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.     

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.     

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.     

Treatments for common superficial fungal infections

Fungal infection of keratinized tissue is caused by any of the dermatophyte species. The topical allylamines and benzylamines have been especially effective in treating these infections because of their in vitro fungicidal activity and short treatment duration. With the development of new oral azoles and allylamine antifungal agents, there has been a renewed interest in treating superficial skin fungal infections. The use of topical and oral antifungal agents in treating cutaneous fungal infections is examined.     

五种新型唑类抗真菌药物

唑类药物是目前治疗浅部和深部真菌感染的一线用药.按照其结构的不同,该药可以分为咪唑类和三唑类.3种咪唑类新药卢立康唑、拉诺康唑和氟曲乌唑已在国外上市,外用治疗皮肤癣菌等浅部真菌病疗效明显且局部无明显不良反应.2种三唑类新药普拉康唑和雷夫康唑则仍在临床试验阶段,但从目前研究来看,两者用于治疗浅部和深部真菌感染亦较安全有效,有望作为新型抗真菌药应用于临床.

Abstract：

Azoles are a primary treatment choice for superficial and deep fungal infections. They can be divided into two groups, i.e., imidazoles and triazoles, according to chemical structure. Three new imidazoles including luliconazole, lanoconazole and flutrimazole have been on the medical market abroad and shown notable efficacy with no obvious local side effects in the treatment of superficial fungal infection including dermatophytosis. Two triazoles including pramiconazole and ravuconazole are still in clinical trials, although they have proved to be safe and effective in the treatment of superficial and deep fungal infection, and have shown some potential as new antifungal agents.     

五种新型唑类抗真菌药物

唑类药物是目前治疗浅部和深部真菌感染的一线用药。按照其结构的不同,该药可以分为咪唑类和三唑类。3种咪唑类新药卢立康唑、拉诺康唑和氟曲马唑已在国外上市,外用治疗皮肤癣菌等浅部真菌病疗效明显且局部无明显不良反应。2种三唑类新药普拉康唑和雷夫康唑则仍在临床试验阶段,但从目前研究来看,两者用于治疗浅部和深部真菌感染亦较安全有效,有望作为新型抗真菌药应用于临床。     

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.     

Cutaneous Fungal Infections in the Oncology Patient

There are two main types of fungal infections in the oncology patient: primary cutaneous fungal infections and cutaneous manifestations of fungemia. The main risk factor for all types of fungal infections in the oncology patient is prolonged and severe neutropenia; this is especially true for disseminated fungal infections. Severe neutropenia occurs most often in leukemia and lymphoma patients exposed to high-dose chemotherapy. Fungal infections in cancer patients can be further divided into five groups: (i) superficial dermatophyte infections with little potential for dissemination; (ii) superficial candidiasis; (iii) opportunistic fungal skin infections with distinct potential for dissemination; (iv) fungal sinusitis with cutaneous extension; and (v) cutaneous manifestations of disseminated fungal infections. In the oncology population, dermatophyte infections (i) and superficial candidiasis (ii) have similar presentations to those seen in the immunocompetent host. Primary cutaneous mold infections (iii) are especially caused by Aspergillus, Fusarium, Mucor, and Rhizopus spp. These infections may invade deeper tissues and cause disseminated fungal infections in the neutropenic host. Primary cutaneous mold infections are treated with systemic antifungal therapy and sometimes with debridement. The role of debridement in the severely neutropenic patient is unclear. In some patients with an invasive fungal sinusitis (iv) there may be direct extension to the overlying skin, causing a fungal cellulitis of the face. Aspergillus, Rhizopus, and Mucor spp. are the most common causes. We also describe the cutaneous manifestations of disseminated fungal infections (v). These infections usually occur in the setting of prolonged neutropenia. The most common causes are Candida, Aspergillus, and Fusarium spp. Therapy is with systemic antifungal therapy. The relative efficacies of amphotericin B, fluconazole, itraconazole, voriconazole, and caspofungin are discussed. Recovery from disseminated fungal infections is unlikely, however, unless the patient's neutropenia resolves.     

Systemic candidiasis

Systemic candidiasis is a disease of increasing incidence and proportions, which appears to be associated with the advances in modern medicine. It involves primarily patients with severe debilitating and malignant disease who are receiving immunosuppressive, cytotoxic, antimetabolite, and antibiotic therapy. Side effects of these otherwise major therapeutic agents predispose patients to opportunistic fungal infections, of which candidiasis is the most common. The high morbidity and mortality of disseminated candidiasis in neutropenic patients are difficult obstacles to obtaining the optimal, if not full, potential of modern chemotherapy for cancer. The inability to diagnose early invasive and systemic candidiasis is a major handicap that delays timely initiation of antifungal therapy. The paucity of highly efficacious antifungal agents with low toxicity severely limits the ability to successfully cure systemic fungal infections in cancer patients. Aggressive research into the basic biology of Candida spp. is necessary for directing the development of better diagnostic methods and improved antifungal drugs.     

