Introduction to therapeutic drug monitoring (TDM)

In this step, we will begin to explore the role of therapeutic drug monitoring (TDM) when treating with aminoglycosides.

What is TDM?

TDM measures the concentration of certain medicines in the blood and is primarily used to ensure a safe and effective dosing schedule.

Last week, you learnt that aminoglycoside levels can be linked to toxicity in the body. Further information on this is provided below, which, in addition to understanding the concentration-dependent PK/PD model described earlier this week, justifies the importance of performing TDM when using aminoglycosides.

How is toxicity linked to aminoglycoside levels?

Patients are at risk due to neurotoxicity associated with aminoglycosides, which causes hearing loss and dizziness, both if they have existing kidney damage or normal kidney function. Associated high-pitched tinnitus, which usually occurs first and can be detected only by audiometric testing, is usually irreversible. This adverse effect can occur in patients who are treated with higher doses and/or for periods longer than those recommended. So high initial levels (Cmax) or sustained high blood levels (AUC and trough levels) will increase the risk of ototoxicity.

Aminoglycosides are potentially toxic to the kidney as they accumulate in the renal proximal tubular cells. Risk is greater in patients with impaired renal function and in those who receive high doses or prolonged therapy. Again, high initial levels (Cmax) or sustained high blood levels (AUC and trough levels) increase the risks.

Now that you have seen how aminoglycosides can be toxic in the body, particularly when administered in high doses or over a long period of time, we will describe more about TDM used to monitor levels of aminoglycosides in the body.

How is TDM performed?

Where is the aminoglycoside concentration measured?

Ideally, we would like to measure the aminoglycoside concentration at the actual site of infection, for example epithelial lining fluid in pneumonia or CSF in meningitis as this is where antimicrobial-pathogen interactions take place.

However, in practice, this is not possible, and measured plasma concentrations of aminoglycosides are used as an alternative. It is important to remember, however, that we cannot assume even distribution throughout the body. A knowledge of how aminoglycosides are distributed is also required and informed use of measured levels is used to maximise the effect. For example, aminoglycosides distribute well into the kidneys but absorption into CSF and bone is poor – see step 2.4 for more detail on the penetration of aminoglycosides to different body sites.

How and when to take serum levels

This will vary between hospitals, and ranges are different depending on the frequency of aminoglycoside given and the type of infection. Measurements taken can be separated into one of two groups:

• Peak level
• Trough level

Take a look at the graph below showing each of these measurements and their definitions.

In the table available in the downloads section below are recommendations from the Bristol Reference Laboratory. These will differ if using a nomogram such as the Urban and Craig nomogram, which may be used in some settings and has specific targets. Gentamicin level monitoring specifically will be discussed in more detail later in this step.

Once-daily dosing of aminoglycosides

When aminoglycosides are given as a single daily dose, a trough level tends to be measured, and there is a window when these levels can be taken between 18 – 24 hours after the start of the infusion. This is because peak levels obtained are reliably high, with a maximum peak-to-MIC ratio and a large total AUC. Peak and trough levels are not thought to be helpful in predicting risk of nephrotoxicity.

Gentamicin level monitoring

Population-based nomograms or equations are often used to adjust initial dosing of aminoglycosides and can provide individualised predictions based on plasma levels measured at a certain time point after a dose for individual patients. These can be used to change doses or time intervals between doses to aim to reach target concentrations. They allow flexibility on sampling time for levels which is useful in clinical practice.

The Urban and Craig nomogram is an example of one such nomogram which is used in some hospitals for patients receiving gentamicin at a dose of 5mg/kg. This was previously mentioned in step 2.4. This nomogram was constructed to a period of 4 hours when the blood concentration is less than 1mg/L and maximum length of post-antibiotic effect of not greater than 16 hours. This nomogram can also be adapted to use with netilmicin or amikacin.

We need plasma levels to be taken between 6 and 14 hours after the start of an infusion of gentamicin to use this nomogram and changes are then made to the dosing interval if required. We will return to this example with gentamicin in a case study step later this week.

Is TDM needed for all patients?

In certain circumstances, for example in patients with good renal function (CrCl >60 mL/min) where the expected duration of treatment is less than 5 days, the risk of toxicity is relatively low when using the recommended dosage of aminoglycosides. In this case, TDM may be considered unnecessary.

Use of TDM

TDM is usually seen as cost-effective because of the risks associated with dosage of aminoglycosides and the successes achieved in managing therapy with the proper interpretation of TDM analysis. However, although TDM is standard practice within the UK, it is not always feasible for this service to be provided within lower-income countries due to the need to have laboratory facilities available and the cost of providing such a service.

In other countries, there is poor uptake of TDM services; for example, a survey carried out in South Korea to find out the extent of usage of TDM in 2019 showed there were barriers to usage such as poor assaying and lack of availability of TDM consultancy services.

Studies in the literature have also suggested it is hard to identify optimum dosage regimes and drug concentrations of aminoglycosides that link to good clinical outcomes. This has led to a wide variety of dosing used in practice.

Advances in TDM

More recently, computerised models have been developed that apply population pharmacokinetics combined with individual patient data to calculate dose and dosing intervals for antimicrobials. These models are thought to provide a more accurate method of predicting effective but non-toxic dosing of aminoglycosides; however, they are not yet in routine practice throughout the UK.

Next we will move on to discuss how levels are measured in the laboratory.