Want to keep learning?

This content is taken from the Taipei Medical University's online course, Clinical Pharmacokinetics: Dosing and Monitoring. Join the course to learn more.

Skip to 0 minutes and 16 seconds Which time values are needed to calculate a new rate of infusion for aminoglycoside dosing A is true. The length or duration of the infusion. B is also true.The dosing interval, the Tau, C is not true The time from the end of the infusion to the trough level is not something that we measure, it would be that the time from the trough level to the beginning of the next dose. So the answer to this question is D.

Skip to 0 minutes and 48 seconds Another approach to administering aminoglycosides is what’s called once-daily or extended interval dosing, where the patient receives a much higher dose four to seven milligrams per kilogram, generally every 24 hours, even if they have normal renal function. Remember the standard interval dosing interval was eight hours. This is 24 hours with a much higher dose of four to seven milligrams per kilogram. Extended-interval dosing shoots for a much higher peak twenty to thirty milligrams per liter, which is more in the target range of 10 times the MIC. So it provides a much bigger knockout punch than standard interval dosing of amino glycosides.

Skip to 1 minute and 32 seconds To avoid toxicity, we even shoot for a lower trough with extended herbal dosing less than 1 milligram per liter as compared to less than 2 milligrams per liter for standard interval dosing. The fact that amino glycosides have a post-antibiotic effect of generally anywhere from 8 to 12 hours helps to facilitate the longer dosing interval and getting the trough level way down below 1. Generally, if the crediting clearance is greater than 60, it’s okay to use a 24-hour interval for extended herbal dosing. If the crediting clearance is less than 60, it might be necessary to go with a Q36 or Q48, our regimen.

Skip to 2 minutes and 17 seconds Advantages over standard dosing or a faster clinical response less nephrotoxicity, decreased potential for resistance easy monitoring and lower cost because fewer serum levels are being measured. But you have to be cautious extender interval dosing should be avoided, if a patient is pregnant or severely ill. In the elderly patients with liver disease or those who have fluid imbalance

Skip to 2 minutes and 51 seconds The Hartford Nomogram is also used to start patients an extended interval dosing when using the Hartford Nomogram a standard 7 milligram per kilogram dose should be given. A serum level is then measured 6 to 14 hours after the start of that infusion. And then the serum level is measured against this chart to identify the dosing interval that should be maintained with the 7 milligram per kilogram dose. So, for example, if the serum level is measured at 7 hours and it turns out to be 4 that would indicate a queue 24-hour dosing interval.

Skip to 3 minutes and 35 seconds If it was 8 at 7 hours that would be Q 36 and if it was 12 at 7 hours that would suggest a Q 48 hour dosing regimen. Now we conducted a study last year and the prevalence of extended interval dosing surveying 43 hospitals in the state of Florida, we found that 15 out of the 43 use extended interval dosing for more than 75% of their patients. 15 used it for 51 to 75% of their patients and 13 used it in less than half of their patients. So in the state of Florida, we found that extended interval dosing of aminoglycosides is a very common practice. We should also consider the impact of changes in volume of aminoglycosides.

Skip to 4 minutes and 31 seconds Aminoglycosides distribute into extracellular fluid and there are many clinical conditions that can alter the extracellular fluid the overall fluid status of a patient. These can impact volume of distribution of amino glycosides and also therefore the elimination rate constant for amino glycosides Normally the volume of distribution is 0.25 liters per kilogram but again it’s dependent on extracellular fluid volume. Fluid retention can significantly increase aminoglycoside volume. Things like a site ease, third spacing after surgery, patients who are septic can significantly increase the volume of distribution. We have to remember that elimination rate constant is equal to clearance divided by volume. So an increase in volume will cause a decrease in elimination rate constant.

Skip to 5 minutes and 29 seconds And this will also cause this trough concentration to rise even if the patient’s clearance does not change. If renal function does not change at all and aminoglycoside clearance does not change at all, trough levels may rise simply because the elimination rate constant has decreased due to the increase in volume. Now the red curve shows a V increased from 20 to 30 liters, so the elimination rate constant dropped in this patient from zero point two, to zero point one three. In this case, simply because of the change in volume, this patient’s trough level would increase from one point three to one point eight milligrams per liter. Let’s walk through an exercise.

Skip to 6 minutes and 18 seconds A gentamicin gentamicin patient retains a large amount of fluid after surgery, his real function has not changed at all. If the original serum levels were a Cpeak of 6.5 and a Ctrough of 1.5, which of the following levels would you most expect to occur? Well let’s consider first that V increased so how would the Cmax change? Well if V increases, we would expect the Cmax to decrease. Secondly, if the increased K will decrease and if K decreases how would we expect the Cmin to change Well if K decreases, Cmin should increase . So what we should be looking for is an option in which the peak will decrease from what it was.

