Onychomycosis in children: a brief overview with treatment strategies

Onychomycosis in children is uncommon. In those children that are affected, a family history of onychomycosis is not uncommon, giving importance to the examination of the entire family for fungal nail infections. In the United States, the newer oral antifungal agents itraconazole, fluconazole, and terbinafine, and the topical nail lacquers ciclopirox and amorolfine are not approved for this indication. More data are needed on the use of these antifungal agents for the treatment of onychomycosis in children.     

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.     

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.     

Topical agents in the treatment of superficial fungal infections

Such newer topical antifungal agents as tolnaftate, haloprogin, clotrimazole and miconazole are effective in the treatment of most superficial fungal infections.     

Six Novel Antimycotics

We have reviewed six new antimycotic agents which have potential applications for human cutaneous and mucosal diseases. Information on these six drugs was obtained via an English language search of PubMed through the US National Library of Medicine. The antimycotic agents reviewed include rilopirox, lanoconazole, NND-502, butenafine, eberconazole and voriconazole. Rilopirox is a synthetic pyridone derivative, related to ciclopirox, with a fungicidal action. Rilopirox is a hydrophobic, topical agent with potential application in mucosal candida infections, tinea versicolor and seborrheic dermatitis. Lanoconazole, an imidazole, is a topical agent with potential application in tinea infections and cutaneous candidiasis. The drug has been available for clinical use in Japan since 1994 and once-daily application to affected areas is recommended. In addition to its antifungal effect, animal data suggest that application of lanoconazole 0.5 or 1% cream is associated with accelerated wound healing. NND-502, a stereoselective analog of lanoconazole, is a topical agent with potential application in tinea pedis infection. NND-502 appears to be more effective in inhibiting ergosterol biosynthesis than lanoconazole or bifonazole and clinical trials comparing these agents are awaited. Butenafine is the first member of a new class of antifungals, the benzylamine derivatives, and has been approved for topical use in Japan (since 1992) and the US. Butenafine has a potent fungicidal action and the drug has been shown to be effective in multiple clinical trials in patients with tinea pedis, tinea corporis and tinea cruris. Butenafine has also been reported to exert an anti-inflammatory action after topical application and this may offer potential benefit over other topical antifungal agents. Eberconazole, an imidazole derivative, is a topical antifungal agent that has been shown to be effective in clinical trials in patients with tinea infections. Preliminary data indicate that the eberconazole is effective against some triazole-resistant yeasts such as Candida krusei and Candida glabrata. Voriconazole is an azole antifungal derivative of fluconazole. The drug is available in both oral and parenteral formulations. Oral voriconazole 200mg twice daily has been effective in treating oropharyngeal candidiasis and apergillosis in immunocompromised patients. After 12 weeks' treatment, a similar dosage of the drug elicited a positive response in 69% of nonimmunocompromised patients with invasive aspergillosis.     

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.     

Non-dermatophyte onychomycosis

Non-dermatophyte organisms are becoming increasingly prevalent in onychomycosis. This apparent emergence might be an artifact of improved diagnostic techniques and increased awareness that these fungi are potential etiologic agents. It is important to bear in mind that all isolated organisms should be evaluated as potential pathogens when diagnosing fungal infections, especially given the increasing use of immunosuppressive drugs and the increasing numbers of chronically immunocompromised individuals. While many patients with non-dermatophyte mold onychomycosis will respond to oral or topical antifungal therapy, poor or incomplete response might still be expected in some patients.     

