Vancomycin trough levels: Upcoming 2019 therapeutic drug monitoring recommendations

Vancomycin trough levels: Upcoming 2019 therapeutic drug monitoring recommendations
19 Nov 2019 Blog

The 2009 guidelines for monitoring vancomycin levels in adult patients recommended patients:

  • Maintain trough serum vancomycin concentrations of at least 10 mg/L for all infections to avoid the potential for resistance
  • Maintain trough serum vancomycin concentrations of 15-20mg/L for complicated infections

The 2019 draft of the revised vancomycin therapeutic guidelines recommends a move away from monitoring vancomycin trough levels to targeting an AUC24:MIC (24-hour area under the curve (AUC) to minimum inhibitory concentration ratio). Dosing vancomycin using trough-only monitoring is no longer recommended.

The proposed guidelines recommend the following:   

  • Drawing two levels, including one trough concentration and one peak steady-state concentration, obtained 1-2 hours post-infusion
  • Utilizing a Bayesian software program to monitor the AUC
  • Maintaining a Bayesian-derived AUC/MICBMD (bone mass measurement) of 400 to 600 for serious infections
Vancomycin dosing auc-based

What is vancomycin?

Vancomycin is an antibiotic used to treat serious, life-threatening infections, including those caused by methicillin-resistant Staphylococcus aureus.

Vancomycin is given intravenously (by injection into a vein) to treat infections such as blood poisoning (septicemia), heart valve infections (endocarditis), bone infections (osteomyelitis), blood infections (bacteremia), certain types of pneumonia, and meningitis.

It is often the drug of choice for methicillin-resistant Staphylococcus epidermidis (MRSE) and methicillin-resistant Staphylococcus aureus (MRSA) infections, especially when they are associated with implanted prosthetic devices such as heart valves, artificial hips, and indwelling catheters.

Vancomycin can also be given before certain surgeries to prevent an infection.

Although it was originally approved by the FDA in 1958, it was not widely used until the late 1970s when resistance to other antibiotics started to emerge

Monitoring the level of vancomycin is important because its effectiveness relies on keeping blood levels above a minimum concentration for the entire duration of therapy (also referred to as total drug exposure).

If the vancomycin dose is too low, an inadequate concentration of vancomycin will not treat the infection and it can lead to the development of resistant bacteria. Increasing resistance to vancomycin means that higher doses are necessary to make the drug effective against infections, and in some cases these higher doses cannot be given safely. If the dose is too high, excessive concentrations of vancomycin can result in serious side effects, including hearing loss (ototoxicity) and kidney damage (nephrotoxicity).  

The goal is to find a dose for vancomycin that is both safe and effective.

Vancomycin Therapeutic Drug Monitoring

Vancomycin blood levels are drawn at timed intervals to measure drug levels during treatment. Vancomycin has a narrow therapeutic index, which is the ratio between the toxic and effective dose of medication.

As soon as vancomycin enters the body, the drug gets distributed throughout, and then the kidneys begin to work to remove it from the body.

For vancomycin to be effective, a person must receive doses at regular intervals with the goal of getting to a point where the drug levels in the body remain stable or consistent, known as steady-state.

To maintain this steady-state, it’s important to individualize the dose because each person’s body will process and remove vancomycin at different rates based upon their age, underlying health status, weight, kidney function, and other medications they are taking.

Other medications used at the same time as vancomycin can increase or decrease the concentration of the drug in the blood so close monitoring and evaluation of patients is advised.

Vancomycin and acute kidney injury

A dangerous side effect of vancomycin therapy is kidney damage (acute kidney injury, or AKI). Acute kidney injury occurs quickly, usually within the first 10 days of therapy.

Although it can be reversed, this is not always the case. Some patients may see an improvement in their kidney function but it doesn’t recover fully. For other patients, they may never recover and will require hemodialysis.

Even mild AKI can significantly reduce patient survival rates, increase concomitant illness, prolong hospitalizations, and escalating healthcare costs. Certain patients are at high risk of developing AKI, including those who are obese, have pre-existing kidney problems, and the critically ill.

In patients receiving vancomycin, a greater risk of nephrotoxicity occurs when doses exceed 4 grams per day and trough levels are higher than 15mcg/mL and an AUC above 600 mg-h/L is present.

Vancomycin associated AKI can be measured in different ways, but a common definition of AKI used is either

  1. An increase in serum creatinine of >0.5 mg/dL or a 50% increase from baseline in consecutive daily readings, or
  2. 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.

AKI can be potentiated in patients that are receiving other medications that also rely on the kidneys for processing.

This is defined as a drug-drug interaction.  Drug-drug interactions are common in seriously ill patients receiving vancomycin.

It is important to monitor kidney (renal) function in patients receiving vancomycin who are also receiving other medications that can damage the kidneys such as antimicrobials (e.g. amphotericin B, aminoglycosides, polymyxins, or piperacillin/tazobactam), loop diuretics, or certain types of chemotherapy such as cisplatin.

In the past, vancomycin doses have been adjusted to target a specific trough level.  It is now increasingly clear that the trough level does not accurately reflect total vancomycin exposure. New retrospective studies also show that AUC-guided vancomycin dosing may reduce the occurrence of vancomycin-associated AKI.

