Treating Onychomycosis In Patients With Diabetes

Dr. Armstrong: Diabetes is becoming far more common both in the developed and the developing world. By the year 2025, there will be at least 300 million people worldwide with diabetes. People are living longer with diabetes thanks to many advances in diabetes care and improvement in care by primary, secondary and tertiary care physicians. They are also living longer with complications and one of the most significant complications in diabetes is the diabetic foot.
We know the most common reason for hospitalization among people with diabetes is not for high blood sugar or a stroke or a heart attack — it’s for an infected foot. That encompasses one-quarter of all diabetes-related hospital admissions in the United States. It’s even higher in parts of the developing world.15,16 We also know when these folks are admitted, they are generally not cared for as adequately as we would like them to be. Unfortunately, inadequate assessment of these patients doesn’t start with hospitalization but rather when they are initially assessed by their primary care provider and even their specialist care provider.

This leads me to the issue of appropriately assessing the diabetic foot. We know the most significant factor associated with development of diabetic foot complications is diabetic peripheral neuropathy. There are other issues as well such as dermatologic issues. One of those significant dermatologic complications is onychomycosis. There are interesting data now from Boyko, et. al., that suggest someone presenting with onychomycosis may be at significantly higher risk for development of a diabetic foot ulceration.17 In fact, a patient presenting with onychomycosis is at a 60 percent greater risk for developing a diabetic foot ulcer than someone who presents, for example, with a clean nail bed. If these patients are at risk for this kind of infection, it stands to reason they might be at risk for other complications as well.
Perhaps a modality that strikes at this problem, both when it is there and perhaps even to prevent the problem from recurring, might be very useful. There are a number of various modalities and pharmaceuticals approved to treat onychomycosis. However, I think an appealing modality would be a topical treatment that not only allows the patient to treat the onychomycosis but also facilitates the patient getting down and evaluating his or her feet.

Is Aggressive Treatment Warranted?
Dr. Armstrong: I do want to pose a question to the panelists. There seems to be a prevailing notion that every patient with diabetes has onychomycosis and that it is not a very significant issue. However, given the potential complications of onychomycosis in this high-risk population, would you actually treat onychomycosis more aggressively in patients with diabetes than in non-diabetic patients?
Dr. Joseph: We know onychomycosis is more common among patients with diabetes. Aditya Gupta, MD, has shown it is 2.8 times more likely among patients with diabetes than those without diabetes.7 Also, some of the data you quoted before shows there is a high association between onychomycosis and other complications.17
Are we doing our patients with diabetes a disservice if we don’t treat them aggressively for onychomycosis? After all, a lot of people are a little hesitant to treat onychomycosis in this population more aggressively and medically because they feel there may be more chances of complications from therapy, more drug interactions and things along those lines. However, I feel it is imperative to treat onychomycosis in the diabetic population extremely aggressively.
I remember sitting in on one advisory board for a company many years ago and one of the dermatologists came out and said, “Not treating onychomycosis in the diabetic patient is tantamount to malpractice.” While I do think it’s important to define treatment, debridement is not treatment. It is palliation in which we are reducing the size of the nail, the thickness of the nail and maybe reducing the fungal load. It is adjunctive therapy. It is palliative therapy. It is not true treatment.
It’s important to know the risks when treating our diabetic population. We’ve all seen things like subungual ulcerations. You debride away a thick nail and all of a sudden, you have uncovered subungual ulcerations. However, I think it is incumbent upon us to provide aggressive medical treatment for patients who have both onychomycosis and diabetes.
Dr. Malkin: The fungal infection of the nails is so intimately related with the tinea pedis scenario and that is the driving force for me in treating my patients with diabetes. As podiatrists, our job is to keep patients’ skin as intact as possible. It serves as the primary barrier to infection. When patients have chronic tinea infections with the concomitant onychomycosis, we can’t eradicate those infections without dealing with the onychomycosis. When patients recognize the connection between these two conditions — that they don’t have dry skin but in fact have tinea — they are more likely to accept treatment when they understand those complications.

