UPMC Physician Resources
Infectious Disease Year in Review 2016
Dr. Neel Shah discusses some of the pertinent issues, topics, and guideline changes in infectious disease that have occurred in within the last year. He focuses on some of the key concepts related to Endocarditis, Zika, HAP/VAP, Candida/Fungal guideline changes, new antifungals, vaccination, infection control, and stewardship/outbreaks.
Upon completion of this activity, participants should be able to:
- Identify pertinent issues and topics that were relevant to the field of Infectious Disease over the past year.
- Recognize key concepts revolving around above issues/topics, specifically those that pertain to the field of clinical internal medicine.
- Familiarize yourself with key changes in practice guidelines within the field of Infectious Disease over the past year.
1. Foy, BD et al. EID, 2011
2. The Joint Commission https://www.jointcommision.org/prepublication_standards_antimicrobial_stewardship_standard/
Dr. Shah has reported no relevant relationships with proprietary entities producing health care goods or services.
All presenters disclosure of relevant financial relationships with any proprietary entity producing, marketing, re-selling, or distributing health care goods or services, used on, or consumed by, patients is listed above. No other planners, members of the planning committee, speakers, presenters, authors, content reviewers and/or anyone else in a position to control the content of this education activity have relevant financial relationships to disclose.
The University of Pittsburgh School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
The University of Pittsburgh School of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits™. Each physician should only claim credit commensurate with the extent of their participation in the activity. Other health care professionals are awarded (0.1) continuing education units (CEU) which are equivalent to 1 contact hour.
For your credit transcript, please access our website 4 weeks post-completion at http://ccehs.upmc.edu and follow the link to the Credit Transcript page. If you do not provide the last 5 digits of your SSN on the next page you will not be able to access a CME credit transcript. Providing your SSN is voluntary.
ABIM MOC Part 2 Credit
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
To receive your ABIM MOC Part 2 credit, you will need to complete the post-test and evaluation process and provided your date of birth and ABIM number, along with the other required fields.
Release Date: 2/24/2017 | Last Modified On: 2/24/2017 | Expires: 2/24/2020
I'm going to be talking about well this is Infectious Disease Year in Review 2016, so I'm going to be talking about all of the pertinent issues, topics, guideline changes that occurred in the last year between the end of 2015 to the - well to now.
So before I start so I have no disclosures, like Dr. Bayer said I'm fairly new faculty, I don't really have any disclosures to address as of yet, maybe when I'm more famous one day. I do have a blog and twitter account which I actually run with Dr. Alex Viehman from the Division of Infectious Disease and we update or we post topics on ID on the blog and twitter page, so the link to the blog is there, our twitter is at IDPittStop and you can get both of those through the Infectious Disease website which is also available through the Department of Internal Medicine website, so I've listed that here as well.
So I'm going to do my best to focus on issues pertinent to you guys, the internists, that relate to infectious disease and there are updates that are occurring all the time. I've had trouble keeping up with things, especially with things like Zika where there is new updates every week. So if you find anything at the end of this presentation that you feel I should have added I am a humble man, please let me know I would be more than happy to get feedback.
So what am I going to be talking about? So like I said I'm going to be taking about pertinent issues and topics related to the field of infectious disease that occurred over the last year. These are some of the major topics I'm going to be discussing today, but more importantly I want you guys to understand the key concepts associated with these issues and see how they relate back to your you know the field of internal medicine. I want you guys to familiarize - at least be familiar with the guideline changes, at least the major ones that have occurred this year. And it is my hope that at the end of all of this you guys will be knowledgeable enough to manage many of these ID problems and in turn hopefully reduce our consult load in the future.
Okay, so let's get started. I'm going to kind of pickup where Dr. Viehman left off with the Year in Review last year and we are going to talk a little bit about endocarditis updates that occurred at the end of - I think it was the end of September/October of 2015. I figured this was a good place to start simply because it's something that you guys are going to see a lot of here and most medical institutions get a lot of patients with endocarditis. So the old guidelines were in 2015, the new ones like I said came out the end of 2015, so what's changed between them? So the old guidelines in 2005 in terms of diagnosis of endocarditis they were - they talked about determining what imaging to choose based on your level of suspicion. So the old guidelines said if your degree of clinical suspicion was high they should get a TEE and if your degree of clinical suspicion was low for infective endocarditis you should proceed with a TTE. That all changed with the new guidelines in 2015 and now the recommendation is to start every patient off with a TTE regardless of clinical suspicion.
