Debate: Vancomycin for MRSA

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Praziquantel86

Praziquantel86

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Been a while since there was a good clinical thread here...let's get one started.

Statement: Vancomycin is no longer the drug of choice for serious MRSA infections.

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MRSA is still sensitive so we still use it.
 
DOC at my institution as well, and we have the nastiest resistance patterns in the state (over half our staph isolates are MRSA). Linezolid is on restriction per our antimicrobial stewardship program and is NEVER used (occasional VRE).
 
I was hoping to generate debate along the lines of whether it should be the drug of choice (i.e., your opinions on the matter). I know what the practice patterns are.
 
Praziquantel86 said:
I was hoping to generate debate along the lines of whether it should be the drug of choice (i.e., your opinions on the matter). I know what the practice patterns are.
Click to expand...

Yes, it should. It works and it's cheap. Nephrotoxicity reversible for the most part. Haven't seen Red Man in a while. Not many are allergic.

From a cost perspective, even with the monitoring, it still beats linezolid and dapto.

From a patient population perspective, if you serve a lot of immunocompromised patients, linezolid isn't going to be that great because it's bacteriostatic. Further, there is the risk of serotonin syndrome-- not THAT common-- but we certainly saw a lot more of it in recent years, particularly with patients who had zofran and an SSRI on board. With dapto, you've gotta watch CPK, especially with the higher doses/longer therapy (as might be the case in severe infections). If people were on a statin, we just stopped it during therapy but still...


EDIT: and unlike with a statin you can't really just stop an SSRI cold turkey 🙂
 
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rxlea said:
Yes, it should. It works and it's cheap. Nephrotoxicity reversible for the most part. Haven't seen Red Man in a while. Not many are allergic.

From a cost perspective, even with the monitoring, it still beats linezolid and dapto.

From a patient population perspective, if you serve a lot of immunocompromised patients, linezolid isn't going to be that great because it's bacteriostatic. Further, there is the risk of serotonin syndrome-- not THAT common-- but we certainly saw a lot more of it in recent years, particularly with patients who had zofran and an SSRI on board. With dapto, you've gotta watch CPK, especially with the higher doses/longer therapy (as might be the case in severe infections). If people were on a statin, we just stopped it during therapy but still...


EDIT: and unlike with a statin you can't really just stop an SSRI cold turkey 🙂
Click to expand...

Regardless of what the FDA says, the SSRI thing seems to be overstated as suggested by the Butterfield/Lodise paper last year.

Based on the Zephyr study and the two retrospectives that precluded it, in addition to the relatively low concentrations of vanco as compared to linezolid in the ELF (eg who's your static agent now?!), I'd venture to say I'd put my grandma on linezolid before vanco for mrsa pna :meanie:

I've not read the recent dapto vs vanco for bacteremia paper, but I hear that's another miss for vanco.

I think Patel, Lodise, et al put it best in reference to the PK/MIC issues with efficacy: Vancomycin, we can't get there from here 😛
 
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Doesn't linezolid suck for pneumonia? Surfactant issues
 
All wrong...until you show me the antibiogram, else Vanco is still the first line therapy for MRSA (emperically assuming pending sensitivities)
 
nafcillin said:
Doesn't linezolid suck for pneumonia? Surfactant issues
Click to expand...

That's dapto. It also has poor tissue penetrations, can elevate CPK. Bacteridial, small Vd and high plasma concentration makes it good for bacteremia.

Zyvox has good tissue penetration but poor plasma concentration, is bateristatic, can cause platelet to bottom out after more than a week of it, then there is the serotonin syndrome warning.

Teflaro is becoming more popular. Bactericidal, spectrum roughly equal vanc + rocephin. Pretty good plasma and tissue penetration. Cost about 1/3 of zyvox and dapto. Good side effect profile being a cephalosporin. But limited by the lack of data due to its newness.

Tygacil also cover MRSA and VRE, with good tissue penetration, but shows poor outcomes data with VAP. Cost about 2/3 of zyvox or dapto.

