Current Trends In Antifungal Therapy

Author(s): 
Panelists: Warren Joseph, DPM, Aditya Gupta, MD, PhD, Benjamin Overley, DPM, Richard Pollak, DPM and Jack Rubinlicht, DPM

Should you use a topical, an oral therapy or a combination of both? This is one of many questions that came up during an intriguing discussion of antifungals. Drawing upon their clinical experience, the panelists discuss their approaches to treating tinea pedis and onychomycosis, indications and contraindications for oral drugs, and other important aspects of prescribing appropriate, effective therapy.

Q: What do you use to treat different presentations of tinea pedis, including moccasin variety, acute vesicular and dermatophytosis complex (severe interdigital tinea)?
Warren Joseph, DPM, says moccasin variety tinea pedis has always been difficult to treat, due to the chronic nature of the condition. He also points out that the body has a blunted immune response to the fungus (almost always T. Rubrum), which causes the chronicity and prevents the natural immune defenses from helping to eliminate the infection.

Traditionally, doctors could only treat this condition with systemic medications but Dr. Joseph notes that with the advent of terbinafine cream (Lamisil), he had his “first real successes in treating the condition topically.” However, lately with the terbinafine cream only being available OTC, Dr. Joseph says he has reverted back to using ciclopirox cream or gel (Loprox) and has been impressed with its ability to treat moccasin tinea. Richard Pollak, DPM, also prescribes Loprox gel bid for two months while Benjamin Overley, DPM, uses Oxistat 1% cream and may also use a topical steroid cream to treat this condition.
In his opinion, Dr. Joseph believes terbinafine and ciclopirox creams are effective for moccasin tinea because, unlike the azoles, they are fungicidal. Due to the fact that the skin needs time to completely turn over and shed the fungus, Drs. Joseph and Pollak note that it usually takes at least a month before you see results.
When it comes to treating acute vesicular tinea, Dr. Joseph says combining a short course of oral therapy with aggressive topical therapy seems to be the best course. Aditya Gupta, MD, PhD, notes that he leans toward using oral antifungals for this condition. Dr. Pollak says he initially uses Domeboro soaks bid, Spectazole cream or Loprox gel, and tinactin powder in the shoes.
If the tinea is acute and aggressive, Jack Rubinlicht, DPM, says he will use a topical, such as Spectazole, and add either Lamisil (250mg 1qd) or one Sporanox pulse pack. If the condition is severe, Dr. Pollak may consider prescribing an oral antifungal for two weeks in addition to Domeboro soaks. If there is a secondary bacterial infection, Dr. Pollak says he does not hesitate to consider an appropriate oral antibiotic.
Given the intense inflammatory response generated by T. mentagrophytes, the usual cause of acute vesicular tinea, topical steroids can also be useful, according to Dr. Joseph. Dr. Overley concurs, noting that he uses Oxistat 1% lotion and may also opt for a topical steroid cream.

How To Manage Interdigital Tinea
For interdigital tinea that is acute and wet, Dr. Rubinlicht uses a topical, such as as Spectazole, and adds either Lamisil (250mg 1qd) or one Sporanox pulse pack. He will also add soaks to dry the area and instruct the patient to change his or her socks several times a day, and use an antifungal powder as well.
When he is treating severe interdigital tinea (aka dermatophytosis complex), Dr. Overley uses various topical treatments in conjunction with oral therapy. For oral therapy, he opts for either Gris-Peg or Lamisil, depending on whether there is co-existing onychomycosis. In regard to topicals, Dr. Overley uses Spectazole cream for interdigital infections while Dr. Gupta opts for ciclopirox gel.
Dr. Joseph says it’s important to consider the origin of dermatophytosis complex, noting that James Leyden, MD, has shown that it is an “environmental” condition. According to Dr. Joseph, mild interspace scaling (dermatophytosis simplex) can be turned into a raging interdigital infection by occluding the toes. Citing Dr. Leyden’s emphasis on reversing the environment that causes the condition, Dr. Joseph urges DPMs to focus on drying the interspaces.
“Harvey Lemont, DPM, taught me a long time ago that the best possible way to do dry these out is with Potassium permanganate (KMN04) wet to dry evaporative dressings,” explains Dr. Joseph. “This is a messy approach, but it works better than anything else I have seen.”
If these dressings are not available, Dr. Joseph recommends Betadine wet to dry “gauntlet”-type dressings. Once you see the interspaces start to come under control, Dr. Joseph says using antifungal powders and lambswool separators can help maintain the dry environment. While you will often see cellulitis associated with this condition, he cautions that this is usually reactive inflammation and not a bacterial infection. Therefore, in these cases, you wouldn’t need antibiotics.