So why did that change occur? So what the authors said was that there were a couple of reasons that this was instituted. One, a TTE is considered a less invasive test and it's more readily available in hospitals when compared to TEE. Two, a TTE is usually done at the end of treatment for endocarditis so it was thought that a baseline TTE would serve as a useful comparison tool for patients who did finish treatment. And then the TTE if it's later decided that TEE is needed the combination of the two would provide the clinician more information than just a TTE or a TEE alone. And for those reasons now TTE is the test of choice, so need to think about oh what's my clinical suspicion, just start off with a TTE. The authors state that either 3-D or 2l-D echo is perfectly fine. They do make mention of the fact that a e-D echo is more sensitive but tends to overestimate the size of vegetations and for the first time the guidelines start talking about other modalities in which to help diagnose endocarditis. They talk about things like PET CT, SPECT imaging, cardiac MRI and CT and I'll touch a little bit about that here shortly.
So like I said this is kind of the new algorithm for endocarditis. So the old algorithm was based on your level of clinical suspicion, now they are just saying if you suspect endocarditis you start with a TTE regardless. And then based on the results of your TTE and subsequent clinical suspicion you then make a decision as to whether or not a TEE is needed or not. They do say that if a TEE is obtained and found to be negative and your clinical suspicion remains high for endocarditis you should repeat a TEE sooner than what the previous guidelines in 2005 recommended, so within 3 to 5 days as opposed to 7 to 10 days and there is a big focus on the guidelines about referring patients like these to a center with cardiologists, cardiac surgeons and infectious disease doctors all present. They call it an endocarditis management team and so basically this is more of a message to smaller community centers that if they don't have the necessary resources or the clinicians to manage this they are encouraged to transfer these patients over to larger institutions. And that is probably in part why we are getting so many more of these patients here.
So one thing that's created a buzz in the last year is the use of PET CT, specifically in the diagnosis of device associated endocarditis. And so this is something that's not again embedded into the guidelines yet but there is mention of it in the most recent guidelines and it could become incorporated into the guidelines in the future. So PET CT is a imaging modality that can be used to determine whether or not someone has a device associated endocarditis, endocarditis from an AICD or a pacemaker. It's known to have very good sensitivity in distinguishing between lead and soft tissue site infections. There was one study that showed I believe it was 42 patients on retrospective review about 15 to 20% of those patients would have not required device extraction had a PET CT been done. So this is something to keep a lookout for in the future. Some institutions are already incorporating PET CT as an alternative means of diagnosing device associated endocarditis, especially when the TEE can't be done or is ambiguous, so it's just something to keep an eye out for.
So what changed with regards to treatment? So the big emphasis with the newer guidelines is everything should basically be done earlier from both an antibiotic and a surgical intervention standpoint when it's indicated. So from a treatment standpoint not too many big changes, the only thing that was incorporated into the new guidelines when compared to 2005 was double beta-lactam therapy for enterococcus species. And so in 2013 there was a CID paper that was published that showed that Ampicillin and Ceftriaxone was just as good as Ampicillin and Gentamicin for the treatment of enterococcus faecalis endocarditis. And so that has sort of made it's way - subsequent studies have supported this finding and that's made its way into the guidelines. The new guidelines supported for either enterococcus species, both faecalis and faecium but the data is mostly with faecalis, that's AM sensitive so that's just a caveat to make note of. With regards to prophylaxis there hasn't been too many big changes, that's basically the same as it was before.
And from a surgical standpoint again all the indications that I've listed over there are all the same for surgery, so CHF, fungal endocarditis, presence of an intervalvular abscess, enlarging or persistent vegetation, vegetations that are more than a cm ini diameter, etc, tec. But they recommend that if surgery is indicated it should be done sooner rather than later. One gap in the new guidelines is the specific management for right sided endocarditis especially in the setting of injection drug use. And that's something that we all I'm sure have seen a lot of and there is just not really any good data or any solid recommendations to make. I mean they sort of say that valve repair for those patients is favored over replacement, and they even mention that it's reasonable to questionably avoid surgery when possible in IV drug use patients. Again this is something that really needs more studies to be done and thee is a lot of ethical and you know evidence based barriers to this. So again we need to stay tuned and see what comes up in the future with regards to this.
Okay, so that brings me to the next topic. This is probably the biggest commercially known infectious disease issue that occurred over the last year, so Zika virus. So I want you guys to be - I'm going to talk a little bit about you know I guess the history of Zika and a little bit about how to diagnose, how to manage patients and what kind of advice you guys should be giving to your patients as internists.