Therapeutic strategies in onychomycosis

Objective: This paper reviews current advantages and limits of modern topical antifungal agents (amorolfine, ciclopirox nail lacquer, bifonazole/urea ointment) and oral antimycotic drugs (itraconazole, terbinafine) in the treatment of onychomycosis, taking into account the results of clinical trials.Results: Clinical studies show that both topical and oral antimycotic therapy are effective in treating onychomycosis. However, topical antimycotic treatment produces high efficacy only in superficial and minor distal subungual onychomycosis. The newer oral antifungal drugs have been relatively well tolerated so far. Nevertheless, if oral antimycotic treatment schedules of several months are used, liver function should be monitored.Conclusion: Knowledge of the advantages and limits of both topical and systemic antimycotic treatment of onychomycosis is a prerequisite for a reasonable and effective therapy. Consequently, a therapeutic strategy in onychomycosis is useful to aid physicians choose a suitable treatment.     

New antifungal agents.

This article, rather than presenting an overview of all available antifungal agents, has provided an update on new information about older agents, as well as evolving information about new agents, including those currently undergoing clinical trials. Among the azoles, ketoconazole will continue to be used as a major antifungal agent in dermatology, but one must keep up with its side effects and drug interactions. The place of the new triazole fluconazole in the treatment of cutaneous fungal infections needs to be clarified by additional controlled studies. Other agents on the horizon which are still undergoing investigation include itraconazole, which should be especially useful for dermatophyte (including tinea unguium) and candidal infections, sporotrichosis, and unusual infections such as aspergillosis and phaeohyphomycosis; and terbinafine, a member of the new class of antifungals called allylamines, which is an orally and topically active fungicidal agent that should be very useful for all types of dermatophyte infections. Research continues into the effectiveness of members of other classes of antifungals, including piritetrate, cilofungin, and amorolfine. In the 1990s, dermatologists should have safer, more effective antifungal agents for treating cutaneous fungal infections.     

新唑类抗真菌药物研究进展

近年来,新研制出一些唑类抗真菌药物,包括口服的伏力康唑、泊沙康唑、雷夫康唑;外用的舍他康唑、硫康唑、噻康唑等。这些药物扩大了现有唑类药物的抗菌谱,提供了更好的抗真菌活性。这些新的唑类抗真菌药物,尤其是系统用药已经在初步的临床实践中显示出较好的应用前景。为此,主要综述了新唑类抗真菌药物的临床应用的最新进展。     

The diagnosis and treatment of nail disorders: systemic antifungal therapy

Systemic antifungals have been used in the treatment of fungal infections since the introduction of griseofulvin in 1958. Since then, new antifungal medications have been introduced, broadening the spectrum of therapies available. Onychomycosis is one of the most common complaints presented to the dermatologist. Fungal infection of the nails, though usually not an urgent medical condition, can be extremely distressing to the patient. Since current topical antifungal medications have little or no efficacy in the treatment of fungal infections of the nail, it is incumbent upon the dermatologist to be familiar with the use of systemic antifungals in the treatment of onychomycosis. In this article, the treatment of fungal infections of the nail with systemic antifungals is discussed. A brief review of the most common types of nail fungal infection is presented and the use of systemic antifungals relevant to dermatology is addressed.     

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.     

Onychomycosis: strategies to improve efficacy and reduce recurrence

Fungal infections may be difficult to treat for several reasons. It is important to obtain the correct diagnosis, and select the appropriate antifungal agent and route. General considerations that may be associated with recurrent infections are, a genetic predisposition and suboptimal bioavailability of drug, resulting in insufficient concentration at the target site. The aetiologic organism, the severity of disease, other coexisting diseases, concomitant drug intake, and the presence of fungal infection at other sites are some factors that determine the choice of antifungal therapy and its route of administration, oral vs. topical lacquer. Local factors such as the thickness of the nail, presence of lateral onychomycosis, longitudinal spike, dermatophytoma and severe onycholysis are some factors that may determine the choice of secondary measures such as mechanical or topical treatment. Booster or supplemental therapy may be of benefit when the response to initial treatment is poorer than expected and unlikely to result in complete response. Steps should be taken to reduce the possibility of recurrence once cure has been achieved.     