Also CA-MRSA are often susceptible to tetracyclines, clinda, sulfa, where HA ones tends to be resistant. Also if you see a culture showing resistant to erythro but susceptible to clinda, consider inducible resistance.
 
joetrisman said:
To be fair, I'd say I'd put the average patient on vanco still depending on disease severity and other patient specific factors
Click to expand...

Agreed. I'm not a big believer in vancomycin nephrotoxicity either, although I may be cautious if a patient is borderline AKI. I've used it routinely in patients with poor renal function (q36, even q48 sometimes) and it's actually a breeze to dose in HD/UF if your institution is good about taking levels. It can actually be trickier in patients with good renal function, specifically if the MIC of the causative organism is relatively high.
 
awval999 said:
Well... give a citation so we can look it up.
I assume we're talking linezolid vs. vancomycin though.
Click to expand...

There's not any one citation...there's a whole body of literature out there and it's still a controversial topic. Take a look through the literature, it's interesting!

joetrisman said:
Regardless of what the FDA says, the SSRI thing seems to be overstated as suggested by the Butterfield/Lodise paper last year.

Based on the Zephyr study and the two retrospectives that precluded it, in addition to the relatively low concentrations of vanco as compared to linezolid in the ELF (eg who's your static agent now?!), I'd venture to say I'd put my grandma on linezolid before vanco for mrsa pna :meanie:

I've not read the recent dapto vs vanco for bacteremia paper, but I hear that's another miss for vanco.

I think Patel, Lodise, et al put it best in reference to the PK/MIC issues with efficacy: Vancomycin, we can't get there from here 😛
Click to expand...

I like the citations...definitely agree with you on the serotonin syndrome issue...way overblown.

So, playing devils advocate here, what do you make of the "hard" outcome in ZEPHyR? The two drugs look pretty equivalent from a holistic perspective. And again playing devils advocate, does cidal vs. static REALLY matter once we look at the data? I'd argue that every trial comparing a static agent to a cidal agent had shown that it really doesn't.

And regarding the ability to achieve goal PD parameters with vancomycin, is it truly the goal that matters, or is it the bug itself? The MRSA folks in Australia are doing a good job convincing me that it isn't necessarily a vancomycin problem.
 
Praziquantel86 said:
There's not any one citation...there's a whole body of literature out there and it's still a controversial topic. Take a look through the literature, it's interesting!



I like the citations...definitely agree with you on the serotonin syndrome issue...way overblown.

So, playing devils advocate here, what do you make of the "hard" outcome in ZEPHyR? The two drugs look pretty equivalent from a holistic perspective.
Click to expand...
I could be quite off, so correct me if I'm wrong (I am still a student 😳 ), but I thought zephyr showed linezolid was superior to vanco in mrsa pna in real world scenario (eg troughs not always at goal). While this doesn't mean linezolid is a better drug in terms of efficacy, its hard to argue outcomes imo.


Praziquantel86 said:
And again playing devils advocate, does cidal vs. static REALLY matter once we look at the data? I'd argue that every trial comparing a static agent to a cidal agent had shown that it really doesn't.
Click to expand...
I agree that its arbitrary. I was playing into the cidal argument for the sake of pointing out that the cidal activity of vanco probably falls into the reign of static based off of the compartmental concentrations to bacterial burden in vivo compared to the in vitro characterization (or at least that's what I get out of it after reading: Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram-
Positive Bacterial Infections CID 2004; 38:864–70 and thinking of the ELF concentrations).

Praziquantel86 said:
And regarding the ability to achieve goal PD parameters with vancomycin, is it truly the goal that matters, or is it the bug itself? The MRSA folks in Australia are doing a good job convincing me that it isn't necessarily a vancomycin problem.
Click to expand...
I'm assuming you're referring to the new CID article from van Hal and Fowler? Thanks for the reading reference 👍
 
vanco is still DOC, but my ID docs are starting to poke holes and talk about time to therapeutic levels and chasing our tails with weird compartmental shifts...

