1. Vancomycin AUC It’s Easy as 1,2,3!
Brian McCullough, PharmD, BCPS
Assistant Professor
Husson University School of Pharmacy

2. Disclosure
I have nothing to disclose

3. Objectives Pharmacists objectives
Describe vancomycin’s pharmacodynamic activity
Identify the current recommendations for vancomycin dosing
Recognize the proper calculation for area under the curve
Technicians objectives
Name a type of bacteria that is killed by vancomycin
List patient factors that may change how vancomycin is dosed
Recognize the current preferred way to dose vancomycin

4. Where is your institution with AUC dosing?
What are you talking about
We’re contemplating it
We’ve implemented it
We don’t plan to implement any time soon

5. Some terms we’ll discuss today
Population pharmacokinetics
Average values based on clinical trials in a human population
Use caution in practice, population models may not fit your patient!
AUC – area under the curve
MIC – minimum inhibitory concentration
Lowest concentration that inhibits bacterial growth
Murine thigh model – An animal (mouse) model of pharmacokinetics
Gives us a starting point for human trials/dosing

6. Pharmacodynamic principles of antibiotics
Peak:MIC – driven by individual doses
Example: aminoglycosides
Time:MIC – driven by frequency
Example: b-lactams
AUC:MIC – driven by total daily dose
Example: vancomycin
Image adapted from Santos Filho L, et al. Braz J Microbiol 2007;38:

7. Vancomycin
Glycopeptide antibiotic active against Gram positive bacteria
Works by binding to D-ala-D-ala subunit in cell wall
Usually used to treat methicillin-resistant Staphylococcus aureus (MRSA)
Negligible absorption orally
2009 vancomycin guidelines: dose using actual body weight
Some hospitals use a dose cap of 2 or 2.5g
Some hospitals use adjusted body weight
We won’t be discussing body weight
Primarily cleared renally
5-20% biliary excretion
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.
Murphy JE, Clinical Pharmacokinetics 6th Edition 2017.

8. Vancomycin – population Pharmacokinetics
Volume of distribution (Vd) ranges from 0.4 – 1 L/kg
0.7 L/kg most commonly used in practice
a-distribution phase ~ minutes
Protein binding 50-55%
No appreciable metabolism
Elimination half-life is 6 to 12 hours in most patients
Renal elimination comprises most of the overall elimination
Factors that may affect dosing include body weight and kidney function
Image adapted from Accessed 9/26/19
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.

9. AUC:MIC is the best predictor of efficacy
Vancomycin efficacy correlated with AUC:MIC
Most effective with AUC:MIC > 400 for S. aureus
Effective against other bacteria at lower AUC:MIC
Ebert et al. [abstract] ACC, 1987.

10. AUC:MIC for bacteremia
Neely, et al studied vancomycin AUC:MIC for S. aureus bacteremia
Retrospective observational cohort study
Primary outcome – 30-day mortality
AUC:MIC > 373 mg•h/L decreased mortality compared to AUC:MIC < 373 mg•h/L
No difference seen in trough levels between survivors and non-survivors
Holmes NE, et al. Antimicrob Agents Chemother 2013;57:

11. AUC24:MIC for pneumonia
Moise-Broder, et al set out to answer the following questions in patients with pneumonia:
Does AUC24:MIC correlate with efficacy?
Does %time above MIC correlate with efficacy
Does time to bacterial eradication correlate with AUC0→24:MIC?
Does vancomycin differ from other antimicrobials with same AUC0→24:MIC?
Does time to bacterial eradication correlate to clinical efficacy?
AUC calculated using the formula:
In study, calculation correlated well
with measured AUC
Moise-Broder PA, et al. Clin Pharmacokint 2004;43(13):

12. AUC0→24:MIC for pneumonia
Moise-Broder PA, et al. Clin Pharmacokint 2004;43(13):

13. AUC:MIC for endocarditis
One study found a cut-off AUC:MIC ratio < was associated with increased mortality in patients with endocarditis and complicated bacteremia
Retrospective cohort design
Etest was used for MIC testing, which often increases MIC fold compared to traditional methods
Brown J, et al. Antimicrob Agents Chemother 2012;56:634-8.

