Tuesday, May 29, 2018

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?

Friday, May 25, 2018

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.




Monday, May 21, 2018

"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.


Tuesday, May 15, 2018

"Balanced Crystalloids" and Hyperkalemia

With the recent publication of the SMART and SALT-ED trials, the chloride rich vs poor (balanced/buffered) crystalloid debate is back in the spotlight after a break post the orginal Yunos JAMA 2012 and SPLIT JAMA 2015. Something I commonly hear from internal medicine residents however is that LR and plasma-lyte should DEFINITELY be avoided in the setting of hyperkalemia, since they contain 4 and 5 meq/L of potassium respectively.
It turns out however that normal saline ( strong ion difference of 0, pH of ~ 5.5) increases potassium more than either of the chloride poor solutions do.
1) Serum potassium level should not be able to exceed 4meq/L (LR) or 5meq/L(PL) since that is the concentration of K in the solution. If a patient's K is greater than 5, PL will actually lower potassium

2) given how acidic NS is (above), the increased hydrogen ion concentration exchanges with intracellular potassium, actually worsening hyperkalemia despite not having any K in the solution

3) several trials in the peri-op setting have demonstrated increased potassium with NS compared to LR or PL


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Jerry Altshuler, Pharm.D., BCPS, BCCCP
Critical Care Pharmacy Coordinator
Director, PGY-2 Critical Care Pharmacy Residency Program 
The Mount Sinai Hospital
1 Gustave L. Levy Place
New York, New York 10029
@hockeypharmd

Friday, May 11, 2018

Does Acidosis Decrease the Response to Catecholamine Vasopressors?

One question I commonly encounter on rounds is "does acidosis reduce the activity of catecholamines?" While I think that at this point it is relatively clear that acidosis likely reduces LV contractility due to reduced intracellular calcium entry as well as H+ competition for calcium binding sites on myocardial troponin, I think that the notion that catecholamines "don't work as well in acidosis" is less clear. The bulk of the data that comprises this idea can be seen in these three pictures and goes as follows:
 
1) A report from 1958 describing the effects of catecholamines on dogs over varying pH values suggested less response at a pH of 6.76 than 7.27 and 7.34 (they also note that they gave 6 human patients sodium lactate, increased their pH and decreased their pressor requirement - that's 1950's publication standards for you).
Calif Med. 1958 Jun; 88(6): 437–440.
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2) A 1988 paper in chickens showed reduced beta receptor expression when the acidotic chicken's pH fell. Isoproteronol responsiveness was concordantly reduced.
Am J Physiol. 1988 Jan;254(1 Pt 2):H20-7.
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3) The most recent paper from 2014, looking at contractile force in Human mammary arteries showing INCREASED catecholamine response as the pH decreased.
J Thorac Cardiovasc Surg. 2014 May;147(5):1698-705.
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In real life this is concept is obviously difficult to pinpoint as usually the degree of critical illness tends to correlate with the degree of acidosis and hypotension and can easily be misidentified as non-causative correlate.
 
What is everyone's thoughts on this question?

Jerry Altshuler, Pharm.D., BCPS, BCCCP
Critical Care Pharmacy Coordinator
Director, PGY-2 Critical Care Pharmacy Residency Program 
The Mount Sinai Hospital
1 Gustave L. Levy Place
New York, New York 10029
@hockeypharmd




Friday, April 27, 2018

Statistics: The Cause Of, And Solution To All Medical Problems

In pharmacy school, there were times where mountains of material coincided with a flurry of exams. Such extreme circumstances called for masterclass test taking skills. For example, when a hundred page packet would account for 10 questions on an exam, and a 20 page packet also accounting for 10 questions, the logical studying strategy would focus on maximizing the number of points from the lower quantity material. Fast forward a decade after these exams and I found myself in the same situation. The BCPS exam is not so different from a test taking perspective.