Q: When, if ever, do you use oral antifungals for the treatment of tinea pedis? Which drug(s) do you prefer for that indication?
Drs. Joseph and Overley frequently combine oral and topical therapy in treating moderate to severe cases of tinea pedis. Drs. Gupta and Pollak occasionally use orals if the condition is severe or if the patient has not responded to several topical antifungal agents.
When oral therapy is necessary, Dr. Overly says he has had the best results with a one-month course of Gris-Peg (250mg bid) or a standard three-month course of Lamisil (250mg daily) if the patient has onychomycosis. Dr. Rubinlicht notes that he always uses an oral in addition to local care when he’s treating tinea that is acute and aggressive. He tends to use Sporanox because of its short-term pulse, but will use Lamisil when there is onychomycosis.
Calling oral antifungals “extremely effective” for tinea pedis, Dr. Joseph has had very good success employing a short two- to four-week course of daily terbinafine or one pulse of itraconazole. He usually employs this regimen for more severely scaling moccasin tinea pedis, especially if it’s a patient with diabetes who may be prone to ulceration or a patient who has acute vesicular disease. While he concedes that this is an off-label use, Dr. Joseph believes there’s enough good data and clinical experience to support it. He also points out that, with the short course, laboratory testing is not indicated.
All the doctors agree that choosing an oral is dependent upon the patient history and appropriate testing measures. Specifically, Dr. Rubinlicht emphasizes reviewing the patient’s current medications while Dr. Overley recommends liver and kidney function tests as well as a CBC prior to initiating therapy and midway through the treatment course. Dr. Pollak notes he also performs a KOH in the office to determine whether the presentation is truly tinea pedis and not another dermatitis that could mimic athlete’s feet.

Q: What has been your clinical experience with oral antifungals? What have you had the most success with?
All the doctors claim that their clinical experience in using oral antifungals has been positive with few adverse reactions. More specifically, the majority of the panelists say they’ve had the best clinical success with terbinafine.
Dr. Pollak notes he predominantly writes for Lamisil (terbinafine) due to the safety features, its higher efficacy over Sporanox (itraconazole) and few drug to drug interactions. However, Drs. Joseph and Gupta say both terbinafine and itraconazole are safe, effective drugs for onychomycosis. In his experience, Dr. Joseph notes that he has not seen “any difference in their efficacy.”
That being said, Dr. Joseph says patients tend to prefer the once-a-day dosing of terbinafine as opposed to the pulse dosing of itraconazole. He concurs with Dr. Pollak about the fewer drug to drug interactions, noting that he prescribes terbinafine more often since many of the patients he sees (especially in a VA hospital setting) are on a significant number of other drugs.

Q: When would you refrain from using oral antifungals? What particular contraindications should you look for in the patient history that would steer you away from using orals?
All the doctors agree that you should avoid using oral antifungals if the patient has a history of primary liver (cirrhosis, hepatitis) or kidney disease (acute or chronic renal dysfunction/failure).
Dr. Overley adds that congestive heart failure and compromised immunity (leukopenia/neutropenia) are also key contraindications. Dr. Rubinlicht rarely uses oral antifungals on IDDM patients and never uses them on pregnant or possibly pregnant patients. If patients are on any cholesterol-lowering drug, Dr. Rubinlicht will not use Sporanox, instead opting for Lamisil.
When it comes to Lamisil, Dr. Pollak says you should avoid using it for patients who are on rifampin. According to Dr. Pollak, you don’t want to prescribe Sporanox if patients are on cisapride, digoxin, fentanyl, glyburide/metformin, phenytoins, proton pump inhibitors, quinidine, statins, sulfonylureas, theophyllines, warfarin, etc.
Drs. Joseph and Pollak point out the cost/benefit ratio may not be worth it for some patients. They also note that patients may come in with preconceived notions about oral antifungals. As Dr. Joseph explains, more and more patients are Internet-savvy and have read the FDA warnings about oral therapy before coming into the office for treatment. These patients may have also been advised by their physicians, friends and family about the “dangers” of oral antifungals, according to Dr. Joseph.

