Vancomycin Dosing and Monitoring for Adults

Full update November 2022

This FAQ addresses common questions about vancomycin dosing and monitoring, including use of target AUC vs target trough, and differences among pharmacokinetic dosing methods.

Question

Answer/Pertinent Information

What are the target vancomycin levels for documented (or suspected) serious MRSA infections?

  • Aim for 24-hour vancomycin AUC/MICBMD ratio of 400 to 600 mg*h/L for serious MRSA infections
    (e.g., bacteremia, sepsis, endocarditis, pneumonia) [Evidence Level C].1 See “How should vancomycin be monitored?” below for 24-hour AUC/MIC estimation options.
    • An AUC/MIC of 400 to 600 mg*h/L seems to preserve efficacy while minimizing kidney damage.1
    • Lower AUC/MIC levels may promote MRSA resistance or intermediate susceptibility to vancomycin.1
  • Ideally, target AUC/MIC should be achieved within 24 to 48 hours.1
  • The data used to develop this target did NOT include many, if any, of these types of infections:1,17
    • less serious MRSA infections (e.g., non-bacteremic skin/skin structure infections, urinary tract infections).
    • Methicillin-susceptible Staphylococcus aureus (MSSA).
    • coagulase-negative staphylococcus.
    • other organisms.

Why is AUC/MIC monitoring now recommended instead of trough levels for serious MRSA infections?

  • We used to aim for trough concentrations of 15 to 20 mg/L for serious MRSA infections as a surrogate marker for AUC/MICBMD >400 mg*h/L.1 Trough goals of 15 to 20 mg/L are no longer recommended due to lack of safety and efficacy data.1 In addition:1
    • A wide range of concentration versus time profiles (AUCs) can lead to the same trough level.1
    • Trough concentrations of 15 to 20 mg/L often lead to AUC/MIC above the goal of 400 to 600 mg*h/L.16 In fact, about 60% of patients can achieve AUC >400 mg*h/L with a trough <15 mg/L, or even <10 mg/dL.15
  • AUC-guided monitoring is associated with a significant decrease in AKI compared to trough-based dosing.1,5,14
    • The risk of AKI increases with above-goal AUC/MIC, especially when AUC/MIC exceeds 650 to 1,300 mg*h/L.1
    • Even an AUC of 600 mg*h/L was associated with kidney damage in 12.9% of patients in one cohort.11
  • Note that although AUC targets seem to have safety benefits, there are no head-to-head studies showing superior efficacy vs using the trough as a therapeutic target.17

How should vancomycin be initially dosed for serious MRSA infections?

  • Initial doses of 15 to 20 mg/kg (using actual body weight) every eight to 12 hours are reasonable for most patients with normal kidney function. This assumes an MICBMD≤1 mg/L.1 (See the row “What do you need to know about MICs?” below for more about MICs.)
  • Can consider using a loading dose of 20 to 35 mg/kg (using actual body weight) to achieve target doses more rapidly in patients with serious MRSA infections, especially those who are critically ill or receiving kidney replacement therapy.1
    • Loading doses should NOT exceed 3,000 mg.1

How should vancomycin be monitored?

  • Check vancomycin levels for all patients with serious infections, at risk for kidney damage, with unstable kidney function, or receiving vancomycin for >3 to 5 days.1 Use clinical judgment to decide how often to check vancomycin levels.1
    • For unstable patients or patients with end-stage kidney disease, daily monitoring may be needed.1
    • For stable patients, weekly monitoring may suffice.1
  • Work to gain buy-in from nursing, lab, and infectious disease staff. New monitoring will be a change in practice and may increase workload.
  • Generally, check two post-dose levels near steady-state (earlier levels [within the first 24 to 48 hours] can be drawn if using Bayesian software), preferably during the same dosing interval.1 Levels should be drawn at least one hour AFTER the end of the infusion.1 The second level can be a random level or a trough. Ideally ensure at least one half-life between levels.4 Then use one of the following calculation methods:
    • Use these levels to estimate the AUC/MIC using first-order kinetic equations (see example below).OR
    • Use the levels in a Bayesian software program (if available at your institution or online) to estimate the AUC/MIC.This approach can be used with levels that are not steady-state and could therefore achieve dose optimization more quickly than the former approach.1
  • Using only one level is not preferred, particularly in special populations.1,18
    • In general adult patients with stable kidney function, a single steady-state level drawn at least 60 minutes after the end of the infusion and an estimated Vd (0.29[age] + 0.33[actual weight in kg] + 11) plugged into an online calculator (VancoPK.com).1,10
      • This Vd equation should NOT be used for patients expected to have large Vd (e.g., critical care patients).10
    • If not at steady state, use a Bayesian method.1

