Optimal Management of Fungal Infections of the Skin, Hair, and Nails

Superficial fungal infections are chronic and recurring conditions. Tinea capitis is a scalp infection, primarily affecting prepubescent children. Ringworm infections, such as tinea corporis and tinea cruris, involve the glabrous skin. Tinea nigra is a rare mycotic infection that may be related to travel abroad. Piedra, black or white, is limited to the hair shaft without involvement of the adjacent skin. Pityriasis (tinea) versicolor and seborrheic dermatitis are dermatoses associated with yeasts of the genus Malassezia that affect the lipid-rich areas of the body. The taxonomy of the Malassezia yeasts has been revised to include nine species, eight of which have been recovered from humans. Tinea pedis, an infection of the feet and toes, is one of the most common forms of dermatophytosis. Onychomycosis is a fungal infection affecting the nail bed and nail plate; it may be chronic and can be difficult to treat. In instances where the superficial fungal infection is severe or chronic, an oral antifungal agent should be considered. Terbinafine, itraconazole, and fluconazole are oral antifungals that are effective in the treatment of superficial mycoses.     

Brief treatment guide for onychomycosis

Most onychomycosis infections result from dermatophyte organisms and present as distal lateral subungual onychomycosis (DLSO). Mild to moderate infections may be effectively treated with topical lacquer medications; however, there is no general consensus on what constitutes mild infection. In general, mild infections involve relatively small areas of the nail plate without infection of the nail matrix or lunula. Characteristics such as nail thickness, the number of nails affected, and the degree of onycholysis will also be taken into account in the categorization of nail severity and may increase the severity to moderate or severe even where nail plate area involvement is low. Similarly, although an infection may be mild, for patients with underlying health issues such as diabetes or immunodeficiency, oral therapy may be recommended as it typically provides the higher treatment efficacy required by these conditions. Severe infections may be treated with oral antifungal agents or combinations of oral agents and oral antifungals or oral and topical lacquer antifungals. Débridement is a technique that may be used in nearly any degree of infection to aid treatment efficacy by reducing the burden of fungal infection. Other treatment issues discussed include superficial white onychomycosis, nondermatophyte mold infection, and infection prophylaxis. Treatment is discussed considering a dermatophyte infection of DLSO presentation, unless otherwise stated. Infections should be confirmed by laboratory culture to eliminate any other diagnosis. Therapy recommendations concentrate on those agents approved in Canada for onychomycosis: oral terbinafine, oral itraconazole, and ciclopirox 8% nail lacquer.     

Therapy of common superficial fungal infections

Superficial fungal infections are common, especially onychomycosis, dermatophytoses, and superficial Candida infections. Most superficial fungal infections are treated with topical antifungal agents unless the infection covers an extensive area or is resistant to initial therapy. Onychomycosis often requires systemic therapy with griseofulvin, itraconazole, or terbinafine. The objective of this review is to provide the practicing dermatologist with the recommended available therapy for the treatment of common superficial fungal infections.     

Advances in topical and systemic antifungals

Topical antifungal agents are generally used for the treatment of superficial fungal infections unless the infection is widespread, involves an extensive area, or is resistant to initial therapy. Systemic antifungals are often reserved for the treatment of onychomycosis, tinea capitis, superficial and systemic candidiasis, and prophylaxis and treatment of invasive fungal infections. With the development of resistant fungi strains and the increased incidence of life-threatening invasive fungal infections in immunocompromised patients, some previously effective traditional antifungal agents are subject to limitations including multidrug interactions, severe adverse effects, and their fungistatic mechanism of actions. Several new antifungal agents have demonstrated significant therapeutic benefits and have broadened clinicians' choices in the treatment of superficial and systemic invasive fungal infections.     

