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To be honest, I've never been a big vancomycin fan.  My chief objections to vancomycin are roughly three-fold:

1. Vancomycin is given too broadly, in clinical situations where MRSA is extremely unlikely (east.g. urosepsis or customs-caused intra-abdominal sepsis).
2. Vancomycin levels are ofttimes high, potentially causing nephrotoxicity.
3. In the rare patient who does wind up having MRSA, vancomycin levels are ofttimes sub-optimal, leading to treatment failure (or at least it seems that way).

Notwithstanding, these aren't purely problems with the drug itself – they're largely problems with how we employ the drug.  We should be able to accost them.  We've already explored issue #1 (misuse of vancomycin) in pneumonia and urosepsis.  This post will focus on #2-3:  pharmacokinetics.

Why vancomycin levels matter (now more ever)

The therapeutic window of a drug is the space betwixt the therapeutic dose and the toxic dose.  Determining the correct dose is harder for drugs with a narrow therapeutic window:  if you're a chip loftier you'll see toxicity, whereas if you're a chip low y'all'll loose efficacy.

The therapeutic window of vancomycin has narrowed over the past couple decades.  When vancomycin was first used in the 1980s, the target trough level was 5-10 mg/50. ^1,2   5-10!!  How quaint!  Unfortunately, over time, bacteria take grown more resistant to vancomycin (a miracle known as "MIC pitter-patter").  To counter this, the latest guidelines on vancomycin apply in 2009 recommended targeting a trough level of 15-twenty mg/L for severe infections. ³

Another reason to avert low troughs is that troughs <x mg/L may promote the emergence of resistant bacteria. ^4,v   Not only is sub-therapeutic vancomycin ineffective, it may actually render the infection harder to eradicate subsequently. ^6,7

Bacteria evolved to resist vancomycin, just unfortunately the homo kidney hasn't:  kidneys are but as sensitive to nephrotoxicity as they were xx years agone.  The target trough levels we're shooting for now (xv-20 ug/mL) would take been considered toxic levels ten or xx years ago.  In fact, many studies show that trough levels above 15 ug/mL are a gamble factor for vancomycin nephrotoxicity. ^viii–11

Thus, the therapeutic window for vancomycin has narrowed.  We are forced to walk a fine line between under-dosing vancomycin (therapeutic failure, fostering of antibiotic resistance) and over-dosing vancomycin (nephrotoxicity).

What are we shooting for?

The antibacterial efficacy of vancomycin is both time- and concentration-dependent.  The best way to account for both factors is the surface area under the concentration-time bend during 24 hours (AUC24).  Clinical success is predicted by the ratio of the AUC24 to the minimum inhibitor concentration (MIC) of the bacterial strain (AUC24/MIC).  The target AUC24/MIC ratio is generally accustomed to be >400 to achieve clinical efficacy.

Staph species sensitive to vancomycin take a MIC of i ml/Fifty or lower.  This implies that when using vancomycin for empiric antibiotic therapy, we should target an AUC24 >400 mg*hours/L.

It'southward unclear how high nosotros can button the AUC24 without causing nephrotoxicity.  The risk of nephrotoxicity increases gradually with higher exposures to vancomycin (figure above).  Overall, it seems reasonable to maintain the AUC24 below 600 mg*hours/Fifty. ^12–fifteen   Thus, the target AUC24 lies between 400-600 mg*hours/L.

Grudge match:  Trough vs. AUC

Calculating the AUC requires a bit of work.  A shortcut approach to guarantee clinical efficacy (AUC>400) is to proceed the trough level above 15 mg/L.  As shown below, mathematically this forces the AUC to be at least 400:

The pharmacokinetic simulation shown below illustrates the relationship between trough and AUC. ¹⁶ A trough above 15 mg/L guarantees that the AUC volition clinically constructive (>400).  The trouble with targeting a trough level between 15-xx mg/L is that occasionally the AUC will be insanely high.

In curt, achieving a trough >15 mg/L ensures efficacy simply not safety.  This issue has been shown clinically also: ¹⁷

Another illustration of why trough levels are a poor surrogate for AUC is that the relationship between trough and AUC is strongly influenced by the dosing interval:

Ultimately the trough level simply fails as a measurement of vancomycin exposure.  By itself, the trough is a poor predictor of treatment success. ¹⁸   When compared with the trough, the AUC better predicts which patients will respond to therapy. ^{nineteen–21}

To ensure optimal AUC/MIC, especially in critically ill patients, estimation of the AUC should be mandatory  –Montiero et al 2018 ⁷

Why conventional dosing fails

Conventional dosing consists of giving a weight-based dose (e.thou. 15 mg/kg q12) and then checking a trough level after four doses, targeting a trough of 15-20 mg/50 for serious infections.   In that location are numerous reasons this strategy fails, especially amid the sickest ICU patients:

