Bayesian Derived Vancomycin AUC/MIC with an Easy and Accurate Bayesian TDM Software: Keeping Up With the Changing Guideline

Vancomycin AUC/MIC was suggested as the preferred monitoring parameter for efficacy in the 2009 consensus review among American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP).¹  In the new vancomycin guideline draft, Bayesian-estimated vancomycin AUC/MIC between 400 to 600 mg*h/L is recommended to maximize the efficacy and minimize the likelihood of nephrotoxicity as a consensus among IDSA, ASHP, SIDP, and Pediatric Infectious Diseases Society (PIDS).² The new guideline draft no longer recommends monitoring for Trough only.² In the past, vancomycin was initially targeted for peak and trough just as much as monitoring for aminoglycosides.³ However, vancomycin’s bactericidal activity was different from aminoglycosides and its bactericidal activity was considered to have worked best if the concentration was maintained above the MIC due to its time dependent bactericidal activity.³ For this reason, monitoring for trough was suggested for vancomycin dosing in the last vancomycin guideline in 2009 along with targeting AUC ≥400 mg*h/L for ensuring efficacy.³ However, trough only targeting has become an issue because vancomycin’s therapeutic index has gotten lower overtime due to the rise of bacterial resistance causing “MIC Creep”.^4–7 Minimum Inhibitory Concentration (MIC) is a minimum serum concentration of the antibiotic that is needed to inhibit the growth of bacteria. When bacteria grow resistant to vancomycin, the MIC “creeps up” requiring higher antibiotic serum concentration to inhibit the bacterial growth. To ensure the efficacy, higher vancomycin trough concentration was targeted to have bactericidal activity rather than simply inhibiting the bacterial growth.⁸ As a result, “MIC creep” caused narrower therapeutic window due to requiring higher trough concentration closer to the toxic serum concentration. Subsequently, today’s vancomycin target trough has increased up to between 15 and 20 mcg/mL in severe infections.¹ Many studies suggested that targeting vancomycin trough above 15 mcg/mL is associated with nephrotoxicity.^9–13 From the graph from Pai et al, vancomycin target trough higher than 15 mcg/mL can increase the vancomycin AUC24 up to 1750 mg*h/L, which can be nephrotoxic.¹³

Graph from Pai et al 2014.¹³

Since vancomycin is considered to be a time-dependent agent with moderate to prolonged persistent effects, the dose is best optimized targeting a specific Area Under the Curve (AUC) to ensure the efficacy.^{1,8,9,14–18} Targeting AUC/MIC means it is maximizing the amount of drug rather than maximizing time duration above MIC. By targeting a Bayesian-derived AUC24/MIC between 400 and 600 mg*h/L, efficacy can be maximized and the likelihood of nephrotoxicity can be minimized.^1,2,13,19

Current practical difficulty is that it takes a lot more computing effort for pharmacists to calculate a dose using a target AUC for concentration-and-time-dependent agents such as vancomycin. For medical doctors and clinical pharmacists to easily target vancomycin AUC, PrecisePK (formerly known as T.D.M.S.) has been used in numerous hospitals world-wide for over 30 years. PrecisePK is an EHR integrated Therapeutic Drug Monitoring (TDM) Precision Dosing platform that is validated to give the most accurate and least biased vancomycin AUC results.²⁰ As a leader in vancomycin AUC dosing, PrecisePK uses cutting-edge Machine Learning technology and Bayesian Analytics to individualize the vancomycin dosing for each patient. As a part of a bigger movement in precision medicine, PrecisePK brings artificial intelligence (A.I.) to individualized patient care and precision dosing. (Book a demo with us at: https://precisepk.com/live-demo/)

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References

1.             Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy 2009;66(1):82–98.

2.             Rybak M, Le J, Lodise T, et al. Therapeutic Monitoring of Vancomycin: A revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious diseases Pharmacists (Draft). 2019;72.

3.             Duffull SB, Chambers ST, Begg EJ. How vancomycin is used in Australasia – A survey [Internet]. Australian and New Zealand Journal of Medicine. 1993 [cited 2019 Aug 19];Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1445-5994.1993.tb04723.x

4.             Tsuji BT, Rybak MJ, Lau KL, Sakoulas G. Evaluation of Accessory Gene Regulator (agr) Group and Function in the Proclivity towards Vancomycin Intermediate Resistance in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 2007;51(3):1089–91.

5.             Elbarbry F. Vancomycin Dosing and Monitoring: Critical Evaluation of the Current Practice. Eur J Drug Metab Pharmacokinet 2018;43(3):259–68.

6.             Schentag JJ, Strenkoski-Nix LC, Nix DE, Forrest A. Pharmacodynamic Interactions of Antibiotics Alone and in Combination. Clinical Infectious Diseases 1998;27(1):40–6.

7.             Schentag JJ. Understanding and managing microbial resistance in institutional settings. Am J Health Syst Pharm 1995;52(6 Suppl 2):S9-14.

8.             Begg EJ, Barclay ML, Kirkpatrick CJM. The therapeutic monitoring of antimicrobial agents. 1999;8.

9.             Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL. Relationship between Initial Vancomycin Concentration‐Time Profile and Nephrotoxicity among Hospitalized Patients. CLIN INFECT DIS 2009;49(4):507–14.

10.          van Hal SJ, Paterson DL, Lodise TP. Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 Milligrams per Liter. Antimicrobial Agents and Chemotherapy 2013;57(2):734–44.

11.          Bosso JA, Nappi J, Rudisill C, et al. Relationship between Vancomycin Trough Concentrations and Nephrotoxicity: a Prospective Multicenter Trial. Antimicrob Agents Chemother 2011;55(12):5475–9.

12.          Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. International Journal of Antimicrobial Agents 2011;37(2):95–101.

13.          Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Advanced Drug Delivery Reviews 2014;77:50–7.

14.          Prybylski JP. Vancomycin Trough Concentration as a Predictor of Clinical Outcomes in Patients with Staphylococcus aureus Bacteremia: A Meta-analysis of Observational Studies. Pharmacotherapy 2015;35(10):889–98.

15.          Song K-H, Kim HB, Kim H, et al. Impact of area under the concentration–time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia. International Journal of Antimicrobial Agents 2015;46(6):689–95.

16.          Ghosh N, Chavada R, Maley M, van Hal SJ. Impact of source of infection and vancomycin AUC0–24/MICBMD targets on treatment failure in patients with methicillin-resistant Staphylococcus aureus bacteraemia. Clinical Microbiology and Infection 2014;20(12):O1098–105.

17.          Holmes NE, Turnidge JD, Munckhof WJ, et al. Vancomycin AUC/MIC Ratio and 30-Day Mortality in Patients with Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 2013;57(4):1654–63.

18.          Monteiro JF, Hahn SR, Gonçalves J, Fresco P. Vancomycin therapeutic drug monitoring and population pharmacokinetic models in special patient subpopulations. Pharmacol Res Perspect 2018;6(4):e00420.

19.          Neely MN, Youn G, Jones B, et al. Are Vancomycin Trough Concentrations Adequate for Optimal Dosing? Antimicrob Agents Chemother 2014;58(1):309–16.

20.          Turner RB, Kojiro K, Shephard EA, et al. Review and Validation of Bayesian Dose‐Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients. Pharmacotherapy 2018;38(12):1174–83.