A Closer Look At Key Treatment Strategies

Dr. Mozena: When I present my treatment plan for onychomycosis to the patient, I always present a step-wise progression with six different options. We can ignore it, debride it, provide surgical treatment, use topical medications, use oral medications or employ combination therapy.
The first option is ignore it. What are the consequences of ignoring onychomycosis? Well, obviously, there are psychological concerns and there are pain issues to consider. Onychomycosis is not only contagious to ourselves, it’s contagious to others.
The second option is debridement. When we talk about debriding, I tell them we can decrease the fungal load and give them a better psychological benefit. We also can reduce pain by reducing the pressure on the nail. However, debridement is not treatment. I explain to my patients that when we debride, we are helping your condition but we are not actually treating it.

The third option is surgical treatment. Surgical treatment is one of the older therapies that we have. When we remove the nail, we have better access to the nail bed. However, are there any consequences to removing the nail? Nail avulsions have proven to be a problem over time. If you remove the nail, you’re actually removing the dorsal pressure so you are relieving the retrograde force on the bone itself. When you release the pressure on the bone, the distal dorsal tuft on the distal phalanx hypertrophies. As it hypertrophies, it stops the distal excursion of the nail over the hyponychium edge.
This leads to distal ingrown toenails, which are extremely difficult to deal with. We have done several exostectomies. We have done distal nail fold release and wedge resections. Often we have to do a total matrixectomy. For a small longitudinal striation, it can be devastating to have to go on to a total matrixectomy. I usually preach against any type of nail avulsion.
The next option is topical medication. Up until 1992, there was no topical medication that actually was able to treat onychomycosis. In 2000, ciclopirox 8% became the first FDA-approved medication for topical treatment of onychomycosis.
The next option is oral medication. From the first medication (griseofulvin) that was introduced in 1958 through the introduction of ketoconazole in the mid-‘80s and the triazoles of the ‘90s including itraconazole and fluconazole, we had some medications that seemed to be mildly effective. However, we had many side effects including liver problems that had to be addressed. The last drug group that came out was the allymines, which includes terbinafine. That particular medication seemed to be very effective. However, we obviously have not had complete efficacy or this would be the only drug we use.

What About The Emergence Of Combination Therapy?
Dr. Mozena: Then there is the option of combination therapy, which advances the idea of using two different medications to get better efficacy rates. The one that is currently being done is combining ciclopirox with terbinafine. What we need to look at first is the mechanism of action. Ciclopirox is a hydroxypyridone and it works by chelating the polyvalent cations, resulting in the inhibition of metal dependent enzymes that degrade the toxic peroxides within the fungal cell.
Now terbinafine’s mechanism of action differs quite a bit from ciclopirox. Terbinafine works by inhibiting ergosterol synthesis. When we have two different mechanisms of action, we are working with an inside-out or an outside-in treatment plan.
There are limited studies now that show there are synergistic activities between these two medications with combination therapy. An empirical study by Notling has shown an 88 percent therapeutic rate.9 Currently, Dr. Gupta is doing a multi-national, multi-center, randomized and evaluator-blinded study that shows terbinafine and ciclopirox are synergistic. He is also showing that we can use less oral medication, which obviously means less side effects. By using a combination therapy of ciclopirox and terbinafine, we can get at least equal efficacy rates that are comparable to using individual drug therapy if not better. In this particular study, they are using one month of terbinafine with a month break and then another month of terbinafine. They are only using two months of terbinafine while using ciclopirox the entire time. It has been recommended to use the combination simultaneously as opposed to sequentially. I do believe combination therapy is the wave of the future.

Discussing Cost Concerns With Patients
Dr. Joseph: When we are looking at combination therapy, we often hear concerns about reimbursement issues. Dr. Mozena, how do you handle that with your patients?

