CHAPTER 23 TINE,A PEDIS AND : Overview of New Systemic Therapies

Bradley D. Castellamo, D.P.M.

Tinea pedis and onychomycosis are the most respectively. Another study, performed in Canada, frequently occurring superficial fungal infections. reported similar results with Recently, new oral antimycotic agents have brought causing 90.70/o of tinea pedis cases and 97.70/o of significant enthusiasm for the treatment of these onychomycosis.' often recalcitrant conditions. Onychomycosis was Non- are sometimes often unsuccessfully treated with topical agents recovered from nall, , and cultures. prior to the introduction of these systemic agents. However, most agree that these organisms are While tinea pedis is often treated successfully with contaminants. In fact, one investigator suggests that topical agents, the author can say that in eight years in order to consider a non-dermatophyte to of practice in podiatry, he has never successfully be considered clinically significant, it must grow cleared a single case of onychomycosis with any of from 5 of ZO inocula.3 However, more recent the topical agents promoted as treatment studies have suggested that nondermatophytic for this toenail infection. In the recent past, molds and are having an increasing role in griseofulvin was the only oral agent with a the pathogenesis of onychomycosis.a Kemna' satisfactory safety profile to allow its long term use proposed a classification system for onychomycosis for the treatment of onychomycosis. However, similar to that used for tinea pedis. even this form of therapy proved to be of little "Onychomycosis complex" was described as a value in the treatment of toenail onychomycosis. A condition resulting when dermatophyic fungi brief overview of superficial fungal infections of the create a condition favorable to the overgrowth of feet will be presented. Special attention is given to saprophytic molds. He also states that though the new forms of therapy for these conditions. saprophyte may not have been the original pathogen, it still may represent "valid growth." In EPIDEMIOLOGY any event, it is probably reasonable to assume that as new therapies emerge so too will infections due The prevalence of fungal infections has gradually to resistant organisms. increased in the United States. Many factors are considered to contribute to this increased DERMATOPTIYTOSES incidence. An aging population, combined with frequent use of systemic antibiotics are considered Fungal infections of the superficial skin, haiq and to be major reasons for the prevalence of these nails are caused by keratinophilic fungi called conditions. It has been estimated that 75o/o to 2oo/o dermatophyes. They are a small fraction of the total of those over 40 years old have onychomycosis. number of know fungi and are generally not The vast majority of superficial fungal considered normal skin flora. These organisms are infections are caused by dermatophyes. Recent found in soil and in infected animals and humans. emphasis has been placed on the occurrence of The infection of a host occurs when an organism is nondermatophyes as etiological agents in these deposited on the skin and secretes keratolltic diseases. However, Kemna found after reviewing enzymes that enable the fungi to invade the 561 specimens, that 94.7o/o of the cases of tinea epidermal layers of skin. Since the organism is being pedis and 87.90/o of onychomycosis cases in the sustained by keratin, it is rare that it invades deeper United States were caused by dermatophytes., tissues that do not contain this food source. Host Tricbophytom rubrum was the most commonly response to the invading fungi may vary depending isolated organism in tinea pedis and onychomy- on the organism involved, location of the infection, cosis, representing 78.9o/o and 76.20/o incidence and the individual host's immune status. CTIAPTER 23 135

TINEA PEDIS Chronic Hyperkeratotic Tinea Pedis This form of tinea pedis is generally caused by Tinea pedis is very common in the shoe wearing the organism Trichopbyton rubrum or T' population. Over-the-counter topical therapy is mentagrophyfes. In general, this form of tinea pedis often successful in the treatment of this condition. is restricted to the soles of the feet. In some cases, However, in many instances the patient treats the the palm of the hand can become involved. This two condition incompletely, or not at all. Therefore, feet one hand presentation is sometimes helpful in chronic infections and acute exacerbations are a distinguishing tinea from psoriatic lesions that are frequent reason the patient seeks medical attention. usually