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# Vancomycin Initial Dosing

# Dose Adjustments by Trough

# Dose Adjustments by Two Levels

# Peak after single dose, and Time from C1 to goal trough

**Description of Calculators**

- Vancomycin initial dosing calculator
- First, ideal body weight (IBW) is determined:
- IBW for men = 50 kg + 2.3(height – 60 inches)
- IBW for women = 45.5 kg + 2.3(height – 60 inches)

- Next, patient data is evaluated for obesity, defined as: actual BW/ IBW ≥ 130%. The calculator uses the Bauer method for estimating creatinine clearance (CrCl) depending on obesity status:
^{1}- For non-obese patients CrCl is calculated using the Cockcroft-Gault equation
^{2}- CrCl = [(140 – age) actual BW] / (72 x SCr) *0.85 if female

- For obese patients CrCl is calculated by the Salazar-Corcoran equation
^{3}- CrCl for men = (137 – age) [(0.285 x weight(kg)) + (12.1 x height(meters
^{2}))] / (51 x SCr) - CrCl for women = (146 – age) [(0.287 x weight(kg)) + (9.74 x height(meters
^{2})] / (60 x SCr)

- CrCl for men = (137 – age) [(0.285 x weight(kg)) + (12.1 x height(meters

- For non-obese patients CrCl is calculated using the Cockcroft-Gault equation
- Vancomycin clearance (CLvanco) is then calculated using the Bauer method:
- CLvanco = [(0.695 x CrCl/ actual BW) + 0.05] (actual BW x 0.06)

- Volume of distribution (V) is the ‘fudge factor’ of vanco dosing. We don’t need to know a true V, we just need a method for estimating V that works well for calculating sensible doses for non-obese and extremely obese patients.
- For patients who weigh up to their IBW, V = 0.7 L/kg of actual BW
- For non-obese patients V has a wide range of about 0.5-1.0 L/kg of actual BW

- For patients who weigh more than their IBW, V is estimated using an adjusted BW equation: V = 0.7 (IBW + 0.5 (actual BW – IBW)
- Estimation of V has important implications. In the initial dosing calculator V is used to calculate the elimination rate constant (K) based on the equation K = CLvanco/ V. K is then used to calculate half-life: T
_{1/2}= 0.693/ K. Also, V and K are used to calculate the dose and dosing interval. Note that the AUC24 calculation is not affected by V in the initial dosing calculator because AUC24 = daily dose/CLvanco, where CLvanco is estimated using BW and CrCl (see equation above). So the AUC24 helps to assess the calculated dose rather than relying on the predicated trough alone. V is very important when estimating AUC24 based on a measured trough concentration, however, because the equation for AUC24 = daily dose/(K*V) when K is calculated based on a measured trough. - Many different methods are used for estimating V in obese patients. This calculator formally used the Bauer method which estimated V as 0.7 L/kg of IBW for obese patients, but this underestimated V which overestimated K, etc. Although Bauer’s method works well for calculating initial doses, sometimes doses would be very low, like 750mg q8h for a 120 kg patient (only 6.25 mg/kg/dose). Also, a small V may overestimate the AUC24 based on a measured trough in the ‘Dose adjustment by trough’ calculator. On the other hand, when actual BW is used to estimate V using 0.7 L/kg for obese patients, it results in very large doses given less frequently, and may underestimate the AUC24 based on trough. The approach used by this calculator for obese patients is loosely based on Adane ED et al (Pharmacotherapy, 2015) who found that V equals about 0.51 L/kg of actual BW or about 0.76 L/kg of adjusted BW in extremely obese patients (median BW was 147.9 kg).
^{4}The calculator method for V works well for estimating initial doses and AUC24 in the dose adjustment by trough calculator.

- Estimation of V has important implications. In the initial dosing calculator V is used to calculate the elimination rate constant (K) based on the equation K = CLvanco/ V. K is then used to calculate half-life: T

- For patients who weigh up to their IBW, V = 0.7 L/kg of actual BW
- Dosing interval (T): T = Ln (Peak/ Trough)/ K
- Dosing intervals are rounded to the nearest 8, 12, 18, 24, 36, 48, and 72 hours.

- Dose = (Peak*V)(1 – e
^{–K*T})- CrCl is capped at 160 mL/min for patients <60 yrs old, which results in initial doses being capped at 1500 mg every 8 hours in most cases. Consider reserving empiric maintenance doses of 1500 mg q8h for patients <55 years old, >110 kg, with CrCl >150 mL/min.
- For non-obese patients consider limiting empiric maintenance doses to about 17.5 mg/kg q8h.
- Doses are capped at 2,000 mg.

