Vancomycin Tips

Vancomycin 2020 Dosing Guidelines ASHP

To Load or Not Load

• Loading doses aren’t always needed, but they are recommended in seriously and/or critically-ill patients with suspected or documented serious MRSA infections.  Consider loading doses for:
  • Patients in the ICU
  • Bacteremia, endocarditis, osteomyelitis, pneumonia, sepsis or meningitis
• Loading doses should also be considered in patients requiring dialysis and CRRT.   They may be considered in patients with chronic kidney disease as infrequent dosing and lower doses will likely be needed.
• Providing a loading dose rapidly achieves targeted ranges of serum vancomycin concentrations and decreases the risk of subtherapeutic concentrations during the first days of therapy.
• The decision of whether to employ a loading dose, as well as the size of this dose, should be driven by the severity of infection and the urgency to achieve a therapeutic concentration rather than body size alone. Dosing software, like InsightRX, have a loading dose feature that can help simulate exposure.

The 2020 vancomycin dosing guidelines offer these guidelines for loading doses:

• For non-obese adult patients with normal renal function, a loading dose of 20-35mg/kg (maximum dose: 3000mg) is recommended.
• For obese patients, a loading dose of 20-25mg/kg using actual body weight, up to a maximum dose of 3000mg may be considered.
• For patients receiving hemodialysis, a loading dose of 20-35mg/kg should be used (see table in guidelines for more information, depends on the permeability of the dialyzer and whether the dose is administered intradialytically or after dialysis end). 
• For patients receiving CRRT, a loading dose of 20-35mg/kg  should be used.

Why Do We Use AUC “Bayesian” Dosing?

Although vancomycin historically has been classified as a concentration-dependent antibiotic.  In more recent years, it has been classified as “exposure” or “AUC-dependent.”  What this means is that the killing action is really dependent upon both the concentrations reached in the body as well as the time that those concentrations are maintained. 

Prior to the 2020 guidelines, trough concentrations were the recommended way to dose and monitor vancomycin. These were a surrogate marker for AUC, as AUC is hard to calculate by hand. Since dosing software, like DoseMe or InsightRx, became more common, many facilities have switched to the latest guideline recommended AUC dosing. There are even free online AUC calculators like VancPK.

A trough value of 15-20 mg/L will almost always ensure a daily AUC in excess of 400 mg*hr/L. However, the majority of patients will have daily AUCs of ≥ 600 mg*hr/L. An AUC above 600 mg*hr/L puts patients at an increased risk of AKI. Studies have found that AUC-guided dosing relative to trough-based monitoring is associated with less nephrotoxicity.  

To put it another way, an AUC of 400-600 assure you get enough vancomycin in the patient’s system to get a clinical cure, but not too much so there is less risks of nephrotoxicity. Daily doses are usually lower than those estimated using troughs. Limited data show that efficacy outcomes are maintained when the daily AUC is above 400 mg*h/L for patients with serious MRSA infections, so new research may give us even lower targets (but that’s not supported currently).

Other Good Things About Bayesian Dosing

• While two levels are still preferred according to the 2020 vancomycin dosing guidelines, when using Bayesian dosing an AUC can be calculated with just a single vancomycin trough level in select patients.
• Levels can be obtained within the first 24-48 hours of therapy, meaning you do not have to wait until steady-state  (after the 3rd or 4th dose)  in order to obtain vancomycin concentration levels.  We can see if patients are achieving targets earlier.
• Bayesian models are dynamic – the individualized PK/PD model is continuously learning over time and can be used to generate a dose recommendation at any time, not just when you have levels.
• Bayesian AUC guided vancomycin dosing can be applied to both pediatric and adult populations.

Bad Model Fits

Bayesian dosing starts by using a studied vancomycin population PK model as the “Bayesian” PK prior. Based on a patient’s dosing history and collected PK data, the software estimates the Bayesian posterior parameter values for that patient based on this PK model. The dose optimization software calculates the optimal dosing regimen based on the specified exposure target. 

When the software claims a “bad model fit” it means the predicted values are not in line with the actual values.  This can be because of an error in data (check to see if all the doses and troughs were picked up, or if the level seem to be drawn accurately) or because the patient doesn’t fit the model population (there are differing  models for different patient populations depending on the software or program you’re using – the default model works with most, but you can try others).

What this means clinically is that the predicted values will be off, and the model isn’t sure how far they will be off.  In some cases, when there isn’t an obvious error like a missing dose and the patient seems to fit the population of the model, a poor model fit should be dosed according to actual troughs (collected =<30 minutes prior to infusion or calculated as such). This is the safest way to dose those patients.  The model may adapt later and give better predictions. If there is an obvious error, most software can be told to ignore the level or dose or you may add a level or dose in for a better fit.