When you consider that the BCPS exam content breakdown consists of 55% patient specific pharmacotherapy - that is a little over half of the exam pulls from ALL OF MEDICINE. Where 45% of the exam is based on a relatively small amount of content: statistics, regulatory issues and system based questions (P&T issues, MTM, etc.). An astute test taker is going to save time by not studying the various mesalamine formulations and their corresponding niches and spend that time knowing stats cold.


Through my years of practice, reading journals, and conducting my own research, I’ve become relatively familiar with stats. One could say I’ve got a pretty good working knowledge. So when the time came to recertify for BCPS, I wasn’t going to take any chances. With so many points on the table for this relatively small subject, I took every opportunity to brush up and learn something new.


Much of my preparation consisted of self-directed reading and learning, but I was falling short on what I expected of myself when studying. With my partnership with High-Yield MED Reviews, I had the opportunity to broaden my biostatistics knowledge from an expert in the field, Dr. Busti. When it comes to statistics, learning from a professional with experience from the likes of the Cochrane collaboration is as good as it gets. High-Yield Med Reviews (HYMR) offers a live webinar for biostatistics, which I was able to participate in.


The webinar itself could have been a difficult presentation to get through, since biostatistics are not exactly the most exciting thing on the planet. But I quickly realized that Dr. Busti wasn’t going to bore anyone by reviewing the application of a Student’s t-test vs and ANOVA- he tied everything back to real world practice. Each learning objective used real examples from existing articles (most of which were landmark studies- another good review), and was presented in a way that each concept was built upon from the previous one. In making the content relatable and applicable, the concepts became easier to grasp.  Grasping the concepts is they key, as Dr. Busti pointed out. The BCPS exam isn’t going to as straight-forward questions; it’s testing your knowledge in application of concepts.


The webinar itself was an excellent compliment to the biostatistic modules. But starting from my level of experience, I was able to jump right onto the webinar content. For a new graduate or young professional, you really need to spend some time reviewing biostatistic concepts before the webinar. Without preparing adequately, key points will fly over your head. Unlike the online module content, the webinar cannot be paused or rewinded. Although you can ask questions, in order to maximize the effectiveness of the webinar, one must be prepared beforehand.


While other professional organization review courses require dedication of your time and resources to travel and attend, the HYMR is 100% online. This allows you to be able to participate from the comfort of your home. However, it’s not brief. The webinar runs about 3-4 hours. Personally, my attention span is not that long. Particularly when a 10 month old is crawling around my ankles. Although long, it is worth it. The time invested here is well spent, especially compared to either traveling to a live review, or attempting to structure a similarly effective program yourself.  


Although my bias is towards recommending HYMR given our partnership, I truly feel it is beneficial. The famous “Stats Table” seen in many study guides will help with BCPS preparation, it will only get you so far, and won’t truly contribute to you becoming a better pharmacist. Since I’m already putting in the effort to study and pass the exam, why not also improve my biostatistic skills at the same time? The benefits extend beyond test preparation into one’s own practice, and improve either your study design skills or at minimum, your literature analysis skills. Furthermore, for residency programs, these modules would be a good investment of the program to provide a didactic element of biostatistics.



Sunday, April 1, 2018

BCPS Recertification- High-Yield Med Reviews

I’ve always been a huge fan of stand up comedy. For the longest time, I admired the ability of comedians to be able to speak so conversationally, and naturally while being hilarious. Over time, I’ve come to learn that some of my favorite comedians (Jerry Seinfeld, Jim Gaffigan, Tom Papa) extensively plan out every minute detail of their jokes, practice like crazy and never stop trying to improve. The grand illusion that most professional comedians natural abilities that don’t require much effort to maintain translates into what it takes to be a pharmacist.  I think many would be surprised at the amount of effort I put in to try to continuously improve (I’d guess the same holds true with folks like Bryan and Nadia). So when the time came to recertify BCPS, I had to find a strategy that would match the level of effort I needed to exert.


