After more than 6 decades of experience with the archetypal glycopeptide, clinicians are still learning how best to optimize its dosing.
In 1987, pharmacokinetic/pharmacodynamic data from mouse thigh models were presented that showed that the 24-hour area under the concentration time curve to minimum inhib­itory concentration ratio, or AUC:MIC, was the best predictor of vancomycin efficacy against Staphylococcus aureus.1 Now, more than 30 years later, we are in the middle of a para­digm shift from trough-guided vancomycin dosing to true AUC-guided dosing.
Consensus guidelines on vancomycin therapeutic drug monitoring, published in 2009, suggest a serum trough concentration range of 15 to 20 mg/L as a surrogate goal for an AUC:MIC ≥400 in patients with moderate to severe S aureus infections.2
More recent evidence, however, suggests troughs are not an ideal surrogate for AUC, with many patients able to achieve a goal AUC:MIC with troughs less than 15 mg/L.3-5 Furthermore, vancomycin troughs of 15 to 20 mg/L have been associated with increased risk of nephrotoxicity,6 with no corresponding benefit in terms of efficacy.7 A growing body of retrospective observational evidence, in addition to a few prospective single-center studies, has supported the efficacy of AUC-guided vancomycin dosing for a number of moderate to severe infection types.8-16 Prospective, multicenter, obser­vational data have been preliminarily presented, and the full results are eagerly anticipated.17
There are a handful of methods of AUC estimation that span a continuum in terms of reliability. The Moise-Broder equa­tion,18 which is the total daily dose of vancomycin divided by a creatinine clearance (CrCl)-based estimate of vancomycin clearance, is a straightforward method requiring no serum concentrations. There is evidence, however, suggesting CrCl-based equations underestimate actual AUC.19
Another equation-based process, and the one chosen by our institution, is the Sawchuk-Zaske method,20 which uses 2-level pharmacokinetics and assumes a 1-compartment model. Two steady state, postdistribution vancomycin levels drawn during the same interval can be used to calculate the area of the linear and logarithmic trapezoids of the vanco­mycin concentration time curve, resulting in a patient-specific AUC estimate. Dosing calculators, whether home-grown, elec­tronic medical record (EMR)-based, or commercially avail­able, can make the Sawchuk-Zaske method achievable for many institutions.
The third major method is map Bayesian modeling, which uses population pharmacokinetic data, as well as 1 or more patient-specific serum vancomycin levels, to create prob­ability distributions. Although this method results in the most accurate AUC predictions, Bayesian modeling software have not historically been widely available for clinical use in a user-friendly format. This has been changing in recent years, and Bayesian modeling may one day be the standard for most hospitals.
The first step is determining the best method for calcu­lating AUC at your institution. Multiple Bayesian modeling programs are available or in development.21 Some can even be incorporated into EMRs, although at a significant cost. AUC calculation based on 2-level pharmacokinetics is likely the least expensive and quickest to implement compared with purchasing and integrating a Bayesian program. Any home-grown calculators, however, will need to be carefully created and validated. If your institution is able to purchase an online software program or create an electronic calculator in the EMR, these would likely be more user-friendly and provide more transparency for physicians and pharmacists. If a significant investment is required (ie, time and money), a simpler approach using a spreadsheet-based or web-based calculator may be preferred.
Once an AUC calculation method is chosen, a new insti­tutional guideline will need to be created for all pharmacists involved in vancomycin dosing. It should provide a clear step-by-step process and outline indications for which AUC-guided dosing is indicated (Table) to minimize errors and confusion. In addition, EMR documentation will need to be updated to incorporate additional vancomycin levels and pharmacoki­netic data points involved in AUC calculations.
Once a plan is in place, the next step is obtaining medical and pharmacy staff support. Prior to the 2009 guideline, pharmacists and physicians routinely measured peak and trough concentrations. Then they were told peaks were unnecessary and only troughs mattered. Now with AUC-guided dosing, peaks and troughs are needed again, but for different reasons. Many current pharmacists and physi­cians haven’t practiced in a world of vancomycin peaks and are unfamiliar with the math involved in AUC-guided dosing. This may result in hesitation and confusion. Gaining support from infectious diseases physicians and the Pharmacy and Therapeutics Committee is vital. They need to understand the impact of the new dosing scheme on patient outcomes and the overall clinical workflow.
Once approved, the next step is education of all impacted members of the health care team. This includes physicians, pharmacists, nurses, and laboratory staff. Physicians need to be aware that multiple vancomycin levels will be obtained for select patients and they shouldn’t panic when they see a vancomycin concentration greater than 20 mg/L. Given the logistics of checking multiple levels and the complexity of AUC calculations, physicians may consult pharmacy for all vancomycin patients, if this is not already common practice. They will also need education on the new documentation process, as well as a best practice for follow-up monitoring for patients discharged on vancomycin. Physician education can occur via email, posters/flyers in the doctor’s lounge, and one-to-one direct detailing.
For pharmacists, we developed a comprehensive training and validation process to ensure all were competent in initial dosing and AUC monitoring. This included a prere­corded voiceover slideshow presentation, several practice cases utilizing the new guideline and spreadsheet calculator, small group discussions to address questions or concerns, and random audit and feedback of individual cases after the new dosing method was rolled out.
Nursing and laboratory personnel, particularly phleboto­mists, need education on the importance of timely collection and documentation of serum vancomycin levels and docu­mentation of doses. Errors may lead to inaccurate estima­tion of AUC, inappropriate dose adjustments, or the need for repeat blood draws. Education can occur via in-services on high-volume units, email, and posters/flyers in staff lounges. Feedback to nursing and laboratory leaders will likely be needed to ensure accountability of staff.
The final step is validation at a local level. This can be accomplished with a simple medication-use evaluation to determine the reliability of the new dosing guideline and calculator in reaching the target AUC:MIC or a larger study evaluating clinical outcomes, including safety and efficacy.
An updated consensus vancomycin dosing and moni­toring guideline is currently under development and is anticipated to support the shift to AUC-guided dosing. Many opportunities remain for prospective studies to add to our current knowledge, and increasing availability of Bayesian modeling software may further revolutionize and simplify AUC-guided vancomycin dosing in the not-too-distant future.
Dr. Kisgen is the antimicrobial stewardship pharmacy lead and PGY1 pharmacy practice residency program director at Sarasota Memorial Hospital in Florida. He implemented AUC-guided vancomycin dosing at his large community teaching hospital in spring 2017. Dr. Seddon is an antimicrobial stewardship pharmacist at Sarasota Memorial Hospital in Florida. She implemented AUC-guided vancomycin dosing at her large community teaching hospital in spring 2017.