Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. James Lewis and Dr. Elizabeth Dodds Ashley. This program is available as read-only and with accompanying audio.
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Slide 1: Welcome to the teleconference, “Serious Fungal Infections: New Opportunities in the Prevention and Management of Invasive Aspergillosis.” This program is jointly sponsored by Medical Education Collaborative (MEC) and Princeton CME. It is supported by an educational grant from Schering-Plough Corporation.
Slide 2: I am Dr. Jim Lewis from the University Health System in San Antonio, and also the University of Texas Health Science Center here in San Antonio. I will be your presenter, along with Dr. Libby Dodds Ashley, Clinical Associate, Department of Medicine, and Division of Infectious Diseases at the Duke University Medical Center in Durham. She will be presenting the case study.
Slide 3: Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form located in the back of the activity booklet. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com. Thank you again for joining us today. Dr. Dodds Ashley will now introduce the case study.
Slide 4: Thank you, Jim. I would like to start by just briefly going over a case that we are starting to see more and more commonly in our clinical practice.
Slide 5: This is a 56-year-old man who was diagnosed with multiple myeloma about 2 years ago. He is being seen in our clinic today for routine follow-up, but he presented with an acute episode of shortness of breath. He has had recent chemotherapy, and he is currently in renal failure. He was an otherwise healthy individual until he was diagnosed in 2006, and he has no known drug allergies.
Slide 6: You can see listed his oncology history in more detail but, basically, from December 2006 through April 2007 he had his initial treatment with chemotherapy. He then underwent an autologous stem cell transplant. He was doing fairly well following that until January of this year, when he was diagnosed with disease progression. We have since begun a salvage regimen of chemotherapy, that has resulted in neutropenia for this patient. He has been doing relatively well but, because of his underlying myeloma, has now gone into chronic renal failure and is hemodialysis-dependent.
Slide 7: He was seen on the day after his most recent hemodialysis session and his weight appeared to be stable. He was waiting to be seen in the clinic, and he was noted to have fever. He had an acute episode of chest pain and then started coughing up blood in the clinic. So, this prompted the admission and further work-up. For sort of standard therapy in this patient, he was started on piperacillin/tazobactam, azithromycin, and caspofungin.
Slide 8: Some pertinent laboratory findings that relate to this case—he obviously had elevated markers of renal function. He has a new chest x-ray today that shows diffuse opacities that were thought most likely to be edema, although you could not rule out atypical infection. He also had a chest CT ordered because of the hemoptysis we were so worried about. And, on that, we found a 1.5-cm nodule in the right lower lobe, and this also was suspicious for atypical infection.
The rest of our diagnostic work-up is really pending at this point. We have ordered a galactomannan that, obviously, isn’t available yet, and cultures of blood sputum and a bronchoalveolar lavage are all pending.
Slide 9: : At this time, it is a common clinical conundrum. What should we do for this patient? Should this patient have already been on antifungal prophylaxis? He was not receiving any prophylactic antibacterials or antifungals at the time of his admission. If we are suspicious for fungal pneumonia, what pathogens are most likely to be causing disease in our patient? And, given the lack of available clinical data from all of these tests we have ordered, should we make an empiric change of therapy or should we stay the course with our normal empiric regimen in this patient population?
I am going to turn things back over to Jim, who is going to review for us the data regarding the use of antifungal agents in these high-risk patients at this time.
Slide 10: So, now, let’s move into the presentation portion of this a little bit.
Slide 11: Let’s start by looking at invasive fungal infections in hospitalized patients. I think when pretty much everybody who is listening to this looks at this list, hopefully there are very few surprises there for you. I think one of the things that I do want you to walk away from with, though, is that we do not take our eye off the ball. Look at the bottom part of this slide and notice that it is still Candida and Aspergillus that really drive invasive fungal infections in US hospitals.
Slide 12: The burden of invasive aspergillosis—moving on to the next slide—really is primarily seen in immunocompromised patients, and this tends to be a group of individuals that seems to expand every year as we use more and more steroids and as we use other agents such as TNF-alpha blockers, that also have some immunosuppression associated with them. Aspergillus fumigatus remains the most common bug that we see, and that is important to remember, but do not lose sight of the fact that other species of Aspergillus are important as well and may be gaining importance as we move forward.