Dr. Armstrong: That’s terrific, Dr. Malkin. People with diabetes, especially if they have had it for awhile, tend to get glycosylation of all their soft tissues, not only in their eye, their kidneys and their nerves, but also in their skin and tendons. The glycosylation tends to turn the tendon, the skin and all these other soft tissues — to misuse a culinary analogy — from a pliable, strong tortilla to a brittle, weak cracker. The poor quality of the skin is exacerbated further by something like tinea pedis. When you also factor in the possibility of neuropathy, these patients are at an even higher risk for getting a sore when they bang on it during the thousands of steps they are going to take every day.
Dr. Malkin: You have brought up a very important point. We know this disease of onychomycosis is progressive. When a patient has a mild to moderate condition that goes untreated, it will eventually progress to a severe state. We know from experience the earlier you treat the condition, the better chance you have of controlling it in the long run.
I think the ubiquitous nature of onychomycosis makes some think they shouldn’t treat all cases but I think we should attempt to treat all cases. Patients will make the decisions for us no matter what our stance is with them. However, I think every patient deserves a cure of this disease and needs to understand it is a disease. It’s not a normal consequence of aging. Studies have shown 59 percent of the patients who know it is an infection want to have it treated.8 What other infection on the body do we not treat?
Dr. Joseph: I would say it is an infection, not a disease.
Dr. Malay: We need to treat this in an aggressive fashion that is obviously safe for the patient. In trying to obtain a cure, combining an oral therapy with concomitant and follow-up topical therapy is the way to go. It’s been shown in very good scientific fashion that patients who have this chronic reservoir of fungus in their nails have a diminished cell mediated immune response to that.18 After therapy with oral terbinafine, the cell mediated response to the Trichophyton antigen was increased after they had cleared it up. In our diabetic patients, there is some degree of immunopathy and certainly you don’t have to be diabetic, as this study showed, to have some degree of cell mediated immunopathy to counter a fungal infection.18

Therefore, I use a combination of oral and topical therapy with the topical being an adjunct to the effective cure of a severely mycotic nail. Just using the topical itself may lead to a possible cure in a mild to moderate mycotic nail.
Dr. Cervantes: As we know, approximately 35 million people have this disease.2 An interesting thing about these figures is that out of those 35 million, 6.3 million were diagnosed with onychomycosis. We need to emphasize to patients that this is not a cosmetic issue. It is definitely a disease and needs to be recognized as a disease because it has psychological effects, systemic effects and symptomatic effects. If we communicate to the patients that onychomycosis is a disease process that needs to be treated and that there are possible complications with this condition, perhaps it will help decrease the risk of complications in the long run.

Taking A Closer Look At The Literature
Dr. Mozena: I go back to Doyle’s 2000 lecture at the American Diabetes Association (ADA) meeting in which he said there is an increased incidence of ulcer and gangrene with onychomycosis in patients with diabetes.19 This is a significant problem. The diabetic population has onychomycosis 2.8 times the normal rate. Approximately 33 percent of diabetics have onychomycosis. Out of those, 15 percent develop diabetic ulcers. It also goes on further to say that 12 percent of those ulcerations are caused by nail trauma and approximately a third of those occur on the hallux. If we take that further, we can say that 20 percent of ulcerations that appear on the hallux go on to amputation.
From there, 35 percent of those who have amputations have five-year mortality rates. Phoebe Rich, MD, stated that every patient with diabetic onychomycosis should be treated given the potent complications that may arise.20
Dr. Malkin: Dr. Mozena, I think we should make it clear that the Doyle study is actually claims data reviewed from an insurance database and there is no shown cause and effect between onychomycosis, ulcer, cellulitis and gangrene.19 Clearly, these conditions do seem to coexist extremely commonly among at-risk patients.
Dr. Armstrong: This is a very interesting point. The only literature on this subject that I’m aware of is the abstract that was presented by Boyko and Ahroni at the ADA meeting in 2002. The report did suggest a significantly higher risk with a direct association between onychomycosis and diabetic foot ulceration.17
Dr. Joseph: Has that ever been published?
Dr. Armstrong: To my knowledge, that specific association has only been published in abstract form. I do think the data that Boyko, et. al., presented is compelling.17 I also think it is within reason and common sense that there is a significant association between onychomycosis and other problems associated with the diabetic foot but obviously, there needs to be more work to help flesh this out.