1. Trough levels cannot ensure administration of a safe dose.Any strategy which is targeted solely to trough levels is fundamentally flawed.
2. The volume of distribution (Vd) is often abnormal amongst ICU patients – especially patients with book overload, burns, pregnancy, morbid obesity, or systemic inflammation.
3. Some patients in the ICU experienceaugmented renal clearance.  In response to stress, these patients takeelevated renal drug clearance.  When treated with standard doses of vancomycin, they will have depression vancomycin levels.
4. Many patients in the ICU endure from acute kidney injury, which often isn't accurately reflected past their creatinine levels (it may take several days for creatinine levels to re-equilibrate post-obit a change in renal function).  These patients are at risk for accumulating high vancomycin levels.
5. For reasons #2-four above, the estimated vancomycin dose will oft be incorrect.  Waiting until the 4th dose to check a trough may crusade patients to receive the wrong dose for 48 hours.

If vancomycin is dosed using conventional strategies among critically sick patients, patients will ordinarily receive inadequate or toxic doses.  A multinational observational study found that target drug levels were achieved in onlyhalf of patients! ²²

­Re-evaluation of current vancomycin dosing recommendations in critically ill patients is needed to more chop-chop and consistently achieve sufficient vancomycin exposure –Absorb et al 2014 ²²

Equation-based pharmacokinetic drug modeling:  a more precise arroyo.

Vancomycin dosing tin can be modeled nicely using a single-compartment model, where vancomycin distributes into a single compartment and is afterward eliminated via the kidneys.  This model appears to piece of work fairly well, except for the starting time few hours after a dose of vancomycin (while the drug is existence distributed to the tissues).

Ii points define an exponential decay curve.  Thus, using a unmarried-compartment model, two drug levels are required to define vancomycin pharmacokinetics.  This is slightly more than effort-intensive than merely measuring a trough, but it provides considerably more information:

• The volume of distribution (Vd) is measured (not estimated based on the patient's weight).  This avoids errors encountered in patients who are significant, obese, or edematous.
• The constant of elimination (Ke) is measured.  This eliminates the vagaries of estimating renal function based on a random creatinine level.
• Measurement of these parameters allows adding of the patient'south AUC.

The basics and bolts of equation-based pharmacokinetic dosing are explored here.  This does crave measuring more vancomycin levels.  The advantage is that this allows for immediate, personalized targeting of therapeutic drug levels.  The math involved can be performed by a variety of pharmacokinetic calculators including a Microsoft Excel spreadsheet:

Alternative method of pharmacokinetic calculations:  Bayesian strategy

Bayesian strategies start with a population database that relates pharmacokinetic parameters to several pieces of patient data (e.m., age, gender, weight, creatinine).  This database is used to create a calculator model which predicts an individual's pharmacokinetics from several pieces of information.

The chief advantage of a Bayesian strategy is reduction in the number of vancomycin levels that need to exist checked (east.chiliad. rather than checking two levels, only i level may be required).  However, Bayesian strategies accept a number of limitations:

• The book of distribution is frequentlyestimated (non measured directly).
• Bayesian models are adult within a certain population, with a specific ethnic makeup and range of body types.  Such models may fail in other populations or unusual torso types.  Alternatively, an equation-based arroyo makes naught assumptions and therefore works equally well on any human beingness (or mammal for that matter ²³ ).
• Numerous unlike Bayesian models exist, so success obtained with i Bayesian model doesn't guarantee that a different Bayesian model will work.  Alternatively, equation-based approaches yield consequent results, making this easier to generalize results across different centers.
• Equation-based strategies are available for gratis.  Alternatively, Bayesian models require purchasing a computer program.  This may create pro-Bayesian bias in the literature, because papers validating Bayesian models may be written by authors with conflicts of interest. ^24,25
• An equation-based approach is easily adaptable to other situations (eastward.g. pediatric patients, aminoglycosides).  This is a versatile, timeless tool which is worth learning.  In contrast, spending fourth dimension and money to learn a Bayesian figurer program is a dubious investment considering any reckoner programme might not exist in 10-20 years.
• An equation-based arroyo provides a real-time measurement of the glomerular filtration rate.  This is probably more accurate than our typical approaches to estimating glomerular filtration rate.  Serial measurement of real-time glomerular filtration charge per unit could provide useful information to detect acute kidney injury rapidly.
• One report directly comparison an equation-based strategy with five Bayesian programs establish that the equation-based approach was equivalent or superior to the Bayesian programs. ²⁵

In fairness, a Bayesian approach appears adequate for more than stable patients (e.thou. flooring patients with a stable creatinine level).  Alternatively, an equation-based approach may be superior in the ICU, where patients tend to take the most bizarre pharmacokinetics (e.yard. augmented renal clearance, severe systemic inflammation with expanded book of distribution).

