A loading dose may be used to rapidly achieve steady-state pharmacokinetics. For drugs with a long half-life, this accelerates the attainment of therapeutic levels:
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2023/12/loaddose.jpg?resize=450%2C373&ssl=1)
For most drugs with single-compartment pharmacokinetics, a loading dose may be calculated using the following formula: (discussed further here)
The graph below illustrates how this equation works:
- If (dosing interval)/(half life) is high, then individual doses don't really overlap much (but rather, each dose of medication is mostly eliminated before the next dose is given). In this situation the loading dose is close to the maintenance dose – so there is actually no need to use a distinct loading dose.
- If (dosing interval)/(half life) is low, this is where a loading dose is actually needed. If the drug is started without a loading dose, doses will overlap considerably leading to accumulation over time. Thus, it would take many doses to reach steady state.
Let's take a look at how this works out for some commonly used antibiotics:
This math explains some aspects of antibiotic dosing:
- For most beta-lactams, the dosing interval is much higher than the half-life, so there is no need for a loading dose.
- Trimethoprim-sulfamethoxazole and especially doxycycline could theoretically benefit from a loading dose. There is some support for these concepts in the medical literature, especially regarding doxycycline. (8225622) For serious infections, initiating doxycycline with a loading dose of 200 mg makes sense. (28819873)
Interestingly, this math casts a little shade on the loading dose of vancomycin. In patients with normal renal function, there theoretically shouldn't be much need for a loading dose. Or, to look at this from a different perspective, if a high initial dose of vancomycin is needed to achieve adequate levels then a similarly high maintenance dose should also be needed. But vancomycin pharmacokinetics is an entire world of pain and I don't want to get lost there today.
Anyway, that's it for now, I'd be interested to hear what antibiotic pharmacology gurus think about this. Is there anyone out there using loading doses for doxycycline and/or trimethoprim-sulfamethoxazole?
Opening image: Photo by Mike van den Bos on Unsplash
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Hi Josh, thanks for this post.
I’m a EM resident in Italy and here it is almost mandatory (if not dogmatic) to give loading dose of Piptazo. If you start with a 4.5g qid people will look at you like you’re some kind of alien. This post was needed. Thanks again.
Between two different and major healthcare systems I have worked for, its an auto-reflex now to dose adjust to 4.5g but we do q8h extended infusion (4hrs). But I normally give the first dose over 30 minutes.
Hi Josh
I’m a first year anaesthetic trainee in Scotland, but am a PGY4. Not in any way a pharmacology guru.
Doxycycline is always given with a 200mg loading dose followed by 100mg maintenance doses here, not just in ICU but in the wards also. It’s interesting to finally see a rational for that. I might delve further into vanc pharmacology though because we have a national vanc dosing calculator that always asks for a much bigger loading dose than your equation suggests
Hello !
Just to make things clear : this only applies to drugs without continuous administration, right ? Because loading dose for beta-lactams still makes sense for me if a continuous regimen is adopted (which is another debate).
Thanks for the topic though, very interesting !
Hi Josh! Thx for a great post on a very interesting topic. Regarding loading dose of doxycycline and minocycline I believe most European sources recommends a loading dose similar to the approach mentioned by the gentleman from Scotland in the comments and by yourself in the original post. I am unaware of this practice with TMP/SMX although it does appear to make sense from a PK-PD perspective. Regarding the optimal dosing strategy for betalactams I believe that the jury is still out. But as shown in the DALI-study (1) in Europe it is clear that one size does not fit… Read more »
very cool comments by our international friends… thanks for this Josh
tom fiero
Here in western Canada a loading dose of doxycycline has always been the “technically correct” way to do it as long as I’ve been around, although it is often skipped, I suspect because it takes slightly longer to write the Rx. I was doing it until I had a few patients vomit up the 200mg dose and come back saying they were allergic. That was finally enough for me to join the crowd and now I skip the loading dose too. Maybe I need to reconsider!
It was an interesting topic. Thanks