When you look at the stem cell transplant population in particular, what you will notice is that the crude mortality rate can still approach 90% in some of these series. Again, though, it is important to remember that stem cell transplants or the hematologic malignancy patients make up the vast majority of these patients and, in many of these patients, it is their underlying malignancy that eventually gets them, but the Aspergillus often times is a very important player as well. Furthermore, not only can this be a highly lethal infection, but if you look at the costs to the US healthcare system, it is substantial as well.
Slide 13: One of the major problems that we run into is how do we know when a patient has invasive aspergillosis because, really, the symptoms are not specific and often times the underlying disease—namely, hematologic malignancies or other forms of immunosuppression—may mask the symptoms. This then leads us to pick up these patients later in the game, resulting in a later diagnosis in a patient who now has a much higher fungal burden. The other problem that we run into is that, on biopsy, fungi in tissue can look indistinguishable from Aspergillus. Things like Fusarium, things like some of your Zygomycetes can look a whole lot like Aspergillus in tissue and make diagnosis very difficult.
Furthermore, as we see some of these other Aspergillus species besides fumigatus pop up—and I think a golden example of this is Aspergillus terreus, which is intrinsically more resistant to amphotericin B—it becomes more and more important for you to know the species of Aspergillus that you are dealing with, again, to remind you that there is no substitute for good microbiology.
Slide 14: In this pie chart on the next slide, you can see the breakdown that we kind of associate with invasive aspergillosis in this very nice paper from Patterson and colleagues in 2000. Again, the thing that I really want you to take home from this is that a significant portion of this chart is represented by allogeneic and hematologic malignancy-type patients as well as solid organ transplant patients. I mean, when you look at this, those individuals make up about two thirds of this slide, with other types of immunosuppressive patients seen in some of the smaller pieces of the graph.
Slide 15: The next slide, again, comes from Kieren Marr’s data set, which again shows that there has been an increase in invasive aspergillosis rates over time, but I would argue that this data is somewhat limited by the fact that it is now about 10 years old and that, since 1998, you have seen something of plateauing as the newer azoles have kind of come online, namely voriconazole.
Slide 16: Now, in a very nice paper that has recently emerged, again out of the Fred Hutchinson Cancer Center in Seattle, Upton and colleagues look at the impact of invasive aspergillosis on survival in their stem cell transplants over time. What you can see here is that between 2002 and 2004 patients appear to have done better than in the previous 15 years looked at in this study.
Now, there are a couple of reasons that may be associated with this, but I think one of the big things that really comes into play here is our improved ability to get to these patients early, namely with chest CTs and with the increasing use of the galactomannan assays. I think the other thing that may come into play here is actually the advent of voriconazole in about 2001, and so you are probably starting to see the impact of that. So, I think you have got kind of a variety of predictors here, or a variety of factors here, that are kind of coming together. Namely, you have got less toxic drugs, such as voriconazole, that are highly effective against Aspergillus in vitro coming into the clinical setting. At the same time, our diagnostics are getting a little bit better, and I think that when you put all of that together you start to see this improvement in survival that we see in this very nice paper.
Slide 17: When you move on to the next slide, which is a continuation of data from this data set, you’ll see that there are a couple of predictors here for high risk of mortality in these patients. And I think none of this is probably too much of a surprise to you, namely the first bullet here in disseminated invasive aspergillosis. I think that one of the places Aspergillus likes to disseminate to is your head, and we know that anytime CNS Aspergillus pops up, the mortality rates are exceedingly high, but I think that this is again kind of a marker for the second bullet, in that if you have disseminated disease, we are getting to you very late in the game and late Aspergillus, disseminated Aspergillus, I think kind of fall into the same pot a little bit, both of which are very hard to treat, probably because you have such established disease and a high fungal burden.
The next 2 bullets, I think, are important because they reflect that once again individuals who have other problems going on at the same time are probably at a higher risk of not being able to be successfully managed from their invasive aspergillosis. Elevated creatinine and an elevated bilirubin are probably markers of multiorgan dysfunction, which is a poor predictor of outcome in almost any disease state you look at, whether it is gram-negative sepsis or invasive aspergillosis or invasive candidacies for that matter. Any time you go into multiorgan dysfunction, you start to see those patients do worse.