What are differences between using Bayesian software and doing manual pharmacokinetic calculations when monitoring vancomycin?

Consideration

Manual Pharmacokinetic Calculations1

Bayesian Software (e.g., DoseMeRX, PrecisePK)1

Cost

  • free
  • hospitals may have to purchase to use

When can levels be checked?

  • steady state levels preferred
  • within 24 to 48 hours of first dose (therefore may allow for earlier dose optimization).

How many levels are needed?

  • minimum of two
  • two preferred. Can use one level in some patients (see below). Calculations using one level may not be accurate for some patients (e.g., obese, critically ill, unstable kidney function).1

Other considerations

  • Can consider developing a site-specific spread sheet pre-populated with equations to save time.
  • Can consider combining with free online dosing calculators (ensuring validation).
  • uses population-based pharmacokinetic data.
  • can integrate creatinine clearance into pharmacokinetic models.
  • not proven superior to other methods.18

What do you need to know about MICs?

  • Determining the MIC using BMD is the gold standard, but today most labs use automated MIC testing (e.g., VitekMicroscan). This automated testing is less precise and many reported MICs of 0.5 or 2 mg/L for MRSA are actually 1 mg/L.1,4 
    • Weigh the potential risk of toxicity and benefits of using higher doses if the MIC is documented to be >1 mg/L.
    • There are no data available to recommend reducing AUC/MIC goal if the MIC is <1 mg/L.
    • Can consider an alternate antibiotic if an MIC of 2 mg/L is suspected to be true (i.e., patient’s clinical status is worsening despite adequate dosing).1 AUC/MIC of 800 mg*h/L or more would likely be required for MICs this high, increasing risk of kidney damage.4

How are patient specific AUC/MICs calculated using first-order kinetic equations?

Definitions used in calculations:2 AUCinf= AUC during infusion; AUCelim = AUC during elimination; C1 = measured peak; C2 = measured trough; Cmax = true peak; Cmin = true trough; t1 = time C1 was drawn; t2 = time C2 was drawn; tau = dosing interval; tinf = infusion duration; ∆t = the time between the end of the infusion and the level being drawn

Formulas (for use assuming steady state levels):2

  • k = (ln [C1/C2])/(t2 – t1)
  • Cmax = C1/e-k∆t
  • Cmin = Cmax(e-k[tau-tinf])
  • AUCinf = tinf x ([Cmax + Cmin]/2)
  • AUCelim = (Cmax – Cmin)/k
  • AUC24 = (AUCinf + AUCelim) x 24/tau
  • AUC/MIC = AUC24/MIC
  • Note that these calculations assume steady state. Some facilities that don’t have Bayesian software may use “first-dose” kinetic calculations (drawing two levels after the first dose) in certain patients (e.g., critically ill, obese) to determine patient-specific parameters to help determine a regimen.
  • Example calculation in a patient receiving 1,500 mg IV every 12 hours who has a measured peak (C1) and measured trough (C2): C1 = 21.6 mg/L; C2 = 9 mg/L; t2 = 6 pm; t1 = 8:30 am; tau = 12; tinf = 1.5 hours; ∆t = 1 hour
    • k = (ln [C1/C2])/(t2 – t1) = (ln [21.6/9])/(6 pm – 8:30 am) = ln (2.4)/9.5 = (0.87/9.5) = 0.091 hr-1
    • Cmax = C1/e-k∆t= 21.6/e-(0.091)(1) = 21.6/e-0.091 = 21.6/0.91 = 23.7 mg/L
    • Cmin = Cmax(e-k [tau-tinf]) = 23.7(e-0.091[12-1.5]) = 23.7(e-0.96) = 23.7(0.38) = 9 mg/L
    • AUCinf = tinf x ([Cmax + Cmin]/2) = 1.5 x ([23.7 +9]/2) = 1.5 x ([32.7]/2) = 1.5 x 16.35 = 24.525
    • AUCelim = (Cmax – Cmin)/k = (23.7 – 9)/0.091 = 14.7/0.091 = 161.5
    • AUC24 = (AUCinf + AUCelim) x 24/tau = (24.525+ 161.5) x 24/12 = 186.025 x 2 = 372
    • AUC/MIC = AUC24/MIC = 372/1 mg/L (assuming MICBMD = 1) = 372 mg*h/L (This is below the desired AUC/MIC goal of 400 to 600 and the dose will need to be adjusted [see below].)

