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.     

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.     

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.     

白念珠菌抗体疫苗研究进展

白念珠菌是免疫力低下患者黏膜和系统的真菌致病源,侵袭性念珠菌感染有很强的致死性.即使是健康的个体,也容易感染阴道念珠菌病和其他皮肤黏膜念珠菌病.传统抗真菌药的疗效有一定的局限性和毒副作用,并且容易产生耐药.近年来,一些新型抗体疫苗已经研发并应用于动物模型和临床,表现出很好的对抗白念珠菌和协同传统抗真菌药物的作用.尽管其疗效和安全性还需要进一步验证,念珠菌抗体疫苗仍具有较好的临床应用前景,有望成为念珠菌病的辅助治疗手段.     

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.     

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.     

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.     

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.     

A Clinician’s Guide to the Diagnosis and Treatment of Candidiasis in Patients with Psoriasis

Many of the molecular pathways associated with psoriasis pathogenesis are also involved in host defense mechanisms that protect against common pathogens. Candida can stimulate the production of cytokines that trigger or exacerbate psoriasis, and many systemic psoriasis treatments may put patients at increased risk for developing oral, cutaneous, and genitourinary candidiasis. Therefore, dermatologists should regularly screen patients with psoriasis for signs of Candida infection, and take steps to effectively treat these infections to prevent worsening of psoriasis symptoms. This review provides an overview of candidiasis epidemiology in patients with psoriasis, followed by a primer on the diagnosis and treatment of superficial Candida infections, with specific guidance for patients with psoriasis. Candidiasis in patients with psoriasis typically responds to topical or oral antifungal therapy. While biologic agents used to treat moderate-to-severe psoriasis, such as tumor necrosis factor-α inhibitors and interleukin-17 inhibitors, are known to increase patients’ risk of developing localized candidiasis, the overall risk of infection is low, and candidiasis can be effectively managed in most patients while receiving systemic psoriasis therapies. Thus, the development of candidiasis does not usually necessitate changes to psoriasis treatment regimens.     

Invasive fungal dermatitis in extremely premature newborns: a specific clinical form of systemic candidiasis

BACKGROUND: Fungal agents, chiefly Candida albicans, are the cause of rising morbidity and mortality in newborn infants weighing less than 1500 g. We studied the particular cutaneous effects during the course of these infections. PATIENTS AND METHODS: This was a retrospective 3-year study in premature infants weighing less than 1500 g and hospitalized in the neonatal department of the Lille University Teaching Hospital. The patients included in the study presented sepsis with isolation of Candida in blood and/or urine culture. RESULTS: Twelve infants were included (1.8%). The risk factors seen are those described in literature (broad-spectrum antibiotics, prolonged mechanical ventilation and parenteral nutrition, corticosteroids and central venous catheters). Infection occurred early (mean: D12) and affected extremely premature infants (mean: 25 weeks' amenorrhea) of low birth weight (mean: 758 g) generally born by vaginal delivery (9 of 12 infants). The sole fungal agent isolated was Candida albicans. In 10 of the 12 patients, a characteristic skin disorder was observed (erythema with erosion and desquamation). In 10 of the 12 patients, too, Candida was isolated from skin and/or mucosal samples. DISCUSSION: Although it is now universally accepted that antifungal treatment should be initiated without delay for candidemia in septic newborn infants at risk, diagnosis of systemic candidiasis remains delicate. However, a specific pattern of skin involvement is very commonly seen that is atypical for candidiasis, but which in addition to its diagnostic value indicates early colonization with Candida (first 2 weeks of life). In this setting of immaturity of the skin and immune system, colonization and proliferation in skin and/or mucosa appear to constitute the first stage of systemic infection and we may speak of invasive cutaneous-mucosal candidiasis in extremely premature infants and initiate treatment designed to prevent the disease becoming systemic..     

Update on therapy for superficial mycoses: review article part I

Superficial fungal infections of the hair, skin and nails are a major cause of morbidity in the world. Choosing the right treatment is not always simple because of the possibility of drug interactions and side effects. The first part of the article discusses the main treatments for superficial mycoses - keratophytoses, dermatophytosis, candidiasis, with a practical approach to the most commonly-used topical and systemic drugs , referring also to their dosage and duration of use. Promising new, antifungal therapeutic alternatives are also highlighted, as well as available options on the Brazilian and world markets.     

Treatment of superficial mycoses: review - part II

Superficial fungal infections of the hair, skin and nails are a major cause of morbidity in the world. Choosing the right treatment is not always simple because of the possibility of drug interactions and side effects. The first part of the article discusses the main treatments for superficial mycoses - keratophytoses, dermatophytosis, candidiasis, with a practical approach to the most commonly-used topical and systemic drugs , referring also to their dosage and duration of use. Promising new, antifungal therapeutic alternatives are also highlighted, as well as available options on the Brazilian and world markets.     