Since my initial certification, I’ve become entrenched in all things emergency medicine. I started to spend more time reading what I enjoyed and had interest in, with little interest or effort put into other topics. While I suppose you could say, an emergency medicine pharmacist should know Nutrition (TPN and the like) inside out, I had zero interest in reading or staying up to date on it. Nutrition to an EM pharmacist consists of turkey sandwiches and graham crackers. So when it came to deciding whether to elect to sit for BCPS recertification or 120 hours of PSAP, the choice was easy.


What wasn’t easy was trying to establish an effective way to prepare for the exam. Through professional connections, I was lucky enough to have been connected with Dr. Anthony Busti, who created High-Yield Med Reviews. Dr. Busti is one of many educators who provide online education and exam preparation. I must say that I’ve partnered with Dr. Busti who is sponsoring the EMPharmD blog, but had nothing to do with this post or me reviewing the program at all. Plus Dr. Busti isn’t just anybody, as you’ll find out later. Nevertheless, I went with the BCPS Premium plan which fit my learning style with a self-directed learning model, online lectures, and many many practice questions.


Before diving into the content and structure of High-Yield Med Reviews, it’s critical to know where (or from whom) the content is coming from. Online pharmacy education can be pretty hit or miss. If you’ve tried to watch pharmacology and pharmacotherapy lectures on YouTube, they’re almost all horrible: somewhere on the spectrum of inaccurate to unwatchable. What stood out to me with High-Yield Med Reviews BCPS preparation and why I’ve been using it for my recertification is the credibility Dr. Busti brings to the online content. Although Dr. Busti is an EM attending physician at UT Southwestern Medical Center in Dallas, he is also a nurse, and a pharmacist. Not only was he a nurse, but an critical care and emergency medicine nurse. Not only was he a pharmacist, but a residency trained clinical pharmacist, faculty at Texas Tech University and residency program director. As if he needed any more credibility, he’s now pursuing a MSc in Evidence-Based Health Care at Oxford University. Needless to say, the online lectures, provided content and practice questions are high quality, effective and reliable.


The structure of High-Yield Med Reviews fits with my learning style and my teaching philosophy. I like to picture medical/pharmacy education as a spiral (Kolb spiral): Experience with structure, Reflection/Refinement, Meta-cognition/abstract concepts, Testing. Visualized as a spiral, rather than a circle, is significant because since each cycle where new knowledge is gained builds upon what was previously known by assimilating new information with prior knowledge.  However, since different people have varying levels of prior knowledge, the knowledge they can gain from a given lesson is limited by their “zone of proximal development.” For example, because of my practice, my knowledge level of acute coronary syndrome (ACS) pharmacotherapy is high, so I would easily be able to learn advanced topics. On the flip side, my knowledge of TPNs and nutrition is pretty basic, so I would require a number of sequential lessons to reach the same level of knowledge as with ACS. High-Yield Med Reviews online lectures compliments this learning method by providing > 100 different lectures to build knowledge.


Clinical practice is the best way to gain experience. But experience can also be acquired through lectures, as long as their effective. Effective lectures that not only provide knowledge, but also context. In the online lectures by Dr. Busti, his lecture style effectively provides this context either through the case based teaching or building upon basic concepts in sequential lectures. There are several lectures ranging from basic pharmacology to detailed evidence based medicine discussions. For example, rather than just a 60-90 minute lecture on hypertension guidelines, High-Yield Med Reviews has 16 lectures on hypertension, each around 10-20 minutes in length covering topics ranging from specific drug classes to guidelines to special populations like hypertension in pregnancy. So I can spend less than an hour on reviewing updates in guidelines rather than have to start with the basic pharmacology. Whereas a new pharmacist would benefit from the pharmacology lectures in order to build up to the guideline reviews. Since I’m a pharmacology geek, I watched the pharmacology lectures anyways - Dr Busti and I share the same attitude towards beta-blockers in the management of hypertension.


