{"id":8978,"date":"2021-10-01T11:01:22","date_gmt":"2021-10-01T01:01:22","guid":{"rendered":"https:\/\/doseme-rx.com\/?p=8978"},"modified":"2021-10-01T11:02:51","modified_gmt":"2021-10-01T01:02:51","slug":"vancomycin-auc-calculation","status":"publish","type":"post","link":"https:\/\/doseme-rx.com\/en-gb\/vancomycin\/article\/vancomycin-auc-calculation","title":{"rendered":"Vancomycin AUC Calculation"},"content":{"rendered":"\n

Vancomycin is a glycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus <\/em>(MRSA)as well as other clinically important gram-positive organisms.1<\/sup><\/p>\n\n\n\n

Vancomycin has found significant use in clinical practice due to its activity against these organisms. Just like any other medication, however, safe and effective dosing and monitoring of vancomycin is essential.<\/p>\n\n\n\n

Vancomycin dosing must be tailored to the patient and closely monitored given its narrow therapeutic index2<\/sup> and risky adverse effects<\/a>.<\/p>\n\n\n\n

In the clinical setting, patients often present with multiple comorbidities, varying ranges of body weight and body mass index (BMI), and rapidly changing creatinine clearance (CrCl).<\/p>\n\n\n\n

Due to this, clinicians can be faced with significant challenges in providing just the right amount of medication at doses and frequencies that will effectively treat the patient without causing harm.<\/p>\n\n\n\n

To most effectively and consistently do this, clinicians must have a thorough understanding of the available therapeutic drug monitoring guidelines, pharmacokinetics, and the tools and calculation methods at their disposal.<\/p>\n\n\n\n

To calculate vancomycin dosage<\/a>, please view the DoseMeRx calculator.<\/em><\/p>\n\n\n\n

A brief History of Vancomycin Pharmacokinetics<\/h2>\n\n\n\n
\"\"<\/figure>\n\n\n\n

What is AUC for Vancomycin?<\/h3>\n\n\n\n

Though vancomycin has been used since the 1950s<\/a>, there was no formal guidance available to assist clinicians with evaluating and dosing the medication until 2009. If drug levels were collected, there was not a well-established method of determining if the patient was adequately treated or at risk for acute kidney injury (AKI).<\/p>\n\n\n\n

When the 2009 vancomycin consensus guidelines for the therapeutic monitoring of vancomycin were released, available literature that could be used to determine the therapeutic monitoring goal for vancomycin was limited.<\/p>\n\n\n\n

While there were some small studies conducted in humans, most were in animals or in a laboratory setting (in vitro).3<\/sup><\/p>\n\n\n\n

Even with the paucity of available human data, the authors of the 2009 consensus guidelines were able to come to some conclusions regarding dosing recommendations.<\/p>\n\n\n\n

This included recommendations on empiric dosing according to the patient\u2019s body weight, adjusting the dose of vancomycin based on the patient\u2019s CrCl, and intensifying the dosing strategy if the patient had a confirmed, serious infection caused by MRSA such as endocarditis.<\/p>\n\n\n\n

They concluded that based on the pharmacokinetics of vancomycin, the monitoring parameter of choice for the drug should be the vancomycin area under the concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC), with an AUC\/MIC ratio \u2265400 needed for reliable efficacy.3<\/sup><\/p>\n\n\n\n

How do you Monitor AUC for Vancomycin?<\/h3>\n\n\n\n

In 2009 when this consensus guidance was released, the only AUC calculation method that was available for the hospital clinician required two serum concentrations to perform pharmacokinetic calculations by hand.<\/p>\n\n\n\n

The readily available software<\/a> we have now for the busy clinician to rapidly and accurately estimate the AUC:MIC ratio using Bayesian estimation did not exist.<\/p>\n\n\n\n

Hand calculations were cumbersome and the several steps involved increased the risks for errors. Seeing that this was not reasonable for clinical practice at the time, the authors decided to recommend trough-only <\/a>monitoring as a convenient surrogate marker for this ratio.<\/p>\n\n\n\n

By targeting a trough level of at least 15 mcg\/mL and ideally no greater than 20 mcg\/mL, the clinician could assume that the AUC\/MIC would be \u2265400 assuming an S. aureus <\/em>vancomycin MIC of 1 mcg\/mL. Thus, the single trough level became the gold standard for vancomycin monitoring.<\/p>\n\n\n\n