So what is Zika virus? It's part of the Flavivirus family, that's like the family with the - that's associated with viruses like Dengue, West Nile, Yellow Fever, etc. It was first isolated in Uganda in 1947 in rhesus monkeys and over time there have been more and more ways we found that this virus can transmit to humans. So initially it was thought to be only transmitted through insects, specifically through Aedes species mosquitos, and I've shown both types of species that transmit the virus there, one is called Aedes aegypti, one is Aedes albopictus. In 2011 it was found that the virus could be sexually transmitted. Blood transfusion was also found to spread Zika and then more recently vertical transmission from mother to child as you all I'm sure know as been discovered. I think it was in April of 2016 that was formally published.
So one thing I want you guys to appreciate, this virus has made a pretty long trip to get to the U.S. So it started in Africa and it stayed there until the 1960s. Over time it made its way into Southeast Asia, Middle East, India, Pakistan and that was in the 1970s. In 2007 there was a Micronesia outbreak through - from that particular outbreak the majority of our Zika virus knowledge actually rests. And over time it's made its way into Central and South America and as you know in the last couple of months it's made it's way into southeastern U.S, into Florida. So this virus has traveled literally around the world to get here.
So what are the symptoms of Zika virus? So the incubation period is about 3 to 12 days. Based on the Micronesia population that was analyzed in 2007 there was a publication in 2009 that showed that of those patients 80% ware found to be asymptomatic whereas 20% had symptoms after they were confirmed to be serologically positive for the virus. The symptoms are pretty nonspecific for a flavivirus. I mean fever, rash, joint pains, conjunctivitis, myalgias, headache, these are - there is nothing very distinct about you know the symptoms that occur with Zika. And in the majority of patients it's self-limiting, it last for a week and it goes away.
More recently the Lancet published the case report of Guillain-Barre being associated with Zika. And then as you know I'm sure like I said in April of 2016 the CDC found that there is congenital abnormalities that can occur in pregnant women who deliver babies after being infected with Zika. The most notable is microcephaly but every week there is something new that seems to be coming out, hearing loss, eye defects, CNS injury, limb defects, fetal death and the list keeps going. So the important thing to understand here is that in the normal population this virus is not life threatening in general maybe with the exception of Guillain-Barre which is a rare occurrence. The risk of course is in women who are pregnant or are thinking of having a child because a the mortality rests mostly within the newborn child.
Okay, so how do we diagnose Zika? So there is two types of tests that can be done, and it all depends on how far out you are from the onset of symptoms. So if you are within the first 7 days of illness reverse transcriptase PCR testing is the test of choice. After 7 days they recommend using the Zika IgM antibody. Even though that antibody can form within 3 days of illness onset it's considered more reliable after the first week of symptomatic illness. Once that antibody is positive it lasts for months and it does cross-react with other flaviviruses, like I said before there is Dengue, West Nile, St Louis Encephalitis, Yellow Fever. So for a test to be accurate there is something called the plaque reduction neutralization test that has to be done and that's done by the CDC. And so they can sort of sort out the positive test and confirm once and for all whether or not that antibody is from Zika or another flavivirus. And multiple things can be used to get these tests, blood, CSF, amniotic fluid and urine are all possible things that can be sent out.
So again because the risk in terms of mortality is associated with newborn or unborn children the screening focus is mostly on pregnant women who have traveled or live in an area that's endemic to Zika virus. So these patients if, if that's the case they get tested for Zika virus again either through reverse transcriptase PCR testing or antibody testing based on whether or not they have symptoms and how long they have been occurring. If the test is positive then the baby is screened for microcephaly and then amniotic fluid testing is obtained at that time. If the test is negative you do do a standard fetal ultrasound I believe at 4 or 5 weeks to look for intracranial calcifications. If there is evidence of microcephaly or calcifications on that ultrasound then again you retest the mother for Zika and also get an amniocentesis checking the baby for Zika as well. But if everything at that ultrasound is good then routine prenatal care is indicated. So I mean it's probably unlikely that you guys are going to need to memorize this but I want you guys to at least be familiar with what's being done from a screening standpoint.
This you may need to know. So what advice should you give your patients when you see them in clinic and they are deciding that they are wanting to go to an area or they live in an area endemic for Zika? So there is 2 big things you guys need to keep in mind. One is because Zika is a vector borne illness any type of mosquito repellant ideally DEEP, Picaridin or Permethrin is ideal to use and I would recommend this to all of your patients who are going into areas endemic for Zika, they are safe in pregnancy. So that's one recommendation you can provide to them. Bed netting, wearing long sleeve clothing, limiting your travel is underestimated and I think the most logical thing. I mean if you don't need to go to an area that's endemic to Zika and you are thinking of having a kid well you shouldn't go. It's not the end of the world if you miss your spring break that year.