A crucial step in the Kolb spiral is reflection and refinement. The learner needs time to reflect on what was learned, and be able to return to the content to sharpen understanding. The lectures are able to be watched as many times as you’d like in a 24 hour period (for up to 3 separate 24 hour periods) where you can pause, rewind, rewatch or fast forward. This allows you to think about the content just presented, identify points of confusion or anything that's unclear, and identify further questions you may have. Being able to rewatch lectures allows refinement of these topics.


However, if cramming for two weeks before the exam is your desired method of preparation, High-Yield Med Reviews is not for you. It’s also not a good idea anyways. As a result of the breadth of content covered on a BCPS exam, sufficient time is required to prepare - somewhere between 1-3 months for most residency trained pharmacists, and 6-12 for non residency trained pharmacists. This time is required for meta-cognition. In other words, you need time to think about thinking and identify gaps in your understanding. High-Yield Med Reviews is a subscription package of 1, 3, 6 or 12 months. Based on my experience, and the degree I stay up-to-date 1 month is right for me, but that is probably pushing it. Sure, I could probably wing it and walk into the exam without preparation, but my earlier career experience with the Dunning-Kruger effect, taught me that the amount of information I DON’T know is greatly outweighed by the information I DO know.


Finally, the last element to this learning cycle is testing and application. With more than 2000 questions to practice from High-Yield Med Reviews provides ample testing to ensure learning and compliment the lecture. The questions are in the format and level of difficulty of the BCPS exam and written by pharmacotherapy experts (including myself). To deliver not just testing and application, but supplementary learning, each question has a detailed explanation and rationale for the correct and incorrect answers, high-yield core concepts, take home points, and are referenced. By putting in the effort to review each question, you still benefit from whether you scored 100% or 20%. If you scored particularly low, or identified things you know you need to know, the questions are able to be flagged for further review at later time.


There are different modes that you can utilize with the practice questions: testing, tutorial and flashcards. Personally, I only use the testing mode. Tutorial provides answers and explanations after each question, rather than the end of your session; Flashcards provide the question with no multiple choices, which forces you to think of an answer rather than simply selecting one.


I’ve been extremely satisfied so far with High-Yield Med Reviews. But there are a few things that I would have liked to be different or improved. While the testing mode for questions tells you what percentage of people got the answer correct, there is no correlation to how you perform overall to your likelihood of passing the exam. While the difficulties of tracking down exam results of subscribers while maintaining privacy would make that sort of data challenging to collect.


Another aspect is practicing in a full length practice exam to not only become familiar with the style of the exam, but also to identify areas of weakness.  While currently, you can set up a mock exam yourself by selecting 200 questions in testing mode, there’s no guarantee the questions will be in the same proportion of the 3 exam domains. However, this will be a new feature where there will be full length mock exams in the near future.


Lastly, is the cost. FOAM (free open access medical education) has spoiled us with high quality medical education. But, as I said before, FOAM is lacking in high quality pharmacology and pharmacotherapeutic content in areas outside of emergency medicine, and anything available for free on Youtube is worth what you pay for it: nothing.  So while I am extremely cheap, and would prefer to not pay for anything, I would say the cost of High-Yield Med Reviews is fair given the quality of content and it’s actually quite a lot more affordable than other “review courses” and PSAP modules.


High-Yield Med Reviews is a high quality, modern educational platform that offers me exactly what I was looking for with BCPS exam preparation. Dr. Busti has a wealth of knowledge and experience that you can benefit from, and become a better pharmacist by securing board certification, and by simply improving your knowledge and expanding your new zone of proximal development. I’m proud to continue my partnership with Dr. Busti through the EMPharmD blog and through contributions to the content of High-Yield Med Reviews.




