Vancomycin Pharmacokinetic Information, Dosing Calculators, and Pharmacokinetic Analyses

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Vancomycin Dosing Tools
Vancomycin Non-Bayesian Trough Based Dosing Charts: Overview of Dosing Charts,  Vancomycin Dosing Chart I & Vancomycin Dosing Chart II
Vancomycin Non-Bayesian AUC Dosing Calculator and Data Fitting For Troughs, Web-Based
Vancomycin Non-Bayesian AUC Dosing Calculator and Data Fitting for a Peak and Trough,Web-Based
Vancomycin Bayesian AUC Dosing Calculator For Steady State Levels Using a Peak and Trough, Downloadable Excel File

Vancomycin Bayesian AUC Dosing Calculator and Data Fitting For Steady-State or Non-Steady State Levels Using A Simplex Non-Linear Data Fitting Algorithm With Database Connectivity Web-Based
Registration is required to use this application. Registration and program use are free. Registered users may save, retrieve, and update data in a database including the following: patient demographic data, dosing, serum level, and serum creatinine history.  Patient data is stored using a user supplied HIPPA compliant identifier. Patient names are not to be used. The patient's fourteen most recent saved doses, levels, and serum creatinines may be retrieved and more data can be added when fitting the patients current serum levels. Up to 30 doses, levels and serum creatinines can be included in the data fitting. Data fittings may be Bayesian or Non-Bayesian. Volume of distribution and clearance or just clearance can be determined during data fitting. Changes in serum creatinine may be incorporated in the data fitting if desired.  Entered data is only available to the entering user so other users may not see the user's data. Users may download an Excel compatible CVS file of their patient data fittings to compare predicted versus actual levels and to perform other data analyses.