bilateral symmetrical. The thickness of the There are three general types of tinea pedis: soles of the feet act as a barrier to the fungus, while intertriginous, chronic hyperkeratotic, and acute allowing a dry scaly infection to occur without inflammatory. Generally, the intertriginous type of causing the host to mount an immune fesponse. infection is subdivided into simplex and complex, Moccasin foot distribution is used to describe the depending on the degree of superinfection and typical presentation of this infection. maceration of the inteftriginous spaces of the toes. The treatment of this condition can at times be difficult. Prolonged topical therapy may be Intertriginous Tinea Pedis curative, however, many practitioners have found The typical intertriginous infection of tinea pedis can be subdivided into fwo types. Dermatophltosis simplex is the condition that produces dry, scaly lesions of the intertriginous areas, often spreading to the dorsum of the foot (Fig. 1). KOH will be positive for dermatophyte. Tricbophytoz, or less frequently, Epiclermopbyton are the organisms most likely encountered. If the conditions exist for progression of the disease process, the organism causes skin damage and build up of macerated desquamated skin. This "media" of detritus can a1low the overgrowth of other organisms to occur, specifically, cocci, diptheroids, and gram negative organisms that are not inhibited by the penicillin- Figure 1. Dry, scaly, intefiriginoLls tinea pedis. Dermatophyle was like substances secreted by the dermatophyes. c,-rlt.rred. One month course of topical successfully cleared This condition of "superinfection" is called this infection. dermatophyosis complex. Usually severe over- growth with gram negative organisms srrch as Pseudomonas, Corytnebacterium minutissimLtm, or M. sedentarius catse a pungent malodor that aids in the diagnosis of this condition (Fig. 2). Treatment of the simplex condition is often successful with various over-the-counter or prescription antifungal agents. However, as the simplex condition gives way to the complex form of dermatophltosis, treatment may need to be altered to reduce bacterial growth and remove macerated tissue. The author has found that improved foot hygiene combined with Castellani's paint (carbol- fushin dye and phenol) is very helpful in drying the webspaces, and as a keratolyic to reduce desqua- Figure 2. This patient suffered a painful intefiriginous infection of the mated cells that have become infected. Eventually, lefi foot. The infection cleared u'ith oral ciprofloxacin. However, he presentecl vr,ith recurrent infections s'ith the same organism inter- treatment of the dermatophye on a long-term basis is ilittently until antifungal therapy follou'ed clearing of the bacterial generally required to prevent recuffent infections. superinfection. 136 CI]APTER 23

that a combination of oral and topical therapy is of 1 part Burrow's solution, 2 pafis aquaphor, and the most successful. In the author's experience, a 4 3 parts Lassar's zinc paste. The acute reaction can week course of terbinafine with a 3 month, once a be quite painful in weight-bearing areas and may day application of a topical agent such as naftifine require several weeks to completely resolve. or has been for the most part successful. Secondary infection is fairly common and bacterial In addition to this therapy, the author recommends culture should be performed and broad spectrum (but rarely witnesses compliance) discarding old antibiotics initiated if this is suspected. Long term shoes worn prior to the therapy. Certainly, preventive therapy with topical antifungal agents is treatment of the shoes with a antifungal powder recommended to prevent recurfence. can be helpful in controlling excess moisture and reducing the colony count of infectious organisms. ONJ'YCHOMYCOSIS Fungal spores, however, are not eliminated by this treatment. Finally, once the active infection appears infection of the plate and nail bed is termed under control and the antimycotic therapy is onychomycosis. There ate four basic types of complete, the author finds that continuous long onychomycosis: white superficial onychomycosis, term treatment with Lactinol or Lachydrin 12o/o is an proximal subungual, distal subungual, and effective keratolytic that helps prevent recurrent candidal. Any of previously mentioned infections infection. may .vary in severity and extent of nail plate involvement. Acute Inflamrnatory Tinea Pedis This form of tinea pedis is caused by the more anti- Superficial Wtrite Onychomycosis genic organism T. mentagropbytes. An allergic Superficial white