Q: What about combining oral and topical therapies for onychomycosis? Have you had any experience in doing this? If so, what kind of results have you seen? Are there any particular patient cases you have seen that stand out?
“Combining oral and topical therapy makes perfect sense,” emphasizes Dr. Joseph, who has frequently lectured about this subject. “The thought is to treat the fungus from the inside out and the outside in.”
Emerging studies seem to support combination therapy for this condition. According to Dr. Gupta, there is in vitro data suggesting that ciclopirox may have synergy with terbinafine or itraconazole, and Dr. Joseph notes there is at least one open label trial showing that the combination of ciclopirox lacquer and itraconazole works better than either alone.
Dr. Gupta says there is data in the literature that suggests the efficacy of combining amorolfine and terbinafine or amorolfine and itraconazole in treating onychomycosis, although he points out that amorolfine is not yet available in the United States. According to Dr. Joseph, there has also been research on combining ciclopirox lacquer with terbinafine and European research combining terbinafine with other topicals not currently available in the U.S.
“Almost all studies show it is sound,” explains Dr. Joseph. “It is now rare for me to give a prescription for an oral agent without also including one for a topical.”
When Dr. Rubinlicht does use an oral antifungal to treat onychomycosis, he always combines it with Restore, Nail Scrub, Mycocide, Penlac or another topical therapy. He says the combination tends to work best when he uses the Nail Scrub.
Dr. Overley often uses combination therapy to treat recalcitrant onychomycosis and has had “great success” with the oral Lamisil and the topical Penlac solution. He says he uses this combination when a patient returns with onychomycotic toenails that have already had one course of Lamisil therapy without a complete cure. Then Dr. Overley places the patient on another course of Lamisil with concomitant use of Penlac.
“Of course, you can do this from the beginning,” points out Dr. Overley. “However, my experience has been that most patients will not adhere to the daily topical applications the first time around.”
Dr. Pollak also believes that you don’t have to start out with combination therapy for onychomycosis. He suggests starting with the three-month course of the oral and then adding a topical agent as a preventive measure at the end of the oral therapy course.
“Personally, I have been pleased with the results of using oral agents alone and only recently in the past year have I been advocating a topical agent to prevent the disease (tinea pedis) from reoccurring,” explains Dr. Pollak.

