The plague that is vancomycin troughs

How important are vancomycin levels? Not very.... at least as a marker of efficacy. True, higher levels probably are associated with increased nephrotoxicity (above 15 mcg/mL) - Antimicrob Agents Chemother. 2013 ;57:734-44
But the notion that troughs of 15-20 mcg/mL are the holy grail of therapeutic drug monitoring targets is simply not supported by data.
What we know: vancomycin AUC/MIC in the mid 300 to 400s (let's just say > 400) or so range is likely the best PK/PD parameter that predicts therapeutic success (pic 1).
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 Much of these data come from the early 2000's when typical vancomycin MICs were less than 1 (Clin Infect Dis. 2007;15;44:1536-42 - pic 2). 
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It turns out that when the MIC is 1 (generally most common these days), the probability of achieving an AUC/MIC of 400 is pretty much equally poor whether the trough is 10-15 or 15-20 (pic 3) but if it is 0.5 or less, the PTA (probability of target attainment is essentially 100% regardless of trough.
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the problem with using troughs to predict efficacy is assuming that they're a good surrogate for AUC (which is kind of reason we use troughs since AUC is more difficult to measure). In reality they are not (pic 4).
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How about some clinical data? Pic 5 (Clin Infect Dis. 2012 Mar 1;54:621-9.) is results from the 2012 vancomycin vs linezolid nosocomial PNA trial: ignore the superiority of linezolid for clinical success and note that the success rate for vancomycin based on day 3 troughs (0-7.9: 48%, 8-12.3: 46%, 12.4-17.4: 45.5%, > 17.4: 45.5%), shocking? Shouldn't be considering the vast majority of MICs was 1 mcg/mL.
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What about post-hoc data from the ATTAIN trial with telavancin vs vancomycin? (pic 6), no difference in cure rate regardless of troughs but more nephrotoxicity with higher troughs.
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Take home point? patient receiving vancomycin for "severe" MRSA PNA and improving, trough comes back at 13 mcg/mL, why increase the dose?

Changing Paradigms in Stress Ulcer Prophylaxis

Obviously any patient that requires mechanical ventilation for 48 hours or has "coagulopathy" should get stress ulcer prophylaxis (SUP) right? maybe not....
when the above risk factors where identified in 1994 by Deborah Cook (N Engl J Med. 1994;330(6):377-81.) and studies validating SUP as an effective means of preventing GI bleeding in critically ill patients were published (Crit Care Med.1993;21:1844-9. and Crit Care Med. 1993;21:19-30 - btw, cimetidine continuous infusion, really?) critical care was quite different than today. Particularly, the emphasis on early enteral nutrition did not really come to fruition until more recently.
In fact, even the 2010 meta-analysis by Paul Marik that supported SUP only found benefit in patients NOT receiving enteral nutrition 
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Recently, several small RCTs have been published challenging the notion that SUP is necessary in modern practice.
The POP-UP trial (CCM 2016) showed no difference in "clinically relevant bleeding" in 214 patients randomized to PPI or placebo (100% received enteral nutrition)
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A 2017 exploratory study in the Journal of Critical Care compared "enteral nutrition vs PPI" in 102 patients and again found no difference in bleeding 
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Finally, another pilot study published last year in CCM, again had similar findings as above in 91 total patients (89% received enteral nutrition.

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the exclusion criteria from these 3 papers are rather mixed but include things like recent GI bleed, dual anti-platelet use and in one case 100 mg prednisone equivalent.
So are these enough data to stop using pharmacological SUP, especially with the possible increased risk of pneumonia and C.diff (see 2018 ICM meta-analysis) or are these data sets just too small? The SUP-ICU trial should give us a better idea, they are expecting completion by August of this year. In the mean time,I know of at least 1 ICU that has already implemented a no SUP for patients being fed policy.




“What is the INR of FFP?”

I frequently encounter people touting that "The INR of FFP is like 1.6 or something". Indeed I learned something similar myself at some point. It turns out however that the mean INR of FFP is actually 1.1 (Transfusion 2005;45:1234-5.). So why does it seem like no matter how much FFP you tend to give, it is very difficult to get the INR much lower than 1.6 or so?
As can be seen from the image below from (Transfusion. 2012;52 Suppl 1:45S-55S.), The relationship between INR and circulating coagulation factors (I am talking about warfarin here) is non-linear. While an INR of 1.7 still considered to be within the zone of "normal hemostasis", it also corresponds to almost 70% of circulating factors being depleted. In contrast, beyond that point, the INR increases more dramatically with small reductions in factor concentrations

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FFP replaces a relatively fixed percentage of coagulation factors (vertical arrows), the difference is, at higher INR values(below 30% coagulation factors), this corresponds to a large change in INR, however when the INR is lower than 1.7 or so, the same fixed increase in factor concentrations translates to a minor/negligible change in INR. This means that to get an INR back to "normal" an unrealistic amount of FFP would be needed.