The other big thing to keep in mind is people because the virus is sexually transmitted the use of condoms and avoiding sexual activity after being in an area that has Zika has been recommended by the CDC as of July of 2017. So what I've listed here is what the recommendations are, how long you should wait to have unprotected sex basically. So if you are a female and you have Zika symptoms or you don't have Zika symptoms you wait 8 weeks regardless. For males if they have Zika symptoms they are told to wait 6 months after returning from the area to have non-protected sex. But if they have no symptoms they are also encouraged to wait at least 8 weeks. There is a website I listed here which is through the CDC and you can let your patients know about that. And we have a travel clinic here at UPMC and we'd be happy to see those patients too, so whenever in doubt you know send them our way and we'd be happy to help out.
So Zika treatment, so a short answer for that as of now there is no treatment; so the focus is primarily on vaccines to prevent the spread of this virus from person to person. So this rests on two major studies that came out this year in 2016, one in Nature and one in Science which showed protective immunity basically in animal models. The Nature study was in mice and the Science study was in monkeys and based on these two studies there have been initiated - there has been an initiative to start research on humans with regards to Zika virus vaccines. So I'm sure you guys have seen some of this in the news but the NIH began working on this back in January of 2016 and other companies have followed suit over the next subsequent months. The first human trial of Zika vaccine is also underway and so we have I guess more is still to come and this is sort of a story that's not completely closed yet, so to be continued.
Okay, so now I'm going to talk a little bit about the updates, so there were updates this year on the management of hospital and ventilator associated pneumonia. It was a joint effort by the ATS and the IDSA. And so I want to talk a little bit about this because this is something you guys are also going to see a lot of, a lot of HAP and VAP especially in the ICUs and in the long term care setting. So before I go into this I wanted to clarify the different definitions of HAP, VAP and HCAP just for you guys as a refresher. So HAP I'm sure you guys already know this, it's any pneumonia that's diagnosed after 48 hours of being hospitalized. VAP is a specific form of HAP that occurs after a patient has been on the vent for more than 48 hours. And the one that's always hard to remember is the HCAP definition, so that is pneumonia that occurs for someone who has been hospitalized for at least 48 hours in a hospital, I'm sorry in a hospital setting in the last 90 days who either resides in a long term acute care center or a SNF or has been to an infusion center, a chemotherapy center or a wound care center in the last 30 days.
So the last guidelines were also in 2005 for this, so what's changed? So the first big thing that's changed is that HCAP, the last definition I talked about is no longer part of these guidelines. These area purely HAP and VAP guidelines. And so why did they make that change? So what they found was between 2005 and 2016 the organisms that were associated with HCAP were not as drug resistant as the ones that were seen in HAP and VAP. And the other thing they also found was that they did a metaanalysis I believe of almost 20,000 patients over time and what they found was that the mortality associated with HCAP was less associated with the resistance of the organism and more so with the underlying medical issues that the patient had. And because of these reasons the authors decided well we are going to take HCAP out of the equation here and they may pair it up it up with the CAP guidelines which are coming up in the future. So we'll see.
The other thing, so what else has changed in a nutshell? So I'm sure you guys have heard of different markers being used to help better diagnose bacterial infections, specifically pneumonia. And what I'll talk about this more in a second but what they've basically found was that at this point in time the recommendation is that clinical assessment alone is sufficient in diagnosing HAP and VAP. Things like procalcitonin, and I'll talk about this in a second, but sTREM-1 they are not - there is not enough data for them to be incorporated into the guidelines at this time. And so at this point in time diagnosis of CAP and VAP is made by clinical assessment and x-ray imaging and such. The most important change that occurred, I outlined it here in yellow, is that each hospital at this point in time they are making no recommendations on what to do for specific organisms. Instead what they point to is using a personalized antibiogram for each institution and using that antibiogram to guide treatment for the institution with regards to empiric therapy, and that's kind of the take home point for the new HAP/VAP guidelines. That being said they do still talk about MRSA, Pseudomonas and resistant gram negative drugs, and I'll touch upon these here in a second a little bit. And they do also emphasize that we can further shorter the duration of therapy from 8 days now to 7 days and I'll talk a little bit about that as well. And as always they've always emphasized the importance of deescalating therapy once you have your culture data in and once the patient is deemed clinically stable.