Skip to 7 minutes and 9 seconds But the trough will increase from what it was. Because volume increased and elimination rate constant decreased. So the answer to this exercise is d. A peak of five point five in a trough of two point five is the only combination that would make sense based on this patients increase in volume. Take-home points are that if V increases without a change in dosing regimen the C peak will decrease. If K decreases without a change in dosing regimen, the C trough will increase. Let’s try a similar one.

Skip to 7 minutes and 48 seconds Again, if a patient is receiving gentamicin retains a large amount of fluid after surgery and his C trough is rising, we know that his renal function has not changed, to restore his serum levels to what they were preoperative, how would you change the dosing regimen? Well let’s think this through. First if V increased, what would we have to do? To compensate for that increase in volume what would need to change? Answer is the dose. if V increased, we would need to increase the dose to prevent Cmax from falling. Secondly if K decreased, what would we need to change to prevent the C trough from rising? And when K decreases, we can compensate for that by changing the tau.

Skip to 8 minutes and 46 seconds So the answer to this question is we would increase the dose and increase the tau, increase the dosing interval. Our take-home points from this exercise if V increases in order to keep the C peak and the C trough from changing the dose needs to be increased. Because the patient’s tank, the volume of the tank is larger. If K decreases in order to keep C peak and C trough from changing, the dosing interval needs to be increased because it will take longer for the Cpeak to drop down to the C trough.

Skip to 9 minutes and 23 seconds Another way to look at this is that to prevent the C peak and the C trough from changing the value of e to the minus K tau must not change. So if K decreased we would have to increase the tau to keep the value of e to the minus K tau the same.

Skip to 9 minutes and 47 seconds Now let’s walk through a couple final brain exercises, as we wrap up lesson 5. Which of the following statements is are true about gentamicin dosing regimens? A, extended interval dosing regimens shoot for a higher C peak than standard interval dosing regimens. That’s a true statement. Extended interval regimens shoot for a peak up around 20 or above and standard interval dosing regimens shoot for a peak of about 4 to 10. B is a false statement. Extended interval dosing regimens shoot for a higher C trough than SID or standard interval dosing regimens. No. Extended interval regimens actually shoot for a lower trough of less than one. Standard interval regimen shoots for a trough of less than 2.

Skip to 10 minutes and 42 seconds C Extended interval regimens take longer to reach steady state than standard interval dosing. I hope you get this one right. The answer is false Dosing regimens have nothing to do with how long it takes to get to steady-state we specified that in an earlier lesson. Time it takes to reach steady state depends only on the half-life. Four point three half-lives are needed to reach 95% of steady state. So the answer is A. Let’s try one more as we wrap this up. For a patient being treated with an aminoglycoside, a rising Ccr could be interpreted to mean what? Athe patient is developing aminoglycoside nephrotoxicity That’s a true statement.

Skip to 11 minutes and 29 seconds A rising serum creatinine might be an indication that the aminoglycoside is beginning to harm the kidneys. B is also true. The patient might need to have the dosing regimen reduced because aminoglycosides are eliminated by the kidneys. and if the serum creatinine is rising it might be an indicator that real function is being diminished. C says the aminoglycoside might not be treating the infection. That’s a false statement. Serum creatinine is monitored for toxicity and for dosing purposes only. It has nothing to do with whether the aminoglycoside is effectively treating the infection. So the answer to this question is D. A and B are correct but C is not.

Skip to 12 minutes and 18 seconds So let’s wrap this up, the key to solving the puzzle of dosing aminoglycosides in vancomycin

Skip to 12 minutes and 26 seconds Give enough drug and knock out the pathogen without harming the patient when it comes to aminoglycosides that means a high peak concentration. Extend internal dosing achieves a peak of 10 times the MIC or more when it comes to vancomycin that knockout punch is more of a continuous gradual punch based upon area under the curve for 24 hours being well above the MIC whether we’re shooting for a high peak concentration or a high area under the curve concentration, ultimately, when we’re treating patients with aminoglycosides or vancomycin what we’re trying to do is give enough drug to kill the pathogen but not give so much drug that it causes harm to the patient.

Skip to 13 minutes and 17 seconds We want to be concerned about both efficacy and safety

Once-daily (Extended-Interval) Aminoglycoside Dosing & Summary

Prof. Brown lists the advantages of Extended-interval aminoglycoside dosing, and its precautions.

He uses the Hartford Nomogram to illustrate how to use a suitable dose. We found the prevalence of EID in 2015 survey of 43 Florida hospitals is high.

What is the impact of Aminoglycoside changes in volume? When volume increases, how does it affect k and C?

This video has several exercises to review this lesson. The key to solving the puzzles of dosing Aminoglycoside and Vancomycin is giving enough drug to knock out the pathogen without harming the patient. We need to concern two things. What are they? Please leave your answer below.

This is the end of this lesson. We are looking forward to your feedback, so please share some of the key points you have learned or any question you may have!


Prof. Daniel L. Brown

Share this video:

This video is from the free online course:

Clinical Pharmacokinetics: Dosing and Monitoring

Taipei Medical University