onychomycosis describes response or id reaction to the organism is infection of the surface of the nail plate with considered the reason for the dramatic presentation dermatophytic fungi. It is a relatively common form of this form of tinea pedis. The distinguishing of onychomycosis, and may be present in feature of this infection is vesicular or bullous combination with the other types fungal nail eruptions, pruritus, and occasionally pain (Fig. 3). infections. Mechanical debridement combined with Treatment is therefore targeted at the inflammatory topical antifungal therapy are usually successful component of the condition rather than the forms of therapy. ablation of the organism itself. Systemic corticos- teroids may be necessary in severe cases. The Proximal Subungual Onychomycosis author has found that deroofing the larger bulli and Proximal subungual onychomycosis the least clusters of vesicles followed by the application of is common form of nail infection. The nail plate topical compresses with Burrow's paste is very becomes involved proximal to the eponychium, helpful for many patients. Burrow's paste consists and grows distally as the infection continues. Onychomadesis (separation of the proximal nail plate from the underlying soft tissue) may occur, with complete onycholysis and shedding of the entire nail plate frequently resulting. This form of onychomycosis has been associated with immune compromise and is sometimes seen in patients with AIDS. Careful history taking is needed when diagnosing this condition. A nail plate that has shed, following total involvement of the nail from another form of onychomycosis, or an infected nail that has been traumatized may mimic proximal subungual onychomycosis. Treatment with systemic agents is generally less protracted than with distal nail involvement. Figure 3. Acute inflammatory tinea pedis in a teenage female. Note the coalesced vesicles of the plantar aspect of the toe. CHAPTER 23 137

Distal Subungual Onychomycosis allylamines, morpholines, and miscellaneous in Distal subungual onychomycosis is the most agents. Topical agents are ger\erully successful pedis. However, systemic common form of fungal nail infection. In this form the treatment of tinea typically been required to treat of onychomycosis, the fungi enter the subungual have of fruition. area through the distal aspect of the nail bed hair and nail infections with any degree (Fig 4). The infection is generally caused by Topical amorolfine nail lacquer has shown some have a ptimary dermatophytes, or in rare instances by non- degree of success, but appears to therapy and as a dermatophyic molds. Many patients present to the role as an adjunct to systemic successful clearing of physician with a history of "ugly toenails" that have prophylactic agent following and allylamine been present for several years. Some have tried the infection. Newer imidazoTe significant enthusiasm for over-the-counter treatment without success. A large agents have provided fungal hair and nail number have not sought therapy until symptoms of the successful treatment of pain or discomfort arose. Many embarrassed infections. for over-the-counter elderly patients are seen each year in physicians' Recently, FDA guidelines treatment of fungal infections offices with extreme elongation and neglect of the topical agents in the the maiot rulings toenails due to this condition. New and relatively have been issued.5 One of safe forms of therapy have recently become discussed by these guidelines is that only one antifungal available that should make treatment of this active ingredient, or single-entity appropriate for over-the- condition more successful. products are considered counter use. Combinations of antifungal agents with antiperspirants, hydrocortisone, broad- spectrum antibiotics, salicylic acid and/or topical anesthetics are considered to have no increase in efficacy or added relief of symptoms. In addition to this ruling, approved labeling for over-the-counter antifungal products must include the statement: "This product is not effective on the scalp or nails'" Systemic antifungals used for the treatment of superficial mycotic infections of the feet include griseofulvin, older imtdazole antifungals such as , and the newer triazoles- and itraconazole. Finally, a new class of antifungal agents called allylamines are now available in the form of the drug terbinafine. While some uses for Figure 4. Severe distal subungual onychomycosis involving all toes in the older agents may still exist for tinea versicolor this 4!