Vancomycin Pharmacokinetic Dosing Information
Spectrum of activity: Most aerobic and anaerobic gram-positive cocci and bacilli including staphylococcal and enterococcus infections, most often used for methicillin-resistant staphylococci and for patients allergic to cephalosporin such as cefazolin. Vancomycin is bactericidal with time-depend killing, but bacteriostatic for most strains of enterococci.  Staph Aureus MIC < 1 are associated with better outcomes than MIC < 2.
Toxicity: Nephrotoxicity rates of 5% to 15%; when combined with aminoglycosides the rate may be as high as 25-35%. Nephrotoxicity has been associated with an AUC > 600 mg/L/Day. As troughs incrementally increased from 10 mcg/ml to 15 mcg/ml,  20 mcg/ml, and 25 mcg/ml there is an incremental increase in renal dysfunction. AUC dosing decreases the risk of acute kidney injury by approximately 50% as compared to trough monitoring.
Bioavailability (F): Oral absorption is less than 5% if the bowel is non-inflamed, administered IV for systemic and urinary infections.
Fraction IV: 1
Salt: 1
Protein binding: 30-55% normal, 20% in ESRD
Vd: 0.65 L/kg Total Body Weight, 0.72-0.9 L/kg in ESRD
Cl: is similar to creatinine clearance with a small amount of non-renal elimination
K:  (0.00107*Clcr(ml/min/1.73 meters²) + 0.0052; normalization of creatinine clearance minimizes bias due to patients with low or high body weight. If creatinine clearance is not normalized heavy patients will receive too high of a dose and small patients will receive too low of a dose, see MUEs below.
T' (Infusion period):  1-2 hour (15 mg/minute to prevent red man syndrome - flushing, itching, tachycardia, tingling, and rash on upper body)
Usual Interval:  every 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours
Usual Dose: Load: 20-25 mg/kg,  Maintenance: 15 mg/kg of total body weight. Loading dose maximum of 3 grams. Higher mortality rates are associated with non-attainment of adequate an AUC in the first 24 hours for MRSA blood stream infections.
Low Flux Hemodialysis: approximately 8% removed during a dialysis session, no supplemental dose is needed after dialysis.
High Flux Hemodialysis Dosing:  Loading dose for high flux dialyzer: 25 mg/kg if not administered during dialysis or 35 mg/kg if administered during dialysis, based on totally body weight, capped at 3000 mg. Maintenance Dose: 750-1000 mg after each HD, 1000-1250 mg if administer during dialysis, depending on the severity of infection and serum level desired. Without an adequate loading dose, it will take more than two weeks before levels stabilize.  Approximately 30-46% of the administered dose is extracted or removed if administered during dialysis. If dosed during HD session a dose 13-34% higher than post HD dosing may be required.  Goal troughs of 15-20 mcg/ml give AUCs ~ 400 - 600 mg*day/Liter for most patient weights and are recommended in the guidelines. Higher troughs produced AUCs above 600 mg*Day/L with the potential to impact residual renal function. Quality of life is better in HD patients with higher residual renal function. Overdosing or excessive AUCs should be avoided to minimize the impact on residual renal function.  Trough goals for hemodialysis dialysis patients are pre-dialysis levels as the post-dialysis level is brief and cannot easily be incorporated into the risk of toxicity and adds little to the AUC. Length of dialysis, HD clearance (filter type, blood flow), residual renal function, and frequency of dialysis impact maintenance dose requirements. More frequent dialysis schedules (daily) require lower maintenance doses to obtain the same trough as compared to three times a week dialysis sessions as less renal elimination occurs.
CAPD Peritonitis: Intermittent dosing 15-30 mg/kg in overnight dwell re-dose when the level is above 15 mcg/ml (every 3-5 days). Up to 90% of the dose may be absorbed when peritonitis is present. Goal serum level is 15-20 mcg/ml. The first trough should be drawn 3 days after the first dose. Duration of therapy: coagulase negative-staphylococci 14 days, S. aureus 21 days, Enterococci 21 days (severe infections add aminoglycoside 0.6 mg/kg/day overnight), other streptococci 14 days. ISPD Peritonitis Recommendation 2016 Update on Prevention and Treatment
Continuous Infusions: Loading dose of 25 mg/kg, and infusion rate based on patient's clearance. Target level 20-25 mcg/ml (AUC of 480-600 mg*day/Liter). Continuous infusions are associated with lower nephrotoxicity rates than intermittent infusions and more rapid attainment of goal AUCs. Must be administered by central line.
Peaks: Historically goal levels of 30-40 mcg/ml were used before AUC dosing.
Troughs: Historically goal levels were 5-10 mcg/ml, and were then increased to 15-20 mcg/ml as a surrogate marker for an AUC  > 400. This placed patients at a risk of nephrotoxicity due to excessive AUCs. Troughs dosing is no longer recommended.
Therapeutic Goals: AUC 400-600 mg*day/L  for efficacy and AUC < 600 mg*day/L to minimize toxicity. Trough goals for hemodialysis dialysis patients are pre-dialysis as the post-dialysis level is brief and can not easily be incorporated into the risk of toxicity and adds little to the AUC.
Serum Sampling Times:
Dosage calculations and predictions are best when samples are drawn close to steady state, after 3-5 doses. Levels twice a week are recommended.
Dosing for AUC goals: Draw both a peak and trough after the same dose. Peak post distribution: 2 hours post completion of the infusion, Trough before the next dose. Bayesian AUC calculations AUC are most accurate with a peak and trough, less accurate with a trough, and least accurate with a peak. The chance of an inappropriate dosage adjustment is lowest when a peak and trough are drawn and highest when only a peak is drawn. Using a peak for AUC dosing is not recommended as the information supplied is of very low quality. See the Monte Carlo Analysis for further details. First-order analytic equations are as accurate as Bayesian methods for AUC calculations (Pai MP 2014).
Accurate and reliable estimation of the AUC with trough-only data is only possible when richly sampled data is used as a Bayesian prior. Richly sampled two compartment models have eight or more levels drawn through out the dosage interval to capture the distribution and elimination phases for each patient during model development and a large number of patients are included in the analysis. Two compartment models built from trough only or peak and trough data sets underestimate the AUC when trough levels are measured by 23% and 15% respectively (Neely MN 2014). Most published models are based on small populations with limited peaks and trough sampling and usually with only trough sampling. Two compartment models derived from trough only data are not as accurate as one compartment models in AUC calculations. One compartment models derived from either trough or peak and trough data are accurate in AUC calculations (Maung NH 2022). It is advisable to review the original publications and vendor documentation for verification of the sampling used during model development. Otherwise a peak and trough are required to accurately calculate the AUC in a Bayesian or non-Bayesian model. AUC dosing decreases the risk of acute kidney injury by approximately 50% as compared to trough monitoring.
Hemodialysis:  A trough level after the loading dose may be helpful to ensure an adequate load has been given and then a trough before the 2nd, 3rd and 4th maintenance dose to ensure levels are stabilizing. AUC Dosing: Peak 2 hours after completion of infusion, trough before next HD. If levels after drawn after dialysis wait at least 6 hours post dialysis obtain a peak, as levels will be falsely low, and will increase over time due to redistribution from tissues. The redistribution phase may last up to 12 hours.  Levels increase 20-40% post redistribution after HD.
Pharmacokinetic Model: A one-compartment open model is most often used, but peak levels must be drawn after the distribution phase as noted above. Vancomycin has been modeled with 1, 2 and, 3 compartment models. If the peak is drawn 2 hours after the end of an infusion (post-infusion) a one-compartment model is adequate for dosage predictions and AUC calculations.

