Clinical decision support for vancomycin is a topic likely to be of interest as many clinicians look towards potential AUC-based vancomycin monitoring and dosing. In this article the founder of DoseMe shares his experiences and insights on the topic.
Interview with: Robert McLeay, B.S., Ph.D.
Interview by: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID
[Last updated 11 January 2019]
Intravenous vancomycin is an antibiotic commonly used in hospitals to provide coverage for Gram positive bacteria such as methicillin-resistant Staphylococcus aureus. Dosing and monitoring of vancomycin can be complex, requiring consideration for patient-specific factors (i.e., renal function, clinical status) that influence vancomycin pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion, [PK]) and pharmacodynamics (i.e., how the drug affects the body, [PD]). Therapeutic drug monitoring (TDM) with vancomycin levels are typically utilized to adjust vancomycin dosing as providers seek to optimize PK/PD, looking to enhance the chances for efficacy while reducing the chances for toxicity.
The last vancomycin monitoring and dosing guideline for adults was published in 2009 (available here). An update to this guideline has been long-awaited, but we still are not sure when it will be released. One thing that many experts are predicting will be incorporated within the new guideline is dosing and monitoring based upon area under the curve: minimum inhibitory concentration (AUC:MIC). An October 2018 article in AJHP authored by numerous leading infectious diseases pharmacists even reviews implementing AUC-based vancomycin dosing (available here).
AUC-based dosing requires calculations based upon patient data and TDM. Recently I reviewed some of the free vancomycin calculators that are available on the internet. One of motivations for composing that article was to contrast available products. In drafting that text, one of the products that came up was DoseMeRx which was developed by the company DoseMe. DoseMeRx complies with federal law and regulations for clinical decision support (CDS) software and is maintained by standards appropriate for a clinical environment.
Considering that many people are likely seeking to acquire and share important information about vancomycin dosing calculators that can be used as CDS tools, it occurred to me that interviewing the creator of one such product could be a worthwhile endeavor. With that in mind I was able to connect with the folks over at DoseMe and Dr. McLeay was gracious enough to entertain several questions about his experiences and perspectives on the topic.
Here are insights on clinical decision support for vancomycin dosing and monitoring from a creator of DoseMe…
1. How did you become interested in precision medication dosing and what motivated you to found DoseMe in 2014?
My original educational background was a combined undergraduate science and information technology (IT) degrees. I ran off to work in IT leading software development teams for a few years in chase of dollars, but fundamentally, I was writing accounting software; important but not fulfilling work. I then returned to study and completed a PhD under Prof Timothy Bailey, the author of a software suite used to understand gene regulation. For me, this was fascinating, as I was able to apply commercial software development expertise to statistics and biological problems. During this I was fortunate to be able to collaborate with other laboratories studying glioblastoma and apply my software directly to medical research.
Funnily enough, part of the gestation of DoseMeRx was being told that I would not be able to do it, so I suppose I have a competitive streak. The first academics to have written software that performs Bayesian dosing did it in 1968, but it never really made it into clinical use. When I reviewed some of the different tools out there it was clear that these were research tools, and not designed for daily use by clinicians.
Betting the farm on being able to build not just an accurate but a usable tool really was the goal from the beginning. And it has paid off – we have more than 1000 clinicians in more than 100 hospitals, across 6 continents. Antarctica will come one day too, I’m sure!
2. What steps went into developing the DoseMeRx clinical support tool that can be used for vancomycin dosing and monitoring?
So vancomycin was actually the second drug that we added to DoseMeRx and pediatric vancomycin was the third.. We have continued to grow support for vancomycin – we have since added a pre-term neonate model and in January 2019 are releasing multiple other vancomycin models including in obese populations.
At the time that DoseMeRx was initially developed, we thought that gentamicin would be the most used drug. Approximately 3 months after we added it, our local hospital who was piloting DoseMeRx essentially stopped using it altogether in favor of piperacillin/tazobactam instead. While globally this is not the case with our customers, today out of the 40+ drug models, vancomycin is easily first, with gentamicin a distant second.
One of the biggest challenges was selecting an appropriate drug model. Researchers (including myself) can be quite opinionated on many things. Ultimately, for our first vancomycin model we selected a simpler one-compartment model (not because of this; DoseMeRx has an eight-compartment model for one drug!), but because it had been externally validated in multiple patient groups. We now have multiple drug models for both vancomycin and other drugs and add additional models for various customers as well – for example, with Texas Childrens’ Hospital we added support vancomycin in pre-term neonates from 22 weeks onwards. We are probably now best considered to be a platform for validated, PK-informed dosing rather than a tool for any specific model.
I guess in a commercial sense we were fortunate that many hospitals globally have focused on reducing vancomycin-associated nephrotoxicity and we were ready to help.
3. How can physicians, pharmacists and others differentiate the various clinical decision support tools currently available for dosing and monitoring vancomycin?
Firstly, it is important to identify your use – are you using it for research or (more likely) for clinical use? Is this a tool that you want your team to use, or do you want to rely on the single expert using a research tool? DoseMeRx has been built for a multi-user, multi-disciplinary team. It is designed to be used by any clinical pharmacist who performs therapeutic dose monitoring – you should not need to memorize pharmacokinetic formulae to use a clinical decision support tool!
Secondly, DoseMeRx has been designed and developed in accordance with regulatory legislation in AU, EU, and the US. Not only does this make it legal for use, it means that we have a big focus on quality and safety. Every time we make a change to DoseMeRx we run more than 20,000 automated tests. Before we design various features, we perform risk analyses. It is not necessarily exciting work – but it is really important. Unfortunately, I have seen a busulfan dosing spreadsheet that had a serious error in converting units. More fundamentally, however, spreadsheets are just not a good tool – you cannot share data, they do not connect to your electronic medical record (EMR), and I doubt many hospitals using spreadsheets have a test suite to make sure that it isn’t inadvertently changed!