-year-o1d patient. or , the newer agents specifically terbinafine, ttraconazole, and fluconazole are the best suited for treatment of onychomycosis or resis- Candidal Onychomycos is tant tinea pedis. Candida is sometimes isolated from cultures of nail infections. Kemna found in 26 of Mechanisms of Action the importance 561 positive nail cultures.'Although Systemic antifungal agents generally target inhibition pathogen in onychomycosis is not of candida as a of sterol synthesis crucial to fungal cel1 membrane well understood, it does appex to have a role in formation. Unfortunately, human cholesterol certain individuals. synthesis is not very dissimilar from that of fungi, and therefore, developing antifungal agents specific for ANTIFUNGAL AGENTS the pathogen versus the host has been difficult. Lack of specificity can cause endocrinologic, hypolipi- Antifungal agents can be divided into two demic, or hematologic changes. The newer systemic categories based on their method of administration. antifungals have significantly improved their speci- Topical and oral agents can be subdivided into one ficity for fungal cholesterol synthesis thereby of five groups of agents: polyenes, azoles, improving their safety in clinical use. I38 CHAPTER 23

Azoles that should be avoided or monitored very closely The azole antifungals have been improved by the include itraconazole with terfenidine (Seldane), addition of a third nitrogen atom to the azole ring. astemizole (Hismanol), lovastatin (Mevacor) and These newer triazole antifungal agents show niacin, simvastatin (Zocor) and cyclosporine, improved specificity for fungal enzyme inhibition midazolam (Valium), aTprazolam (Xanax), triazolam compared to the imidazole ketoconazole. This has (Halcion) and cisapride (Propulsid). Drugs resulted in less hepatotoxicity, increased potency inducing hepatic enzymes including rifampin, and shorter courses of therapy. While azole anti- isoniazid, carbamazepin, phenytoin and others may fungals at high concentrations can be fungicidal, result in increased metabolism of itraconazole with these agents are generally considered fungistatic at subsequent failure of antifungal therapy. Clinicians levels achieved with therapeutic dosing. are cautioned to reuieu tbe package insert for Itraconazole, Itraconazole (Sporonox) was complete lkt of drug interactions before prescribing discovered in 1980 and is currently being used in this or any clrug. the United States for the treatment of superficial The approved dosing regime for itaconazole fungal infections. It has a high affinity for kerarin for the treatment of onychomycosis is 200 mg/day with drug levels 3 to 10 times that of plasma found for 3 months, with a cure rate at 18 month follow- in the skin. Excretion of intraconazole in the sebum up of 57o/0. Tinea pedis is treated with 100 mg/day increases the level of the drug reaching the stratllm for 30 days with a cure rate after 4 weeks of 790/0. corneum. Itraconazole is metabolized in the liver Pulse therapy is described and used with and excreted in the urine and feces primarily as itraconazole although FDA approval is still pending inactive metabolites. Fortunately, renal disease and for this method of dosing. Generally, itraconazoTe the age of the patient appear to have little effect on 200 mg taken twice daily for 7 days with 21 days the pharmacokinetics of the drug. off is the most commonly reported dosing regimen. Itaconazole has proven to be a relatively safe A recent investigation of itraconazole pulse therapy and effective drug for the treatment of superficial for onychomycosis reported a clinical cure rate at fungal infections. The incidence of untoward 12 months between 75o/o and 84o/oJ Therefore, an effects are repofied to be approximately 13% with insignificant difference in cure rates appears to be durations of therapy greater than one month. The present with continuous versus pulse therapy of side effects most commonly encountered in order itraconazole. of frequency include nausea, headaches, Fluconazole. Fluconazole (Diflucan) is a abdominal pain, and . In addition to these, triazole antifungal agent. This agent has not been elevated liver function tests have occurred in .3o/o to studied or promoted as extensively as itraconazole 50/o of patients. Rarely, intraconazole may cause for the treatment of onychomycosis. However, sympromatic drug-induced hepatitis. In the preliminary studies repofi low incidence of adverse reported cases, liver function tests returned to reactions and similar cure rates with both pulse and normal following cessation of therapy. Liver continuous therapy. In a pilot study, Assaf and function studies are recommended for patients