And then, finally, the middle bullet here of corticosteroids, again reinforcing that the fungus food that is known as corticosteroids really is important, in that higher doses greater than 2 mg/kg per day of prednisone equivalent does result in a significant risk of mortality in your patients who have invasive aspergillosis. Interestingly, too, when you look at this paper, what you find is that the voriconazole had a very nice protective effect, again, kind of reinforcing what we saw on the Herbrecht study and reinforcing the fact that probably clinicians have a willingness to start these newer agents sooner than they did the more toxic and historically represented amphotericin B.
Furthermore, when you look at this data set, there is a subgroup of 33 patients there—and it is a small number—that were treated with voriconazole plus caspofungin, but the authors were unable to show any benefit of the combination of voriconazole plus caspo over voriconazole alone, and that is important in this data set because, again, these are the authors, or this is the center, that brought us the voriconazole plus caspo data that is so routinely quoted from Clinical Infectious Diseases a couple of years ago that seem to show a benefit. So, again, reinforcing that one of the biggest needs we have in antifungal pharmacotherapy today is the need for a combination invasive aspergillosis study. This paper also further really kind of drives home the point that we have touched on a little bit already, about the importance of a prompt and early diagnosis in individuals with invasive aspergillosis.
Slide 18: Now, when you look at the next slide hopefully this is something you have seen before, and these are the brand-spanking-new IDSA guidelines for the management of invasive aspergillosis that were published in Clinical Infectious Diseases earlier this year. They are a very, very nice set of very evidence-based recommendations that do a nice job of updating us on a lot of the changes that have occurred since the previous set of guidelines were published in the year 2000.
Now, if you stop and think back, a lot has gone on in the world of invasive aspergillosis since 2000. We have had the voriconazole data come out; we have had posaconazole arrive. Those have been the 2 major moves on the azole front. The echinocandins have markedly expanded with caspofungin, micafungin, and anidulafungin all now being available. We have seen the polyenes kind of move out of fashion for invasive aspergillosis, although I will hint that maybe that is not necessarily the case in a study that I will show you a little bit later. And, also, the guidelines again reiterate the need for good, solid clinical trial data examining the impact of combination therapy for invasive aspergillosis, which we desperately need. I think that for those of us who are kind of familiar with this literature, I do not think that there were too many surprises in here, but it really was a much-needed update and it kind of gives you a hint at some of the things that are coming up and kind of where the authors who are really the world’s experts in the field think we need to be going from here. So, if you haven’t pulled them, I would strongly encourage you do to it.
Slide 19: So, let us talk specifically about prophylaxis in immunocompromised patients.
Slide 20: When you think about prophylaxis, I mean, one of the big things to really pin down is that this works great as long as you can pin down the right patient groups. You do not want to be walking into your hospital and sprinkling mold-active agents across all types of patients and expect to see a significant benefit. Remember that all of the currently available antifungals that we have, have strengths and limitations—whether it’s the azoles with their oral formulations being a great strength, but the drug interactions come back and get you, or it’s the echinocandins, where they are safe, but they are only in IV forms—and you kind of get my gist that we do not really have the perfect antifungal right now. I think one of the other things that has been hugely important for us is: How important is mold coverage? You know, for years voriconazole has kind of been the gold standard here, but really no mold activity there. And so, the question is: If we bring a mold activity to our prophylaxis regimens, do we really buy anything from a survival standpoint? We will talk about that a little bit going forward.
Another thing to remember as we look at this data is, tolerability is huge here because you are giving a large number of patients who are never going to have the disease a drug and, therefore, the drug has got to be well-tolerated and safe enough to justify the risk that you are exposing that patient to. And then, also, with prophylaxis, it cannot be a situation where you put them on prophylaxis and turn your brain off and forget about fungal infections, because breakthroughs are going to occur. Very similar to what we see in the bacterial world, the fungi are not going to sit still. If you put somebody on an agent that covers x, y, and z fungi, and you let them sit there and they remain profoundly immunocompromised, you are going to see fungus x appear at some point in time if you wait long enough. So it really does become a balancing act across the risk of causing shifts in epidemiology, the toxicity and tolerability of the drugs versus the benefit, and really there are a lot of important factors to think about when you are considering prophylaxis in a large number of patients.