14. AUC:MIC for all sources of infection
Alosaimy, et al found that persistent bacteremia increased with AUC:MIC < mg•h/L
Retrospective cohort study consisting of skin/soft tissue (39.4%), pneumonia (25.5%), and osteoarticular (16.8%) infections, among others
Patients with AUC24h ≤ were more likely to have PB compared with those with AUC24h > (59.4% and 35.2%, respectively; P = 0.002)
After controlling for age, intensive care stay, and concomitant β-lactam therapy; AUC of ≤ (aOR 2.767, 95% CI 1.212–6.318) and endocarditis (aOR 2.87, 95% CI 1.079–7.638) were independently associated with PB.
Alosaimy, et al. Open Forum Infect Dis 2019;6:S582. [Abstract]

15. If AUC is best, why are we using troughs?

16. Time warp! A look back to 2009
“Trough serum vancomycin concentrations are the most accurate and practical method for monitoring efficacy.”
“Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance. For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC:MIC of 400.”
“There are limited data supporting the safety of sustained trough concentrations of 15–20 mg/L. Clinical judgment should guide the frequency of trough monitoring when the target trough is in this range.”
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.

17. Also from 2009 guidelines
Based on these study results, an AUC/MIC ratio
of ≥400 has been advocated as a target to achieve clinical
effectiveness with vancomycin. Animal studies and limited
human data appear to demonstrate that vancomycin is not
concentration dependent and that the AUC/MIC is a predictive
pharmacokinetic parameter for vancomycin.
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.

18. So why did we choose troughs?
Answer: Convenience
“However, because it can be difficult in the clinical setting to obtain multiple serum vancomycin concentrations to determine the AUC and subsequently calculate the AUC/ MIC, trough serum concentration monitoring, which can be used as a surrogate marker for AUC, is recommended as the most accurate and practical method to monitor vancomycin.”
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.

19. Troughs do not correlate well to AUC
Biagi, et al. J Appl Lab Med 2019;3(4):743-6.

20. Trough > 15 mcg/mL not associated w/ ↓ mortality
Meta-analysis found no benefit for patients with trough > 15 mcg/mL compared to patients with troughs < 15 mcg/mL
Consistent in both prospective and retrospective analyses

21. Vancomycin toxicity Correlated with:
Patients with chronic kidney disease
Concomitant nephrotoxins
Most notably IV contrast dye, aminoglycosides, and piperacillin/tazobactam
Trough levels > 20 mcg/mL
Some studies show toxicity ↑ with trough > 15 mcg/mL
AUC above ~ 700 mg•h/L
Filippone EJ, et al. Clin Pharmacol Ther (3): 459–69.
Suzuki Y, et al. Chemotherapy 2012;58:308–12.

22. AUC-guided therapy ↓ toxicity
Nephrotoxicity lower in AUC-guided group compared to trough-guided group
Corrected for concomitant nephrotoxins, comorbidity, and severity of illness
Main difference was ↓ drug exposure in AUC group
Median troughs of 12.5 mcg/mL produced median AUC of 532 mg•h/L
Finch NA, et al. Antimicrob Chemother 2017;61(12).

23. Ok. Use AUC. But what the heck is AUC?

24. Area under the curve (AUC)
Literally the area under the concentration curve
Approximated in clinical practice
Usually from two data points
More concentration vs. time values = better accuracy
Uses trapezoids to estimate area

25. AUC determination – graph
Blue = AUCinf, yellow = AUCelim
Antimicrob Agents Chemother 1996;40(1):

26. Assumptions with AUC-based dosing
Clearance remains constant
Volume of distribution remains constant
Vancomycin levels are either drawn at steady state or directly after first dose
Steady state will give actual AUC, after first dose will give estimation of steady-state AUC
Calculated AUC approximates actual AUC
Calculated AUC may over- or under-estimate AUC depending on method used
These changes are typically small % of AUC
Pai MP, et al. Adv Drug Deliv Rev 2014;77:50–7.