Oral candidiasis

Oral candidiasis is one of the more common infections encountered by man. It manifests itself in a variety of forms, and can arise in any region of the mouth. A generally innocuous and treatable disorder in healthy individuals, it can be the herald of underlying disorders that affect the endocrine or immune systems. In the debilitated or seriously ill, the capacity for seemingly benign oral candidiasis to progress into fulminating fatal infections by hematogenous dissemination must not be ignored. Oral candidiasis in the otherwise healthy patient challenges the physician's ability to identify the contributing factors and associated diseases that predispose to the infection. In the cancer and transplant patient, oral candidiasis is a harbinger of systemic infection, and has become a significant obstacle to successful management of patients with life-threatening diseases. Although several efficacious agents are available for uncomplicated candidiasis, there remains a need for better prophylactic agents to prevent dissemination and better therapeutic agents to treat established infections in immunocompromised patients.     

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.     

Molecular techniques in the diagnosis of deep and systemic mycosis

Making an early and sensitive diagnosis of invasive fungal infections in high-risk patients is mandatory, because it has major consequences on the effectiveness of antifungal therapy. Molecular assays have the potential to become the cornerstone of diagnosis, allowing for rapid, reliable detection of minute amounts of fungal DNA in various specimens at a low cost. PCR is gaining popularity as the platforms become more automated and commercially available; however, further studies are needed to explore the diagnostic value in patient subgroups (ie, children) and to define whether the underlying disease or the use of antifungal prophylaxis may influence assay results. Individualized management of high-risk patients would be desirable to integrate preemptive therapy strategies, and individual host and genetic factors. Pharmacological and epidemiological considerations should also be evaluated.     

Candidiasis and other fungal diseases of the mouth

The advent of the human immunodeficiency virus (HIV) and the increasing prevalence of immunocompromised individuals due to surgical and medical advances have resulted in a resurgence of opportunistic infections including oral candidiasis and other rare mycoses which were once considered exotic. It is now recognized that oral candidiasis may present in many clinical guises that may confound the unwary clinician. Other mycotic diseases such aspergillosis, cryptococcosis, histoplasmosis, and mucormycosis may manifest intraorally both as primary lesions and as secondary manifestation of systemic disease. The primary oral pathology of most of the latter mycoses is ulcerations that respond well to systemic therapy with the polyene, amphotericin B. In general, the management of oral fungal infections has been revolutionized by the triazole group of drugs, fluconazole and itraconazole, although recent reports indicate an alarming increase of resistant organisms in particular to fluconazole. The first part of this review attempts to provide an overview of clinical variants of oral candidiasis and current therapeutic techniques, while the latter part outlines the rare oral mycoses and their management.     

Disseminated candidiasis in a patient with acute myelogenous leukemia

Disseminated candidiasis is a frequently fatal condition that is rising steadily in immunocompromised patients. We present the case of a 62-year-old African American woman with acute myelogenous leukemia who developed characteristic cutaneous signs of systemic candidiasis. Early cultures and biopsies resulted in early diagnosis, which prompted proper antifungal therapy and a positive outcome.     

白念珠菌基因组结构与遗传、致病相关基因

白念珠菌是一种重要的机会致病菌,在人的多个系统或器官与宿主共栖生存,可导致口腔和阴道念珠菌病,在免疫力低下或患严重疾病的患者,可引起系统疾病.由于早期准确诊断系统性念珠菌病存在困难,合适有效的抗真菌药物数量有限,病原体的耐药性增加,导致系统性念珠菌病病死率居高不下.因此,对白念珠菌基因组序列及结构、功能的研究对指导临床的诊断和治疗显得尤为重要.     

Itraconazole therapy for white piedra affecting scalp hair

BACKGROUND: Treatment of white piedra remains an area of therapeutic frustration. Several topical and systemic antifungal agents have failed to eradicate the fungus and prevent disease recurrence. Itraconazole is a safe and effective systemic antifungal agent for various superficial and deep mycotic infections of the skin and hair. In vitro studies have shown significant antifungal activity against Trichosporon beigelii. OBJECTIVE: Our study was intended to assess the efficacy of itraconazole in the treatment of uncomplicated white piedra affecting the scalp hair. METHODS: The study was designed as an open trial involving 12 female patients with white piedra of the scalp hair. They were administered oral itraconazole 100 mg once daily until culture negativity was achieved; they were then followed up for 3 months. RESULTS: Eleven patients (91.67%) showed disease remission after 8 weeks of treatment. One patient (8.33%) showed no improvement, and the disease recurred in 2 patients (16.67%) after completion of therapy. No significant side effects were noted.