Therapeutic potential of terbinafine in subcutaneous and systemic mycoses

Mycoses vary widely in severity, and may present as superficial, subcutaneous and/or systemic infection. Effective treatments for most superficial mycoses now exist, but new agents with convenient dosing regimens and a low level of adverse events are still needed to reduce morbidity and mortality from serious subcutaneous and systemic fungal infections. In vitro , terbinafine exhibits a broad spectrum of activity against the pathogenic fungi responsible for deep mycoses. Clinical data, while not abundant, suggest that this in vitro activity of terbinafine is reflected in its in vivo efficacy. The limited data show that terbinafine is a useful first-line treatment in chromoblastomycosis patients and has efficacy in pulmonary aspergillosis. There are also data to suggest that terbinafine may be effective in treating histoplasmosis, Pneumocystis carinii infection, fungal mycetoma, and cutaneous leishmaniasis. Moreover, there is some evidence of terbinafine having synergistic activity with amphotericin B, itraconazole, and fluconazole against clinical isolates of Candida species. Thus, the therapeutic potential of terbinafine extends well beyond its current use in acute and chronic dermatophytoses to include a wide range of subcutaneous and systemic mycoses. Studies are needed to determine the optimum dose in each disease, and whether combination therapy would have advantages in certain circumstances.     

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.     

Review of antifungal therapy, part II: treatment rationale, including specific patient populations

This portion of the antifungal review focuses on treatment rationale and suggestions, including special populations such as the elderly, children, and pregnant and immunocompromised individuals. In elderly individuals, the pathogen may be associated with certain comorbidities; treatment should begin with local treatments such as debridement (mechanical or chemical) and a topical. In children, the pathogen most commonly isolated is Trichophyton rubrum. Children should be examined for concomitant tinea and treatment options can begin with a chemical debridement (non-painful) and a topical, with non-responders being treated with combination therapy as in adults. It is suggested that blood tests are monitored at baseline and every 4-8 weeks in children on systemic therapy. Terbinafine is the only systemic in category B and local therapies should be the primary treatment modalities in pregnancy. Prevalence of onychomycosis is high in immunocompromised patients with higher relapse rates after treatment. The same fungal infections that are seen in healthy populations are usually represented in the immunocompromised host. There is a stepwise approach that is suggested in the treatment of onychomycosis. Before treatment, several factors should be determined, which include risk for failure and compliance issues. Strategies for therapy include monotherapy, combination therapy, supplemental therapy, and intermittent therapy. Topical monotherapy is effective in early distal nail disease and for the prevention of reinfection of the cured nail. Combination therapy is an appropriate progression of therapy for patients who failed monotherapy or are at risk for failure. Combined therapies are shown to increase cure rates. Mechanical interventions are essential in reducing fungal burdens to allow other modalities to penetrate, especially in dermatophytomas and onycholysis.     

Primary cutaneous cryptococcal cellulitis secondary to insect bite in an immunosupressed patient after liver transplantation

Cutaneous cryptococcosis is usually a manifestation of disseminated disease, especially in immunosuppressed patients. Primary cutaneous cryptococcosis has also been described in some patients without evidence of systemic disease. Distinguishing between primary and secondary cutaneous cryptococcosis may be difficult as patients can be asymptomatic or cutaneous lesions may precede systemic involvement by some months. Features supporting primary disease are a history of cutaneous inoculation, and solitary superficial lesions on uncovered parts of the body. We present a liver transplant patient with cutaneous cryptococcal cellulitis subsequent to an insect bite, without systemic involvement and with excellent response to treatment with amphotericin B for 15 days and surgical debridement plus oral fluconazole for 3 months. In immunosupressed patients with cellulitis a cryptococcal infection must be excluded. If cutaneous cryptococcosis is diagnosed, systemic evaluation and prompt lengthy treatment 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.     

The emergence of mucormycosis as an important opportunistic fungal infection: five cases presenting to a tertiary referral center for mycology

BACKGROUND: Mucormycosis, a rare opportunistic fungal infection, is re-emerging in importance with the increase in prevalence of immunosuppressive states, both as a result of therapy and disease. METHODS: We report five cases of mucormycosis diagnosed by the Dermatology Department and managed jointly with the Medical and Surgical Services of "Dr Manuel Gea Gonzalez" General Hospital in Mexico City, a tertiary referral center for mycology. We also review the current literature including recent advances in medical therapy. RESULTS: Four of the five cases were of the rhino-orbital-cerebral variant, commonly associated with significant mortality, and one of these patients died despite early diagnosis and aggressive management. The fifth case was primary cutaneous mucormycosis and this patient survived infection without relapse. Diabetic ketoacidosis predisposed to infection in four cases and the other was associated with advanced human immunodeficiency virus infection. Radiologic imaging was important in cases of facial involvement in order to evaluate the extent of disease and possible intracranial involvement. All cases were managed with systemic antifungals and surgical debridement, together with the treatment of predisposing factors. CONCLUSIONS: These cases illustrate the need for early clinical recognition and prompt therapy, as well as the requirement for tissue biopsy in order to demonstrate the characteristic morphologic features of this fungal agent in the absence of positive mycology culture results. This report also highlights that, although rhino-orbital-cerebral mucormycosis requires effective multidisciplinary management, the disease not uncommonly presents to dermatologists for diagnosis.     