The significance of itraconazole for treatment of fungal infections of skin, nails and mucous membranes

Itraconazole is an antifungal drug from the triazole group with distinct in vitro activity against dermatophytes, yeasts and some molds. Itraconazole has a primarily fungistatic activity. Itraconazole accumulates in the stratum corneum and in nail material due to its high affinity to keratin, as well as in sebum and vaginal mucosa. Together with terbinafine and fluconazole, itraconazole belongs to the modern highly effective systemic antifungal drugs with a favorable risk-benefit ratio and for this reason is a preferred therapy option for fungal infections of skin, nails and mucous membranes. Compared to terbinafine in the treatment of fingernail and toenail fungal infections, itraconazole offers the advantage of a broad antifungal spectrum and better effectiveness against onychomycosis caused by yeasts yet appears inferior with regard to the more common dermatophyte infections. Itraconazole constitutes an important therapy option, along with fluconazole, terbinafine, ketoconazole and griseofulvin, for the treatment of dermatophyte infections of glabrous skin (tinea pedis, tinea manuum, tinea corporis and tinea cruris) in adults following unsuccessful topical therapy. In the oral therapy of tinea capitis, itraconazole plays an especially important role, in particular for disease caused by Microsporum canis (for children, however, only off-label use is feasible currently). In the treatment of oropharyngeal candidiasis, candidiasis of the skin and vulvovaginal candidiasis, itraconazole and fluconazole are the preferred treatment options in cases in which topical therapy has proven unsuccessful.     

Itraconazole and terbinafine in perspective: from petri dish to patient

Objective To compare the antifungal activity of itraconazole and terbinafine in vitro and to relate them to their experimental in vivo activity and to their efficacy in patients with superficial fungal infections (tinea pedis and onychomycosis).Results Fungal infections such as onychomycosis and tinea pedis are often treated with oral antifungals. With the introduction of newer agents such as terbinafine and itraconazole, efficacy and safety have been improved. In vitro evaluation showed somewhat better results against dermatophytes for terbinafine than for itraconazole, but in vivo results were at least equivalent. Moreover, itraconazole is a broad-spectrum agent with higher cure rates for infections other than dermatophytosis (e.g. for Candida infections) than terbinafine, according to ex vivo studies. A review of all published clinical trials, comparing the efficacy and safety of terbinafine and itraconazole in a meta-analysis revealed similar and high cure rates (>70%) for both anti-fungal agents and similar adverse event profiles. Both treatments were safe and well tolerated.Conclusions Antifungal research has responded to the challenges of treating superficial infections by developing effective, well-tolerated, fast-acting antifungal therapies. The reduction in treatment duration has also led to improved patient's compliance. The most noticeable difference between itraconazole and terbinafine is the 1-week pulse concept of itraconazole in contrast to the continuous treatment concept of terbinafine.     

侵袭性丝状真菌感染的流行病学趋势

随着感染真菌高危人群的增多,丝状真菌引起的侵袭性感染亦日益增多.虽然烟曲霉是最常见的病原菌,但非烟曲曲霉(如土曲霉)以及非曲霉丝状真菌(如镰刀霉属,赛多孢霉属及接合菌)也已经成为重要的感染因素.这些菌种对两性霉素B或其他常用的抗真菌药物天然耐药或不敏感,在临床上常导致较高的病死率.概述侵袭性丝状真菌感染的流行病学研究现状,旨在强调早期病原学诊断和选择敏感抗真菌药物的临床意义.

Abstract：

The prevalence of invasive filamentous fungal infections has been rising with the increase of high-risk population. Although Aspergillus fumigatus remains the most frequent cause of these infections, nonfumigatus Aspergillus species such as Aspergillus terreus and non-Aspergillus filamentous fungi such as Fusarium species, Scedosporium species and Zygomycetes have emerged as important pathogens. These fungal species are inherently resistant or less susceptible to amphotericin B or other antifungal drugs, and often cause a high mortality in patients. The epidemiology of invasive filamentous fungal infections is reviewed here to emphasize the clinical importance of early pathogenic diagnosis and selection of active antifungal agents.     