Q: What about treating onychomycosis in the diabetic patient? What considerations come into play when you’re choosing an appropriate antifungal? What have you had the best results with in this situation?
Drs. Joseph, Overley and Pollak agree that treating onychomycosis in the diabetic patient population is of utmost importance.
According to Dr. Pollak, diabetic patients have a significantly higher incidence of onychomycosis (33 percent) than non-diabetics (3 to 12 percent). More specifically, Dr. Pollak emphasizes that diabetic patients with onychomycosis are three times more likely to have a foot infection, foot ulcer, gangrene or amputation than the diabetic patient who does not have onychomycosis.
Dr. Overley concurs, adding that, in his opinion, out of all the different patients he sees, diabetic patients have the greatest risk of ingrown toenail infections and digital amputation due to severe onychomycosis and onychogryphosis. Despite these complication risks, Dr. Overley believes the diabetic patient population is probably the most undertreated when it comes to onychomycosis.
As far as treatment goes, Dr. Joseph says debridement is useful in thinning the nail, making it less painful and decreasing the incidence of nail bed ulceration. However, he says this is palliative therapy and emphasizes that antifungal therapy (whether it’s oral, topical or a combination) is essential.
“The importance of doing this is evidenced by the fact that almost all insurers will pay for antifungal therapy in his patient population, no questions asked,” points out Dr. Joseph. “In fact, it is just about the only time many will pay for it.”
Dr. Joseph tends to use the ciclopirox lacquer for this patient population and if he does use an oral antifungal, he will opt for terbinafine. While Dr. Joseph says the safety of both orals has been shown in small diabetic trial populations, he feels more comfortable using terbinafine since it has fewer interactions than itraconazole with drugs such as sulfonylureas.
In his opinion, Dr. Pollak says if any group warrants oral agents for onychomycosis, it’s the diabetic patient population. He says he has had the best results treating these patients with Lamisil. Dr. Rubinlicht always uses topicals for these patients. If they are NIDDM patients who are in good health, then he will also write for an oral antifungal, usually opting for Lamisil.
For diabetic patients with onychomycosis, Dr. Overley re-emphasizes the importance of obtaining a thorough history, reviewing current medications and getting appropriate lab studies before and during the treatment course.

Q: What should you take into account when prescribing oral antifungals to treat onychomycosis in elderly and immunocompromised patients? Which medication has given you the best results?
When you are treating these patients, Dr. Gupta says an appropriate history, examination and review of the patient’s current medications (prescription, non-prescription and herbal medications) is essential. If you are considering itraconazole, Dr. Gupta says you must ensure the patient doesn’t have congestive heart failure or a history of ventricular dysfunction. He obtains baseline liver function tests prior to initiating terbinafine or itraconazole.
Dr. Rubinlicht does not prescribe oral antifungals for elderly or immunocompromised patients, noting that they are “truly sick patients who have too much to lose.” Drs. Joseph and Pollak say they strongly consider the cost/benefit ratio of using oral therapy for this patient population. As Dr. Pollak points out, you have to take into account the seriousness of the disease state, the cost of the medication, other drugs the patient is on and whether the patient truly needs oral antifungal treatment.
Dr. Joseph agrees. If an elderly patient has lived with onychomycosis for decades and it doesn’t really bother him or her other than the occasional need for debridement, Dr. Joseph doesn’t think there is a justification for oral therapy. He also notes that the longer elderly patients have had the disease, the harder it is to cure with topicals or orals.
However, Dr. Joseph says oral therapy is less “elective” for immunocompromised patients. Since the fungus can cause major medical and psychosocial issues in this population, Dr. Joseph believes in treating them aggressively.

Q: Are there any emerging antifungals that you’ve heard about that could have an impact in the near future? If so, how do you think they’ll compare with currently available modalities?
Dr. Joseph says there are a number of new topical agents being considered. Some, such as the aforementioned amorolfine and bifonazole+urea, have been in Europe for years, according to Dr. Joseph, while other currently available topicals (such as naftifine gel or butenafine) have also been considered. He adds that unique delivery systems, including occlusive patches, are undergoing clinical trials.
Some of these new agents may be fairly far along in clinical trials, but to the best of Dr. Joseph’s knowledge, none of them have filed with the FDA. Therefore, he thinks it will likely be over a year before anything new will be available.

Dr. Joseph is an Adjunct Associate Professor of Internal Medicine within the Section of Infectious Diseases at the Temple University School of Medicine. He is a Fellow of the Infectious Diseases Society of America.
Dr. Gupta is an Associate Professor in the Division of Dermatology, Department of Medicine at the Sunnybrook and Womens’ Health Sciences Center and the University of Toronto Medical School in Toronto, Canada. He is also the Laboratory Director at Mediprobe Labs in Toronto.
Dr. Overley practices at Chestnut Hill Podiatry Associates in Philadelphia.
Dr. Pollak is a Clinical Assistant Professor in the Department of Orthopedics at the University of Texas Health Science Center.
Dr. Rubinlicht, a Fellow of the American College of Foot and Ankle Surgeons, practices at Pennsylvania Foot And Ankle Associates in Philadelphia.

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