Dr. Mozena: Oregon has one of the highest managed care insurance rates in the entire nation. Because of that, many of the carriers now have taken all antifungals off their formularies. I present it in a straightforward manner. I say the topical medication of 6.6 ml bottle will run around $120. I tell them the oral medication will run around $800 for three months’ supply. We can do the topical or the oral or do combination therapy of the two.
Most of the patients, because of the cost involved, have to pay out of pocket. Given the costs, many patients are opting for the topical medication. They say “Why don’t we buy the topical medication? It’s cheaper and safer. I’ll see how it works. If it works, great. If it doesn’t, we can always go on to either oral medication or combination therapy.” They’re willing to pay that. When you think about how much medication costs these days, this isn’t really out of line. People are used to paying this kind of money for prescriptions so it hasn’t been too much of a stumbling block for a topical medication. Oral medications obviously have been much more of a stumbling block.
Dr. Malay: Dr. Mozena, how long do you tell your patients they are going to need to use the topical therapy?
Dr. Mozena: It comes down to how many nails are involved. When you look at the average amount of nails involved, it’s four. Now if you have one nail involved, obviously there’s going to be a different cost factor than if there’s 10 nails involved. So what I tell my patients is they’re going to be using the medication on a daily basis. I tell them to take it off once a week with either alcohol or fingernail polish remover. I tell them they will be using the medication until the nail is clear or for 48 weeks or for approximately a year.
That being the case, the patients then say, “How much is that going to cost me?” Obviously, with the one nail involved, the average number of applications is approximately a thousand out of a 6.6 ml bottle. That one bottle may last them anywhere from three to six months to the entire year, depending on how thick they are applying the medication. Cost is huge when you’re talking about how many nails in particular are involved.
Dr. Joseph: I think we once compared it to the cost of getting a newspaper a day or something like that, or even the cost of treatment is less per day than getting a cup of coffee at Starbucks.
Dr. Mozena: We calculated it to be 75 cents a day for ciclopirox lacquer versus $8 a day for terbinafine.
Dr. Cervantes: Educating the patient regarding the cost of medications is very important. Comparing the cost of applying ciclopirox daily for the next two months or less is equivalent to 70 cents per day. I think by using this rationale at the time of the treatment, patients will be more compliant and they will be willing to purchase these topical medications. I think we do need to emphasize the cost. In California, everything is expensive. The 6.6 ml bottle of ciclopirox is approximately $160 and terbinafine runs for $325.

Is Nail Avulsion A Valid Option?
Dr. Cervantes: I also tell the patient this is the way it needs to be treated. If it’s only one or two nails, I suggest removing the nail, forgetting about the oral antifungal medication and saving the $300, which the patient can pay for the procedure. I tell them to buy the ciclopirox, apply it and wait to see what happens. Why do you want to put this patient at risk when there is only one or two nails involved? Avulse the nail when you have severe onychomycosis. Obviously, if the onychomycosis is mild or moderate, there’s no need to remove it. If it’s a severe nail, though, just remove the nest of this source of onychomycosis. Remove the nail, apply the topical and I think you will be very happy with the success.

Dr. Mozena: I agree with your assessment of attacking the problem. However, I disagree with your surgical option involvement. There is a lot of literature out there that discuss how devastating avulsion can be.11,12 I think it shouldn’t be so nonchalantly performed by our peers and, in particular, by primary care providers because they may not be able to handle the potential complications of nail avulsion.
I think nail avulsion should be put on the back burner and almost reserved as a last resort. Given the potential consequences of nail avulsion that I discussed earlier, such as possible dorsal distal hypertrophy, a matrixectomy or the possibility of nail deformity, I would place more emphasis on medical treatment of this particular condition.
Dr. Joseph: I would tend to agree. I don’t believe in avulsing a nail unless I’m going to do a matrixectomy. Unless it’s going to be a permanent nail removal, I don’t want to avulse the nail because distal ingrown toenails are one of the most difficult things to try to treat.
Dr. Malkin: Distal ingrown toenails are isolated to the hallux in my experience. I’ve never seen one on the lesser nails. If that is not one of the nails that is involved and you have an isolated fungal nail that you have clinically proven is fungal, a matrixectomy is not an unreasonable option for the patient.
Dr. Joseph: There’s a difference between matrixectomy and avulsion. I agree with you. If you have a really bad nail, a single isolated nail, a severely infected nail, even a hallux nail or a nail that has a traumatic component to it, nothing is going to work. My guess is no topical is going to work and no oral is going to work. I think those single or double nail avulsions with matrixectomy are indicated.
Dr. Cervantes: I was referring to a severe nail.
Dr. Joseph: Okay. I think what Dr. Mozena is taking issue with is doing an avulsion and then trying to treat the nail bed. Whenever I lecture on these topics, I always get the question: What if I avulse the nail? Can I avulse the nail and then treat the nail bed with an antifungal because we know the organisms live in the nail bed stratum corneum? My recommendation is always not to do the avulsion. I agree with Dr. Mozena.