...eh, i don't buy it, zyvox restrictions still in place...i'll personally let orders slide for septic 20 year olds with kidneys like niagara falls, but that's about it.

though i'm curious about AKI incidence w/ linezolid + zosyn vs. vanco + zosyn for empiric anti-psuedomonal/gram+ coverage.
 
who says its not the DoC? I would think this **** would be on NEJM or CID or something... my email would blow up.

I did co-presentation on my ID rotation of vanco vs linezolid for MRSA pneumonia, and tbh TLDR... vanco still wins... yes linezolid has some pros but not enough to beat vanco.
 
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Dapto much easier to dose, especially in the obese. Vanco limited by ability to actually attain goal MIC/AUC due to underdosing based on legitimate concern for toxicity and practitioner trepidation in pushing the dose.
 
I always had a mental image of a pharmacy director with a knife...waving it around threateningly... clothes slightly tattered from fights from the very recent past...telling the ID people to "stay back!" Guarding the Zyvox and Cubicin vials...
 
WVUPharm2007 said:
I always had a mental image of a pharmacy director with a knife...waving it around threateningly... clothes slightly tattered from fights from the very recent past...telling the ID people to "stay back!" Guarding the Zyvox and Cubicin vials...
Click to expand...

Dammit, now I have a mental image of my director and clinical coordinator doing that.
 
WVUPharm2007 said:
I always had a mental image of a pharmacy director with a knife...waving it around threateningly... clothes slightly tattered from fights from the very recent past...telling the ID people to "stay back!" Guarding the Zyvox and Cubicin vials...
Click to expand...

add me to the list...goddamn it, cannot be unseen.
 
We need to stir the pot a bit more -- this discussion is too tame!

For those who aren't familiar with the ZEPHyR study: http://www.ncbi.nlm.nih.gov/pubmed/22247123
It represents one of the largest studies for nosocomial MRSA pneumonia -- randomized to vancomycin versus linezolid. While there are limitations (most notably unbalanced baseline characteristics), linezolid was associated with greater "clinical success" (57.6% vs. 46.6%, NNT 9, p=0.042) and less nephrotoxicity (8.4% vs. 18.2%, NNH 10). 60-day mortality was no different between groups (but wasn't the primary endpoint of the trial).

So, playing devils advocate here, what do you make of the "hard" outcome in ZEPHyR? The two drugs look pretty equivalent from a holistic perspective. And again playing devils advocate, does cidal vs. static REALLY matter once we look at the data? I'd argue that every trial comparing a static agent to a cidal agent had shown that it really doesn't.
Click to expand...
100% agree -- it's great for test questions in pharmacy school, not great for patient-care decisions in lieu of randomized controlled trials comparing two agents

Dapto much easier to dose, especially in the obese.
Click to expand...
And linezolid is even easier to dose!

I did co-presentation on my ID rotation of vanco vs linezolid for MRSA pneumonia, and tbh TLDR... vanco still wins... yes linezolid has some pros but not enough to beat vanco
Click to expand...
Although linezolid didn't have a mortality benefit versus vancomycin, isn't the benefit of clinical success and less risk of nephrotoxicity worth something? The study didn't report the difference in need for new renal replacement therapy, but such a benefit could offset the cost of linezolid. What benefit would you need to see in order to "beat" vanco?
 
CritCare PharmD said:
We need to stir the pot a bit more -- this discussion is too tame!

For those who aren't familiar with the ZEPHyR study: http://www.ncbi.nlm.nih.gov/pubmed/22247123
It represents one of the largest studies for nosocomial MRSA pneumonia -- randomized to vancomycin versus linezolid. While there are limitations (most notably unbalanced baseline characteristics), linezolid was associated with greater "clinical success" (57.6% vs. 46.6%, NNT 9, p=0.042) and less nephrotoxicity (8.4% vs. 18.2%, NNH 10). 60-day mortality was no different between groups (but wasn't the primary endpoint of the trial).