31例深部真菌病临床和尸检分析

目的 了解尸解患者中真菌感染状况及其与临床的关系。方法 非选择性总结30年来本院成人(年龄≥16岁)尸检资料,依据病理切片真菌形态确定真菌感染的存在,并进行临床和病理对照分析。结果 396例尸检中发生真菌感染31例(7.8%),其中曲霉感染17例,占全部真菌感染的54.8%。真菌感染受累脏器频率高低依次为肺(83.87%)、肾(48.39%)、脑(35.48%)和心脏(29.03%),其中21例成为直接致死的原因。结论 深部真菌感染是危重患者死亡的重要原因之一,曲霉已成为尸检病例中深部真菌感染主要的致死真菌。     

Cutaneous zygomycosis

Cutaneous zygomycosis is a fungal infection caused by zygomycetes that affects the skin. It occurs in uncontrolled diabetic patients and immunosuppressed individuals. It has 2 clinical forms: primary cutaneous zygomycosis and secondary cutaneous zygomycosis. The first is characterized by necrotic lesions and the fungus is usually inoculated by trauma. If diagnosed early, it generally has a good prognosis. Secondary zygomycosis is usually a complication and extension of the rhinocerebral variety that starts as a palpebral fistula and progresses to a necrotic lesion with a poor prognosis. The diagnosis is made by identification of the fungus by direct KOH examination, culture, and biopsy. Treatment for the primary disease is surgical debridement plus amphotericin B. The secondary type is treated with amphotericin B and/or posaconazole.     

Diagnosing onychomycosis

The diagnosis of onychomycosis may require the use of mycological diagnostic testing to supplement the clinical presentation. In order to verify that onychomycosis is present, the viability, penetrance, and species of the fungal infection should be determined. The most common diagnostic tests are mycological culture, direct microscopic examination, histopathologic study, and polymerase chain reaction (PCR)-based tests. Each of these tests has individual strengths in satisfying the three criteria, with a minimum of two positive diagnostic tests being the gold standard for confirming all three diagnostic criteria.     

Moderne mykologische Diagnostik

Mycological diagnosis is an integral part of dermatology. Modern aspect include not only the identification of causative agents but also sensitivity testing against topical and systemic antimycotic agents and more detailed molecular biological diagnosis using fingerprinting and PCR. In routine practice, the essential question is if a fungal infection is present or not. A positive culture identification should precede use of systemic antimycotic agents especially when dealing with advanced onychomycosis, tinea capitis and chronic candidosis. Determination of resistance is important when dealing with recurrent infections with special candidal species. PCR is most useful in diagnosing otherwise difficult to identify causative agents and in analyzing the chain of infection.     

Two cases of primary cutaneous nocardiosis caused by intralesional injection

Nocardiosis is a rare localized or systemic suppurative disease caused by the actinomycete Nocardia species. The respiratory tract is the most common site of infection, but primary cutaneous nocardiosis can also be induced by direct inoculation. Nocardiosis is usually reported in immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection, chronic obstructive pulmonary disease, autoimmune diseases, cancer, or in those who have had organ transplantation or corticosteroid administration. However, it can also affect individuals with no serious underlying condition. We reported two cases of primary cutaneous nocardiosis in immunocompetent patients after intralesional injection of steroid.     

二次PCR用于临床标本真菌感染快速分子诊断的研究

目的 探讨二次PCR技术诊断疑似真菌感染临床标本的敏感性。方法 收集临床疑似真菌感染的深部位痰及肺泡灌洗液标本共29份,分别进行真菌直接镜检、真菌培养、真菌通用引物单次与二次PCR扩增rDNA的ITS区,并对真菌检出阳性率和多种真菌菌种检出率进行比较分析。结果 临床疑似病例痰及肺泡灌洗液标本真菌镜检、真菌培养、单次PCR和二次PCR真菌检出阳性率分别为20.7%（6/29）、37.9%（11/29）、17.2%（5/29）和48.3%（14/29）。真菌培养、单次PCR和二次PCR提示二种以上真菌菌种检出的比例分别为6.9%（2/29）、3.4%（1/29）和24.1%（7/29）。二次PCR与单次PCR的真菌检出率差异有统计学意义（χ2 = 6.34,P < 0.05）。在两种以上菌种检出率方面,二次PCR与真菌培养和单次PCR间差异均有统计学意义（χ2 = 4.09,6.30,P值均 < 0.05）。结论 二次PCR技术有助于提高临床标本真菌分子诊断的敏感性。     

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.     

