Once-daily Vs. multiple daily doses

Traditionally aminoglycoside antibiotics have been administered as multiple daily dose regimens (2-3 divided doses over 24 hours) due to their relatively short half-life, as illustrated in step 2.4.

Think back to the question you were asked at the bottom of step 2.4. Considering aminoglycosides’ short half-lives, you would not expect that the antibiotics are effective over a full 24-hour period as there would be a large period of time when the blood concentrations of the aminoglycoside are below the pathogen’s MIC. However, in both laboratory and clinical use, we see a continued effect on preventing bacteria regrowth – termed the post antimicrobial effect (PAE), which you were introduced to back in Week 1.

PAE

PAE is seen due to intracellular accumulation of aminoglycosides within the bacterial cells, which remains therapeutic even after the blood concentrations are below the MIC. This effect has been shown in a variety of other antimicrobials.

A number of different factors can affect the PAE:

• The antimicrobial
• The organism and its MIC
• Drug concentration
• Length of exposure to antimicrobial
• Renal function

The PAE seen with aminoglycosides means that once-a-day dosing can be possible, and this dosing pattern has largely superseded traditional multiple-daily dose regimens.

Once-daily dosing

Once-daily dosing uses a higher weight-based dose of antibiotic administered once per 24-hour period (or longer in some patient groups with reduced renal function). This approach achieves a higher Cmax compared with smaller weight-based doses delivered multiple times across the day.

There are a number of reasons why a once-a-day dosing of aminoglycosides may be more effective and preferred practically. Some of these are explored below.

To inhibit the regrowth of resistant bacteria

As explained above, once-daily dose can give a higher Cmax. To inhibit the growth of the small drug-resistant population present at the initiation of therapy, a concentration of aminoglycosides significantly above the MIC is required, i.e. a concentration of:

• 3 x the MIC for gentamicin against Gram-negative infections
• 8 x the MIC for amikacin against Gram-negative bacteria

Obtaining higher peak (Cmax) levels

The higher Cmax levels seen with once-daily dosing are beneficial when considering the PK/PD model for aminoglycosides, which are concentration-dependent (Peak/MIC) agents. Therefore, when using aminoglycosides, their concentration is directly related to bacterial killing thereby ensuring a greater overall clinical effect.

Improved clinical effect

A meta-analysis of the comparative effect and safety of aminoglycosides by Barza et al looked at 21 randomised controlled trials and more than 3000 patients, and showed a trend towards fewer clinical failures in the once-daily dosing group. Results indicated a larger positive effect of using aminoglycosides when treating infections caused by Pseudomonas species. Overall, the clinical effect of once-daily dosing has been shown to be comparable, with some trials showing it to be a superior method of dosing.

Less Toxicity

Studies have shown mixed evidence regarding toxicity of aminoglycosides. The meta-analysis mentioned above by Barza et al showed a significantly lower incidence of toxicity to the kidneys with once-daily dosing. Whilst this has not been shown in all studies, greater toxicity with once-daily dosing has not yet been demonstrated.

Less cost

Avoiding multiple aminoglycoside administrations can save the cost of consumables and nursing time. In addition, it is also associated with a reduction in the number of blood tests required for monitoring (which you will learn more about later this week).

• Can you think of any other reasons why once-daily dosing might be more effective and preferred practically?

Let us know in the comments below!