Is Combination Therapy The Most Cost-Effective Option?
Dr. Joseph: Dr. Mozena, in regard to combination therapy, are you aware of any data that shows that it maybe speeds up the progress or increases the rate of clearing?
Dr. Mozena: Combination therapy is relatively new so the literature on this is very scant. There are very few articles published right now. I haven’t seen anything on an accelerated time to healing with combination therapy, just preliminary findings on the increase of efficacy.
Dr. Joseph: I bring that up because at last year’s American Academy of Dermatology meeting, Gupta had a poster in which he showed the rate of mycological clearing was much faster with combination therapy versus either ciclopirox lacquer by itself or terbinafine by itself.13
Dr. Malkin: I am extremely excited about Gupta’s work in the area of combination therapy.13 Dr. Gupta’s study is the only study that I’m aware of that looks at severe onychomycosis.

Dr. Gupta used one month of terbinafine 250 mg daily, then gave the patient a one-month drug holiday, followed by an additional month of terbinafine 250 mg daily. During the entire study, patients used ciclopirox nail lacquer daily. While the study was small, it appears this regimen is more cost-effective than three months of terbinafine orally. Cost has been a barrier to treatment and this may be a new approach.
With my patients, I may provide some terbinafine samples along with writing a prescription for the additional amount in addition to having them use ciclopirox. With this scenario, it becomes more cost effective for treatment.
In regard to the previous question about how long you tell patients they’re going to be using the topical agent, I tell them there are two phases to treatment. The first is the active treatment where we’re going to attempt to eradicate the organism. The second phase is going to be long-term. There is a good chance you are going to end up needing to use ciclopirox lacquer 8% a couple of times a week indefinitely. I tell them we haven’t changed the environment and that their chances of getting an infection are great so they need to do something.
Dr. Mozena: Dr. Malkin, you bring up a really good point. I brought up earlier that we now only need two months of terbinafine rather than the traditional three months if we are using the combination therapy. I had brought up a safety point. I think your issue is a cost point. I think that’s very well taken. We have decreased the cost to our patients with the availability of samples. Someone who may not have had the opportunity to use oral medication because of cost now has that opportunity.
Dr. Malkin: We’ve talked about safety issues with terbinafine. I think most of us around the table feel extremely comfortable using the drug, taking the appropriate lab work and screening our patients. Terbinafine is a very important aspect of treatment for onychomycosis along with topical agents. Being able to combine terbinafine and ciclopirox lacquer together and come up with a cure that patients can afford is a great advance.

Defusing The Hype Over Cure Rates
Dr. Mozena: When we look at cure rates, we have to ask ourselves: what is the definition of cure? Is it mycological cure? Is it clinical response? Is it clinical cure itself? Some people in their studies describe cure as less than 25 percent involvement. In the case of ciclopirox, the package insert defines the cure rate as 8.5 percent. I think this percentage is due to more stringent testing procedures.
I think there is more and more confusion on what constitutes a cure. Then how do we determine if there is a cure? Is it determined by human detection, a grid system or by computer planimetry? In this process, the computer digitizes the pictures of nails that have been treated with ciclopirox and then interprets the pictures. This takes the human element completely out of this particular problem. Visualization is obviously different than a grid system that could have human influence and especially remember that some of these settings are influenced by drug companies or the particular person studying it. The computer takes all the human element out of it and this is why I like this particular system. However, this is not being used across the board.
If you look at cure rates and you study them, the package inserts all say something different. For example, the package cure rate for ciclopirox is 8.5 percent. Is this low compared to the others? For example, itraconazole reportedly has a 14 percent cure rate whereas the cure rate is 8.5 percent for ciclopirox. What is it for terbinafine? It’s approximately 38 percent.
When you look at all of these, one might suggest comparing these particular statistics against each other but I think it’s too blurred and cloudy because of the different ways you look at cure rates and how the actual studies have been done. Doing a meta-analysis is one way to look at it but probably the best way to look at it, in my particular practice, is through patient expectations.
There is a study out by Seebacher that talks about expectations.14 The first question I ask patients is: What are you expecting from our treatment plan? Many of them say they want a cure. I tell them sometimes we may not get cure but we may get improvement and ask them what they think of that. They say they would like that as well. In this study by Seebacher, 88 percent of the patients perceived improvement with using something like a topical medication such as ciclopirox.14
Is conservative care the way to go? I think the stepwise progression is a great way to work with any medications. Start with the safest medication and work up to a more aggressive medication as needed.
Dr. Malkin: When oral agents came out, we were promised we were going to have almost a 100 percent cure. Physicians were concerned about losing their practice over the fact that this disease was going to be eradicated. We know at this point in time that nothing gives us a 100 percent cure that stays forever so the actual cure rates mean absolutely nothing to me.