Slide 21: So, let’s start by looking at some of the data that we have available to us and see kind of what this shows us. First, I think we are obliged to start with a very nice paper that was done by Kieren Marr and published in Blood in 2004, that looked at fluconazole versus itraconazole for prophylaxis. What this study does, I think, is drive home a couple of very important points. One, mold-active therapy does appear to give you some benefit over fluconazole alone. However, if you look at this study very carefully and you just look at it on the surface and see what happened in the invasive fungal infections, you go, “Jim, this looks a whole lot better. What’s the issue here?” But what happened here was that, if you read this study, you find that the tolerability and drug interactions of itraconazole really erased all of the benefits that were seen from a standpoint of invasive fungal infections. So it drives home the point that any agent that you are going to use for prophylaxis has got to be very well-tolerated and relatively safe, otherwise you undo all of the good that you have done by preventing any fungal infections.
And when you move over to the other study presented on this slide namely the fluconazole versus micafungin study—you again see that there appears to be a little bit of a benefit, although, if you pull this study and look at it, there are a couple interesting things here. There is a relatively low incidence of fungal infections, as is represented by the 2.4 and 1.6% that you see on the graph but, also, the only difference here was in invasive aspergillosis, again. So, fluconazole is very good at dealing with Candida and preventing Candida from becoming a problem in these patients, and really the 7 cases of invasive aspergillosis that were prevented in the micafungin arm, or that represented the difference between the 2 arms, was really the only benefit here. So, you are able to pick up a small number of patients with regards to invasive fungal infections.
Slide 22: Now, let’s look at a study that I think is really nice because it gives you 2 mold-active agents head-to-head. You have caspofungin versus itraconazole, and both drugs did very nicely preventing Candida infections, and the Aspergillus was really kind of a wash as well, but when you look at this, you kind of have a golden chance to look at and think about the limitations that you have got to consider here. Caspofungin looked great, very well-tolerated, did a nice job of preventing Candida infections, did a nice job of knocking down Aspergillus infections as well. However, it is IV only, and are your patients going to be willing to come in and get daily IV infusions for prophylaxis? Probably not, I know our patients really frown upon that. They want as little to do with the hospital as they can possibly get.
Now, itraconazole, you look at here, and again, you have got a very nice job of preventing both Candida and Aspergillus infections, but the drug interactions are going to be a consideration for you. So, again, you kind of see the risk-benefit here, and it is stuff that you really have to think about as you consider prophylaxis.
Slide 23: Now, let’s talk about the drug that really has had 2 major studies come out here in the last couple of years. I am going to start talking about posaconazole in a little more depth here in the prophylaxis section because, really, we are not going to deal with it a whole lot in the treatment section because really it does not have much data in the treatment section or in treatment really at all at this point. So, when you look at posaconazole, the strengths of the compound are really, first and foremost, in the spectrum. You have basically got the spectrum of voriconazole with the ability to pick up some Zygomycetes, which is really unheard of for an oral agent until now. The tolerability of the compound looks very good, and if you look at the 2 studies we are going to go through, the tolerability appears very comparable to fluconazole, which is, I think, what we really want to see in a mold-active agent as we go forward. And, also, the outcomes data is impressive as you will see here in a minute.
The weakness that you get into with posaconazole is that really you have no IV formulation to fall back on in patients who you are extremely concerned about whether or not they’re going to absorb the drug. The pharmacokinetics of this drug are a little bit tricky. It appears you have saturable absorption at about 800 mg/day and you really need to be able to get food down there in order to ensure that people are absorbing the drug. The other thing too is that you have to consider whether or not you need to be getting levels in these people, and I think that adds a whole new layer of complexity that we will continue to talk about as we move forward.
Slide 24: Now, when you look at posaconazole pharmacokinetics, notice the importance of food. Your Cmax and your AUC are hugely impacted on an empty stomach versus adding a high-fat nutritional supplement. The half-life, you look at it and you go “24 hours?” You go, “Why are we not giving this drug once a day?” Well, it comes down to the fact that if you give small doses more frequently, you get a better area under the curve. So, 200 mg 4 times a day is going to give you a better AUC, better levels than 800 mg once a day.
Slide 25: Now, when you look at this drug from a prophylaxis standpoint, you look at the data that is out there, there are 2 very nice studies in the New England Journal early in 2007. I am going to present 1 of them today for the sake of time, but know that if you go find this study in the New England Journal, the other study is right there in the same issue.