Elewski reporled successful treatment of eleven receiving continuous itraconazole therapy for patients with onychomycosis utilizing fluconazole in greater than one month or in any patient with various pulse dosing regimens.8 Efficacy is generally history of hepatic dysfunction. Signs and symptoms believed to be equal to or better than itraconazole for of hepatic disease must be carefully monitored.6 the treatment of dermatophyic onychomycosis. Unfortunately, several significant drug interac- Drug interactions with fluconazole ate tions are associated with concomitant therapy with basically the same as those reported for itracona- ilraconazole. Some severe reactions can occur such zo1e. Again, liver enzyme levels are monitored as life-threatening cardiac dysrhythmia when throughout continuous therapy. iffaconazole is combined with terfenidine (Seldane) or astemizole (Hismanol). Contraindicated drug Allylamines combinations prevent itraconazole from being Allylamines have very successfully achieved considered first line therapy for most long term specificiry for fungi by acting at the squalene treatment of superficial fungal infections such as epoxidase level of ergosterol synthesis. This has dermatophl,tic onychomycosis. Drug combinations two important beneficial effects. First, the CFIAPTER 23 r39 cytochrome P-450 isoenzymes do not mediate The second most frequently repofted untoward squalene epoxidase inhibition. This results in effect is cutaneous eruptions. The majority of these improved safety profile having little interaction reactions are mild, and reverse with cessation of with other pharmacologic agents that are acted on therapy. Acute generalized exanthematous pusfulosis by the P-450 system. Second, the inhibition at this has recently been repofied in lwo patients taking25) level causes fungicidal levels of squalene to mg daily for suspected superficial fungal infections. accumulate within the organism. This fungicidal Patients should be infonned of the side effects before activity is achievable at normal therapeutic levels, instituting therapy and insilarcted to discontinue and is the reason for the reported lower relapse therapy if signs of skin rash or pruritus occur. rates following treatment of onychomycosis. Terbinafine. The newest systemic antifungal CONCLUSION agent is terbinafine (Lamisil). It is classified as an allylamine antifungal and demonstrates unique and Systemic therapy for fungal infections of the foot has advantageous pharmacokinetics. It is the first significantly improved with the recent development systemic antifungal agent considered fungicidal of trrazole and aTTyTamine agents. Most skin infections rather than fungistatic. It has a broad spectrum of ate probably best treated with topical agents. activiq against dermatophytes, Sporotrix s cb enc kii, However, the treatment of onychomycosis requires aspergilli, Scbopulariopsis breuicalis and Candida systemic therapy. Grisofulvin would appear to no parapsilosis. Terbinafine has fungistatic activity for longer have a role in the treatment of onychomycosis. Candida albicans, Terbinafine, witl-r its relative lack of drug interactions Terbinafine has proven to be the most and greater degree of efficacy is considered the drug effective form of systemic antifungal therapy for of choice for onychomycosis caused by sensitive onychomycosis in several comparison studies. organisms. More investigation is needed to determine DeBacker et al. performed a double-blind study if pulse terbinafine therapy provides the same efficary comparing ilraconazole 200 mg a day to 250 mg of and safety profile. Pulse dose therapy with itracona- terbinafine daily for the treatment of onychomy- zole or fluconazole provide an alternative treatment cosis.e Both drugs were dosed for 72 weeks. At 48 method in patients that may not tolerate continuous weeks follow-up, clinical cure rates were therapy with terbinafine. Significant drug interactions compared. The terbinafine treated group revealed a prevent itraconazole and fluconazole from being cure rate of 75.30/o versus 58.7o/o for itraconazole. considered first line therapy for onychomycosis. In another double-blind study, 195 patients were treated for clinically diagnosed onychomy- cosis. Half of the patients received terbinafine and REFERENCES half received itraconazole. Again, both groups were 1. Kemna ME, elewski BE: A U.S. epidemiologic suruey of superfi- treated for 72 months. At" 52 weeks follow up cial fungal drseases. J Am Acad Dermatol 31:539-542, 1996. mycologic cure rates (negative microscopy and 2. 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