Vancomycin and Hemodialysis/CRRT

Vancomycin is excreted unchanged in the urine and cleared with dialysis. Old literature and package inserts may claim that vancomycin is poorly dialysisable, but it is generally well dialyzed with modern dialysates. 

For patients receiving hemodialysis, weight-based dosing is recommended until serum concentrations have been determined.  The guidelines recommend a 25 mg/kg loading dose and 7.5-10 mg/kg maintenance doses after each dialysis session. Typically, you will give a loading dose and draw levels after the next dialysis before giving a maintenance dose.  Pre-dialysis serum concentration monitoring should be performed and drive subsequent dosing. Levels and subsequent doses are recommended after each hemodialysis session to ensure therapeutic serum concentrations throughout the dosing interval.

Pre-dialysis concentrations between 15 and 20mg/L are likely to achieve the AUC of 400 to 600mg.h/L in the previous 24 hours, based on expert opinion in the guidelines, 

These AUC targets were determined in non-dialysis patients. The upper limit of AUC targets associated with AKI might not seem relevant in dialysis or CRRT patients, but drug exposure can cause other toxicities and those target and toxicities rates are still unclear. Trough dosing is more studied in these patients.

CRRT has been shown to be an independent risk factor for mortality in patients with sepsis, so it is important not to UNDERDOSE these patients.  CRRT emulates the kidneys. Provided uninterrupted CRRT, vancomycin clearance is relatively constant and strongly correlates with dialysate flow rate.  For patients on conventional CRRT, IDSA recommends a vancomycin loading dose of 20– 35 mg/kg with an initial maintenance dose of 7.5–10 mg/kg every 12 h to reach an adequate AUC/MIC, though some studies have found vancomycin doses of ≥15 mg/kg/day are needed to achieve early therapeutic targets in patients on high intensity CRRT.

How Often To Monitor

At minimum, levels should be obtained for all patients by 72 hours of therapy and at least weekly thereafter.  Levels should be obtained 48-72 hours after dose changes.

• For conditions where quick attainment of AUC is important to morbidity and mortality, levels should be taken earlier. It is recommended that patients with central nervous system infections, S. aureus sepsis w/ clinical instability, osteomyelitis, VAP, HAP and endocarditis reach target AUC within 48 hours. Levels should be measured 24-48 hours after the initial dose to make sure the patient is meeting that goal.
• More frequent levels should be taken in rapidly changing renal function, dialysis or poor renal function, co-administration with nephrotoxic drugs. If SCr changes >0.3 within 48 hours, consider ordering a level. Patients with estimated CrCl <10 should have levels ~24 hours after each dose.
• Pre-dialysis levels are preferred for dialysis patients.
• CRRT patients should get levels 24 hours after the first dose, and should generally get levels at the same frequency as a patient with normal kidney function after that.
• It is recommended to obtain a level for most patients who are on home health or outside facility vancomycin prior to dosing.

Chemistries and CBCs should also be checked at least weekly.  

Extrapolating and Misdrawn Levels

The most common type of incorrectly drawn vancomycin level when using AUC to dose  is a level drawn while the dose is infusing.  Dosing software usually can catch this and fix the predictions, but sometimes the actual time a dose is hung and when it is charted vary.  If a level looks off and it was taken close to the time the drug was infused, it might be helpful to question the level.

Dosing software, like InsightRx, can also estimate troughs, but if you are using troughs, quick bedside checks are easier than estimating AUC at bedside. 

Remember that vancomycin has mostly linear pharmacokinetics.  You can roughly estimate the true trough by extrapolating the measured value using the first-order elimination equation: 

Ctrue trough = Ctrough measured × e^−Kt

• K is the vancomycin elimination rate ([CrCl in mcg/ml × 0.00083] + 0.0044)
• t is the time difference in hours (positive if the trough was early and negative if it was late)
• e is Euler’s constant (2.71828…..).  

For example, my patient is on 1.25 g every 12 hours and the trough came back as 22 mcg/ml.  They have a CrCl of 96 mcg/ml. I notice that the trough was drawn 2 hours before it was scheduled.  I would use the following equation:

K = (96 * 0.00083) + 0.0044   K=0.084

21 * (2.71828 ^ (-0.084*2) = 17.8 mcg/ml.  

We likely would have told the nurse to hold the dose at 21, but in reality, we should give it.

If it was late:

21 * (2.71828 ^ (-0.084*-2) = 25 mcg/ml.   

We would likely hold that one.Your brain can also tell you if the dose is probably ok or not.  Vancomycin elimination is usually linear so a quick proportion is often enough to double check if you have previous levels.

There’s a quick and dirty estimate of what trough you’ll get if you change the dose too.