Dosage Calculations:

Lean Body Weight:
LBW_(kg) Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater than 60 inches)
LBW_(kg) Adult Female (18 years and older): 45.5 + 2.3*(Height in inches greater than 60 inches)

Body Surface Area in Meters Squared = ((Weight in kg)^0.425)*((Height in centimeters)^0.725)*(71.84/10000)

Dosing Weight_(kg) = TBW_kg

Creatinine Clearance:
Adult Males: Creatinine Clearance _(mL/min)= (140-age_(years))*(LBW or actual weight if lower) /(serum creatinine_(mg/dl)*72)
Adult Females: Creatinine Clearance _(mL/min) = 0.85 *( (140-age_(years))*(LBW or actual weight if lower)/(serum creatinine_(mg/dl)*72))
Crcl_{(ml/min/1.73 meters²)} = above *1.73/(BSA of patient)
Serum creatinine is rounded up to 0.7 mg/dL for all adult patients at my institution without paralysis or malnutrition. LBW is recommended to be used in the creatinine clearance equations, even in obese patients, as dosing predictions are improved. The equation below was derived using the lower of LBW or actual body weight in the calculation of creatinine clearance and with the serum creatinine rounding practice as described above.

Population Based Calculations Before Levels

K_(1/hours)= (0.00107*Crcl_{(ml/min/1.73 meters2)} + 0.0052, Example of Renal function versus K and Half-Life

Tau_(hours) = ((ln(Cmaxxss_(mcg/ml) desired)/Cminss_(mcg/ml) desired))/K) + T',     T'= Infusion period in hours

Vd_(L) = 0.65*Dosing weght_(kg)

Loading Dose_(mg) = Cp_(mg/L)desired *Vd*K*T'/(1-e^(-K*T'))

Maintenance Dose_(mg) = Cpmaxss desired*(Vd*K*T'*(1-e^(-K*Tau))) / (S*F*(1-e^(-K*T')))

Cmaxss = Rounded Maintenance Dose * (1-exp(-KT')) / (Vd*K*T'*(1-exp(-K* Rounded Tau))

Cminss = Cmaxss*exp(-K(Rounded Tau-T'))

AUC (mg*Day/Liter) = (Dose_mg/Clearance_L/hr)*24/Tau

AUC (mg*Day/Liter) = (Dose_mg/(Vd_L*K_1/hr))*24/Tau

AUC (mg*Day/Liter) =
[(Cmaxss_(mg/L) - Cminss_(mg/L))/K)  + ((Cmaxss_(mg/L) + Cminss_(mg/L))* Infusion Period_Hours/2)]*24/Tau

 

Individualized Calculations After Levels Drawn At Steady State

K_1/hours = ln(Cmaxss Drawn / Cminss Drawn) / Time_hours between levels

Vd_liters=Dose mg (1-exp(-K*T'))*exp(-K*Time Cmaxss Drawn Post Infusion _hours) / (Cmaxss_Drawn*K*T'*(1-exp(-K*Tau))

AUC (mg*Day/Liter) = (Dose_mg/(Vd_L*K_1/hr))*24/Tau

Cmaxss Extrapolated at end of  infusion = Cmax Drawn / exp(-K* Time Cmaxss Drawn Post Infusion _hours)

Cminss Extrapolated before next dose = Cmaxss Extrapolated * exp(-K*(Tau-T'))

AUC (mg*Day/Liter) =
[((Cmaxss Extrapolated at end of infusion _(mg/L) - Cminss extrapolated before next dose_(mg/L))/K)  +

((Cmaxss Extrapolated at end of infusion_(mg/L) + Cminss extrapolated before next doseh_(mg/L))* Infusion Period_Hours/2)]*24/Tau

Vancomycin Dosing Chart With AUC Non-Dialysis Patients

 

Dialyzability of Drugs

Vancomycin Use in Hemodialysis Patients:

Drug removal or clearance by dialysis is determined by the type of dialyzer (high flux, low flux), blood and dialysate flow during dialysis, duration of dialysis, and frequency of dialysis. The clearance for the same dialyzer unit using the same blood flow and dialysate flow rates in patients of various body sizes, in the same physiological condition, is the same.  Dialysis clearance is not weight-related.