While this was a necessary step towards more appropriate dosing and monitoring of vancomycin, patients were still at risk for side effects<\/a> from the drug.4-7<\/sup><\/p>\n\n\n\n

These side effects were prevalent even when kept within the trough goals of 15-20 mcg\/mL for severe infections and most commonly involved AKI.<\/p>\n\n\n\n

AKI can be a very unfortunate finding in patients receiving vancomycin. First, since vancomycin is primarily cleared in the kidneys,1<\/sup> AKI makes dosing the patient\u2019s vancomycin much more difficult and imprecise.<\/p>\n\n\n\n

AKI has also been associated with progression to dialysis, longer length of stay, and significantly higher costs for the health system.8,9<\/sup><\/p>\n\n\n\n

It is in the interest of patients, providers, pharmacists, and stakeholders that AKI is prevented. From 2009 to 2020, several articles and meta-analyses evaluating the safety and efficacy of trough-only monitoring were released.4-13<\/sup><\/p>\n\n\n\n

In these articles, trough-only monitoring was not well correlated with improved clinical outcomes and maintaining a trough level in the range of 15-20 mcg\/mL consistently failed in predicting clinical cure and AKI risk.<\/p>\n\n\n\n

One potential cause for this finding was with the inability of the trough to function as a surrogate for the AUC.<\/p>\n\n\n\n

While a trough goal between 15 and 20 mcg\/mL usually represented an AUC of at least 400, it also had the tendency to overshoot the therapeutic range of the drug, predisposing patients to the aforementioned complications of kidney damage.<\/p>\n\n\n\n

Clinicians and researchers were then faced with a challenge. With the literature further supporting the AUC as the ideal monitoring parameter for the drug, and the trough level not being sufficient as a surrogate marker of the AUC, how should the new therapeutic dosing guidelines proceed?<\/p>\n\n\n\n

The only solution was to forego surrogate markers and calculate the AUC directly.<\/p>\n\n\n\n

In the 2020 update to the consensus guidelines for the therapeutic monitoring of vancomycin, trough-only monitoring was officially no longer recommended with direct monitoring of the AUC used in its place.14<\/sup><\/p>\n\n\n\n

For health systems, this meant that anyone monitoring and adjusting vancomycin doses needed to move away from the traditional trough goals and towards a method of calculating the AUC. To get from trough to AUC,<\/a> clinicians needed to have a thorough understanding of pharmacokinetics.  <\/p>\n\n\n\n

Zero Order and First Order Pharmacokinetics<\/h2>\n\n\n\n
\"\"<\/figure>\n\n\n\n

Drug elimination pharmacokinetics can be divided into two main categories: zero order and first order.<\/p>\n\n\n\n

Zero order kinetics is a time-dependent process where the same amount of drug is eliminated from the body per unit time regardless of the concentration of the drug in the patient.15<\/sup><\/p>\n\n\n\n

Drugs that follow a zero order model will at low doses appear to follow first order (linear) elimination up until the point that the elimination mechanism becomes saturated.<\/p>\n\n\n\n

Alcohol is a commonly used example of zero order (nonlinear) kinetics. Alcohol dehydrogenase, one of the major enzymes involved in alcohol metabolism, has a low Km, which is a measure of the affinity of the substrate for an enzyme. Translated \u2013 this suggests that the alcohol dehydrogenase enzyme has a high affinity for alcohol.16<\/sup><\/p>\n\n\n\n

This high affinity causes the enzyme to be saturated with substrate at low concentrations. When this saturation takes place, the rate of alcohol metabolized through this pathway no longer increases in relationship to increasing alcohol amounts.15,16<\/sup><\/p>\n\n\n\n

 Increasing alcohol ingestion will also prolong the elimination half-life, as the elimination rate no longer increases proportionally with the drug concentration.15,17<\/sup><\/p>\n\n\n\n

These factors contribute to increasing the complexity of estimating the concentrations of alcohol at a given time point.<\/p>\n\n\n\n

The distinguishing factor between zero order and first order pharmacokinetics is the ability of the elimination system to become saturated by the drug.15<\/sup><\/p>\n\n\n\n

