Cidofovir in hemodialysis

[Praziquantel86]

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We have an HIV+ patient on hemodialysis for ESRD admitted for treatment of recurrent genital HSV infection. She's failed acyclovir in the past, and due to the current shortage of foscarnet, we don't have any left (we were treating her with it). So, the possibility is that we may have to start cidofovir.

I know it's a long shot, but do any of the ID folks on here have any experience dosing cidofovir in hemodialysis? I was able to find one paper stating that it is ~50% cleared by high-flux, but no recommendations were made. Gilead was no help either. Any insight would be very much appreciated.

By the way, if you're wondering about ganciclovir, we may attempt that as well, but I'd just like to cover my bases in case the need arises.

 

[Praziquantel86]

Thanks for the help! Don't go crazy looking for anything - it's not as urgent as it might seem (we have a couple of doses of foscarnet remaining). I was hoping somebody from your institution might reply 🙂

 

[Quiksilver]

We have an HIV+ patient on hemodialysis for ESRD admitted for treatment of recurrent genital HSV infection. She's failed acyclovir in the past, and due to the current shortage of foscarnet, we don't have any left (we were treating her with it). So, the possibility is that we may have to start cidofovir.

I know it's a long shot, but do any of the ID folks on here have any experience dosing cidofovir in hemodialysis? I was able to find one paper stating that it is ~50% cleared by high-flux, but no recommendations were made. Gilead was no help either. Any insight would be very much appreciated.

By the way, if you're wondering about ganciclovir, we may attempt that as well, but I'd just like to cover my bases in case the need arises.

So which are you going to go with first, cidofovir or the ganciclovir

 

[ttopping]

And the follow up email:

Cidofovir is an odd choice. It's contraindicated with a Scr >1.5. Cidofovir administration must be accompanied by oral probenecid and NS I.V. prehydration to reduce possible nephrotoxicity. Probencid may decrease the metabolic clearance of zidovudine; patients on concurrent zidovudine therapy should decrease dose by 50% or hold dose on days of cidofovir..From Lexicomp.I would use Ganciclovir prior to Cidofovir to me Cidofovir is contraindicated and unless they had some overwhelming susceptibility study (which I've never seen) I wouldn't use it.
-Mayo RPh

Looks like you're stuck with the ganciclovir, my friend... And you should work on getting that foscarnet.

Just curious...why is the pharmacist worried about nephrotoxicity if the patient is already on HD from ESRD. You aren't going to do any further damage unless I'm looking at it the wrong way...

 

[Praziquantel86]

Just curious...why is the pharmacist worried about nephrotoxicity if the patient is already on HD from ESRD. You aren't going to do any further damage unless I'm looking at it the wrong way...

That was actually a reason for us thinking of using it. The primary toxicity associated with cidofivir is nephrotixicity and, in this case at least, frankly doesn't matter. Ganciclovir has substantial hemtalogic toxicities, which, when coupled with the natural immunodificiency and HIV medications, could potentially be magnified (obviously it is used frequently in HIV patients, but still). The difficulty arises from determining the correct dose if cidofovir, made more difficult from the near complete inability to perform any sort of therapeutic drug monitoring.

I appreciate you looking into this, though! Nice to see that we're still a community here.

This actually does raise a few interesting questions though. At what point does nephrotixicity cease to be a concern? Take vancomycin for example. Levels between 15-20 are targeted to reach adequate serum/site concentrations while balancing out the well-known risk of nephrotixicity. We also know that these doses may not reach therapeutic levels, particularly in hVISA isolates or those with elevated MIC values. Yet in dialysis patients, we target those same levels even when the main toxicity is no longer an issue. It's not until substantially higher concentrations that other things become a concern. Correct me if I'm completely off base, but shouldn't we be more liberal with the dosing, especially in more serious infections in dialysis patients? Or is it just easier (and more data-driven) to switch to daptomycin?