TroughNew/24 hours Dose = TroughOld/24 Hour Dose

If we wanted to change the dose to 1250 mg daily, we can roughly calculate what level we’d get:

25/2500 (daily dose) = newTrough/1250   New trough= 12.5

Unless the patient’s renal function has changed, that’s probably too low. We might try 1000 mg every 12 hours:

25/2500 (daily dose) = newTrough/2000   New trough= 20

That might be a better choice.

These calculations are not as accurate as our Bayesian models so they should only be used to double check doses or in emergency situations (ie: extended InsightRx downtime).

There are very complicated equations we were taught at school.  Most need two levels (some need a peak and trough). Those are more accurate than these quick, bedside calculations. There are also online calculators  that use various equations (some need two levels) that may be more accurate.

Vancomycin in AKI and Vancomycin Induced AKI

Vancomycin associated AKI can be measured in different ways, but a common definition of AKI is an increase in serum creatinine of >0.5 mg/dL or a 50% increase from baseline in consecutive daily readings, or a decrease in calculated creatinine clearance of 50% from baseline on two consecutive days in the absence of an alternative explanation. 

Newer studies suggest that a more sensitive threshold of an increase in serum creatinine >0.3 mg/dL over a 48 hour period may be an indicator of AKI.

Patients with AKI, CKD, elderly patients,or other kidney injuries,  tend to accumulate vancomycin, so regimes need to be closely monitored in these patients so they don’t become supratherapeutic. 

Vancomycin Infusion Reaction 

 “Vancomycin infusion reaction” or “Vancomycin flushing syndrome” or “Red Man’s Syndrome is characterized by flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body. Pains and muscle spasms in the back and chest, dyspnea, and hypotension may also occur. Signs of VFS appear about 4–10 minutes after starting an infusion or soon after its completion.

It is not an allergy.  It is caused by the release of histamine from basophils and mast cells. It is a direct activation of mast cells to release histamine.

If this occurs, slow the infusion rate or increase the dilution volume.  You can recommend diphenhydramine 25-50 mg premedication to the provider for future doses.

An anaphylactic allergy, or T1 hypersensitivity, causes IgE stimulation of mast cells. IgE related reactions to vancomycin are rare, but they do occur. Symptom onset occurs within a median of two minutes during infusion of the dose in patients who have anaphylactic reactions (so usually faster than vancomycin infusion reactions). The clinical manifestation includes the following: angioedema, bronchospasm, respiratory distress, generalized pruritus, hypotension, urticaria, tachycardia, nausea and vomiting, and lightheadedness. Treatment for anaphylaxis consists of immediate discontinuation of the glycopeptide and immediate treatment with epinephrine, antihistamines, or corticosteroids as indicated.

References:

1. de Waele JJ, Danneels I, Depuydt P, Decruyenaere J, Bourgeois M, Hoste E. Factors associated with inadequate early vancomycin levels in critically ill patients treated with continuous infusion. Int J Antimicrob Agents. 2013; 41(5):434-438. 
2. Hodiamont CJ, Juffermans NP, Berends SE, van Vessem DJ, Hakkens N, Mathôt RAA, de Jong MD, van Hest RM. Impact of a vancomycin loading dose on the achievement of target vancomycin exposure in the first 24 h and on the accompanying risk of nephrotoxicity in critically ill patients. J Antimicrob Chemother. 2021 Oct 11;76(11):2941-2949. doi: 10.1093/jac/dkab278. PMID: 34337660; PMCID: PMC8521408.
3. Lewis, Susan J.; Nolin, Thomas D.. New Vancomycin Dosing Guidelines for Hemodialysis Patients: Rationale, Caveats, and Limitations. Kidney360 2(8):p 1313-1315, August 2021. | DOI: 10.34067/KID.0000192021
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5. Ocampos-Martinez E, Penaccini L, Scolletta S et al. Determinants of early inadequate vancomycin concentrations during continuous infusion in septic patients. Int J Antimicrob Agents. 2012; 39(4):332-337.
6. Matzke G.R., McGory R.W., Halstenson C.E., Keane W.F. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob. Agents Chemother. 1984;25:433–437. doi: 10.1128/AAC.25.4.433.
7. Mohammedi I, Descloux E, Argaud L, Le Scanff J, Robert D. Loading dose of vancomycin in critically ill patients: 15 mg/kg is a better choice than 500 mg. Int J Antimicrob Agents. 2006; 27(3):259-262.  
8. Rybak MJ, 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. doi: 10.1093/ajhp/zxaa036. PMID: 32191793.
9. Srour N, Lopez C, Succar L, Nguyen P. Vancomycin dosing in high-intensity continuous renal replacement therapy: A retrospective cohort study. Pharmacotherapy. 2023 Oct;43(10):1015-1023. doi: 10.1002/phar.2852. Epub 2023 Jul 26. PMID: 37458062