Alternative approaches to antifungal therapies

The expansive use of immunosuppressive medications in fields such as transplantational medicine and oncology, the higher frequency of invasive procedures in an ageing population and the HIV/AIDS pandemic have increased the frequency of systemic fungal infections. At the same time, increased resistance of pathogenic fungi to classical antifungal agents has led to sustained research efforts targeting alternative antifungal strategies. In this review, we focus on two promising approaches: cationic peptides and the targeting of fungal virulence factors. Cationic peptides are small, predominantly positively charged protein fragments that exert direct and indirect antifungal activities, one mechanism of action being the permeabilization of the fungal membrane. They include lysozyme, defensins and cathelicidins as well as novel synthetic peptides. Among fungal virulence factors, the targeting of candidal secreted aspartic proteinases seems to be a particularly promising approach.     

Invasive synergistic fungal infection after motor vehicle collision

Primary invasive fungal infections occur after direct contact or direct inoculation of the skin with fungal spores. Rhizopus species and Aspergillus terreus are opportunistic fungal species that rarely cause disease in immunocompetent hosts. In susceptible patients, infection may progress rapidly. Aggressive surgical debridement and use of systemic antimycotic agents may successfully control disease and prevent systemic dissemination. We describe the case of a patient with a scalp infection, caused by Rhizopus species and A. terreus, that occurred after contact with pavement during a motor vehicle collision. Control was achieved with repeated debridement and use of systemic antifungal therapy.     

Successful Treatment of Candida albicans Septicemia in a Preterm Infant with Severe Congenital Ichthyosis (Harlequin baby)

Abstract:  Candida infections are a major cause of fungal septicemia in neonates and are associated with marked morbidity and mortality. Despite the spectrum of antifungal drugs being dramatically extended during the last decade, invasive fungal infections remain a serious challenge for neonatologists. Amphotericin B and its lipid formulations are the drugs of choice for the treatment of systemic candidiasis in neonates. The combination of antifungal drugs with different sites of action, like caspofungin and amphotericin B, may improve antifungal efficacy. Severe congenital ichthyosis often leads to death within the neonatal period. Main causes of death are dehydration, electrolyte disturbances, and respiratory or systemic infections. We report the case of a preterm infant with severe congenital ichthyosis and sepsis caused by Candida albicans . The infection did not improve despite proper liposomal amphotericin B treatment. After addition of caspofungin, the baby recovered. To our best knowledge, a case of a preterm infant suffering from severe congenital ichthyosis and Candida albicans sepsis, who survived, has not been previously described.     

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.     

白细胞介素17相关生物制剂治疗银屑病过程中浅部真菌感染的发生及应对策略

本文综述白细胞介素（IL）-17与皮肤黏膜真菌感染易感性的基本机制,以及与IL-17相关的生物制剂,如司库奇尤单抗、依奇珠单抗、布罗达单抗、拜莫克珠单抗和乌司奴单抗在治疗银屑病中发生的浅部真菌感染。与IL-17相关生物制剂治疗相关的浅部真菌感染以轻度或中度为主,多呈局限性,且抗真菌治疗效果良好。此外,本文介绍了对相关浅...     

系统性真菌感染的药物治疗进展

随着系统性真菌感染的发病率急剧上升,寻找新型抗真菌药物,特别是对耐唑类菌株有效的药物研究已成为临床治疗系统性真菌感染的迫切需要。本文分类综述近年来临床常用的以及最新研究开发的抗真菌药物,为临床治疗系统性真菌感染提供新的选择。     

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.     

The efficacy and safety of terbinafine in children

Terbinafine is an allylamine antifungal agent that has been effective and safe in the treatment of superficial and some deep mycotic infections in adults. An increasing amount of data is available where terbinafine has been used in the paediatric population to treat superficial fungal infections, in particular tinea capitis. The data suggest that terbinafine is effective and safe using treatment regimens that involve short duration therapy, leading to an increased compliance and providing a cost-effective means of treating paediatric superficial fungal infections such as tinea capitis. Terbinafine has been approved for the treatment of tinea capitis in many countries worldwide, and provides good efficacy rates for Trichophyton tinea capitis using shorter regimens than the gold standard griseofulvin. The adverse events profile for children is similar to that in adults with few adverse effects associated with its use. The evidence favours the use of terbinafine in the treatment of superficial infections in children.     

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.     

Evaluation and management of fungal infections in immunocompromised patients

As the population of chronically immunosuppressed individuals continues to grow, the prevalence of fungal infections is increasing. Fungal infections in this patient population represent challenges in diagnosis and management. This article will review the common superficial and invasive mycoses that occur in the solid organ transplant and HIV-infected populations. Disease presentations are reviewed, but emphasis is placed on cutaneous manifestations. Recent advances in antifungal therapy and their direct application to specific diseases provide important new approaches to this complex and often seriously ill patient population.     

Fungal melanonychia

Fungal melanonychia is a relatively rare nail disorder caused by nail infection that produces brown-to-black pigmentation of the nail unit. The number of organisms implicated as etiologic agents of fungal melanonychia is increasing, and the list currently tops 21 species of dematiaceous fungi and at least 8 species of nondematiaceous fungi. These superficial infections may clinically mimic subungual melanoma and are often not responsive to traditional antifungal therapy. This article reviews the literature on fungal melanonychia and the role of fungal melanin in infection.