100% agree -- it's great for test questions in pharmacy school, not great for patient-care decisions in lieu of randomized controlled trials comparing two agents


And linezolid is even easier to dose!


Although linezolid didn't have a mortality benefit versus vancomycin, isn't the benefit of clinical success and less risk of nephrotoxicity worth something? The study didn't report the difference in need for new renal replacement therapy, but such a benefit could offset the cost of linezolid. What benefit would you need to see in order to "beat" vanco?
Click to expand...

Excellent points on all. Tacking onto this last point - if vancomycin were a new drug, with linezolid and daptomycin as the "gold standard" comparator agents, would anyone use vancomycin? I think the main advantage for vancomycin currently is its longevity - despite decades of use and ~15 years of substantial overuse, high-level resistance has not become a problem (in Staph, at least). We can't say the same holds true for either linezolid or daptomycin, despite their comparatively lower market penetration.
 
Praziquantel86 said:
Excellent points on all. Tacking onto this last point - if vancomycin were a new drug, with linezolid and daptomycin as the "gold standard" comparator agents, would anyone use vancomycin? I think the main advantage for vancomycin currently is its longevity - despite decades of use and ~15 years of substantial overuse, high-level resistance has not become a problem (in Staph, at least). We can't say the same holds true for either linezolid or daptomycin, despite their comparatively lower market penetration.
Click to expand...

Tacking on further I do recall hearing about inducible daptomycin resistance but this is something I'd gladly pass off to my student for drug info purposes.

Don't forget the cost of vancomycin, not just its longevity.

There's something to be said about AKI w/ vanco + zosyn, however. There were a few research projects looking at this problem at WSC, I'm curious to know the RRT requirements are.

The other issue is duration of therapy and pancytopenia w/ zyvox, but at that point you'd go dapto for outpt and that's that.

damn i'm verbal diarrhea today....c. diff...vanco PO, see it all fits.
 
rxlea said:
Yes, it should. It works and it's cheap. Nephrotoxicity reversible for the most part. Haven't seen Red Man in a while. Not many are allergic.

From a cost perspective, even with the monitoring, it still beats linezolid and dapto.

From a patient population perspective, if you serve a lot of immunocompromised patients, linezolid isn't going to be that great because it's bacteriostatic. Further, there is the risk of serotonin syndrome-- not THAT common-- but we certainly saw a lot more of it in recent years, particularly with patients who had zofran and an SSRI on board. With dapto, you've gotta watch CPK, especially with the higher doses/longer therapy (as might be the case in severe infections). If people were on a statin, we just stopped it during therapy but still...


EDIT: and unlike with a statin you can't really just stop an SSRI cold turkey 🙂
Click to expand...

totally agree with this. if it works, you should use it, if for no other reason, to preserve the utility and effectiveness of the other drugs. regarding the paper that was posted, the real question is if no difference was seen in mortality, what's the point of going with the more expensive drug? Clinical improvement is all well and good, but if it just delays death by a few days, I wouldn't consider that more effective. Of course these study populations tend to have really bad co-morbidities and its hard to attribute death directly to pneumonia. Either way, for a blanket DOC I'd say to go with what works and is cheapest. However, each hospital, institution, area will have its own resistance pattern that will ultimately drive what's routinely chosen.
 
MRSA in what kinds of infections? Because that can change the discusion.
 
I think everyone should get vanco 1gm q12h. For the rest of their lives.
 
joetrisman said:
I could be quite off, so correct me if I'm wrong (I am still a student 😳 ), but I thought zephyr showed linezolid was superior to vanco in mrsa pna in real world scenario (eg troughs not always at goal). While this doesn't mean linezolid is a better drug in terms of efficacy, its hard to argue outcomes imo.
Click to expand...

If you walked into Barnes-Jewish today you'd see they're still using vancomycin in their MRSA pneumonias.

If it hasn't changed the practice of the actual authors of the paper, it's not going to change my practice.
 