Tinea capitis: current concepts

Tinea capitis is an important fungal infection that may at times be a clinical, diagnostic and therapeutic challenge. It is common in childhood around the world, becoming almost epidemic in some communities. The central European and American experience with it is somewhat variable, due to different etiologic fungi. The use of topical antifungal agents and other approaches is stressed as of value alongside the use of systemic antifungal medication.     

Primary cutaneous cryptococcosis: the importance of early diagnosis

The species of the Cryptococcus neoformans complex show different epidemiological patterns in the infection of immunosuppressed or immunocompetent individuals, and a common tropism peculiarity for the central nervous system. Primary cutaneous cryptococcosis is a rare clinical entity, with manifestations that are initially restricted to the skin through fungal inoculation, and the absence of systemic disease. The authors report in the present study the case of a 61-year-old immunocompetent man, with a rapidly evolving mucoid tumor on abrasions in contact with bird droppings on the forearm. The early identification of the polymorphic skin manifestations and treatment are crucial for the favorable prognosis of the infection, which can be life-threatening.     

Palatal necrosis in an AIDS patient: a case of mucormycosis

We report a case of rhinocerebral mucormycosis presenting in a patient with AIDS and review the literature on mucormycosis occurring in the setting of HIV disease. Mucormycosis in HIV is rare. However, it can be the presenting opportunistic infection in AIDS. Predisposing factors for Mucor infection in HIV disease include low CD4 count, neutropenia, and active intravenous drug use. Mucormycosis can present in the basal ganglia, the skin, the gastrointestinal tract, the respiratory tract, or may be disseminated. The disease may develop insidiously or may progress rapidly with a fulminant course. Therapy usually consists of surgical debridement/excision accompanied by intravenous amphotericin B.     

Cutaneous sarcoidosis presenting as leonine facies

Cutaneous sarcoidosis often masquerades as many other disease entities. We describe the case of a 56-year-old African American man with a 1-year history of progressively enlarging nodules and plaques of the face resulting in a leonine appearance and madarosis. The diagnosis of cutaneous sarcoidosis was made after skin biopsy results revealed noncaseating granulomas without evidence of foreign body, mycobacteria, or deep fungal infection. A thorough systemic workup was void of other comorbidities. The reports of tumoral sarcoidosis or sarcoidosis presenting with leonine facies are rare, and those cases that have been reported have been linked to other systemic findings.     

Oral histoplasmosis after radiation therapy for laryngeal squamous cell carcinoma

Histoplasmosis is a usually asymptomatic deep fungal infection of tropical origin with respiratory entry and possible oral, pharyngeal, or metastatic localization. The condition represents an important imported systemic mycosis with oral involvement. We report the case of a patient who developed an oropharyngeal reactivation of a latent Histoplasma infection after receiving local antitumoral radiation therapy of the neck. H capsulatum was shown to be present in the lesion by both histopathology and staining, and was deduced to be the causative organism of the disease.     

Cutaneous primary paracoccidioidomycosis

Paracoccidioidomycosis is a common fungal infection in Latin America. Few cases have been described in non-endemic countries and their diagnosis without the correct suspicion, bearing in mind that the latency period might be up to 60 years, may not be easy. We report the case of a 59-year-old man who worked as a taxi driver for 25 years in Venezuela. Cutaneous paracoccidioidomycosis was diagnosed one year after he returned to Spain. No internal signs or symptoms of the disease were found and cell-mediated immunity showed no depression. Our case suggested us to consider direct cutaneous infection, although respiratory tract is believed to be the most frequent portal of entry for this infection.     

Sporotrichosis

Sporotrichosis is a cutaneous fungal infection with a global distribution. The disease has several clinical forms, primarily cutaneous with associated lymphadenopathy. However, dissemination to osteoarticular structures and viscera may occur, both in healthy and immunosuppressed individuals; such disseminated forms usually follow spread after inhalation of fungal spores. Cutaneous infection is usually associated with trauma during the course of outdoor work, and treatment is required for the majority of patients. Potassium iodide (the treatment of choice in endemic areas) is an effective and inexpensive therapy; however, its adverse effects and complicated dosage regimen often weigh against its use in developed countries, where itraconazole is the antimycotic of choice.