- Using lower doses more frequently helps to reduce the daily dose requirement while maintaining troughs and AUC24 within goal range because the dosing interval greatly affects trough levels while the dose greatly affects peak levels. A large meta-analysis suggested that a constant vancomycin concentration of 25 mcg/mL (AUC24 of 600 mg*hr/L) through continuous infusion is less nephrotoxic than standard intermittent dosing.
^{5}The AUC24 is probably a better measure for assessing the risk of nephrotoxicity than trough levels. - Peak = Dose [1 – e
^{–K*ti}] / [(K*V*ti) (1 – e^{-K*T})]- Goal peaks: less than about 45 mcg/mL.

- Infusion time (ti): ti = 1000 mg/hr
- 1000 mg/hr is generally considered the maximum infusion rate. Infusion-related reactions occur in about 1-5% of patients and may include flushing, pruritus, erythema, rash, and hypotension. Symptoms are often related to the infusion rate and are sometimes referred to as red man syndrome because they often involve the face, neck, and upper torso. Symptoms are believed to result from non-immunologic histamine release from mast cell activation, but some patients could have a true allergic reaction to vancomycin. If any symptoms occur, stop the infusion and contact a physician. For mild symptoms, providers may slow the infusion rate to 750 mg/hr (12.5 mg/min), and/or premedicate with antihistamines to prevent recurrence.
- If vancomycin is ordered by a pharmacy consult, consider attaching a nursing text order to the consult to improve communication and management of infusion reactions.
- To reduce the risk of infusion-related reactions, some hospitals use standardized infusion rates at 750 mg/hour or keep rates ≤ 15 mg/min. Infusion rates of 1000 mg/hour can still be used to estimate dosage calculations.

- Trough = Peak*e
^{-K (T – ti)}- For patients with normal renal function, troughs are usually drawn prior to the 4th or 5th dose or within 36 hours from the loading dose. Full steady-state should occur after 4-5 half-lives. For patients with chronic kidney disease, troughs are drawn within 48 hours from the loading dose to assess therapy; waiting for the 4th dose may delay the time to reach goal.

- Loading dose = V * Peak
_{SS}- Loading doses help to decrease the time to attain effective vancomycin concentrations.
- This equation is based upon administration of the loading dose as the first dose on the maintenance dosing schedule.
- Adjust loading doses as needed so maintenance doses may be scheduled around convenient (morning) lab times.
- Loading doses are capped at 2,500 mg.

- The ratio of the 24-hour area under the concentration-time curve to the MIC of an organism:
- AUC
_{24}/MIC = [(total daily dose)/ CLvanco]/ MIC

- AUC

- First, ideal body weight (IBW) is determined:
- Dose adjustments based on a trough calculator
- First, K is estimated using this equation:
- K = Ln [((dose/ V) + Trough)/ Trough]/ [(time to trough + T)/2]

- Next, iteration is used to improve precision of K so that K can be used in the following equation to calculate the measured trough:
^{6}- Trough = [(dose/V)* e
^{-K*(time to trough)}]/ (1 – e^{-K*T})- Use the population estimate for V from the initial dosing calculations.

- Trough = [(dose/V)* e
- After K is calculated, measured troughs can be extrapolated:
- Trough drawn early:
- Extrapolated trough = Measured trough *e
^{-K*t}

- Extrapolated trough = Measured trough *e
- Trough drawn late:
- Extrapolated trough = Measured trough/ e
^{-K*t}

- Extrapolated trough = Measured trough/ e

- Trough drawn early:

- First, K is estimated using this equation:
- Dose adjustments based on two levels: K = Ln (C1/C2)/ ∆t
- This calculator may be used to calculate a dose based on two random levels, as long as no vancomycin is given between the two levels.
- Since vancomycin peaks are not measured in clinical practice, use the population estimate for V from the initial dosing calculations. V can be calculated directly if the time of a true peak is known (see the aminoglycoside dose adjustment calculator), but vancomycin is given over various infusion times and has 2-phase distribution which makes calculations of V prone to error.

