Vancomycin Pharmacokinetic Dosing Information

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-dependent killing, but bacteriostatic for most strains of enterococci. Staph Aureus MIC < 1 are associated with better outcomes than MIC < 2.

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.

Low Flux Hemodialysis

Approximately 8% removed during a dialysis session, no supplemental dose is needed after dialysis.

High Flux Hemodialysis Dosing

• Loading dose: 25 mg/kg if not administered during dialysis or 35 mg/kg if administered during dialysis, based on total body weight, capped at 3000 mg
• Maintenance Dose: 750-1000 mg after each HD, 1000-1250 mg if administered 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/L 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 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/L). 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 (Historical)

Historically goal levels of 30-40 mcg/ml were used before AUC dosing.

Troughs (Historical)

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. Trough dosing is no longer recommended.

Current Therapeutic Goals

Trough goals for hemodialysis patients are pre-dialysis as the post-dialysis level is brief and cannot easily be incorporated into the risk of toxicity and adds little to the AUC.

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

Important Note on Trough-Only AUC Estimation

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 throughout 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 Sampling

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 are drawn after dialysis, wait at least 6 hours post dialysis to 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.

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.

Lean Body Weight

• LBW (kg) Adult Males (18 years and older): 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

BSA (Meters Squared) = ((Weight in kg)^0.425) × ((Height in centimeters)^0.725) × (71.84/10000)

Dosing Weight (kg)

Dosing Weight (kg) = TBW_kg

Creatinine Clearance

• Adult Males: CrCl (mL/min) = (140 - age(years)) × (LBW or actual weight if lower) / (serum creatinine(mg/dl) × 72)
• Adult Females: CrCl (mL/min) = 0.85 × ((140 - age(years)) × (LBW or actual weight if lower) / (serum creatinine(mg/dl) × 72))
• CrCl (ml/min/1.73 m²) = 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

Individualized Calculations After Levels Drawn At Steady State