Now, this is an open-label study, kind of a real-world snapshot, and that is one of the things that I like about it, and it is fluconazole or itraconazole, depending on what the standard was in the center that was enrolling patients. So, if your center was a fluconazole center, you did that, and if you were an itraconazole center, you used itraconazole. And then patients were randomized to either that or posaconazole at 200 mg 3 times a day. These were patients who were receiving chemo for induction AML therapy or myelodysplastic syndrome. And the composite end points were proven or probable invasive fungal infection, the need for systemic antifungal therapy, or death. Patients were evaluated at 7 days post-the-end-of-therapy and at 100 days postrandomization.
Slide 26: Now, what you saw here was that there was a statistically significant difference in proven or probable invasive fungal infections, but it is very important to recognize what you have got here. All of the difference is in Aspergillus. There is no difference in Candida whatsoever, again driving home the point that really the newer generation azoles offer you nothing over fluconazole for Candida, but when you come down here to the invasive aspergillosis section, there is a rather impressive reduction there. You had 20 cases in the fluconazole-itraconazole arm versus only 2 in the posaconazole arm, again with a P value of .001.
However, if you go and you look at this study, there is 1 slightly disturbing trend here, and that is that there appears to be a large number of Aspergillus cases in the itraconazole arm, which I am kind of at a loss to explain; that is not something that I would have expected to have seen here. And also, you know, there is really no explanation for that. Was it that the patients all got colds? What happened? So I think we are kind of left scratching our head a little bit as to what happened there.
Slide 27: However, if you look at the end point of death at 100 days postrandomization, you actually saw a statistically significant difference in favor of the posaconazole with a P value of .048. Now, this is really the first time that we have seen this. And I think that it has caused a lot of us to kind of step back and take a long, hard look at this, try and figure out who the patients are that might benefit most from this type of therapy, again, understanding the risks and benefits of prophylaxis. But I think this is exciting data, and I would encourage you to look at it as well as the other paper that was published simultaneously in the New England Journal.
Slide 28: Now, let’s talk about voriconazole for prophylaxis because this has really kind of been something that a lot of centers have been doing even though the data has not really been there. And we have now got our first snapshot or topline look at the voriconazole for prophylaxis study that was presented initially at the American Society for Hematology meeting last December and was again presented very nicely by John Wingard at the American Society for Bone Marrow Transplantation a couple of months ago.
Now, when you look on this on first go-through, you see that there was not a statistically significant difference between voriconazole and fluconazole in patients with invasive fungal infections. And you can see it was about 10.6 versus about 6.6%.
Slide 29: Now, moving on to the next slide, though, again, you kind of see why. There are a couple of important points in this stack graph that I have got here. First and foremost, notice again, no real difference in Candida; you would not expect there to be. Reassuringly though, there is not a difference in Zygomycetes either. I think a lot of people were concerned that voriconazole, because of its inability to cover Zygomycetes, might result in a lot of Zygomycetes breakthroughs in people who were getting voriconazole for prophylaxis. And that was really not borne out here.
The other thing I want to drive home is that the major difference—again, as we saw with posaconazole and what we have seen with itraconazole and micafungin—is really the ability to cut down on Aspergillus infections and that voriconazole was able to do with 16 in the fluconazole arm versus 7 in the voriconazole arm.
Slide 30: Now, the voriconazole prophylaxis study also had a very interesting end point for me. One of the things I was very interested in is whether or not voriconazole would be tolerated that long-term because we have seen some tolerability issues with that drug. And interestingly, there was really no difference in tolerability noted between the fluconazole arm and the voriconazole arm. I think that brings up a couple of other questions that we can go into on another day, but I think it is something that bears looking at a little more closely.
The other thing, too, is that there was intensive galactomannan monitoring done in this study and they are sitting on a huge data set within this study looking at galactomannan that has not been presented yet. I think that is something to really look forward to as this study gets rolled out in a more peer-reviewed form.
The other thing this study did very nicely was encourage and allow early empiric therapy. So, you are again allowing patients to be treated early, hopefully getting good response rates there if you are seeing suspicion or breakthrough or anything that you are concerned about. But there really was no difference in fungal-free survival between the fluconazole and voriconazole. So again, I think we have some continued questions here that we need to kind of look at as we go forward with these prophylaxis studies. I think that when Dr. Wingard is able to get this full study published in peer-review form, I think we will get a much better sense of kind of how to tease all of these different agents out at this point.