27. AUC empiric calculations
AUC = dose/Clearance
Clearance is difficult to measure real-time, but can be estimated
Clest = [(CrCl • 0.79) ] • 0.06
Where 0.06 is a correction factor to convert mL/min to L/h
AUCest = dose/[[(CrCl • 0.79) ] • 0.06]
Example: A 45 y.o. M with CrCl 70 mL/min and a dose of 1500 mg IV Q12h
AUCest = 3,000 mg/[[70 mL/min • 0.79) ] • 0.06]
AUCest = 707 mg•L/h

28. You said AUC:MIC. What about MIC?
MOST Staphylococcus aureus vancomycin MIC is less < 1 mcg/mL
This trend holds true in Maine
MIC distribution varies depending on site
If MIC is 2 mcg/mL, required AUC for maximal efficacy is > 800 mg•h/L
Note that this is in the toxic range
Best to find alternatives to vancomycin if MIC > 2 mcg/mL
Take home – assume MIC is 1 mcg/mL, adjust therapeutic plan if MIC > 2 mcg/mL

29. Vancomycin AUC calculations
Linear calculation of AUC
AUC = 0.5(C1 + C2)(t2-t1)
Log-linear or logarithmic trapezoidal calculation of AUC
AUC = [(C1 – C2)/(ln(C1) – ln(C2))] x (t2 – t1)
This can be rewritten as (C1 – C2)/ke
Linear up, log-linear down
Most accurate calculation of vancomycin AUC
Adds together linear interpolation during infusion, log-linear for clearance
Bayesian
Based on population-specific formulas
Advantages – uses population averages, only requires one drug level
Disadvantages – requires a LOT of data, requires software, not every patient fits population
Beyond the scope of this presentation

30. Vancomycin AUC calculation
Each “linear up, log down” segment is calculated for each dosing interval (e.g. 12h interval for Q12h frequency)
Segments are then added up to complete a 24 hour AUC
Ex AUC0→t = AUCinf + AUCelim
AUC0→24 = AUC0→t x 24/t
Where AUCinf is AUC during infusion (linear up), AUCelim is AUC during elimination (log down), t is frequency, and AUC0→24 is daily AUC

31. Important!!! The true peak and true trough must be extrapolated
Example: Levels drawn 1 hour and 11 hours after the end of the infusion are 25 mcg/mL and mL respectively for a dose of 1g Q12h with 1 hour infusion
Ke = ln(C1/C2)/Dt = ln(25 mcg/mL/12.5 mcg/mL)/10 h =
True peak (level at end of infusion) = Cmax/e-ket* where Cmax is measured maximum and t* is time from measured maximum to true peak
Peak = (25 mcg/mL)/e-0.693h-1*1h = 26.8 mcg/mL
True trough = Cmin * e-ket* where t* is time from measured Cmin to actual Cmin
In this case, measured trough = actual trough (11 h after end of 1 h infusion for Q12h drug)

32. Enough talking. Let’s calculate!

33. Example AUC calculation
Vancomycin 1g infused over 1 hour Q12h
At steady state: true peak = 30 mcg/mL, true trough = 10 mcg/mL
AUCinf = 0.5(10 mg/L + 30 mg/L) x (1 h – 0 h) = 20 mg*h/L
AUCelim = (30 mg/L – 10 mg/L)/(ln(30) – ln(10)) x (12 – 1) = 200 mg*h/L
AUC0→12 = AUCinf + AUCelim = 220 mg*h/L
AUC0→24 = AUC0→12 x 2 = 440 mg*h/L

34. Continuous infusion vancomycin
Continuous infusion (CI) has shown to increase target AUC attainment
No benefit in terms of outcomes (mortality, etc)
However, no evidence of harm
CI rate (g/24 hr) = [0.029 × CrCl (mL/min) ] × [target Css × (24/1,000)]
AUC24/MIC = (Css × 24 hr)/MIC
Use this formula for AUC calculation because concentration is flat
Essentially, calculate the area of a rectangle
Murphy JE, Clinical Pharmacokinetics 6th Edition 2017.