Linezolid might be superior in some aspects, but that's not the only thing to think about. Fact is, we're already seeing linezolid-resistant staph in transplant wards that rotate it one week a month; the LAST thing we need to do is overuse this when vanco still works and has equal outcomes for mortality. The goal should not be to switch to linezolid to prevent vanco-associated adverse outcomes; the goal should be to hire more clinical pharmacists to be doing PK and adjusting dosing for optimal troughs.
 
UMterps said:
totally agree with this. if it works, you should use it, if for no other reason, to preserve the utility and effectiveness of the other drugs. regarding the paper that was posted, the real question is if no difference was seen in mortality, what's the point of going with the more expensive drug? Clinical improvement is all well and good, but if it just delays death by a few days, I wouldn't consider that more effective. Of course these study populations tend to have really bad co-morbidities and its hard to attribute death directly to pneumonia. Either way, for a blanket DOC I'd say to go with what works and is cheapest. However, each hospital, institution, area will have its own resistance pattern that will ultimately drive what's routinely chosen.
Click to expand...

I think the bolded gets to the heart of the matter. 60-day attributable mortality in a critically ill population is so hard to assess. There are a number of variables that randomization is simply unable to control for that affect mortality in unpredictable ways. For antimicrobial trials, I think microbiologic eradication using a highly sensitive methodology is probably the best we can hope for, at least in that population.

Carboxide said:
Linezolid might be superior in some aspects, but that's not the only thing to think about. Fact is, we're already seeing linezolid-resistant staph in transplant wards that rotate it one week a month; the LAST thing we need to do is overuse this when vanco still works and has equal outcomes for mortality. The goal should not be to switch to linezolid to prevent vanco-associated adverse outcomes; the goal should be to hire more clinical pharmacists to be doing PK and adjusting dosing for optimal troughs.
Click to expand...

Does tweaking a vancomycin trough really make a difference? While there hasn't been a trial comparing one goal trough to another published yet (although I believe on in Australia is recruiting), the published literature leaves me less than impressed that pushing the troughs to 15 - 20 provides anything more than marginal benefit. I think there is a benefit there, but I don't think its the panacea that fixes the vancomycin problem like people make it out to be.

I think the resistance problem, with both linezolid and daptomycin, is what is going to be the major problem going forward. As more and more clinicians buy into the data coming from Detroit that daptomycin IS better than vancomycin and more people start buying into ZEPHyR, we're going to see more frequent empiric use. Stewardship can delay this, but I think in hospitals without a strong stewardship presence (and even in those with) we may start to see some serious problems in a few years.
 
Praziquantel86 said:
Does tweaking a vancomycin trough really make a difference? While there hasn't been a trial comparing one goal trough to another published yet (although I believe on in Australia is recruiting), the published literature leaves me less than impressed that pushing the troughs to 15 - 20 provides anything more than marginal benefit. I think there is a benefit there, but I don't think its the panacea that fixes the vancomycin problem like people make it out to be.

I think the resistance problem, with both linezolid and daptomycin, is what is going to be the major problem going forward. As more and more clinicians buy into the data coming from Detroit that daptomycin IS better than vancomycin and more people start buying into ZEPHyR, we're going to see more frequent empiric use. Stewardship can delay this, but I think in hospitals without a strong stewardship presence (and even in those with) we may start to see some serious problems in a few years.
Click to expand...

Trough tweaking is what limits toxicity as well....which is a big reason to monitor it. If you've got a trough of 25, that nephrotox is a lot more likely...and needs to be prevented by dose adjustment.

Trough of 10-15 or 15-20 as far as goals is debatable, sure.
 