Friday, March 23, 2018

StoweEM18 Day 3

StoweEM18 Day 3 audio

Also available on iTunes

Credit:
Meghan Groth, PharmD BCPS @EMpharmgirl
Kyle DeWitt, PharmD, BCPS @EmergPharm
Blake Porter, PharmD, BCPS @RxEmergency

Show notes:

https://www.ncbi.nlm.nih.gov/pubmed/27276234

Thursday, March 1, 2018

StoweEM18 Day 1

StoweEM18 Day 1 audio

Speakers at the Emergency Medicine Update conference in Stowe, Vermont discuss success, failure, evidence-based medicine, and controversy encountered in the emergency department on a daily basis. In this podcast series Meghan Groth (@EMpharmgirl), Kyle DeWitt (@EmergPharm), and colleagues recap memorable conference moments and provide clinical pearls that can be taken directly to the bedside to improve patient care. Check out the conference website for more information and videos of each presentation



Also available on iTunes

Credit:
Meghan Groth, PharmD BCPS @EMpharmgirl
Kyle DeWitt, PharmD, BCPS @EmergPharm
Blake Porter, PharmD, BCPS @RxEmergency

Show notes:






















Monday, February 19, 2018

ID in the ED: C.difficile- New Guidelines, Not the Same old S*!%

The Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) convened a group of experts to publish an update to their 2010 C.difficile infection (CDI) guidelines. Below is a summary of the new guidelines from the perspective of an emergency medicine (EM) pharmacist.

Clostridioides is the new Clostridium

Diagnosis
  • A multi step algorithm is now recommended  for diagnosis:1
  • Only patients with risk factors for CDI and  ≥ 3 unformed stools in a 24 hour period should be tested

Pertinent Changes From Previous Guideline
  • Metronidazole is no longer recommended first line for any severity of CDI.
    • This change is based on data to support vancomycin and fidaxomicin providing patients with a better chance of sustained symptom resolution one month after treatment.
  • Serum creatinine (Scr) values for classification of severity is an absolute value rather than being compared to a change from baseline values
    • Justification by the authors was that baseline values are often unavailable, which is certainly common in the ED setting, making the scoring easier for us to complete.
  • For the first time fecal microbiota transplantation (FMT) is mentioned as a therapeutic option. Although not something that will be completed in the ED, it is something we should be aware of as this practice will continue to increase.

CDI Prevention & Control
  • Antimicrobial Stewardship
    • The most important modifiable risk factor for the development of CDI is exposure to antibiotic agents, making the appropriate use of antibiotics of paramount importance. The new guidelines flat-out recommend implementing a stewardship program. The ED is a great place for stewardship, ripe with opportunity, including decreasing CDI incidence.
      • Consider restricting antibiotics that are most strongly associated with CDI such as fluoroquinolones, clindamycin, and broad-spectrum cephalosporins.
      • Appropriate duration of therapy is also extremely important. There is a growing body of evidence for many infections that a shorter course of therapy than what has been historically used is equally efficacious. A  great read on this is The New Antibiotic Mantra—“Shorter Is Better” by Dr. Brad Spellberg.2  
      • EM pharmacists have a unique opportunity to be major players in antimicrobial stewardship activities. We can potentially decrease the risk of CDI by advocating for patients and recommending narrower-spectrum antibiotics when appropriate. Additionally, we can recommend evidenced-based, appropriate durations for patients being discharged with an antibiotic prescription.
  • Proton Pump Inhibitors (PPIs)
    • There is an epidemiologic association between PPI use and CDI, though the authors of the guidelines felt there is insufficient evidence for discontinuing PPIs solely to prevent CDI.
      • Avoiding the use of unnecessary PPIs, and using them for limited durations is never a bad idea.
  • Probiotics
    • Primary prevention- while there are multiple meta-analyses suggesting probiotics may prevent CDI in patients taking antibiotics, the data was not deemed sufficient to recommend their use.
    • Secondary prevention- Saccharomyces boulardii (Florastor®) and Lactobacillus spp. (Culturelle®, Yakult®) may be of benefit to decrease CDI recurrence, although significant and reproducible results have yet to be shown in controlled trials.
    • Ultimately, the data isn’t yet strong enough to make recommendations for or against. Probiotics are certainly not without risk, as the contents can cause invasive disease, and they can be costly.3 Last I checked, no one has died of a yogurt-related complication, so that is probably a safe recommendation to make.
  • C.diff Scoring Tool
    • While the new guidelines don’t make specific recommendations on the use of a predictive risk scoring system, such a tool would be very useful for identification of patients who would most benefit from risk mitigation.
      • A study by Kuntz et al. produced such a tool that proved useful for stratifying CDI risk following an outpatient healthcare visit.4
      • A more recent study by Reveles et al. produced a clinical prediction tool to be used to identify patients at high risk for CDI recurrence.5