35. What we still don’t know
Does serum AUC correlate to efficacy in other deep-seated infections?
Minimal data in meningitis, osteomyelitis, etc.
Can we use a lower target AUC for UTI, skin infections?
Can we really aim for AUC of 200 for MIC of 0.5 mcg/mL?
Selection of resistance with lower trough values?
Is this practical for ALL hospitals? ALL patients?
Should this be reserved with hospitals with robust clinical services?
For AUC, should we use clearance based, or trapezoidal formula?
Guidelines should clarify this

36. Time warp! A look back to 20 minutes ago
“Trough serum vancomycin concentrations are the most accurate and practical method for monitoring efficacy.”
“Minimum serum vancomycin trough concentrations should always be maintained above 10 mg/L to avoid development of resistance. For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L to generate the target AUC:MIC of 400.”
“There are limited data supporting the safety of sustained trough concentrations of 15–20 mg/L. Clinical judgment should guide the frequency of trough monitoring when the target trough is in this range.”
Ryback M, et al. Am J Health-Syst Pharm. 2009; 66:82–98.

37. Conclusion
Body weight and kidney function altar dose and clearance, which influences AUC
Trough based monitoring not evidence-based
AUC:MIC > 400 mg•h/L accurately predicts treatment response
AUC24 above ~ 700 mg•h/L associated with toxicity
Target goal AUC is
Updated vancomycin dosing guidelines will recommend AUC-based dosing in select patients
Particularly those with invasive MRSA infections

38. Helpful AUC conceptual video

39. Questions? Brian McCullough, PharmD, BCPS mcculloughbr@husson.edu
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40. References
Santos Filho L, Kuti JL, Nicolau DP. Employing pharmacokinetic and pharmacodynamic principles to optimize antimicrobial treatment in the face of emerging resistance. Braz J Microbiol ;38:
Ryback 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. Am J Health Syst Pharm 2009 Jan 1;66(1):82-98.
Vancomycin. In Murphy JE, Clinical Pharmacokinetics 6th Edition 2017.
Spruill WJ, Wade WE, DiPiro JT, Blouin RA, and Pruemer JM, Concepts in Clinical Pharmacokinetics 6th Edition 2014.
Vancomycin. In: Bauer LA. eds. Applied Clinical Pharmacokinetics, 3e New York, NY: McGraw-Hill
Ebert S. In vivo cidal activity and pharmacokinetic parameters for vancomycin against methicillin-susceptible and -resistant S. aureus [abstract 439]. In: Program and abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy (New York) Washington, DC American Society for Microbiology (pg.  )
Holmes NE, Turnidge JD, Muckhof WJ, et al. Vancomycin AUC/MIC Ratio and 30-Day Mortality in Patients with Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother ;57:
Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycinand other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokint 2004;43(13):
Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC Ratio in Patients with Complicated Bacteremia and Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus and Its Association with Attributable Mortality during Hospitalization. Antimicrob Agents Chemother Feb;56(2):634-8.
Alosaimy S, Jorgensen SCJ, Lagnf A, et al. Open Forum Infect Dis;6:S582. [Abstract]
Filippone EJ, et al. The nephrotoxicity of vancomycin. Clin Pharmacol Ther (3): 459–69.
Suzuki Y, et al. Is Peak Concentration Needed in Therapeutic Drug Monitoring of Vancomycin? A Pharmacokinetic-Pharmacodynamic Analysis in Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia. Chemotherapy 2012;58:308–12.
Biagi MJ, Butler DA, Wenzler E. AUC-Based Monitoring of Vancomycin: Closing the Therapeutic Window. J Appl Lab Med 2019;3(4):743-6.
Finch NA, Zasowski EJ, Murray KP, et al. Antimicrob Chemother 2017;61(12):e
Pleasants RA, Michalets EL, Williams DM, et al. Pharmacokinetics of vancomycin in adult cystic fibrosis patients. Antimicrob Agents Chemother Jan;40(1):
Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 2014;77:50–7.