Clinical recommendations on the therapeutic monitoring of Vancomycin

Hi everyone. Welcome to the last section of the clinical applications of Pharmacokinetics dosing and monitoring course. My name is Marcy Wu. I’m a clinical pharmacist from Wanfang Hospital Taipei Taiwan. I’m sure you all have learned a lot from Dr. Brown’s previous lectures. Today I’m going to focus on the clinical recommendations in clinical practice on the therapeutic monitoring of vancomycin, and making dose adjustment to vancomycin and aminoglycosides. Today’s outline, we will start with vancomycin. Go through the current consensus of recommendations on vancomycin therapeutic monitoring, we will introduce the common clinical use of aminoglycoside, and briefly talk about a new 2016 hospital-acquired pneumonia, HAP guideline. Using hospital acquired pneumonia as an example to introduce the clinical role of vancomycin an aminoglycoside.

And at the end, we will have some practice. Vancomycin is classified as a glycopeptide. It is a large hydrophilic molecule works by inhibiting bacterial cell wall synthesis. it is an old drug approved in 1958. Vancomycin is used to treat serious gram-positive infection involving MRSA,methicillin-resistant Staphylococcus aureus. Common and well-known side effects of vancomycin includes infusion related toxicity, which is known as threatening syndrome. And in this case, you should slow down the infusion rate. Other toxicity such as nephrotoxicity and possible ototoxicity.

The incidence of this toxicity is now believed to be much smaller than we previously thought from the old reports, unless when we use vancomycin in combination with other renal toxic or ototoxic medications I apologize if this table may appear small. It shows that currently known pharmacokinetics and pharmacodynamic parameters of antibiotics. Because of the increasing resistance and the limited antibiotic choses, nowadays we often talk about utilizing PKPD characteristic of the antibiotics to maximize the treatment effects. For example, we know aminoglycoside is concentration dependent antibiotics. So the clinical optimization strategy is to use high dose once daily or extended interval dosing to get higher C max to MIC ratio. However these are the concepts and theories.

Some of the clinical relevant targets of this antibiotics have not been well established. But this is the direction to work on. In terms of vancomycin’s pharmacodynamic, we used to think that vancomycin is a time-dependent antibiotics. But if this is a case, than the specific pharmacodynamic parameter that best describe vancomycin activity should be the time above MIC, and making it reasonable to monitor trough for vancomycin therapeutic effect. However, why is that often we still see therapy fail in some patients when the trough level was maintained between fifteen and twenty? One of the possible explanation is that, the wrong PKPD target has been accepted as correct throughout the past decades.

We have old and more recent evidence suggesting that this is the case And here you can see the data published in 1987. In look at the in vivo side of activity of vancomycin against MRSA, and compare the result using different pharmacokinetics parameters, you can see that the change in colony forming units, which is the y-axis, is in correlation with the 24-hour AUC, area under the curve, to MIC ratio. The higher the AUC to MIC, the lower the colony number. But such correlation is not clear, what does not exist, was either peak to MIC ratio or time above MIC, which means it’s not concentration dependent nor time dependent. Here is the data published in 2004.

You can see the similar results that the 24-hour AUC to MIC correlated best with vancomycin bacterial killing effects. And to the right, you can see when they reach a hundred percent the time above MIC goal for vancomycin, does not predict its clinical or biological outcomes. Therefore more data is telling us that maybe trough level is not what we should be looking for. A consensus review of ASHP, IDSA, and SIDP on the therapeutic monitoring of vancomycin was first published in 2009. You can see the consensus is old, and I think that they have been in the process of updating it for a couple of years. But in the meantime, here we will just review the current recommendation.

Here’s the recommendation on how to start the dose of vancomycin. 15 to 20 mg per kg based on actual body weight dose every 8 to 12 hours to achieve optimal trough level. And this is assumed that MIC is equal to or lower than 1. If the MIC is equal to or greater than 2, then the AUC to MIC ratio of 400 is not achievable. It also recommend using a 25 to 30 mg per kg loading dose. In 2009 recommendation they did not encourage the use of continuous infusion of vancomycin, because there was not enough data showing the superiority of doing so. The recommended TDM parameter for vancomycin in the 2009 recommendation is still the trough level.

Timing of monitoring is to measure the searing level, which is prior to the fourth dose at a steady state. For pathogen with MIC of 1, we need a trough level of at least 15 to generate the target AUC to MIC of 400. Remember that almost all the data supporting AUC to MIC target is based on MIC determined by E test. If you are using a different testing method, you’re AUC to MIC should not be 400. And we want to maintain child concentration between 15 and 20, in order to improve clinical outcome. Therapeutic dose monitoring for vancomycin used induce nephrotoxicity. Because no data has suggests the correlation of peak in nephrotoxicity, monitoring peak level is no longer recommended.

And for trough monitoring, we pretty much use the clinical judgment to guide the monitoring frequency. Increase the frequency when there is high risk of sign of nephrotoxicity, unstable renal function, or in patients who are hemodynamically unstable.