Are online vancomycin dosing calculators accurate?

  • Using two steady-state levels, VancoPK, ClinCalc, TDMx, and DMC agree with the Sawchuk-Zaske method
    (a guideline-recommended method), 63.3% to 78.6% of the time in regard to classifying patients as having sub- or supratherapeutic AUCs. AUCs computed by the calculators were 89% to 110% of the AUCs values calculated using the Sawchuk-Zaske method.12
  • Calculators vary in their ability to adjust to special populations (e.g., amputees, trauma patients, obese patients).12
  • Some pharmacists note differences in ease of use among online calculators.12
  • At steady-state, calculators using Bayesian methods (e.g., ClinCalc) do not seem superior to other methods.12,18

How should doses be adjusted to achieve AUC/MIC goals?

  • For patients with stable kidney function and when NOT changing the dosing interval, use the following equation to calculate new doses if patients are not at goal AUC/MIC based on steady state calculations:
    new total daily dose = current total daily dose x (AUC24 [desired]/AUC24 [calculated]).7
  • Example calculation for a patient that is receiving vancomycin 1,500 mg every 12 hours with a steady state calculated AUC24= 372 mg*h/L. Assume the goal AUC/MIC is 500 mg*h/L and the MIC = 1.
    • New total daily dose = current total daily dose x (AUC24 [desired]/AUC24 [calculated]).
      New total daily dose = 3,000 mg x (500 mg*h/L / 372 mg*h/L) = 3,000 mg x (1.34) = 4,020 mg.
    • If rounding to the nearest 250 mg/dose a reasonable new dosing regimen is 2,000 mg every 12 hours.
  • There may be cases where the dosing interval must be adjusted, or the adjustment is more complex due to changing kidney function, reporting of a non-steady-state blood level, etc.In these cases, use patient-specific information
    (e.g., kidney function, vancomycin clearance) and calculations to determine a new dose.
  • After dosage changes, check follow-up vancomycin levels to be sure goal AUC/MIC is achieved.

What are special dosing/monitoring considerations in patients who are obese?

  • To avoid overshooting in obese patients, lower mg/kg dosing is likely necessary. This is because volume of distribution (Vd) increases with body weight but not proportionately, so Vd in liters/kg is often lower in obese patients compared to non-obese patients. Calculate initial doses using population pharmacokinetics. Generally, avoid empiric maintenance doses >4,500 mg per day.1
  • Monitor vancomycin levels early and more frequently in patients with initial total daily doses >4,000 mg.1
  • If using a loading dose, start with a slightly lower loading dose of 20 to 25 mg/kg (based on actual body weight) limiting to maximum loading dose of 3,000 mg.1

What are special dosing/monitoring considerations in patients with acute kidney injury?

  • Vancomycin clearance is unpredictable and often significantly reduced in patients with AKI.4
  • Can consider continuing trough-based dosing or redosing vancomycin when levels fall to about 15 mg/L in patients with AKI.4 There are not data to support AUC/MIC monitoring in patients with AKI.1
  • Expect to use an initial dose of about 15 mg/kg.8 Check a level within 24 hours of the initial dose and adjust future doses based on levels.8 Generally, avoid redosing vancomycin until the level falls to about 15 mg/L.8

What are special dosing/monitoring considerations in patients receiving kidney replacement therapy?