The fraction eliminated during dialysis is 1-exp(-Clearance Dialysis + Clearance Renal)* Length of Dialysis(hours) /Vd

As the volume of distribution increases due to increasing body size the fraction eliminated during dialysis decreases as does the fraction eliminated between dialysis sessions. The required peak to maintain the desired trough decreases as Vd increases due to elimination rate decline. These all couple in the replacement dose calculations. Slower elimination and lower required peaks for large patients cause the calculated required replacement dose to maintain the desired pre-HD trough to be similar to smaller patients.  The graphic below and downloadable spreadsheet demonstrate the affects of Vd on elimination and the effect of Vd on the replacement dose. Note that the replacement dose is basically the same for the various patient weights.

The AUC calculated is greater than 400 mg*Day/L with troughs of 15 mg/L. The AUC calculated is greater than 600 mg*Day/L for troughs of 20 mcg/ml.

Replacement dose calculation:

The replacement dose replaces that which is removed during dialysis plus the amount lost between dialysis sessions.

The peak required to achieve the pre dialysis trough desired = Pre HD Trough Desired / [exp((-Clearance Renal/Vd) *(Time Between HD Sessions(Hours) - Length of Dialysis(hours)))]

Post HD Level = Pre HD Trough Desired*exp(-(Clearance HD +Clearance Renal)*Length of Dialysis/Vd)

Post HD replacement dose (mg) = (Peak Required to Maintain PreHD trough - Post HD level)*Vd(liters)

AUC (mg*Day/Liter) =
[((Peak - Pre-Dialysis Trough)/Krenal) + ((Pre-Dialysis Trough - Post Dialysis Trough)/(Krenal+Kdialysis)) + ((Peak + Post Dialysis Trough)* Infusion Period Hours/2)]*24/Tau

AUC (mg*Day/Liter) abreviated equation (~ 5% error in calcualtion)
[((Peak - Pre-Dialysis Trough)/Krenal) +  ((Peak + Pre-Dialysis Trough)* Infusion Period in Hours/2)]*24/Tau

The following educational tool may be used to observe the effects of length of dialysis, time between dialysis sessions, desired pre-HD trough, and volume of distribution on the post-HD dose required to maintain the desired pre-HD level.

The Vancomycin Elimination During and Between Dialysis Sessions In High Flux Dialysis Patients Dosed Once Dialysis Complete may be downloaded (Excel File). This tool has been updated to demonstrate the impact of length of dialysis, frequency of dialysis, HD clearance, and residual renal function on required post-HD dose.

As the patient's weight increases so does their volume of distribution. The loading dose is related to the weight and Vd. If a patient receives a loading dose and is dialyzed the same day the replacement dose after dialysis would be the amount lost during dialysis and is less than the normal maintenance dose.

Clearance is unrelated to weight and the elimination rate constant decreases as weight increases (K=Cl/Vd). As a patient's weight increases the total amount of drug in the body must increase to maintain the same level. These factors cause the amount of drug lost during dialysis not to change much for varying weights and the required maintenance doses are similar.

Even though renal clearance is very low compared to dialysis clearance the time for renal clearance is much longer and a significant amount of drug is eliminated between dialysis sessions.

Length of dialysis, HD clearance (filter type, blood flow), residual renal function, and frequency of dialysis impact maintenance dose requirements. More frequent dialysis schedules (daily) require lower maintenance doses to obtain the same trough as compared to three times a week dialysis sessions as less renal elimination occurs.

HD clearance has little impact on the AUC  if the dose is adjusted to maintain the same pre-dialysis trough as most of the AUC is impacted by the post dose peak and pre dialysis trough.

