Summary : Case practice

Let’s do some practice. When we do pharmacokinetic calculations, the peak and trough, or Cmax and Cmin are calculated using IV infusion equations for aminoglycosides. With vancomycin, why is it justified to use IV bolus equation to calculate Cmax and Cmin instead of using IV infusion equation? A. Vancomycin has a lower clearance which results in a smaller fluctuation B. Vancomycin has a higher clearance which results in a larger half-life C. Vancomycin has a smaller volume of distribution which results in a larger fluctuation D. Vancomycin has a longer half-life which result in a smaller fluctuation E. Vancomycin has a smaller half-life which results in smaller fluctuation Do you have your answer already？ Let’s take a look. Yes, the answer is D.

Vancomycin has a longer half-life which result in a smaller fluctuation. Gentamicin or aminoglycoside is rapidly eliminated, therefore drug loss during infusion is significant, so we cannot use bolus model. Here is a case practice for vancomycin. A 68 years old female, height 156cm, and weight of 43kg, pursuing heightening was 1.2, she was started on vancomycin 500mg IV q12h for MRSA hospital acquire pneumonia.

Infusion time was 1 hour, dose was given at 9:00AM and 9:00PM every day. So first of all, please recommend an appropriate time to draw vancomycin serum level. Remember, we don’t do peak level for vancomycin anymore, so we need to monitor trough level at steady state. Which will be based on the kind of recommendation about right prior to the fourth dose,

And normally I would give a specific time, like tomorrow evening at 8:30 p.m. or something for them to follow. Vancomycin level on the third day at 6 a.m. came back 28, so the physician ask your opinion on whether he should revise the dosing? And if he should, how? Usually the first thing I do when I write a measured level is to calculate the estimated CrCl first. Because the level was most of the time not measured at the exact trough time. In order to do this, I can only use the population PK to estimate the elimination rate of vancomycin in this patient. You may see different equation from different reference, use the one that you feel comfortable.

So here we use Cockcroft and Gault to calculate creatinine clearance, and we estimate the volume of distribution. Here I use 0.9L per kg. The patient is 43 kg. And estimate vancomycin clearance, then K equals clearance divided by volume of distribution. We can get a K of 0.6 . Use the concentration equation Ctrough equals C1 times e-kt’, and plug in the measured trough level which is 28, and putting the time difference here, which is 9 a.m. - 6 a.m. is three hours.

Then you have the estimated true trough level of about 23.4 right at 9:00 a.m. This true trough is above our desire target level of 13 to 20, so yes, you should recommend making those adjustment of vancomycin. If the measure level was let’s say 22, and the calculate true trough level is 18, then we don’t need to make any adjustment. In order to calculate patient’s specific K , we will need to at least 2 measure levels. Since we only have one measure level here we’ll have to do more estimation. We can calculate the estimated peak using C max equals to C min plus dose of the volume of distribution.

In this case, the calculated peak level is 36, the calculated peak level is 35.6, and we can calculate elimination rate constant K with the equation K equals natural log of C1 over C2, and divided by T, which is the dosing interval. If we use peak and trough level, you can get a K of about 0.037. Once we have K, we have half life. And we can estimate dosing interval of about one to two half-lives. Here we pick 24 hours as our new dosing interval. The final step, we use our target trough level to calculate the maintenance dose.

Refer to the equation on the slide here, blocking the new K and the new Tau we just got, and you can get a dose of about a thousand mg. Therefore, the new dosing regimen is to give vancomycin 1g, and dose it once daily. Note that in this case, it happens that the new total daily dose is the same as the original total daily dose, but we increase the dosing interval, so that the trough can be lowered. Clinically in practice, you may often see people use propulsion method to quickly estimate dose adjustments. This is because vancomycin has a first order elimination, and can be considered as having a linear PK.

Dosing in propulsion is fast, but doing calculation with the pharmacokinetic equation if you have time, it still considered more accurate. Vancomycin dosing is still controversial topic. It is anticipated that the upcoming new guidelines will have recommendations for an approach to dosing based on attaining AUC to MIC goal. In this case, we use target AUIC to calculate 24-hour vancomycin dose. Dose equals AUIC times and vacomycin clearance times MIC. One of the problem here you can see is that, we don’t have the MIC value in the beginning, and we’ll have to wait for the result.