  • Maintenance vancomycin doses can be difficult to determine in patients receiving kidney replacement therapy
    (i.e., intermittent hemodialysis, hybrid hemodialysis, continuous kidney replacement therapy). Vancomycin clearance varies based on the timing, type, and duration of dialysis; the permeability of the dialyzer; and flow rates.1,4
  • Can consider continuing trough-based dosing or redosing vancomycin when levels fall to about 15 mg/L in patients receiving kidney replacement therapy.4 There are not strong data to support AUC/MIC monitoring in patients receiving kidney replacement therapy.1,4 However, in patients receiving intermittent dialysis, pre-dialysis vancomycin levels between 15 and 20 mg/L may correspond with an AUC/MICBMD of 400 to 600 mg*h/L in the last 24 hours.1
  • Vancomycin is cleared more readily with continuous kidney replacement therapy compared to intermittent hemodialysis. Therefore, expect more frequent dosing in patients receiving continuous kidney replacement therapy (e.g., every 12 hours, every 24 hours).1

How should vancomycin be dosed/monitored in patients with MRSA meningitis?

  • More data are needed to provide high-quality, evidence-based recommendations for dosing and monitoring vancomycin in patients with MRSA meningitis.
  • Previous guidelines recommended using troughs of 15 to 20 mg/L for patients with meningitis, to ensure central nervous system (CNS) penetration. However, this recommendation was based on low quality data.3,4
  • The most recent vancomycin guidelines recommend using 24-hour vancomycin AUC/MICBMD ratio of 400 to 600 mg*h/L for patients with MRSA meningitis. There were not data for patients with meningitis in the development of these targets.1,4

How should vancomycin be dosed/monitored in patients with less severe MRSA infections or in infections caused by other organisms?

  • It is not clear in the latest vancomycin guidelines how to address vancomycin use in less severe infections (e.g., urinary tract infections, skin/soft tissue infections) or infections caused by other organisms. More data are needed before evidence-based AUC/MIC monitoring can be recommended in these patients.
    • Some institutions may continue to use trough-based dosing with goals of about 10 to 15 mg/L for less severe MRSA infections.3Other facilities may use AUC/MIC-guided dosing to keep things simple.
    • It is expected that targeting an AUC/MIC of 400 to 600 mg*h/L will effectively treat infections caused by other gram-positive organisms, as MRSA is considered the most invasive of the bacteria treated with vancomycin.4 However, practice antibiotic stewardship during antibiotic selection.

How should patients be dosed/monitored who are discharged on vancomycin?

  • If possible, continue to use two levels and AUC/MIC-guided dosing for patients discharged home on vancomycin.1 However, drawing two levels for AUC/MIC-guided dosing may not be practical for some home health agencies.
  • Though trough-only monitoring is no longer recommended for patients with serious MRSA infections, after achieving the target AUC/MIC at steady state, some protocols may suggest only checking trough at least weekly until completion of therapy, especially in stable patients with stable kidney function.9
    • For example, if you get an AUC/MIC of 500 mg*h/L when the patient had a measured peak of 33 mg/L and trough of 11 mg/L, troughs of about 11 mg/L from that point forward (assuming stable doses, dosing intervals, kidney function, etc) are likely to produce an AUC/MIC of about 500 mg*h/L.
  • Be aware that increasing the dose to achieve the target trough with a longer dosing interval can result in excess vancomycin exposure (i.e., AUC >600 mg*h/L).13

Abbreviations: AKI = acute kidney injury; AUC = area under the serum drug concentration-versus-time curve; BMD = broth microdilution; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; Vd = volume of distribution.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