New antifungal agents

Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates, and drug resistance. New formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungals have demonstrated therapeutic potential. These new agents may provide additional options for the treatment of superficial fungal infections and they may help to overcome the limitations of current treatments. Liposomal formulations of AmB have a broad spectrum of activity against invasive fungi, such as Candida spp., C. neoformans, and Aspergillus spp., but not dermatophyte fungi. The liposomal AmB is associated with significantly less toxicity and good rates of efficacy, which compare or exceed that of standard AmB. These factors may provide enough of an advantage to patients to overcome the increased costs of these formulations. Three new azole drugs have been developed, and may be of use in both systemic and superficial fungal infections. Voriconazole, ravuconazole, and posaconazole are triazoles, with broad-spectrum activity. Voriconazole has a high bioavailability, and has been used with success in immunocompromised patients with invasive fungal infections. Ravuconazole has shown efficacy in candidiasis in immunocompromised patients, and onychomycosis in healthy patients. Preliminary in vivo studies with posaconazole indicated potential use in a variety of invasive fungal infections including oropharyngeal candidiasis. Echinocandins and pneumocandins are a new class of antifungals, which act as fungal cell wall beta-(1,3)-D-glucan synthase enzyme complex inhibitors. Caspofungin (MK-0991) is the first of the echinocandins to receive Food and Drug Administration approval for patients with invasive aspergillosis not responding or intolerant to other antifungal therapies, and has been effective in patients with oropharyngeal and esophageal candidiasis. Standardization of MIC value determination has improved the ability of scientists to detect drug resistance in fungal species. Cross-resistance of fungal species to antifungal drugs must be considered as a potential problem to future antifungal treatment, and so determination of susceptibility of fungal species to antifungal agents is an important component of information in development of new antifungal agents. Heterogeneity in susceptibility of species to azole antifungals has been noted. This heterogeneity suggests that there are differences in activity of azoles, and different mechanisms of resistance to the azoles, which may explain the present lack of cross-resistance between some azoles despite apparent structural similarities. The mechanisms of azole action and resistance themselves are not well understood, and further studies into azole susceptibility patterns are required.     

Clotrimazole/betamethasone diproprionate: a review of costs and complications in the treatment of common cutaneous fungal infections

The use of antifungal/corticosteroid combinations as topical therapy for dermatophytoses has been criticized as being less effective, more expensive, and the cause of more adverse cutaneous reactions than antifungal monotherapy. The combination of clotrimazole and betamethasone diproprionate (Lotrisone) is a mix of an azole antifungal and a high-potency corticosteroid, and is one of the most widely prescribed of these combinations. Our objective was to describe the beneficial and deleterious effects of Lotrisone in the treatment of common cutaneous fungal infections and its relative cost-effectiveness. We did a literature review documenting clinical trial data and adverse reactions to Lotrisone and collected a cost analysis of topical antifungal prescribing data over a 2-month period from a large midwestern staff-model health maintenance organization (HMO). Lotrisone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of tinea pedis, tinea cruris, and tinea corporis in adults and children more than 12 years of age. Treatment is limited to 2 weeks in the groin area and 4 weeks on the feet. The most concerning adverse effects of Lotrisone were reported in children and included treatment failure, striae distensae, hirsuitism, and growth retardation. This combination was also reported to have decreased efficacy in clearing candidal and Trichophyton infections as compared to single-agent antifungals. Lotrisone was considerably more expensive than clotrimazole alone and was found to account for more than 50% of topical antifungal expenditures as prescribed by primary care physicians, but only 7% of topical antifungals prescribed by dermatologists. We found that Lotrisone was shown to have the potential to induce many steroid-related side effects and to be less cost effective than antifungal monotherapy. This combination should be used judiciously in the treatment of cutaneous fungal infections and may not be appropriate for use in children.     

Multitherapy approach to onychomycosis therapy

New medications and new formulations have provided an increase in the cure rates for onychomycosis. Many cases of infection, however, are still not cured. It is not always obvious which factors are most relevant to reduction of cure, and factors may vary with each patient. For these reasons, a multitherapy approach to onychomycosis may be needed to individualize treatment to each patient's specific condition. Different presentations and severity levels of onychomycosis may respond differently to treatment modalities and require varying amounts of intervention. Nail débridement may be used to lessen the burden of infection in cases in which drug penetration may not occur adequately otherwise, such as dermatophytoma, onycholysis, or lateral infection. Ciclopirox nail lacquer has been approved for use in conjunction with regular débridement and represents the first approved multitherapy approach. Topical antifungals may be combined with oral antifungals to provide dual fronts of drug penetration. Similarly, two oral medications may be combined to provide a wider spectrum of antifungal activity and differential mode of action against the organisms, which may increase fungistatic or fungicidal action. There is a nonclinical component of therapy, represented by patient education on onychomycosis infection and treatment, which should be used to ensure that patient expectations are realistic and to encourage patient compliance with the chosen regimens.     