Pharmacokinetic equations:  evidence

The principles of pharmacokinetic equations were described in 1976 by Sawchuk and Zaske. ²⁶   They oasis't changed over the past twoscore years.  Although no multi-heart RCTs has been performed on these equations, decades of feel support their efficacy.   Some newer studies using pharmacokinetic equations are equally follows.

Hong 2015:  Morbid obesity

This is a earlier/after study which compared traditional vancomycin dosing to two-point pharmacokinetic equations in patients with morbid obesity. ²⁷   In both groups, the therapeutic goal was to achieve a specific trough level (10-15 mg/L for mild infections; fifteen-20 mg/Fifty for severe infections).  The accurateness of the starting time trough level was the same between groups.  Dose adjustment using pharmacokinetic equations doubled the likelihood of achieving a target trough level on the 2nd measurement (65.two% vs 31%; p = 0.024).

The volume of distribution and drug clearance measured using pharmacokinetic equations was compared to the total body weight and estimated creatinine clearance (figure above).  Total trunk weight failed spectacularly in predicting the volume of distribution, which makes sense (inflammation may increase the volume of distribution by a factor of ii-3).  Two patients were identified with augmented renal clearance.  Overall this written report suggests that conventional weight-based dosing will often neglect these patients, who may be better served with personalized equation-based dosing.

Fitch 2016:  Patients in multi-center hospital network

Finch et al performed a before-after study documenting the transition from conventional trough-based vancomycin dosing to dosing based on 2-point pharmacokinetics at 4 hospitals. ^fifteen   Post-obit introduction of two-point pharmacokinetics to target an AUC>400, patients had lower vancomycin troughs.  This is exactly what would be predicted based on the human relationship between trough levels and AUC explored higher up.

Patients in the mail-intervention group were sicker (e.g. higher comorbidity and APACHE-II scores).  In unadjusted assay in that location was no difference in nephrotoxicity between the two groups.  However, using a diversity of different multivariable models, the use of 2-point pharmacokinetics was associated with a reduction in nephrotoxicity.

Truong 2022 & Miller 2018:  Pediatric and developed patients at Loma Linda University

This infirmary transitioned from conventional vancomycin dosing to equation-based pharmacokinetic modeling.  Their pharmacokinetic strategy involves checking two levels after the outset vancomycin dose, which were used to optimize subsequent doses.  Pharmacokinetic modeling was used to target a vancomycin trough level (not an AUC24).

In both developed and pediatric populations, the implementation of pharmacokinetic modeling hastened the achievement of target vancomycin troughs. ^28,29   Although choosing to target a trough level is debatable, these studies demonstrate that pharmacokinetic modeling works and it will facilitate reaching whatever goal you choose.

Parting shot:  employ vancomycin more selectively & more precisely

Pharmacokinetic dosing might seem like a lot of piece of work, only that'southward not necessarily a terrible thing:

• This might cause us to re-consider whether or not the patient truly needs MRSA coverage (rather than merely reflexively blanketing every critically ill patient with vancomycin).
• This might cause u.s.a. to re-consider whether linezolid might be better for some patients (e.g. patients with pneumonia or patients with extremely dynamic renal part).  Because linezolid is mostly metabolized past the liver, it doesn't require renal adjustment.

Given the narrowing therapeutic window for vancomycin, it'due south probably advisable to utilize it more selectively.  Nonetheless, when nosotros practice cull to use it, nosotros should practise so with thoughtfulness and precision.

• Increasing resistance to vancomycin is making it harder and harder to achieve vancomycin levels which are both condom and effective.
• Efficacy and toxicity of vancomycin appear nigh closely related to the surface area nether the concentration-time curve over 24 hours (AUC24).  The optimal balance of efficacy versus toxicity seems to occur within an AUC24 range between ~400-600 mg*hr/L.
• Traditionally, vancomycin doses have been adjusted to target a specific trough level.  However, it is increasingly clear that the trough level is an inadequate measurement of vancomycin exposure.  Furthermore, the practise of waiting until the fourth dose to measure the trough level may expose the patient to days of suboptimal therapy.
• Upwardly-front two-point pharmacokinetic modeling allows adding of drug clearance and volume of distribution.  This facilitates immediate optimization of drug doses, maximizing efficacy while simultaneously avoiding nephrotoxicity.
• Equation-based pharmacokinetic modeling isn't rocket science.  This tin be done with free online calculators or an Excel spreadsheet (explored further here).

Related

• Nuts & bolts of vancomycin PK monitoring (PulmCrit)

References

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Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Disquisitional Intendance Medicine at the University of Vermont.

maycrues2000.blogspot.com

Source: https://emcrit.org/pulmcrit/vanco/

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