So there are two big biomarkers that you may or may not know about that have been sort of discussed in the last couple of years with regards to the diagnosis of pneumonia, bacterial pneumonia specifically. One I think you guys probably know is called procalcitonin, there has been a lot of European studies and a lot of studies here now about its utility in helping to distinguish between viral and bacterial infections in the ER especially. There is also something called a soluble trigger receptor enzyme that is expressed by myeloid cells, sTREM-1. I don't think it's commonly used here, I don't think we use it at all in fact but other institutions are using this. This is a test that can be obtained through a BAL and it is thought that it can be - it's more specific and sensitive in diagnosing bacterial pneumonia. The key thing I want you guys to know about this is the bottom line is the authors analyzed studies, I think 6 each for each biomarker and found that there was no cutoffs in what was considered a positive test for any of these studies. There was no consistency measuring the values for these studies and they didn't - when they pooled the studies together they found that the overall sensitivity and specificity were low, less than 90%. And based on these data they couldn't incorporate these two tests into the guidelines yet. And so that's again something to stay tuned for, maybe as we get more data these things will be incorporated in
So this is also just a reminder, again the underlying theme of the new guidelines is to use the antibiogram at your institution to guide empiric therapy for treatment of VAP and HAP. And so these are just examples of antibiograms that are in our own EMR for two different institutions. And I know it's hard to see and I don't expect you guys to look at it right now but when you guys have a chance have a look at - you know look at different institutions, you'll see that sensitivities are varying even amongst our different institutions, even Presby and Monte have different antibiograms. So it shows that there is a degree of individualization that is now needed to address these infections empirically based on the institution you are at. So be sure to use your antibiograms. I think there are antibiotic books there and so if you guys don't have one I believe the antibiograms are in there as well, so feel free to take some, or one actually, I don't know how many we have, before you guys go if you don't have one already.
So what are the recommendations that they provided on specific organisms? So what they found was that for MRSA empiric treatment for MRSA is only indicated now if there is a greater than 10% incidence of MRSA pneumonia at the institution where the patient is diagnosed with their pneumonia. The caveat is there is also certain risk factors which I'll talk about in the next slide that can also contribute to initiating MRSA therapy empirically. Basically the main risk factor is prior antibiotic exposure which is kind of a broad blanket statement but right now that's what they are recommending. With pseudomonas and gram negatives for VAP now again double coverage for these organisms is indicated if there is a greater than 10% rate of resistant organisms present at the institution where the pneumonia is diagnosed, or if an antibiogram is not available to help guide therapy.
For HAP it's a little bit higher cutoff from MRSA. Empiric therapy is indicated if there is greater than 20% incidence of MRSA at the hospital or if there is a high risk of death. And with gram negatives and pseudomonas again if the risk factors, which I'll mention here in the next slide, or if there is high risk of death you start the double coverage at that point in time. So basically if the patient is sick and there is concern for HAP the guidelines are saying at this point in time okay to start coverage for MRSA, pseudomonas, gram negatives until you sort out what's going on.
For MDRs there was - so the guidelines suggest combination inhaled and IV antibiotic therapy, and that's based on I believe a metaanalysis of 9 studies which showed improved outcomes when they used a combination. I'm talking about organisms that are only sensitive to very limited antibiotics, Colistin/Polymyxin B/Aminoglycosides. In that setting the combination of the two is indicated. So these are all the risk factors that I just mentioned for multidrug resistant pathogens. You can see that almost all of them have antibiotic exposure as part of their risk factor assessment. So again this is just something to keep in mind. I mean for MDR VAP there are more risk factors basically, if the patient is in septic shock, ARDS, if they are on renal replacement therapy these are risk factors to sort of pull the trigger on empiric therapy for MDR organisms if needed.
So a question I always get asked a lot about is for VAP and HAP which is the better drug? Is it Vancomycin or Linezolid? And I've had a lot of residents ask me this, a lot of attendings also are not fully familiar with this. So overall the - multiple studies have shown that both antibiotics are essentially equal in efficacy. There is no real difference in overall mortality, duration of ICU stay, time to extubation, etc, etc. This was the only study I found that showed maybe there was some benefit to Linezolid when compared to Vancomycin in the acute period. This was a randomized double blinded multicenter study that was done comparing fixed dose Linezolid with fixed dose Vancomycin, a g IV q12. And in the acute period, in they are both at the end of therapy and in their modified intention to treat study Linezolid was slightly better, but they do make note of the fact that the overall 60 day mortality was the same between the two. And the time in the ICU was no different. So again the bottom line here is that Vancomycin and Linezolid are basically the same.