Onychomycosis: a review

Onychomycosis is a fungal infection of the nail, causing discoloration and thickening of the affected nail plate, and is the most common nail infection worldwide. Onychomycosis was initially thought to be predominantly caused by dermatophytes; however, new research has revealed that mixed infections and those caused by non-dermatophyte moulds (NDMs) are more prevalent than previously thought, especially in warmer climates. Microscopy and fungal culture are the gold standard techniques for onychomycosis diagnosis, but high false-negative rates have pushed for more accurate methods, such as histology and PCR. As NDMs are skin and laboratory contaminants, their presence as an infectious agent requires multiple confirmations and repeated sampling. There are several treatment options available, including oral antifungals, topicals and devices. Oral antifungals have higher cure rates and shorter treatment periods than topical treatments, but have adverse side effects such as hepatotoxicity and drug interactions. Terbinafine, itraconazole and fluconazole are most commonly used, with new oral antifungals such as fosravuconazole being evaluated. Topical treatments, such as efinaconazole, tavaborole, ciclopirox and amorolfine have less serious side effects, but also have generally lower cure rates and much longer treatment regimens. New topical formulations are being investigated as faster-acting alternatives to the currently available topical treatments. Devices such as lasers have shown promise in improving the cosmetic appearance of the nail, but due to a high variation of study methods and definitions of cure, their effectiveness for onychomycosis has yet to be sufficiently proven. Recurrence rates for onychomycosis are high; once infected, patients should seek medical treatment as soon as possible and sanitize their shoes and socks. Prophylactic application of topicals and avoiding walking barefoot in public places may help prevent recurrence.     

Terbinafin-Topika

Superficial fungal infections are common and worldwide in distribution. Latest estimates suggest one- third of the population in Europe has a fungal infection of their feet, with dermatophyte infections of the skin of the feet (tinea pedis) most common. Tinea pedis interdigitalis is by far most common and can be effectively treated topically. Common agents include azoles, hydroxypyridones and allylamines, with morpholines used less frequently. While most antifungals have mainly fungistatic effects on dermatophytes, the causative agents of tinea pedis, terbinafine--an allylamine--is fungicidal. Due to this feature shorter treatment periods are possible using topical terbinafine. For effective treatment of uncomplicated tinea pedis interdigitalis, azole cream preparations are often used twice daily for four weeks whereas 1% terbinafine cream can be applied once a day for one week. Since 2006, 1% terbinafine is also available as a film-forming solution (FFS), which makes single-dose treatment possible. FFS may prove superior in daily practice with increased compliance and thus reduced recurrences.     

Efficacy and tolerability of amorolfine 5% nail lacquer in combination with systemic antifungal agents for onychomycosis: A meta‐analysis and systematic review

The efficacy and safety of amorolfine 5% nail lacquer in combination with systemic antifungal agents in the treatment of the onychomycosis were evaluated. According to our meta‐analysis, combination treatment of amorolfine 5% nail lacquer and systemic antifungals can result in higher percentage of complete clearance of onychomycosis. It showed that the experimental combination group was more effective than monotherapy of the systemic antifungals [OR (odds ratio) = 1.97, 95%CI (95% confidence interval) = 1.44–2.69], and no more adverse events happened with the addition of amorolfine 5% nail lacquer (OR = .96, 95%CI = .56–1.63, p = .95). This effect strengthens the fact that amorolfine 5% nail lacquer in combination with systemic antifungal agents was better than the monotherapy of systemic antifungals like itraconazole and terbinafine.     

A rationale for systemic treatment in onychomycosis with negative results on fungal examination

Background. Fungal infection of the nail affects millions of people worldwide, and has an estimated prevalence of about 10% of the general population. Laboratory confirmation of fungal infection is currently accepted as a requirement before initiation of antifungal treatment in clinical practice. Aim. To examine the rationale for systemic treatment in cases of clinical onychomycosis with negative results on fungal examination (potassium hydroxide test and fungal culture). Methods. In total, 147 patients with suspected clinical toenail onychomycosis but with negative results on fungal examination underwent up to three consecutive fungal examinations of the affected nails. Patients who were negative after these examinations underwent a fourth set of investigations, including PCR. Results. Of the 147 cases initially thought to be negative, 138 (94%) were rated as positive after up to four consecutive sets of laboratory mycological investigations including PCR. Trichophyton rubrum was by far the commonest dermatophyte cultured from all samples. Conclusions. In the majority of cases of initially negative examinations, consecutive laboratory fungal tests will eventually produce positive results. These findings suggest that systemic antifungal treatment should be started in patients with suspected fungal infections, even if they have negative laboratory fungal examinations.     