Praziquantel86 said:
I think the bolded gets to the heart of the matter. 60-day attributable mortality in a critically ill population is so hard to assess. There are a number of variables that randomization is simply unable to control for that affect mortality in unpredictable ways. For antimicrobial trials, I think microbiologic eradication using a highly sensitive methodology is probably the best we can hope for, at least in that population.
Click to expand...

if looking at certain bacterial indications that's a possibility, but you also need to see what's clinically meaningful. If there's adequate tissue penetration and eradication of the offending pathogen, it could be argued that it's "working". However, is that clinically meaningful if it doesn't improve survival? It's kind of like chemo and if tumor stasis is meaningful if in the end there's no real affect on PFS. Something definitely needs to be done in terms of endpoints, but there's a real divide on what that should be
 
vanco should still be the drug of choice. the zephyr trial was a nice idea but it was probably underpowered to detect a mortality difference (and there wasn't even an encouraging trend -- iirc it was nonsignificantly lower in the ITT analysis but higher in the mITT...). and keep in mind, the patients in the vanco arm were sicker. do not buy the 'nephrotoxicity' some people read from this trial either; it's not terribly shocking that people who got vanco -- who at baseline were more likely to be bacteremic, had worse kidneys, and were more likely to be on a vent -- ended up ever-so-slightly worse off.

this (http://www.ncbi.nlm.nih.gov/pubmed/20639754) is imo the go-to when we're talking about vanco or linezolid for MRSA pneumonia. in this meta-analysis there was no difference in mortality or clinical cure rates between the two classes. they looked at blinded and unblinded trials -- in the unblinded ones, doctors tended to blame worsening renal function on vanco. in the blinded ones, there wasn't a difference. weird, right? staph aureus is really bad for kidneys. vanco not so much

another thing to keep in mind is that mortality correlates with vanco MIC regardless of the therapy we give them
 
Vain Brother said:
vanco should still be the drug of choice. the zephyr trial was a nice idea but it was probably underpowered to detect a mortality difference (and there wasn't even an encouraging trend -- iirc it was nonsignificantly lower in the ITT analysis but higher in the mITT...). and keep in mind, the patients in the vanco arm were sicker. do not buy the 'nephrotoxicity' some people read from this trial either; it's not terribly shocking that people who got vanco -- who at baseline were more likely to be bacteremic, had worse kidneys, and were more likely to be on a vent -- ended up ever-so-slightly worse off.

this (http://www.ncbi.nlm.nih.gov/pubmed/20639754) is imo the go-to when we're talking about vanco or linezolid for MRSA pneumonia. in this meta-analysis there was no difference in mortality or clinical cure rates between the two classes. they looked at blinded and unblinded trials -- in the unblinded ones, doctors tended to blame worsening renal function on vanco. in the blinded ones, there wasn't a difference. weird, right? staph aureus is really bad for kidneys. vanco not so much

another thing to keep in mind is that mortality correlates with vanco MIC regardless of the therapy we give them
Click to expand...

I never meta analysis I liked (terrible pun)...I agree with you that there are multiple confounding factors at play here, including baseline discrepancies between the two groups. I think either one is justified from a clinical point of view, which is why we have yet to see a switch en masse away from vancomycin.

As far as the nephrotoxicity goes, though, I'm going to disagree with you. I believe the preponderance of evidence supports vancomycin as a nephrotoxin, in a dose-dependent manner. I'll see your meta-analysis and raise you one: http://www.ncbi.nlm.nih.gov/pubmed/23165462. As far as the short- and long-term significance of this nephrotoxicity, I'm not so sure there is a good answer for that.

And couldn't agree with you more about the vanco MIC issue being significant beyond vancomycin itself. I'm interested in seeing if this holds true for linezolid as well, given that it is not a cell-wall active agent. Not sure if there's any data on that yet.
 
i would tend to agree that from a clinical perspective, the two are pretty darn close to equivalent. of course, when you have two equally-efficacious drugs from which to choose, we should choose the cheaper one. preserving newer agents, particularly if their use is not essential at the moment, seems prudent as well, given the dearth of newer antibiotics and resistance trends

thanks for that article, i'll read that -- i'll say beforehand though that my impression of most of the vanco toxicity literature has been that the apparent risks are heavily confounded. it's certainly true that patients with higher trough levels tend to have more nephrotoxicity, but is that because of the vanco, or is it because people who are sicker (and more likely to deteriorate clinically) tend to get bigger doses of vanco? it's a somewhat controversial area, as i'm sure you know.
 
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