Because Vancomycin is cheaper, because it has potentially less side effects it's usually considered the drug of choice to use upfront unless there is direct contraindications. The only potential exception may be based off of a statement that came from ASHP recently. And what they point out is there was a study that showed that - well basically for Vancomycin to be therapeutic the AUC/MIC, the target AUC/MIC has to be at least 400. And what they found was that as you increase the MIC of the organism, or the MRSA isolate to Vancomycin the probability of you achieving that AUC/MIC becomes lower and lower. They did a series of what's called Monte Carlo simulations and what they found was that when the Vancomycin MIC reached 2 mg/liter or more achieving the AUC/MIC with Vancomycin was almost 0% basically compared to 100% of the MIC was 0.5. So if you have a patient who has MRSA pneumonia in the ICU who has a Vanc MIC of 2 you may be justified in not using Vancomycin upfront for those patients and you may benefit from switching them to Linezolid. That might be the one exception, so just a caveat to what I just mentioned before.
So this is a study that was published in Chest in 2013. So there was two metaanalysis studies that were done, this was one, I'm just posting here. This was a metaanalyses of 4 studies pooling together over 800 patients, the other one was 6 studies with 300 or 400 patients I believe. And the bottom line here is that long and short course there was really no difference in overall outcome in these patients. And so based on these two metaanalyses, the one I listed here and the one I just mentioned, the guidelines are saying that shorter course antibiotics, meaning 7 days compared to the 8 to 15 days that were given previously, is considered just as effective and has lower risk of side effects, C DIFF and other complications. So as we are seeing over time the duration of treatment for pneumonia just keeps getting shorter and shorter, and maybe one day it will be the same as CAP which is 5 days, I don't know. But the data seems to be supporting shorter and shorter courses, so we'll what happens in the future.
Okay, so moving on. So there are a lot of updates this year. So this is the new guidelines that came out the middle of this year on the management of candidemia or candida in the blood. So the prior guidelines were in 2009, so what's changed between 2009 and 2016? So the big change that occurred was that now they are recommending that basically for all patients with candida in the blood regardless of their immune status, the severity of infection and the echinocandins. do caspofungin, micafungin, anidulafungin is to be considered the drug of choice upfront. And the reason in part as to why they made that decision is because there's been a shift in the type of candida species that have been present between 2009 and 2016. We are seeing less and less fluconazole susceptible isolates like candida albicans and we are seeing more isolates like candida glabrata, krusei and parapsilosis. And so in part because of that change and the shift in the organisms that we are seeing in the hospital the recommendation now is that it kind of echinocandins are considered the more reliable upfront drug to use. The guidelines also do recommend identifying the candida species as soon as possible and obtaining susceptibility data to see if it's susceptible to azoles, so I'm talking about Fluconazole and such. And if possible at that point the recommendation is to step down to an oral regimen whenever possible.
Otherwise the recommendations as before are the same. Eye exam should be done within one week of clearance, within diagnosis - from the diagnosis of fungemia, there should be at least 14 days of treatment for fungemia and longer if there is cardiac involvement. All lines should be removed and important for you guys, candida in the lungs is usually almost - it's almost always a contaminant, never ever call an ID person and say candida in the lung.
So in addition to what I just said there is actually data to support why echinocandins should be used up front. There was a study by Reboli published in the New England Journal of Medicine, it was a double blind non-inferiority study comparing Anidulafungin which is an echinocandin to Fluconazole for invasive candidiasis. They used 245 patients and they had an endpoint of looking at resolution of symptoms in the acute treatment period as well as fungemia and then also at the 2 and 6 week follow-up. And in short I mean at every single time point the Anidulafungin group just did way better. And so following this there were 3 separate studies that compared Anidulafungin with Caspofungin and Micafungin and found they were all equivalent. And other studies have supported these findings as well and that's also a reason why the guidelines basically changed.
That being said I also want to talk about anew antifungal drug that kind of came in that's actually, it's only been a year actually, yeah, it's very new. It's an azole class drug called Isavuconazole, I don't know - some of you may have already seen it on the floors, on the ICUs being used. It basically exists in this prodrug form called Isavuconazonium and it's broken down into its active form in the body. The actual drug itself is - so a couple of things that you should make note of, unlike other azoles which prolong the QTC this shortens the QTC, which is actually a great thing. Its volume of distribution is high, it has a long half life and it was recently FDA approved for both Aspergillus and invasive Mucor infections in adults. So especially with Mucor given our limited option this is a great, it's almost like a God-send for us infectious disease doctors.