Topical antifungal treatment prevents recurrence of toenail onychomycosis following cure

Recurrence rates are high for onychomycosis, with prophylactic topical antifungal use proposed to counter recurrence. Although this is a reasonable action for many clinicians, few studies have been conducted on the efficacy of topical prophylaxis. A retrospective chart review (2010–2015) was conducted in patients receiving oral terbinafine or itraconazole for toenail onychomycosis. Following complete cure, a topical antifungal (amorolfine, bifonazole, ciclopirox olamine, or terbinafine spray) was used weekly as prophylaxis. Recurrence was recorded along with patient characteristics including demographics and concomitant medical conditions. Data from 320 patients were collected. Recurrence was significantly lower in patients receiving topical antifungal prophylaxis than in no prophylactic treatment following oral terbinafine (p < .001), but not itraconazole (p = .185). Regardless of oral treatment, the use of topical antifungals as prophylaxis (p < .001) decreased, and the number of affected toenails (p = .048) and family history of fungal infections (p < .001) increased the likelihood that recurrence would occur. This study supports the use of topical antifungal medications as prophylactic treatment to help prevent recurrence of toenail onychomycosis and suggests that those with a family history of fungal infections should be closely monitored.     

Treatment of nondermatophyte mold and Candida onychomycosis

Mold onychomycosis often can be clinically suspected because of the presence of periungual inflammation. Treatment with systemic antifungals is very effective in onychomycosis caused by Aspergillus sp. Scopulariopsis brevicaulis and Fusarium sp. infection are difficult to eradicate and treatment with systemic antifungals should always be associated with topical treatment with nail lacquers. Candida onychomycosis is always a sign of immunodepression. Systemic treatment with itraconazole or fluconazole is usually effective, but relapses are very common.     

Tinea corporis in human immunodeficiency virus-positive patients: case report and assessment of oral therapy

Dermatophytosis in immunocompromised hosts is more varied and often more severe than in immunocompetent hosts. Early recognition and treatment with systemic therapy are important in human immunodeficiency virus (HIV)-positive patients in order to prevent severe infection. Potential drug resistance can occur due to chronic usage of systemic azole therapy in such patients, or the existence of atypical fungi. Although warnings have been made of possible drug interactions between certain antifungals and antiretroviral medications, only one combination has shown a clinically significant interaction. A case treated aggressively with oral terbinafine at the onset is presented. BACKGROUND: Dermatophytosis in immunocompromised hosts is more varied and often more severe than in immunocompetent hosts. Early recognition and treatment with systemic therapy are important in human immunodeficiency virus (HIV)-positive patients in order to prevent severe infection. OBJECTIVE: To analyze potential therapies for dermatophyte infections in immunocompromised patients and risk of drug resistance and interactions with antiretroviral medications. METHODS: Literature search based on MEDLINE (1966-March 2003) and additional references obtained from cross-referencing retrieved articles. All information deemed relevant by the reviewers was included. A case study was employed to exemplify the usage of this information in patient care. RESULTS: Although warnings have been made of possible drug interactions between certain antifungals and antiretroviral medications, only one combination has shown a clinically significant interaction. CONCLUSIONS: When considering drug interactions and side-effects, there are no clinically significant reasons to avoid any oral antifungal for dermatophytosis in the HIV-positive patient.     

Recalcitrant tinea corporis as the presenting manifestation of patch-stage mycosis fungoides

Mycosis fungoides is a cutaneous T-cell lymphoma. Its presence, which denotes an altered immune system, may make treatment of otherwise simple cutaneous infections difficult. In the case presented here, a patient with widespread tinea corporis poorly responsive to several oral antifungals was noted as having a background poikilodermatous slightly scaly eruption. Results of a skin biopsy during therapy with oral antifungal medications showed evidence of tinea corporis; atrophy of the epidermis; a superficial, perivascular, and interstitial lymphocytic infiltrate with numerous atypical lymphocytes; and exocytosis of atypical lymphocytes into the epidermis with formation of microabscesses-findings consistent with the diagnosis of mycosis fungoides. Treatment with PUVA (oral psoralen and UVA light) and oral itraconazole led to long-term remission of the mycosis fungoides and the associated tinea corporis. Immune suppression may have contributed to the recalcitrant nature of our patient's dermatophyte infection. Underlying cutaneous, systemic, or iatrogenic disorders associated with immune dysfunction should be considered in patients with recalcitrant dermatophyte infections.     