Treatment Considerations
  • Discontinue Systemic Antibiotics as Soon as Possible
    • If discontinuing antibiotics isn’t possible, use the narrowest spectrum agent that will be effective.  
  • Patients with Active CDI Requiring Antibiotics
    • One retrospective study has been published and suggests no benefit to extending anti-CDI therapy beyond 14 days for patients receiving concurrent systemic antibiotics. Relapse rates were similar for the regular and extended treatment groups in the univariate (17% and 23%, respectively; odds ratio [OR]: 1.4, 95% confidence interval [CI]: 0.7–2.7, p = 0.286) and multivariate analyses (OR: 0.7, 95% CI: 0.3–1.7, p = 0.425).6
    • With only one retrospective study evaluating this topic, and minimal risk of extending therapy until after systemic antibiotics have been completed, many clinicians may still opt to do so. The new guidelines state that vancomycin 125mg PO daily may be sufficient to prevent recurrence after the initial course is complete.
  • Patients Who Have Completed Anti-CDI Therapy and Now Require Antibiotics
    • Two retrospective studies have been published that investigate the utility of giving oral vancomycin as secondary prophylaxis to patients requiring systemic antibiotics. Both studies showed decreased incidence of CDI for patients given prophylaxis.7,8
    • One of these studies showed oral vancomycin prophylaxis decreased the risk of further recurrence in patients whose CDI itself was a recurrence (AHR, 0.47; 95% CI, 0.32–0.69; P<0.0001) but not in those whose CDI was an initial episode (AHR, 0.91; 95% CI, 0.57–1.45; P=0.68). This suggests patients with multiple recurrences of CDI will benefit most from prophylactic therapy when requiring systemic antibiotics.8
    • While lacking prospective trials, it may be prudent to prophylax patients who have a history of CDI and now require systemic antibiotics with vancomycin 125mg PO daily. Patients with multiple recurrences may benefit most from this practice. While lacking data, metronidazole IV is an option when patients are unable to receive oral medications, but preference should be given to vancomycin when enteral administration is available.
  • Antimotility Agents
    • Historically, antimotility agents, such as loperamide, have been discouraged in CDI out of concern for worse outcomes like toxic megacolon. Koo et al. published a review article where they sought to study the literature to determine the basis of this practice. They found that all patients who experienced complications or died were given antimotility agents alone initially, without concurrent anti-CDI therapy. The authors of the new guidelines suggest that it may be safe to give antimotility agents adjunctively to patients also receiving anti-CDI therapy.9
  • Intravenous Vancomycin
    • IV vancomycin has no effect on CDI as it is not excreted appreciably into the colon and therefore is not discussed in this, or any other guideline as a therapeutic option.
  • Duration of CDI Treatment
    • Nearly all randomized trials utilized 10 day regimens which are usually sufficient.
    • If patients improve but do not have symptom resolution at 10 days, extending the course to 14 days can be considered.
    • If metronidazole is used, it should be limited to one course out of concern for neurotoxicity (including irreversible peripheral neuropathy) which has been associated with treatment durations > 4 weeks.10
  • CDI Treatment Recommendations:

    Logistics of First Line Therapy
    • Vancomycin capsules and fidaxomicin are both expensive, and often not covered by insurance. Estimated cash prices are below.11
      • Vancomycin 125mg PO capsules (40 caps) ~ $1,250.00
      • Fidaxomicin 200mg PO capsules (20 caps) ~ $4,400.00
    • Intravenous vancomycin is often utilized orally in the inpatient setting to minimize cost, and compounding pharmacies may offer more affordable options using this method. However, compounding pharmacies typically have limited hours and often retail pharmacies do not have compounding capabilities which can make this option difficult.
    • FIRVANQTM, a commercially manufactured vancomycin oral liquid has recently been approved by the FDA. Per their website, CutisPharma is targeting a launch date of April 2, 2018. We will have to wait to see how much FIRVANQ costs to ultimately determine its role, though a commercially available, reasonably priced vancomycin liquid is appealing.

    Take Home Points
    • IDSA/SHEA have released new CDI guidelines.
    • Emergency medicine pharmacists should play a huge role in antimicrobial stewardship, which is a key component in minimizing the occurrence of CDI.
    • Vancomycin PO or fidaxomicin are now the recommended first line agents for CDI, however, the high cost associated with these therapies may prohibit their use in some patients.
    • Metronidazole should only be considered when vancomycin PO or fidaxomicin are unavailable for adults. It is still a first line option for children.
    • Vancomycin PO therapy may be extended in patients with active CDI, or used prophylactically in patients with previous CDI episodes to prevent recurrent infection while on systemic antibiotics.
    • FIRVANQTM, a new oral liquid vancomycin formation, will soon be available, but cost information is currently unknown.

    Tony Mixon, PharmD, BCPS
    Emergency Medicine/Infectious Disease Clinical Pharmacist

    Peer reviewed by:
    Craig Cocchio, PharmD, BCPS

    Scott Dietrich, PharmD
    @PCC_PharmD
    Emergency Medicine Clinical Pharmacist


    References
    1. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Disease. 2018.
    2. Spellberg B. The New Antibiotic Mantra-"Shorter Is Better". JAMA Intern Med. 2016 Sep 1;176(9):1254-5.
    3. Gouriet F, Million M, Henri M, Fournier PE, Raoult D. Lactobacillus rhamnosus bacteremia: an emerging clinical entity. Eur J Clin Microbiol Infect Dis 2012; 31:2469–80.
    4. Kuntz JL, Johnson ES, Raebel MA. Predicting the risk of Clostridium difficile infection following an outpatient visit: development and external validation of a pragmatic, prognostic risk score. Clin Microbiol Infect. 2015 Mar;21(3):256-62
    5. Reveles KR, Mortensen EM, Koeller JM et al. Derivation and Validation of a Clostridium difficile Infection Recurrence Prediction Rule in a National Cohort of Veterans. Pharmacotherapy. 2018 Feb 2. doi: 10.1002/phar.2088.
    6. R Kaki, A Brooks, C Main, P Jayaratne, D Mertz. Does Extending Clostridium Difficile Treatment In Patients Who Are Receiving Concomitant Antibiotics Reduce The Rate Of Relapse?. The Internet Journal of Infectious Diseases. 2016 Volume 15 Number 1
    7. Van Hise NW, Bryant AM, Hennessey EK et al. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016 Sep 1;63(5):651-3
    8. Carignan A, Poulin S, Martin P et al. Efficacy of Secondary Prophylaxis With Vancomycin for Preventing Recurrent Clostridium difficile Infections. Am J Gastroenterol. 2016 Dec;111(12):1834-1840
    9. Koo HL, Koo DC, Musher DM, et al. Antimotility agents for the treatment of Clostridium difficile diarrhea and colitis. Clin Infect Dis. 2009 Mar 1;48(5):598-605
    10. Tiffany A. Goolsby, Bernadette Jakeman, Robert P. Gaynes, Clinical
      relevance of metronidazole and peripheral neuropathy: a systematic review of the literature,
      International Journal of Antimicrobial Agents (2017), http://dx.doi.org/doi:
      10.1016/j.ijantimicag.2017.08.033
    11. Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; February 17, 2018.


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