So how do these approvals come to play through the FDA? So it's based on three Phase III clinical trials. The first two are the most important. So there was something called the SECURE trial which compared Isavuconazole to Voriconazole for Aspergillus and found that Isavuconazole was non-inferior to Voriconazole as well as other molds that Voriconazole was being used to treat. The VITAL study compared Amphotericin B to Isavuconazole for Mucor infections and found that Isavuconazole was non-inferior to Amphotericin B. So based on these two studies the FDA approval for Mucor and Aspergillus was established.
There was another study called the ACTIVE study, another phase III clinical trial, in which Isavuconazole was compared to Caspofungin for Candida infections. In this study which was a non-inferiority study Isavuconazole was not non-inferior, if that makes sense. So basically couldn't be used as a - there was not enough evidence to use it as a first line drug for Candida infections when compared to Caspofungin.
So one thing - so it definitely is a great drug, but you can see here that the cost difference between Fluconazole, Caspofungin and Isavuconazole is quite large. I've sort of pulled values together for a 14 day course of therapy for fungemia and you can see that Fluconazole is no more than $99 for 14 days of therapy whereas Isavuconazole is almost $4,000 for 14 days of therapy. So the take home point - I want you guys to appreciate that there is a difference in cost, Isavuconazole is not necessarily better in all aspects and if you have an isolate that susceptible to Fluconazole you are going to be doing your patients a big favor by just simplifying to Fluconazole and saving them some money.
So what is Isavuconazole's role in other guidelines? We talked a little bit about the Candida guidelines also but Aspergillus guidelines came out in 2016 as well and with the advent of this new drug the new guidelines for Aspergillus show that Isavuconazole is an alternative to Voriconazole for invasive Aspergillus infection and can also be used as salvage therapy for patients who have breakthrough on Posaconazole prophylaxis. So the arrival of this drug is going to be effecting a lot of these fungal guidelines so we are going to be seeing a lot of changes probably in the next couple of years.
Okay, so the other thing I want to talk about is the importance of vaccination. This is something unfortunately I have to talk about but I shouldn't have to talk about quite honestly because these infections, polio, mumps and measles, should be gone and they are not. Worldwide we are seeing you know polio, mumps, there was that Disneyland outbreak with measles even in the U.S. and this is just to emphasize the importance of vaccination and educating your patients about vaccines because there is a lot of misinformation out there, there is a lot of confusion among patients which then leads them not taking vaccinations and then you get stories like this. And so I want you guys to have an appreciation for the fact that you know as internists it is your kind of the first line in sort of preventing these stories like this from occurring indirectly. And by talking with your patients, educating them on the vaccinations that they need you can outbreaks from occurring in this country and you know and save a lot of problems down the road.
And that being said, I did want to just touch on the most relevant vaccine for this season which is the influenza vaccine and I want to make sure you guys are all aware of when it's given and you know what options you have with regards to your patients and what you can give. So the influenza vaccine, it's indicated for anyone who is 6 months or older and the new guidelines, which are not that new anymore, is saying that everyone should be getting it yearly. There are different formulations of the influenza vaccine, so if you are under 65 and have no issues, meaning no egg allergy, you are not pregnant, you are not immunosuppressed, you are not scared of needles well the standard dose flu vaccine, what we are all getting, is indicated. So it's the quadrivalent is favored over the trivalent vaccine because you get more strains introduced. It's for everyone 6 months or older, it's an intramuscular shot.
If you are over 65 there is a new recommendation now for something called high dose trivalent or inactivated - I'm sorry, high dose trivalent inactivated vaccine or it's called high dose Fluzone vaccine. This is something, it's basically a double dose of the influenza vaccine. What clinical trials have shown through the CDC is that patients over 65 they lose their immunity to influenza over time, and so the thought is that by giving them double dose vaccine they can sort of retain that immunity because they are sort - they are at higher risk of acquiring serious influenza complications over the course of their lifetimes. And there is a study from the New England Journal of Medicine recently done that showed that in patients who got the high dose Fluzone vaccine compared to the standard Fluzone vaccine there was a 25% greater immune response in those patients over 65 when compared with the standard Fluzone vaccine that was given. So again more studies are going to be needed to sort of legitimize this higher dose flu vaccine but so far the results seem to be convincing.