References

  1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by 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. Am J Health Syst Pharm. 2020 May 19;77(11):835-864.
  2. ClinCalc. Vancomycin calculator. https://clincalc.com/Vancomycin/?example. (Accessed October 8, 2022).
  3. 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. Am J Health Syst Pharm. 2009 Jan 1;66(1):82-98. Erratum in: Am J Health Syst Pharm. 2009 May 15;66(10):887.
  4. Heil EL, Claeys KC, Mynatt RP, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health Syst Pharm. 2018 Dec 15;75(24):1986-1995.
  5. Lodise TP, Rosenkranz SL, Finnemeyer M, et al. The Emperor's New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE). Clin Infect Dis. 2020 Apr 10;70(8):1536-1545.
  6. Karakonstantis S, Kalemaki D. Evaluation and management of Staphylococcus aureus bacteriuria: an updated review. Infection. 2018 Jun;46(3):293-301.
  7. Berry T, Bennett N. 2019 ASHP competency assessment module: vancomycin dosing and monitoring. http://elearning.ashp.org/Files/Org/c52850f8e2e14ca8b14b32c98105999d/site/2019_ASHP_Competency_Assessment_Module_-_frontmatter.pdf. (Accessed October 27, 2022).
  8. Stanford Health Care. SHC vancomycin dosing guide. March 2022. https://med.stanford.edu/bugsanddrugs/guidebook/_jcr_content/main.html. (Accessed October 8, 2022).
  9. Agency for Healthcare Research and Quality. Discharged with IV antibiotics: when issues arise, who manages complications? February 2020. https://psnet.ahrq.gov/web-mm/discharged-iv-antibiotics-when-issues-arise-who-manages-complications. (Accessed October 8, 2022).
  10. Fewel N. Vancomycin area under the curves estimated with pharmacokinetic equations using trough-only data. J Clin Pharm Ther. 2021 Oct;46(5):1426-1432.
  11. Suzuki A, Hamada Y, Ikeda H, et al. Comparison of trough concentration and area under the curve of vancomycin associated with the incidence of nephrotoxicity and predictors of a high trough level. J Infect Chemother. 2021 Mar;27(3):455-460.
  12. Belz SN, Seabury RW, Steele JM, et al. Accuracy of 4 Free Online Dosing Calculators in Predicting the Vancomycin Area Under the Concentration-Time Curve Calculated Using a 2-Point Pharmacokinetic Approach. Ann Pharmacother. 2022 Aug 18:10600280221117256. doi: 10.1177/10600280221117256.
  13. Nix DE, Davis LE, Matthias KR. The relationship of vancomycin 24-hour AUC and trough concentration. Am J Health Syst Pharm. 2022 Mar 21;79(7):534-539.
  14. Abdelmessih E, Patel N, Vekaria J, et al. Vancomycin area under the curve versus trough only guided dosing and the risk of acute kidney injury: Systematic review and meta-analysis. Pharmacotherapy. 2022 Sep;42(9):741-753.
  15. Neely MN, Kato L, Youn G, Kraler et al. Prospective Trial on the Use of Trough Concentration versus Area under the Curve To Determine Therapeutic Vancomycin Dosing. Antimicrob Agents Chemother. 2018 Jan 25;62(2):e02042-17. doi: 10.1128/AAC.02042-17.
  16. Lodise TP, Drusano G. Vancomycin Area Under the Curve-Guided Dosing and Monitoring for Adult and Pediatric Patients With Suspected or Documented Serious Methicillin-Resistant Staphylococcus aureus Infections: Putting the Safety of Our Patients First. Clin Infect Dis. 2021 May 4;72(9):1497-1501.
  17. Jorgensen SCJ, Spellberg B, Shorr AF, Wright WF. Should Therapeutic Drug Monitoring Based on the Vancomycin Area Under the Concentration-Time Curve Be Standard for Serious Methicillin-Resistant Staphylococcus aureus Infections? - No. Clin Infect Dis. 2021 May 4;72(9):1502-1506.
  18. Olney KB, Wallace KL, Mynatt RP, et al. Comparison of Bayesian-derived and first-order analytic equations for calculation of vancomycin area under the curve. Pharmacotherapy. 2022 Apr;42(4):284-291.

Cite this document as follows: Clinical Resource, Vancomycin Dosing and Monitoring for Adults. Hospital Pharmacist’s Letter/Pharmacy Technician’s Letter. November 2022. [381121]



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