 

[Praziquantel86]

You make a good point and I thought about this myself... but, being only a first year, I don't know enough about dialysis to make a substantial contribution. OK, so you need to school me here.... we learned about the CPK elevation with daptomycin. If you are talking about increasing the dosing of vanco in dialysis patients for VISA with MICs in the 4-8 range, wouldn't it actually be less of a risk to do that (instead of dapto) because the kidneys are already shot? I guess you would have to worry about ototoxicity (although it's low incidence) and neutropenia, tho, right?

EDIT: ok I posed your question to that same pharmacist. We will see what she says.

Essentially, although I think therapeutic vancomycin against a MRSA isolate with an MIC of 8 might be unreachable, even in a patient with no risk of nephrotoxicity. Once levels reach >45 (I think, I'll have to double check the exact number), is when you have to start worrying about other systemic toxicities.

The CPK elevations in daptomycin were found early in its lifetime, when it was still dosed twice-daily. With the way daptomycin is dosed in dialysis, I wouldn't worry too much about CPK elevations unless the patient had multiple other concomitant risk factors.

 

[ttopping]

That makes sense... so is the neutropenia related to the serum level of the vanco or more to the duration of the therapy?

Yeah, I have only seen daptomycin dosed q24h where I work so I guess the CPK elevation wouldn't be that much of a concern.

So, what MIC do you think is the outer limit for vanco, even dosing 25mg/kg for severe infections? Also, since you want more time above the curve, couldn't you just lower the dose a bit and dose more often?

I personally haven't seen any neutropenia from vancomycin but maybe I just don't have enough experience with it (therefore might be a systemic effect as praz said, with very high levels). From what I've learned through ID preceptors doing a lot of vancomycin stuff, MIC of 2 seems to be a solid limit where you probably want to start looking at other therapies due to toxicities (not taking into effect the whole HD thing). Also, vanco isn't about time>MIC, its an AUC/MIC ratio that's important.

 

[rxlea]

I personally haven't seen any neutropenia from vancomycin but maybe I just don't have enough experience with it (therefore might be a systemic effect as praz said, with very high levels). From what I've learned through ID preceptors doing a lot of vancomycin stuff, MIC of 2 seems to be a solid limit where you probably want to start looking at other therapies due to toxicities (not taking into effect the whole HD thing). Also, vanco isn't about time>MIC, its an AUC/MIC ratio that's important.

Thanks for the clarification. I am actually studying for my ID exam right now and this very topic is on it. So, it is extremely helpful to "talk" to you guys about it. And, yeah, I just got to the page in my notes about AUC/MIC-- with a goal of greater than or equal to 400.

 

[tungsten87]

That was actually a reason for us thinking of using it. The primary toxicity associated with cidofivir is nephrotixicity and, in this case at least, frankly doesn't matter. Ganciclovir has substantial hemtalogic toxicities, which, when coupled with the natural immunodificiency and HIV medications, could potentially be magnified (obviously it is used frequently in HIV patients, but still). The difficulty arises from determining the correct dose if cidofovir, made more difficult from the near complete inability to perform any sort of therapeutic drug monitoring.

I appreciate you looking into this, though! Nice to see that we're still a community here.

This actually does raise a few interesting questions though. At what point does nephrotixicity cease to be a concern? Take vancomycin for example. Levels between 15-20 are targeted to reach adequate serum/site concentrations while balancing out the well-known risk of nephrotixicity. We also know that these doses may not reach therapeutic levels, particularly in hVISA isolates or those with elevated MIC values. Yet in dialysis patients, we target those same levels even when the main toxicity is no longer an issue. It's not until substantially higher concentrations that other things become a concern. Correct me if I'm completely off base, but shouldn't we be more liberal with the dosing, especially in more serious infections in dialysis patients? Or is it just easier (and more data-driven) to switch to daptomycin?

First of all this is a very interesting topic. I think a lot of it depends on if the patient is on high/low flux hemodialysis. If high-flux, I'd think the main concern would be actually getting the trough to 15-20. In low-flux, maybe? Here's a decent article partially related to this subject:

http://www.ncbi.nlm.nih.gov/pubmed/20182415