When administered intravenously<\/a>, vancomycin is eliminated renally<\/a> with >80% of the administered drug recoverable unchanged in the urine.1<\/sup><\/p>\n\n\n\n

While there are other means of vancomycin elimination, renal function plays the most central role in determining how quickly a patient can remove vancomycin from the central compartment. Luckily, patients of average weight receiving vancomycin at appropriate doses and frequencies for their renal function will exhibit first order elimination kinetics.1,3,5,6<\/sup> <\/p>\n\n\n\n

In first order (linear) pharmacokinetic models, drug elimination can be represented as a straight line on a logarithmic scale. In an ideal scenario where elimination of drug is consistent, drug concentration can be estimated at any time point by the first order equation C = C0<\/sub> * e-kt<\/sup> where C = drug concentration, C0 <\/sub>= initial drug concentration (extrapolated), e = the base of the natural logarithm, k = the elimination rate constant, and t = time.18<\/sup><\/p>\n\n\n\n

If two drug levels are collected over the same dosing interval, the clinician can then solve for the elimination rate constant (k) and use this equation to provide an estimation of vancomycin concentration.<\/p>\n\n\n\n

The simple first order equation above for vancomycin dosing does have limitations.<\/p>\n\n\n\n

First, it can only be used to inform the clinician of the drug concentration at a certain time point. While this can be an effective method for drug monitoring of some medications, it alone cannot be used to determine the AUC.<\/p>\n\n\n\n

Since drug level monitoring alone was found to be less effective than directly monitoring the AUC, more complex calculations are needed. <\/p>\n\n\n\n

How do you Calculate AUC MIC Ratio for Vancomycin?<\/h2>\n\n\n\n
\"\"<\/figure>\n\n\n\n

Calculation of the AUC Using the Sawchuk-Zaske Method<\/h3>\n\n\n\n

To hand calculate the AUC using first order equations, the Sawchuk-Zaske method can be used.18<\/sup><\/p>\n\n\n\n

This method relies on having two post-dose drug levels from the same dosing interval ideally collected at steady state.<\/p>\n\n\n\n

Typically, the first level will be a post infusion peak and the second level is a trough level. This equation also allows the elimination rate constant of the drug to be calculated, starting with the following equation:<\/p>\n\n\n\n

k = ln<\/em>(Cpeak<\/sub>\/Ctrough<\/sub>)\/\u2206t<\/p>\n\n\n\n

Where k = the elimination rate constant, Cpeak <\/sub>is the observed peak level collected, Ctrough <\/sub>is the observed trough level, and \u2206t is the difference in time in hours between the Cpeak <\/sub>and the Ctrough <\/sub>levels.<\/p>\n\n\n\n

From here, the true peak (Cmax<\/sub>) can be extrapolated using the difference in time between the expected peak and the first drug level (Cpeak<\/sub>) using the following equation:<\/p>\n\n\n\n

Cmax <\/sub>= Cpeak<\/sub>\/e-kt\u2019<\/sup><\/p>\n\n\n\n

In this case, t\u2019 is the time between the \u201cobserved\u201d peak (i.e., the drug level drawn from the patient) and the \u201ctrue\u201d peak, back-extrapolated.<\/p>\n\n\n\n

From here, the true trough (Cmin<\/sub>) can be calculated using the Cmax <\/sub>from the following formula:<\/p>\n\n\n\n

Cmin <\/sub>= Cmax <\/sub>* e-k(Tau<\/em>-t\u00adinf)<\/sup><\/p>\n\n\n\n

Where Tau <\/em>is the dosing interval and tinf is the infusion time in hours.<\/p>\n\n\n\n

Now, the AUC can be calculated. Commonly, the trapezoidal rule is used to calculate the AUC by hand. A full description of how to perform these calculations can be found here<\/a>.<\/p>\n\n\n\n

With all of the necessary parameters and an understanding of how to calculate the AUC, any adjustments to the dose of vancomycin or modifications in dosing frequency can all be calculated by the user.<\/p>\n\n\n\n

It should be noted, however, that there are limitations to using the first order equations in the calculation of the area under the curve.<\/p>\n\n\n\n

Limitations of the First Order Equations<\/h2>\n\n\n\n
\"\"<\/figure>\n\n\n\n

While the first order calculations can be performed \u201cby hand\u201d, they do have some significant limitations:<\/p>\n\n\n\n