Framing the future of antifungals in atopic dermatitis

Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease. Some fungal colonization or infection of the skin may exacerbate AD severity, particularly the so-called head and neck variant. In addition, excessive intestinal colonization by Candida albicans may represent an additional triggering factor. Hence, there is a rationale to use antifungals in selected AD patients. Early trials with topical ketoconazole in head and neck AD showed a decrease in Malassezia colonization, but no significant improvement was observed in the clinical severity. In contrast, clinical improvement and decreased serum IgE were obtained in patients with positive Malassezia radioallergosorbent tests (RASTs) who were treated by oral ketoconazole. Some preliminary data suggested that oral itraconazole treatment in AD patients reduced the need for topical corticosteroids, provided clinical improvement particularly in head and neck AD, reduced the cutaneous and intestinal fungal colonization that may trigger AD, reduced the percentage of positive Malassezia cultures and demonstrated a decrease in C. albicans and Malassezia RAST values. Furthermore, beside its antifungal action, itraconazole in part relieves pruritus and inflammation. In conclusion, oral itraconazole treatment can alleviate AD severity in selected patients. Fluconazole is also effective. Further research is warranted to identify whether the load in skin surface fungal agents, the fungal RAST values and specific prick testing should be assessed in order to optimize the antifungal management in AD patients.     

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.     

Stellenwert von Itraconazol in der Behandlung von Pilzinfektionen der Haut,Nägel und Schleimhäute

Itraconazole is an antifungal drug from the triazole group with distinct in vitro activity against dermatophytes, yeasts and some molds. Itraconazole has a primarily fungistatic activity. Itraconazole accumulates in the stratum corneum and in nail material due to its high affinity to keratin, as well as in sebum and vaginal mucosa. Together with terbinafine and fluconazole, itraconazole belongs to the modern highly effective systemic antifungal drugs with a favorable risk‐benefit ratio and for this reason is a preferred therapy option for fungal infections of skin, nails and mucous membranes. Compared to terbinafine in the treatment of fingernail and toenail fungal infections, itraconazole offers the advantage of a broad antifungal spectrum and better effectiveness against onychomycosis caused by yeasts yet appears inferior with regard to the more common dermatophyte infections. Itraconazole constitutes an important therapy option, along with fluconazole, terbinafine, ketoconazole and griseofulvin, for the treatment of dermatophyte infections of glabrous skin (tinea pedis, tinea manuum, tinea corporis and tinea cruris) in adults following unsuccessful topical therapy. In the oral therapy of tinea capitis, itraconazole plays an especially important role, in particular for disease caused by Microsporum canis (for children, however, only off‐label use is feasible currently). In the treatment of oropharyngeal candidiasis, candidiasis of the skin and vulvovaginal candidiasis, itraconazole and fluconazole are the preferred treatment options in cases in which topical therapy has proven unsuccessful.     

Terbinafine exacerbates psoriasis: case report with a literature review

Oral terbinafine is a widely used antifungal agent. Adverse effects occur in about 11% of patients taking terbinafine. A rare case of the exacerbation of pre-existing psoriasis after oral terbinafine treatment is reported. A 63-year-old male patient with stable psoriasis vulgaris developed extensive tinea cruris. For this reason, he was treated with oral terbinafine 250 mg/day and topical 1% terbinafine cream. After 6 days of this therapy, a widespread flare-up of psoriasis developed. Oral terbinafine was discontinued, and the psoriasis was treated with topical corticosteroids and tacalcitol. Tinea cruris was cured with topical terbinafine. This case points out that terbinafine can influence the course of psoriasis. Moreover, the literature data indicate that terbinafine may not only exacerbate pre-existing psoriasis, but may also be responsible for de novo development of psoriasis. Therefore, oral terbinafine should not be considered the first line drug for superficial fungal infections in psoriatic individuals.