Slide 31: So, we have talked a little bit about background; we have talked a little bit about prophylaxis. Now, let’s talk specifically about treating patients who actually have proven or strongly suspected invasive aspergillosis.
Slide 32: One of the things you have kind of heard me talk about several times going forward through this presentation has really been the need to get to these patients early and the importance of diagnostics. And I think this slide here, in a paper presented by Greene and colleagues in CID last year, really does a nice point of driving that home. What they did is they took data from the Herbrecht’s study, mainly the voriconazole versus amphotericin study, and they went back and looked at all the chest CTs in that study. What they saw was that patients who had a halo sign did better than patients who did not have a halo sign. A halo sign is basically an area of low attenuation that kind of lights up and gives you a halo appearance around a nodule in somebody you think has invasive aspergillosis.
And it has been considered that a halo sign may be a marker of early disease. And again, that is kind of borne out by these results because patients who had halo signs and were started on therapy did better than those individuals who did not have halo signs. So again, I think it is critical that we use all the tools at our disposal to try and get to these individuals early and get them on effective therapy when we can.
Slide 33: Something else that is continuing to evolve is really the understanding of the newer generation of azoles, the pharmacokinetics, and the need for therapeutic drug monitoring. Let’s look specifically at the posaconazole salvage study that was published by Walsh and colleagues in CID last year. And what I think is most striking about this paper is the table that is in front of you on the slide that seems to suggest that there is some correlation between serum levels of posaconazole and outcomes. I think this is going to be something—if you remember back to the issues of absorption with posaconazole, food driving absorption up, dose fractionation, and the lack of an IV—I think there are going to be a lot of questions going forward about how do we best monitor posaconazole therapy, and what do we need to do with drug levels or therapeutic drug monitoring in these patients?
Right now, I think we are severely hamstrung by the lack of readily available levels. There are only a few centers around the country that are doing these levels right now. And so, they are not really clinically practical for a lot of settings. I think this is the data set that you kind of need to keep in mind as you use posaconazole and think about things that you can do to try to optimize these levels and it appears that more drug may be better in treating proven or strongly suspected disease.
Slide 34: Now, what about voriconazole? Voriconazole has some major strengths, significant weaknesses, as do all of the drugs that we have talked about thus far. Voriconazole, I think you are all familiar with the strengths, namely the data. The Herbrecht study was a groundbreaking study where we all went to bed treating Aspergillus with amphotericin one night and woke up the next day, and everybody switched to voriconazole based off that study. Really, it brings nothing to the table for Candida, but the oral bioavailability is excellent and allows you to do IV to PO.
The weaknesses, I think the cyclodextrin vehicle remains problematic in people who have creatinines less than 50. A lot of individuals get fired up about that, but I think it is important to remember, you use the IV in a risk-benefit form and you get them switched to oral when you can. The drug interactions with voriconazole, as with all of the extended spectrum azoles, are very problematic and are something to be taken extremely seriously. I think the other question that is going to come up is: Is this drug as predictable from a PK standpoint as we thought? And what is the role for therapeutic drug monitoring?
Slide 35: The next slide looks at the Herbrecht data, which I am sure all of you have seen and really revolutionized how we treat invasive aspergillosis.
Slide 36: Now, at ICAAC this year, we saw a poster come out that had Wookies on it and really kind of exemplifies some of the issues that we are running into with voriconazole, where, perhaps, as the levels get higher, namely above 5, you start to see more hallucinations. And this was driven home in a paper published by Pascual and colleagues in 2008 in Clinical Infectious Diseases, where they saw that patients with serum levels greater than 5 were more likely to have some CNS side effects.
Slide 37: However, you got it up there on the high end causing CNS effects, but Smith and colleagues and Pascual and colleagues were both able to show that perhaps low drug levels result in suboptimal responses.
Now, I think before we run off and start doing voriconazole levels on everybody all the time, we need to remember these are limited by small populations, single-center studies. We clearly need more data here, but again, I think you are going to get buried in the next few years under data looking at voriconazole therapeutic drug monitoring. I think it is going to be something that we are all going to have to keep an eye on as we get a better sense of how to use this drug and how important the therapeutic drug monitoring is.