Evaluation of in vitro resistance in patients with onychomycosis who fail antifungal therapy

BACKGROUND: With the increased awareness of onychomycosis and the increasing use of antifungals for this indication, it is prudent to be concerned about the possible emergence of resistant strains. There has been substantial work on the development of standardized methods for testing the in vitro resistance of various fungi and yeasts to the currently available antifungal agents. However, relatively little research has been published concerning the resistance of dermatophyte species. OBJECTIVE: We report the results of a retrospective study analyzing the relationship between in vitro and clinical resistance in strains of Trichophyton rubrum cultured from patients with recalcitrant dermatophyte toe onychomycosis. MATERIALS AND METHODS: We analyzed the in vitro resistance of dermatophyte strains obtained from 18 patients with chronic onychomycosis who failed antifungal therapy with itraconazole or terbinafine. Multiple-sequential strains from 11 patients were included in the study. Susceptibility testing of these strains was performed against 4 antifungals, itraconazole, ketoconazole, terbinafine and ciclopirox, using the broth microdilution method as per the NCCLS M27-A guidelines. A record of clinical characteristics that may relate to patient treatment and therapy was maintained. RESULTS: All of the strains were susceptible to 3 of the 4 antifungal agents tested. Although there was no direct correlation between clinical resistance and in vitro resistance, increased minimum inhibitory concentration values for ketoconazole were observed in strains obtained after treatment from 3 of 18 patients evaluated in the study. In all but 1 patient, we were able to identify other factors that may have been responsible for treatment failure. CONCLUSIONS: With the more common use of antifungals to treat various fungal infections, development of increased resistance in the causative organisms remains a possibility. However, factors other than fungal resistance may also be implicated in treatment failure.     

双相型真菌耐药性的研究

双相型真菌是真菌病的一类重要致病菌,其引起的双相型真菌病常需要使用抗真菌药物进行系统治疗.尽管大部分双相型真菌病对抗真菌药物敏感,但近年来有关双相型真菌耐药的病例时有报道.对其耐药机制的研究发现,对唑类药物产生的耐药性与CYP51基因突变和外排泵基因表达异常有关.双相型真菌分泌的黑素在体外可降低两性霉素B的抗真菌活性,但其与体内双相型真菌对两性霉素B产生的耐药性是否有关尚无研究.     

Topical treatment of tinea capitis in a neonate

Tinea capitis is the most common fungal skin infection in children. Given that this infection invades the hair shaft and the pilosebaceous unit, systemic antifungal therapy is the gold standard of treatment. Despite the neonate's increased susceptibility to infections, tinea capitis is rare in this population. We present the case of a 16-day-old infant with tinea capitis caused by Microsporum canis and effectively treated with topical bifonazole 1%.     

Candida infections today--how big is the problem?

Thirty years ago, superficial fungal infections were common, but systemic fungal infections were not as frequent as today. Since that time incidence in both superficial and systemic fungal infection has been increasing. The reasons are many. Due to advances in medicine, human life span is extended and many people suffer from various immunodeficiencies. Transplantation of organs and tissues, wide application of parenteral feeding and parenteral administration of drugs, infection with human immunodeficiency virus (HIV), and long-term peroral administration of antibiotics are the main reasons for appearance of many immunologic dysfunctions and thereby systemic fungal infections. The most usual predisposing factors for systemic fungal infection are skin and mucosal damage, hypofunction of T-cell-mediated immunity, decreased function of neutrophiles, long-term administration of corticosteroids, as well as dysfunction of microbial flora. Systemic fungal infections are a great problem, because they are very difficult to prove and to treat. This is why prevention of systemic infections is extremely important today, including the removal of predisposing factors as well as rational drug administration.     

Nails in systemic disease

Nail abnormalities secondary to systemic disease could be classified as nail abnormalities associated with systemic disease, disease of specific organ system or associated with syndromes and genodermatoses. Because nail findings are easily observable and yield valuable information, careful examination of nails could be an important diagnostic tool for a dermatologist. A brief review of the common and not so common nail changes in systemic illness is presented.