For patients who are scared of needles there is an intradermal flu vaccine, I'm not sure if you guys knew that. But it's a quadrivalent inactivated vaccine, it's intradermal, it's approved for anyone under 65. It's 18 to 64 years of age. Or in those patients who can't stand needles you can always use the live vaccine which is an intranasal vaccine.
If you are immunosuppressed or pregnant though you can't give any - you can't give the live vaccine, it has to be any form of inactivated vaccine.
And if you have an egg allergy in theory all of the vaccines are still thought to be safe but if your patients are very persistent there is something called RIV3, it's a recombinant influenza vaccine that has no ovalbumin, so has no egg content at all. So if your patient is still resistant this is something you can offer them that you know sort of makes them take the vaccine.
And then again I want to emphasize this, autism is not associated with any vaccine. If your patients start talking about that, you need to educate them that that's just not the case and they can take any vaccine safely, there is no risk for that being - for that developing, there is no good studies at all.
Okay, and I think this leads me to my last big topic. So there was antibiotic stewardship guidelines that came out this year as well amongst other things. And I don't need to go over the specific of what they recommended in this, in these guidelines, I don't think that's - that's probably beyond the scope for you guys to know but what I want you guys to appreciate is that this is becoming a bigger and bigger issue as time goes on. And regardless of what field of medicine you are going to go into you are going to get exposed to antibiotic stewardship issues basically. There is a National Initiative that came out recently that has a goal of reducing the rate of inappropriate antibiotic use by 50% by 2020. And so there is going to be a lot of push to get people to use antibiotics in a intelligent and efficient way rather than giving everyone Vanc, Levo and Zosyn you know every time the patient comes in.
There were two studies that came out I believe in JAMA in May of 2016. One study attempted to quantify how I guess basically quantify the problem. And what they found was that out of 500 patients that were given antibiotics 40% of them were given antibiotics inappropriately. And a subsequent study showed that interventions that were implicated afterwards through the use of the EMR actually reduced the rate of inappropriate antibiotic use by 24%. And so I mean the bottom line with this slide is that there is a problem with the inappropriate antibiotics, it's been quantified now and the bigger issue or the bigger thing is that there is something we can do as doctors to prevent it. There are interventions that can be initiated and this is something that's gong to probably play a bigger and bigger role in future year in review presentations, at least I'm guessing.
Okay, so what is going to be coming up in the future? So everyone is going to be looking out for the next big outbreak because you know we had Ebola, we had H1-N1, we had Zika now and so every hospital is anxiously awaiting and trying to prevent having the next big outbreak. More recently, I believe in the last month, there was a CDC announcement showing that a new type of - well not a new type of Candida but a new Candida species to the U.S. called Candida Auris has made it's way here. This was a species of Candida which was initially isolated I believe in 2009 in Japan and it's made its way all the way here now. What's particularly concerning about this is that this species of Candida unlike the other ones I mentioned previously are potentially resistant to all antifungal classes and they also have the potential to spread within the nosocomial environment almost like an outbreak. So this is something the CDC is watching very carefully. So we may already have our next big outbreak in the works, hopefully not but we'll see.
The other thing that will be interesting to see is the long term impact of Zika in this country. I mean we know right now that it's here but what does this really mean for pregnant women in our population? How many birth defects are we going to truly see? What other findings are we going to find out in the next year? And so that's something we need to I guess wait and see on.
HIV I didn't mention much in this presentation because there weren't any major changes but in the future there are now plans for initiating long term or long acting HIV regimens, things that last for weeks and months rather than you know taking a - one pill once a day just wasn't enough, now they are thinking one pill once a week or one pill once a month in an effort to further improve compliance and reduce side effects. As many of you already know there is more multidrug resistant organisms out there and more treatments are going to be needed and so our institution here as well as other research facilities are working on novel treatment options to address these organisms over time. I believe doctor Viehman mentioned Ceftazidime Avibactam and Ceftazidime Tazobactam last year, but we are going to need more than just those two drugs over time, hopefully we get some.
Newer diagnostics including molecular testing, improving MALDI which is a mass spectrometry test that's done in our labs, all this is being sort of worked on at various research institutions to better identify infections, more accurately define them. And so these are things we need to look at for in the future as well.
And then novel vaccines, things that there is research out there for Zika virus vaccine like I mentioned recently. Dengue, HIV, Malaria all have research for vaccine development. And so development of vaccine in any one of these infections would be big news so we'll have to stay tuned.