In the case if you use 400 as the AUIC goal, we can get the dose 24 hours of about 1000mg, which is exactly equal to the original 500 q12 hour dosing. So if we use AUC to MIC as our pharmacodynamic target, then we don’t need to increase the dosing frequency to 24 hours just to meet the target trough. So you can see now that you know, dosing frequency does not affect AUC to MIC ratio, but it will result in different trough and now we use trough as our surrogate outcome. So how should we do vancomycin therapeutic dose monitoring.

As a clinician, at the end of the day it is just a goal, but not the rule that we need to take the patient clinical context into account. If they are improving on the current dose, but not technically meeting a perfect trough, or AUC MIC goal, then maybe we don’t need to get too excited about adjusting things just to meet a certain number, when the patient is improving clinically and in a reasonable dose exposure. Dose adjustments should be more tailored to individual patient severity of illness, since higher exposure will be associated with increased toxicity. Lastly we’ll do an aminoglycoside calculation practice. Mr. Chen is a 60 year old male who is admitted for the treatment of acute DVT .

However, on the morning of day 4 he rapidly deteriorated. His O2 saturation dropped requiring supplemental oxygen, and he spiked a fever and his white count was significantly elevated. He also reported a cough. A subsequent chest x-ray shows evidence suggestive of right lower lobe infiltrate, consistent with ammonia. Also of note, he was treated with ciprofloxacin four weeks ago for acute pyelonephritis. He received three days of IV therapy as an inpatient before completing a full seven day course of therapy with oral ciprofloxacin. He reported a penicillin allergy. This case is apparently a hospital acquired pneumonia case again. Since the symptoms appears longer than 48 hours after the admission.

And the patient has respective having multi drug-resistant pathogens because he had prior IV antibiotic use within 90 days. Ceftazidime 2g IV q eight hours plus gentamicin 120 mg q 8 hours was prescribed for this patient, and expected to achieve steady-state gentamicin peak and trough concentration of 9 and 1, respectively. After the third dose, steady-state gentamicin peak and trough concentrations were measured and were 12 and 1.4 mg per ml, respectively. Calculated new gentamicin dose that will provide a steady-state peak of nine. Dose time at 9AM. Infusion time is 30 minutes. Peak was drawn at 10AM,

and the trough was drawn at 4:30 in the afternoon. So now we have two measure level. So we can calculate the elimination rate constant K for this patient. C2 equals to C1 times e to -kt’ , plug in the two levels 1.4 and 12, t’ 6.5 hours. You can see the illustrations. Then we can get a K of 0.33. Then we use the K to estimate the true peak and trough, using the same concentration equation. True peak is the level right at the end of infusion and, true trough should be the lowest point right prior to the max dose.

Put the number in, we can get a true peak of 14.15, and true trough of 1.18 We gave a maintenance dose of 120 mg gentamicin, τ is every eight hour, infusion time is point four hour. We also have the K and the peak concentration. so now we can use this big equation to calculate the volume of distribution. Take out your calculator, we can get a volume of distribution is 8.42 Now we need to calculate the new dosing interval tau(τ), using the peak and trough level we want. So which is in this case we want nine for peak and one for trough. Tau(τ) equals to natural log of Cpeak over Ctrough, divided by K, plus infusion time.

And we can get 7.2 hours. We round it to eight hour, which is the same with the original dosing interval. Now that the first part, know that the first part of the equation determines the time from when the peak is measured to the time when the trough is measured. The final step is to calculate the new dose by referring to the same equation we use earlier for volume of distribution calculation. We can get a new dosing regimen of 80 mg, and we dose it every eight hour. If you use a once daily dosing or extended interval dosing aminoglycoside, you can just refer to the half of normal gram for once daily dose aminoglycoside dose adjustment. That’s concludes today’s course.

Thank you for your listening today. I hope you can find something useful from this lecture in your future practice.