Slide 38: I think another important point on the next slide that was very nicely illustrated by Pascual and colleagues, is that 200 mg PO BID is probably not the right dose for voriconazole. In San Antonio, we do not grow 70-kilo patients. The Mexican food and the margaritas are way too good. And so our typical patients are 90 to 100 kilos. And if you do the math on that, and you are giving 200 mg PO BID, you are significantly below the 4 mg/kg Q12 that is recommended for treatment. And I think again, maybe that comes back into why you see lower levels, why you see suboptimal responses sometimes.
You can see here on this side that at greater than or equal to 8 mg/kg per day, you are up around 3 mcg/mL. But it is important to note that not all authors have consistently shown that going up gives you higher levels. So again, I think we are kind of in a gray zone right now on how to handle the therapeutic drug monitoring of posaconazole and voriconazole.
Slide 39: I think that another worrisome trend is starting to emerge in the literature. And this is all from Paul Verweij’s group in the Netherlands where they have started to see some multiple triazole-resistant Aspergillus. I am far from encouraging everyone at this point to run out and start doing MICs on every aspergillosis islet they get. But, I do think that this is something you need to be aware of is going on out there and, though it is only being reported in the Netherlands thus far, may present problems for us as the drugs go into wider and wider clinical use and are used more and more for prophylaxis.
Slide 40: So let’s talk about the polyenes. And, you know, if you had asked me a year or 2 ago about the polyenes for invasive aspergillosis, I would have told you I put them on the shelf and kind of forgotten about them. The strengths of the polyenes, I think, are legendary, as are the weaknesses. The strengths, really first and foremost, spectrum. Very broad spectrum, very fungicidal against a variety of yeasts as well as molds. And clinicians know these drugs; they have been in use clinically for the last 40 years. But that has allowed their weaknesses to become famous as well. I think first and foremost, there is really the nephrotoxicity; we know that the polyenes, especially conventional amphotericin B, are very nephrotoxic in at-risk patients, and I really think should be avoided for patients with invasive aspergillosis.
Now, the lipid formulations, on the other hand, I think, if you would have asked me again about a year ago, I would have said, I do not know really if there is much of a role here. But the nephrotoxicity with the lipids is not completely a nonissue. Patients at higher risk will develop nephrotoxicity, though it will be later than what you would have seen with conventional. We are also limited by a lack of an oral form. There are some intriguing inhalation data that I am still not quite sure what to do with, and the fact that Aspergillus terreus is basically intrinsically resistant to the polyenes.
Slide 41: But, a very nice paper by Oliver Cornely and colleagues in CID last year that looked at liposomal amphotericin B at 10 mg/kg per day given for the first 14 days, then switched over the 3 per kilo, compared to 3 per kilo the whole time. And, what they saw was really that the efficacy was no different between the 2 arms. And that all you really saw was more toxicity in the higher-dose liposomal amphotericin B arm.
Again, though, it is important to note that probably these patients were early Aspergillus cases and that a lot of them had halo signs and there was a lot of galactomannan monitoring going on in this study. So I do not know that it totally puts the issue to bed, but it gives you confidence again in liposomal amphotericin B. And, if you look at these response rates, what you notice is they are strikingly similar to the response rates that were seen in the voriconazole study.
Slide 42: Now, what about the echinocandins? Where do they kind of fit in the realm of invasive aspergillosis? I think we are all familiar with the strengths of these compounds, namely how well-tolerated they are and how few drug interactions there are, as well as their excellent activity in vitro against the majority of Candida species.
The weaknesses of them—I think that really, they are static against Aspergillus. As soon as you remove the drug from Aspergillus, it starts to grow again. And, also, there is no oral formulation, so it makes prophylaxis somewhat difficult.
Slide 43: What do the new guidelines say about how to treat invasive aspergillosis with echinocandins? Because really, we do not have a ton of clinical data here. And what they say I think, is probably what all of us are pretty much doing. We consider them alternative therapy in the guidelines, you know. The only data that is there is really salvage data. And they say in the guidelines again, that because of their distinct mechanism of action, the echinocandins have the potential for use in combination. But again, they reiterate the fact that we really need a well-done study to elucidate how to use these drugs and what the benefit of them is in a combination therapy scheme.
Slide 44: So when we start to wrap all of this up and kind of think about what we have talked about, and kind of the higher points here, I think first and foremost, we can say that prophylaxis appears to be beneficial for both Candida as well as aspergillosis if you can target the drugs right, minimize toxicities, and pick out the right group of patients to give it to because there are clearly risks and rewards to prophylaxis. Posaconazole and voriconazole, I think you have now very exciting data sets for both of these drugs for prophylaxis that warrant very close scrutiny in individual centers to figure out how to best use them in the patient populations that you may be seeing day-in and day-out.