We have a goal to be the everyday therapeutic drug monitoring tool. Most of the users of DoseMeRx are pharmacists or specialist physicians – while some do research (even using DoseMeRx), DoseMeRx is their daily tool for dose individualization.
4. When should clinicians look to clinical decision support tools for assistance in dosing and monitoring vancomycin?
Studies (e.g. van Hal SJ, Paterson DL, Lodise TP. Antimicrobial Agents and Chemotherapy. 2013) show that vancomycin-associated nephrotoxicity is common (5% to 43%), in patients with trough targets of 15-20mg/L. While AKI might be commonly thought of as a temporary problem, it appears to have serious long term effects on morbidity and mortality (Schiffl H, Fischer R. Nephrology Dialysis Transplantation. 2008).
Given this research, I personally think that it is insupportable not to monitor vancomycin courses as a matter of course. The cost of monitoring and adjusting is very low per patient, especially in contrast to the cost per patient of managing nephrotoxicity.
And this is before we even discuss efficacy – DoseMe has had the opportunity to work with several hospitals and look at their dosing performance pre-DoseMeRx. With a broad trough targets of 10-20mg/L, we find that only 54% of doses achieve this target. Perhaps most concerningly, the data show that some hospitals focus on AKI risk (and systemically underdose) while others focus on treatment failure (and systematically achieve supra-therapeutic troughs).
We also see the pending move to AUC24-based vancomycin dosing as imminent – and this requires CDS.
5. What do you see as key pharmacokinetic and pharmacodynamic considerations clinicians should note as they approach vancomycin dosing and monitoring using clinical support tools?
In terms of interpretation of data, it is important to note that while DoseMeRx has demonstrated improvements in dosing at 100+ sites, it’s not a replacement for pharmacists or physicians, but a support tool! Of course, the biggest consideration when using any tool is to focus on treating the patient. For example, if your patient has recently become anuric (and you have not got another serum creatinine yet), then you have not told DoseMeRx yet – but you obviously need to take that into account!
Secondly, the other consideration is the flexibility that a full modelling tool provides. With a CDS tool like DoseMeRx, you can take concentrations at any time, from the first dose – no wait for steady-state. If you are concerned about your individual patient, you can use CDS to help with their dosing sooner.
Finally, variability is huge. If you were to give a random 1000 patients 1 gram of vancomycin IV twice daily, your troughs would range from 5.3–72.6 mg/L (Neely MN et al. Antimicrobial Agents and Chemotherapy. 2014). While worrying about what population a patient falls into is important (we regularly field questions about weight, height, disease state), it is also important to consider the huge intra-group variability too! Bayesian dosing tools take this into account because they are focused on calculating individual clearance and volume rather than just applying a population average.
6. What can the new free DoseMeRx vancomycin calculator be used for and who should use it?
We made the new free vancomycin dosing calculator available for two reasons: firstly, to demonstrate how Bayesian dosing works (i.e., for study/learning purposes), but have given it enough flexibility to handle simple cases. The biggest restriction currently is that it by default will calculate a dose for a target of 15mg/L, and only supports a single dose amount given one or more times previously.
We will continue to build and develop this tool, and while we hope it is useful, it is no replacement for the real thing!
The full DoseMeRx platform, which anyone can try for free for 14-days, supports EMR integration (no data entry!), recording and sharing patient history, continuous infusions, arbitrary dosing times, AUC targets, minimum inhibitory concentration support, simulating outcomes of specified dosing regimens, multiple vancomycin models down to 22 weeks gestational age, and many more features. It also supports 40+ other drug models from antimicrobials including anti-fungals to transplant to oncology.
7. What do you anticipate the future holds for DoseMeRx and vancomycin dosing using clinical decision support tools?
We anticipate that the move to AUC-based vancomycin dosing is both inevitable and imminent. Given that traditional pen-and-paper AUC-calculation methods as well as most Microsoft Excel solutions require a minimum of two levels on the same dose, and Bayesian methods do not, we think that there is a great opportunity to use Bayesian dosing to improve patient outcomes.
DoseMeRx now has more than 100 hospitals and more than 1000 clinicians using it to improve dosing. While we have come a long way, I still think we are just at the beginning of the journey.
Resources & Recommended Readings
- van Hal SJ et al. Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 Milligrams per Liter. AAC. 2013; 57(2): 734-44.
- Schiffl H, Fischer R. Five-year outcomes of severe acute kidney injury requiring renal replacement therapy. NDS. 2008; 23(7): 2235-2241.
- Neely MN et al. Are vancomycin trough concentrations adequate for optimal dosing? AAC. 2014; 58(1): 309-16.
I would like to express my utmost gratitude to Dr. McLeay for taking the time to voluntarily complete this interview sharing his experience and perspectives.
ABOUT THE INTERVIEWEE
Robert McLeay founded DoseMe in 2012, combining his experience in modelling biological data and in delivering large IT projects with the goal of providing access to best-practice dosing via easy-to-use software aimed at clinicians rather than researchers.
Originally trained in software development, Robert has had a range of roles culminating in leading software development teams to successfully deliver IT projects in the telecommunications sector. Robert then returned to university to complete a PhD in Bioinformatics, using computational techniques to model and understand genetic and biological data.
Robert holds a Bachelor of Information Technology, Bachelor of Science (Hons), and a PhD (Bioinformatics) from The University of Queensland.
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