Key Insights On Treatment Considerations
Dr. Joseph: Dr. Cervantes, do you approach diabetic patients with onychomycosis any differently than your non-diabetic patients with onychomycosis?
Dr. Cervantes: Definitely, it’s important to recognize the risks versus the benefits of putting patients on oral antifungal medications. Primary care physicians and specialists may be leery of using oral medications for older patients as they are more likely to be taking multiple medications so there is the fear of possible drug interactions. I think education and being aware of the drug interactions would really help physicians be more aggressive on treating this disease with orals. Appropriate patient selection is the key. If the oral medication is indicated, let’s put the patient on the oral medication. However, if there are more risks than benefits in putting a particular patient on an oral medication, then we should consider topicals.
Dr. Malkin: Dr. Armstrong mentioned a tremendous side effect of the use of topical medications. It is daily inspection of the feet. This is vital. We must convince patients that either they or someone else needs to look at their feet on a daily basis. Only the use of a topical antifungal ensures patients will look at their feet because they are obligated to put this medication on and at least look at their toenail areas.
Dr. Malay: Another thing that comes to my mind in this specialty population is the vasculopathic aspect of it. Even though I am a fan of combination therapy, the topical approach is extremely important for patients who have peripheral vascular disease, whether they are diabetic or not. In using the topical, I am getting a more effective concentration of antifungal at the site where it needs to be for these patients who perhaps have less ability through their circulatory system to get an oral or systemic medication to the site. In my aggressive approach to treating onychomycosis in this specialty population, I am definitely combining therapies.
Dr. Cervantes: Patient education plays an essential role in the successful treatment of onychomycosis, but we also need to address expectations. Dr. Malay just mentioned the issue of vascular compromise with these patients. When we put these patients on oral antifungal medications, it really takes time to see improvements in these patients. Many patients expect results in a few weeks or a month. We need to convey to them that it may take anywhere from three to six months to see improvement. As long as the patient understands the process of this treatment, I think that also will improve compliance.
I think combination therapy works great. I think the goal here is to minimize the length of time on the oral antifungal medication and maximize the results. How do you do that? Perhaps you could have the patient on an oral medication for a month and have him or her use ciclopirox at the beginning of the treatment. Then after two months, perhaps you could resume the oral antifungal. I think that would be a success for treatment.

Convincing DPMs To Get More Aggressive
On Onychomycosis In Patients With Diabetes
Dr. Joseph: We all agree that it is perhaps more important to treat onychomycosis in our diabetic population than it is to treat it in our non-diabetic patients. However, I’m not aware of any good data that shows podiatric physicians are any more likely to treat onychomycosis in the diabetic population. If you look at the prescribing data out there for either orals or ciclopirox lacquer, in any given month, maybe only 50 percent of the profession is actively writing for therapy, either oral or topical, for onychomycosis. We all see these diabetic patients on a daily basis whether it is 10, 15, 20 or 30 times a day. How would you convince our peers of the necessity to get more aggressive in treating onychomycosis in this special population?
Dr. Mozena: Obviously, it is important to treat onychomycosis in this at-risk patient population. We know onychomycosis is more prevalent among patients with diabetes and the emerging issue is the possibility for more devastating complications.
Dr. Cervantes: We know patients with diabetes have a greater risk of developing wounds, gangrene, amputation and perhaps losing their legs or their lives. There should be a little more awareness of these complications among podiatrists. The gray area is we are not familiar with the drug interactions and I think that is an issue that needs to be addressed. Even though these patients are likely taking several medications, there are choices for treating onychomycosis safely without putting the patient at risk.

Dr. Armstrong: First of all, I am not convinced that we should be trying to convince our colleagues about this. There are some emerging data on this issue and I think the data may become more convincing over time. For now, all we can do is discuss common sense, particularly when it comes to emphasizing patient self-inspection, something we have been working on now for the past few years.
We are currently working on a randomized trial in which patients are either receiving ciclopirox 8% or no topical. We are following these high-risk patients, all of whom are either International Diabetic Foot risk categories 2 or 3, over a course of 18 months to look for re-ulceration or pre-ulceration, hospitalization, bacterial infection and amputation.21 The thought is just the act of these patients getting down there with the brush and applying ciclopirox on their toenail might get them to look at their feet a little bit better and thereby reduce their risk for a problem.
If we can convince these patients that onychomycosis is an infection and they have a prescription driven to reduce the severity or help ameliorate the complications of that infection, then they are more apt to use it. The nice side effect is they or their caregivers may get a better look at their feet.
Again, I don’t really think we should be trying to convince our colleagues to use antifungals. We just need to convince our colleagues to care more about the diabetic foot. If they care more about that, they are going to care more about all the rest of the adjunctive things that amount to good quality care.
Dr. Malkin: Dr. Armstrong, you and I have worked on a project that we are calling the comprehensive diabetic foot exam. I think what we have been hearing from physicians is they are seeing patients with diabetes regularly and they are performing procedures on these patients every couple of months. Unfortunately, the real benefits of what a podiatrist can do for patients with diabetes are lost in the reimbursement system. By taking a time out and doing an annual comprehensive diabetic foot examination, which would include examination of the nails, we may have a better shot at people having the time to properly explain the disease state to the patient and initiate treatment. We’ve been suggesting that type of exam along with a planned pressure measurement on an annual basis. I think this could be a driving force to get people to take the time to do that.
Dr. Armstrong: Dr. Malkin, you are absolutely right. Unfortunately, prevention doesn’t pay yet. If we can get that changed, I think things like this will facilitate a much higher prevalence of treatment for these kinds of conditions and we’ll see a whole lot more attention and importance placed on prevention.

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