I think the question for this going forward, especially with the azoles, is what is going to be the role of therapeutic drug monitoring? I think you are going to really get buried under data regarding voriconazole therapeutic drug monitoring, and I think that posaconazole therapeutic drug monitoring will be close on its heels as individuals try to figure out the absorption and efficacy issues with posaconazole and the tolerability issues with voriconazole.
The other thing to keep an eye on is what is going on over in Europe with these reports of multiazole-resistant Aspergillus and whether or not we start to see that pop up in other centers as well. I think we will definitely bear watching. And that maybe the polyenes are not as dead as we thought that they were. And the role of the echinocandins, I still think remain hazy at best, and even these new guidelines that we have really do not provide us, I think, an answer that really helps us all sleep well at night. I think we still are not quite sure what we are doing with combination therapy and we desperately need that study.
So with that, I will thank you guys for your attention here, and I will turn it back over to Dr. Dodds Ashley to finish up her case.
Slide 45: Now, let’s get back to the case and follow up with what happened in our patient.
Slide 46: As you may recall, this is a 56-year-old man with multiple myeloma, who had initially responded to therapy, but his disease has relapsed. And now, as part of his retreatment, he had recently gotten his second cycle of chemotherapy. He was being admitted to the ward with shortness of breath and hemoptysis, and he had started an empiric regimen of piperacillin/tazobactam, azithromycin, and caspofungin.
Slide 47: Since his initial presentation, and because of his persistent hemoptysis, he actually was taken to the OR and underwent a right lower wedge resection to get some more details about what was going on with that nodule in the right lower lobe.
The galactomannan test that we ordered on admission has now come back. It was positive but, unfortunately, he received a dose of piperacillin/tazobactam on his way from clinic over to the emergency room and, because of that, we cannot fully rely on the results of this test because, as you may be aware, piperacillin/tazobactam can result in false-positive galactomannan results.
Tissue cultures that were sent as part of this wedge resection are now positive for Aspergillus fumigatus and, based on this, the therapy for the patient was switched to voriconazole. As Jim mentioned, according to the new IDSA guidelines, that is listed as a first-line treatment option for patients with invasive aspergillosis. Our patient responded well to this current course of treatment and, obviously, because this is a recent diagnosis—only being in the last several weeks—we will continue therapy for a very prolonged course, at least through his time of all immunosuppression, and then well beyond that.
Slide 48: What are some thoughts that we may have about his initial empiric regimen? His initial regimen was caspofungin. Although this patient was not neutropenic at the time of admission, he had recently received a significant course of chemotherapy. And, he was admitted sort of on the febrile neutropenic protocol. He did receive caspofungin; echinocandins are listed as appropriate agents in all the guidelines, including the recent National Comprehensive Cancer Network guidelines related to empiric therapy in this patient population. However, when you have a patient that really moves from true empiric therapy to high suspicion for a fungal disease, you want to make sure you are using the best therapy possible. And, I think that you could definitely make an argument to switch that patient over to an extended-spectrum azole at that point in treatment.
Now, the other big question that Jim has just reviewed for us is: Should this patient have received antifungal prophylaxis coming into this second round of treatment for his malignancy?
Slide 49: What you can see on the next slide is a summary statement of the 2007 National Comprehensive Cancer Network guidelines for prophylaxis in patients who are intermediate- to high-risk. Multiple myeloma is not specifically addressed here; however, our patient represents a more common challenge—the patients who have had significant prior therapy for their malignancy—and, where they fall in this. And, that is an issue of some debate that we could get into. But, Jim has already discussed with you how antifungal prophylaxis is gaining more of a role in these patient populations and that we certainly do need to consider Aspergillus when we are prophylaxing in these high-risk patients.
So, no firm answers for these complicated patients, but we are getting more and more data, as time goes on, on how to use the antifungal drugs. I think the rule is that you need to know your patients; you need to know what they are at risk for. And then, you need to know what the antifungal agents we have available to us will do for you. You need to know their holes in therapy when you start them, and you need to know exactly where you are going to go next, if you have a problem or a breakthrough in fungal infection.