Increasing Vd  lowers the achieved AUC, even if the dose is adjusted to maintain the same pre-dialysis trough in larger patients, as a lower peak level is required to maintain the same pre-dialysis trough.

Increasing renal clearance increases the achieved AUC, even if the dose is adjusted to maintain the same pre-dialysis trough in smaller patients, as a higher peak level is required to maintain the same pre-dialysis trough.

The obtained peak and trough has the greatest impact on AUC. Target troughs of 15 - 20 mcg/ml give AUCs ~ 400-600 for most weights and are recommended in the guidelines. Higher troughs produced AUCs above 600 mg*Day/L with the potential to impact residual renal function. Quality of life is better in HD patients with higher residual renal function. Overdosing or excessive AUCs should be avoided to minimize the impact on residual renal function.

 

 

 

Dialysis Dosing - Dose During High Flux Dialysis

Approximately 30% of the infused dose of vancomycin is removed if given during dialysis. Residual renal function impacts vancomycin levels and the appropriate maintenance dose.  If residual creatinine clearance is 5 ml/min the maintenance dose would need to be increased by 200 mg and 400 mg if creatinine clearance is 10 ml/min to obtain equivalent levels to a patient without residual renal function.  The following chart demonstrates serum levels during a typical three-times-a-week dialysis scenario (M/W/F or T/Th/Sat) with 750 mg during the last hour of each dialysis without a loading dose being administered. The method of superposition was used to calculate levels. Note weight has little impact on the steady state levels achieved. As weight increases K decreases and T_1/2 increases due to increasing volume of distribution with heavier patients reaching steady state later, but with similar levels as smaller patients. This highlights the need to give adequate loading doses, otherwise, initial levels will be low leading to too high of a maintenance dose being ordered.

 

 

Elimination occurs during and between dialysis. Bolus dosing equations may be applied.
Cpmaxss = S*F*D/(Vd*(1-e^{(-((Krenal*Tau)+(Kdialysis*Tdialysis))})), assuming dialysis every Tau
Cpminsspredialysis = Cpmaxss*e^{(-Krenal*(Tau-Tdialysis))} , assume trough drawn just before dialysis and dialysis is at end of dosage interval.

As dialysis is usually 3 days a week the method of superposition would be give a more accurate representation of levels.
Cpmax after Dose1-3 = S*F*D/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3))})), each dose administered once weekly, with 3 dialysis sessions.

The highest level of the week is after the dose on the last dialysis day of M/W/F or T/Th/S series. The highest trough is before the third dialysis in the series. The lowest tough is before the first dialysis in the series.
Highest Peak in the series. Dose1 is Monday or Tuesday depending on series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*4+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Highest Cmaxss in series = Cmax1+Cmax2+Cmax3
Lowest Trough in series is just before first dialysis is the series = Highest Cmaxss in series*e^{(-(Krenal*(3*24)-Tdialysis))}

The lowest trough and peak is just before and after the dose in the first dialysis in M/W/F or T/Th/S series.
Lowest Peak in the series. Dose1 is Wednesday or Thursday in the series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*3+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Lowest Cmaxss in series = Cmax1+Cmax2+Cmax3

The highest trough is just before the third dialysis in M/W/F or T/Th/S series.
Highest trough in the series. Dose1 is Friday or Saturday in the series.
Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}
Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}
Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))
Cmaxss after middle dose in series = Cmax1+Cmax2+Cmax3
Highest trough in series = Cmax after middle dose *e^{(-(Krenal*(2*24)-Tdialysis))}
 

 

Vancomycin Medication Usage Evaluation - Dose During Dialysis (Printable Copy)

 

Vancomycin Medication Usage Evaluation - Vancomycin Dose After High Flux Dialysis (Printable Copy)

 

 

 

 

 

 

 

 

Comparison of Vancomycin Dosing Predictions For A One-Compartment Open Model Versus Optimized Goti and Carreno Two-Compartment Open Models 3/2023 (Printable Copy)

 

 

 

 

 

 

 

 

 

 

Vancomycin Dosing Predictions One-Compartment Open Model Versus Two-Compartment Open Models (Printable Copy)

 

 

Comparison of Vancomycin Dosing Predictions for a One-Compartment Open Model Versus Optimize Goti and Carreno Two-Compartment Open Models During A Concurrent MUE (Printable Copy)

 

Optimized Carreno Model for All Patients

Optimized Goti Model for Patients BMI less than 30