Emphasizing A True Management Plan
And Evidence Based Treatment For Onychomycosis
Dr. Malkin: We need to understand that this is a condition that requires a management plan that includes topicals, orals, combinations of both, other types of treatment at some stages and follow-up. It is just not as simple as giving a single type of product and saying that because this has a higher cure rate, this is a better treatment option. It’s recognizing and getting across to the patient what the expectations are and expecting to use all these things in one’s armamentarium for treating onychomycosis.
Dr. Mozena: That’s very well said. I think that when you look at the Tosti study in which it says there is a 22 percent relapse of onychomycosis after three years and the Heikkila and Stubb study in which they talk about 33 to 35 percent relapse after four years, you have to ask what will the relapse rate be after five and 10 years?5,6 I think your point is well taken. Do we actually ever get cure? It’s a good question that is starting to be posed now and because of that, what we need to do is shift the dialogue away from cure rates and discuss what we do to manage this condition.
Dr. Malkin: What’s exciting to me about this is my patients don’t come back to me and say, “Doctor, I was cured. Now I have it back. You’re a jerk.” They come back and they say, “Please give me another shot at having a normal nail.” This is not a negative practice situation in which the patients are coming back disappointed. The patients want another shot at having a nail that looks as good as it did after treatment. That’s what’s exciting to me. It’s not a negative that we can’t cure.

Dr. Malay: Dr. Mozena and Dr. Malkin, I agree with what both of you have said. However, Dr. Mozena, I think the problem in trying to combine some of these smaller studies in what you referred to as a meta-analysis is there is no set definition of cure across these studies so you would be comparing apples and oranges. Therefore, this meta-analysis really would be somewhat meaningless with the data or the papers that are available now.
What really needs to be done is a well-designed, prospective cohort study that can look at these outcomes with the definition that the investigators want to use for “cure” spelled out so everyone who reads that knows what it is. From the more practical standpoint, cure to me and to my patients is improvement from the standpoint of symptomatology.
In other words, the patient’s nail doesn’t hurt, it’s not as thick, it’s less difficult for the patient to manage from an hygienic standpoint. When you are treating at-risk patients, they are at less risk for cutaneous compromise in and around the nail.
Dr. Joseph: I like the idea of getting away from all the conflicting stories you hear from different companies about cure rates. It is important to emphasize that all of these drugs play a role in the management of onychomycosis cases.
Can you cure a patient or can’t you cure a patient? I think you can cure a patient. You can cure a patient with orals. You can cure a patient with topicals. However, as we discussed earlier, the patients are predisposed and they will get it back. It doesn’t really matter what the cure rate is overall of the drug and how you define cure. We need to focus on how we can best manage this patient in order to prevent the complications of this disease. By complications, I’m talking about pain, embarrassment, an inability to wear shoes and, in the diabetic population, ulcerations and amputation.
Dr. Malkin: No one is better positioned to be the leader of this management program than podiatrists. This is our field. We need to own this condition. This is a disease that’s becoming more and more rampant and a lot of cases are left untreated. Podiatrists essentially should be the owners of this disease.
Dr. Malay: To do that in the perspective of the rest of the world, it needs to be shown in a properly designed and executed study, not just anecdotally. We know we can take care of it and we have the weapons to take care of it. We encourage our patients and we educate them on why we are recommending this form of treatment. However, we need to document it appropriately.
Dr. Joseph: We need the evidence. We still need to change the way our profession approaches this disease in many cases.
Dr. Malkin: Again, is it our profession’s fault? No. We had no viable options for treatment when we graduated podiatry school. I think times change and your approach has to change, and sometimes we’re a little bit slow to adopt some things and a little bit too fast to adopt others.
Dr. Cervantes: I think the problem is you can’t have a standard treatment for everybody. Patient selection is a factor. You can go with three months of terbinafine or you can go with ciclopirox. It’s not like somebody has a heart disease or some systemic disease where you have parameters that you follow and that is it. These patients might require perhaps one month of treatment versus three months or four months so that is an issue.

Why ‘Doing Nothing’ Should Not Be An Option For Patients
Dr. Malkin: I just want to talk about the concept of presenting options to patients. I think our patients are looking for us to give them the option of doing nothing. However, if patients came in with some orthopedic condition that was amenable to management with foot orthotics, we wouldn’t give them an option. We would tell them this is what they need. They could choose not to take it, but we wouldn’t give them an out.
We should do the same thing with onychomycosis. We shouldn’t really give them the option of not treating it. They may elect to do that but I think we should avoid presenting that as an option, especially when we are treating patients with diabetes.
You should tell them they really don’t have a choice, that they need to get treatment. They need to check their blood sugar, they need to look at their feet and they need to have their eyes checked. It’s just part of the deal of having diabetes.

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