In hospitalized patients who were using trough-only dosing, there was an 8% incidence of AKI compared to those using AUC dosing who had a 0%-2% incidence of AKI. Study results show that AUC is the driver of effectiveness and the risk of AKI is related to trough, and potentially AUC. As a result, the new guidelines focus on measuring AUC 24.

Vancomycin guideline update 2019

Vancomycin Dosing: 2009 vs 2019

Vancomycin dosing depends on a variety of factors, including kidney function (renal function), other nephrotoxic drugs the person may be receiving, age, and weight.

Historically, the primary reference designed to guide vancomycin use is the “2009 Therapeutic Monitoring of Vancomycin in Adult Patients: A Consensus Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists. 

 The 2009 guidelines recommend doses of 15–20 mg/kg (based on actual body weight) given every 8–12 hours for most patients with normal renal function to achieve the suggested serum concentrations for infections where the bacteria are relatively sensitive.

In seriously ill patients, a loading dose of 25–30 mg/kg (based on actual body weight) can be used to quickly meet the target trough serum vancomycin concentration. These recommendations have been changed for 2019.

In the 2009 vancomycin dosing guidelines, it was recommended that vancomycin troughs remain above 10 mcg/mL to prevent antibiotic resistance from developing and that concentrations of 15 to 20 mcg/mL should be targeted for certain patients with complicated infections.

It was expected that the higher trough goal would reach the goal of an AUC24:MIC ≥400 mg∙h/L in most patients with complicated infections when the organism’s minimum inhibitory concentration was ≤1 mcg/mL. The trough should be collected before the 4th dose is administered (prior to steady state).

Unfortunately, the practice of waiting until the fourth dose to measure the trough level may expose a patient to several days of sub-optimal therapy.

In 2019, a new set of draft guidelines were posted for public review.

According to these proposed guidelines, a loading dose of 25-35 mg/kg can be administered to quickly reach targeted concentrations in critically ill patients with serious MRSA infections and normal renal function.

Although loading doses should be based on actual body weight, the maximum dose should not exceed 3000 mg.  More frequent therapeutic monitoring should also be performed in obese patients, patients with frequently changing kidney function, or in patients who are receiving vancomycin for 3 days or more.

New research suggests for many patients, an effective AUC24:MIC target of 400-600 mg.h/L can be achieved with significantly lower trough concentrations than previously recommended in 2009.

The new 2019 draft guidelines now recommend a different dosing regimen.

A Bayesian approach allows vancomycin levels to be drawn within the first 24 to 48 hours instead of waiting for steady-state conditions (after the 3rd or 4th dose).

This information can be used to change subsequent dosing. As part of their output, Bayesian software programs may recommend new treatment regimens such as front-loading doses with a transition to a lower maintenance dosing regimen to achieve target drug concentrations within the first 24 to 48 hours among critically-ill patients.

A benefit of using Bayesian AUC estimates is it can be applied to all patients (including obese, critically-ill patients, pediatrics, and patients with kidney dysfunction).

Currently, it is preferred to estimate the Bayesian AUC on two vancomycin concentrations (peak and trough).  The goal is to target a Bayesian-derived AUC/MIC-BMD ratio of 400 to 600 to maximize drug efficacy while minimizing the risk of AKI.

The most accurate way to dose vancomycin is through AUC-guided dosing and monitoring. The preferred approach to monitor AUC involves the use of Bayesian software programs, and drawing two vancomycin levels (i.e. shortly after the end of infusion and at the end of the dosing interval) to estimate the AUC.

The frequency of drawing levels following therapy can vary from once weekly for stable patients to once daily for most other patients (such as those with kidney dysfunction, or those who are critically-ill).

If you use a Bayesian dosing software with richly sampled PK data you may be able to accomplish this with minimal PK sampling (i.e. a single trough level) that provides AUC-guided vancomycin dosing recommendations in real-time.

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Sources

Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, Mueller BA, Pai MP, Wong-Beringer A, Rotschafer JC, Rodvold KA, Maples HD, Lomaestro B; et al. “Therapeutic Monitoring of Vancomycin: A Revised Consensus Guideline.”. Accessed November 6, 2019.

American Journal of Health System Pharmacists. “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.” Published 2009. Accessed November 6, 2019.

Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42 Suppl 1:S5-12. https://academic.oup.com/cid/article/42/Supplement_1/S5/275962. Accessed November 6, 2019.

MedlinePlus Drug Information. Vancomycin Injection. Available online at https://medlineplus.gov/druginfo/meds/a601167.html. Accessed November 6, 2019.

ANI Pharmaceuticals. Vancocin (vancomycin) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/060180s047lbl.pdf. Revised January 2017. Accessed November 6, 2019.

Hale CM, Seabury RW, Steele JM, Darko W, Miller CD. Are vancomycin trough concentrations of 15 to 20 mg/L associated with increased attainment of an AUC/MIC ≥ 400 in patients with presumed MRSA infection? J Pharm Pract.2017;30(3):329-335. doi: 10.1177/0897190016642692. https://journals.sagepub.com/doi/abs/10.1177/0897190016642692. Accessed November 6, 2019.

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