- AUC
_{24}/MIC = [(total daily dose)/ (V*K)]/ MIC- Besides this classical equation, other methods include the Moise-Broder equation, log-linear trapezoidal rule, and Bayesian methods.
^{1,7} - Using a steady-state trough to calculate the AUC
_{24 }is the most practical way of estimating vancomycin exposure. - Troughs do not correlate well with the AUC
_{24}, because troughs largely depend on dosing intervals whereas the AUC_{24}is calculated based on total daily dose and clearance. For example, a trough may be similar for a dose of 1,750 mg every 12 hours compared to a dose of 1000 mg every 8 hours, but the peak and AUC_{24}are higher for the dose of 1,750 mg every 12 hours. Acute kidney injury (AKI) is a well-known potential adverse effect of vancomycin. An AUC_{24}of 700 mg*hr/L represents a conservative upper level of safe vancomycin exposure with minimal risk of nephrotoxicity.^{9} - Goal AUC
_{24}/MIC ratios have not been determined for coag-negative staph or Enterococcus which more often have higher vancomycin MICs compared to*S. aureus*. An AUC_{24}/MIC ratio of at least 400 has been suggested to treat*S. aureus*infections such as bacteremia, pneumonia, and complicated skin and soft tissue infections.^{7-9}When a vancomycin MIC = 1 mg/L, a trough of 13 to 15 mcg/mL is often adequate to achieve the goal AUC_{24}/MIC ratio. When a vancomycin MIC = 0.5 mg/L, using a goal trough of at least 10 mcg/mL may help to prevent selection of vancomycin-intermediate*S. aureus*(VISA). For hard to penetrate*S. aureus*infections like CNS infections, endocarditis, and osteomyelitis, using higher doses to target a trough range of 15-20 mcg/mL may improve drug delivery at the infection site, even with an MIC of 0.5 mg/L. When*S. aureus*has a vancomycin MIC ≥ 2 mg/L, targeting an AUC_{24}/MIC ratio >400 begins to noticeably increase toxicity, so providers should consider switching to a different antibiotic.

- Besides this classical equation, other methods include the Moise-Broder equation, log-linear trapezoidal rule, and Bayesian methods.
- Time from C1 to C2
- C2 = C1*e
^{-K*t} - This calculator may be used to determine the number of hours from a supra-therapeutic vancomycin level (C1) to a therapeutic level (C2).

- C2 = C1*e
- Peak after a single dose
- ∆C = Dose/ V
- This calculator estimates a peak after a single dose, taking into account a vancomycin serum level prior to the dose.

**Symbol Key:**

- AUC
_{24}/MIC = The ratio of the 24-hour area under the concentration-time curve to the MIC of an organism - C1 and C2: C1 occurs before C2. Sometimes C1 and C2 are referred to as Cmax and Cmin, but the terms Cmax and Cmin usually refer to true peak and true trough levels.
- CLvanco = Vancomycin clearance
- CrCl = Creatinine clearance
- IBW = Ideal body weight
- K = Elimination rate constant
- PK = Pharmacokinetic
- SCr = Serum creatinine
- T
_{1/2}= half-life - ti = infusion time (hrs)
- T = dosing interval (hrs)
- V = Volume of distribution

**References:**

- Bauer LA. Vancomycin. In: Applied Clinical Pharmacokinetics, 3rd Ed. New York: McGraw Hill, 2014:197-213,241-243.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.
*Nephron**.*1976;16(1):31-41 - Salazar DE, Corcoran GB: Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass.
*Am J Med*. 1988;84:1053–1060. - Adane ED, Herald M, Koura F. Pharmacokinetics of vancomycin in extremely obese patients with suspected or confirmed
*Staphylococcus aureus*infections.*Pharmacotherapy.*2015;35(2):127-139 - Cataldo MA, Tacconelli E, Grilli E,
*et al*. Continuous versus intermittent infusion of vancomycin for the treatment of gram-positive infections: systematic review and meta-analysis.*J Antimicrob Chemother*. 2012;67:17-24 - Ambrose PJ, Winter ME. In: Winter ME. Basic clinical pharmacokinetics, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004: Equation on page 470.
- Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with
*Staphylococcus aureus*lower respiratory tract infections.*Clin Pharmacokinet.*2004;43:925–942 - 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):889–898 - Neely MN, Youn G, Jones B,
*et al.*Are vancomycin trough concentrations adequate for optimal dosing?*Antimicrob Agents Chemother.*2014;58(1):309-16. - Fewel NP. Comparison of open-access vancomycin dosing websites.
*J Clin Pharm Ther.*2016 Oct.

**Downloads:**

Vancomycin-Monitoring-Form.doc

Vancomycin-Monitoring-Form.pdf

**Inappropriate Populations:** This calculator is NOT appropriate for the following patient populations or those who require a higher degree of clinical judgment: < 18 years old, unstable renal function, severe renal impairment (CrCl <25 mL/min), hemodialysis, or hematological malignancies.

**IDMS:** The Cockcroft-Gault and Salazar-Corcoran equations have not been updated for use with the serum creatinine methods traceable to IDMS. Use with IDMS-traceable serum creatinine methods may overestimate renal function; use with caution.

**Disclaimer:** The author and contributors make no claims of the accuracy of the information contained herein; these suggested doses are not a substitute for clinical judgment. The persons involved in the preparation of this program shall not be liable for the use of or reliance upon this material.