Sarocladium and Acremonium infections: New faces of an old opportunistic fungus.

The genera Acremonium and Sarocladium comprise a high diversity of morphologically and genetically related fungi generally found in the environment, although a few species, mainly Sarocladium kiliense and Acremonium egyptiacum, can also be involved in many human infections. Clinical management of opportunistic infections caused by these fungi is very complex, since their correct identification is unreliable, and they generally show poor antifungal response. More than 300 clinical cases involving a broad range of Acremonium/Sarocladium infections have so far been published, and with this review we aim to compile and provide a detailed overview of the current knowledge on Acremonium/Sarocladium human infections in terms of presentation, diagnosis, treatments and prognoses. We also aim to summarise and discuss the data currently available on their antifungal susceptibility, emphasising the promising results obtained with voriconazole as well as their impact in terms of animal infections.

Granulomatous polyarthritis caused by Talaromyces georgiensis in a dog.

A 6-y-old, 3.5-kg, spayed female Toy Poodle was presented with left forelimb lameness of 2-d duration. Two months before the initial presentation, radiography showed osteolysis of the medial epicondyle of the left humerus, and the left forelimb was amputated. Grossly, the articular villi of the elbow joint were markedly thickened, and the articular cartilage surfaces of the distal humerus and proximal radius had partial erosion. Histologically, granulomatous arthritis and osteomyelitis characterized by the presence of abundant macrophages containing numerous fungi were observed. ITS and ß-tubulin sequences amplified from the isolate from the specimen were 100% and 99% identical to type strain UTHSC D16-145T of Talaromyces georgiensis, respectively. Canine osteoarthritis caused by T. georgiensis has not been reported previously, to our knowledge.

Mo-CBP4, a purified chitin-binding protein from Moringa oleifera seeds, is a potent antidermatophytic protein: In vitro mechanisms of action, in vivo effect against infection, and clinical application as a hydrogel for skin infection.

Dermatophytes belonging to Trichophyton ssp. are important anthropophilic and zoophilic pathogens, which developed resistance to griseofulvin, the common antifungal drug used to treat dermatophytosis. In this context, Moringa oleifera seed proteins have been described as antifungal agents with potential applications. Thus, this work aimed to evaluate the antidermatophytic in vitro, focusing on mechanisms, and in vivo potential of Mo-CBP4, purified from M. oleifera seeds. Mo-CBP4was purified after protein extraction with 50 mM Tris-HCl buffer, pH 8.0, and chromatography on chitin and CM Sepharose™ columns and antidermatophytic potential of Mo-CBP4 evaluated in vitro and in vivo. In vitro, Mo-CBP4 reduced in 50% the germination of microconidia of Trichophyton mentagrophytes at 45 µM; but did not show inhibition of mycelial growth. Mo-CBP4 (45 µM) presents the inhibitory activity even when incubated with N-acetyl-d-glucosamine (NAG). Analysis of the mechanisms of Mo-CBP4 revealed an increase in membrane permeability, ROS overproduction and damage to cell wall leading to microconidia death. Furthermore, using in vivo models, Mo-CBP4 (5, 10 and 20 mg g-1) reduced the severity and time of dermatophytosis. Altogether, these findings indicate that Mo-CBP4 has great potential for the development of novel antifungal drugs for the clinical treatment of dermatophytosis.

The Development of an Antimicrobial Contact Lens - From the Laboratory to the Clinic.

Contact lens wear is generally safe and provides excellent vision. However, contact lens wear is often associated with the risk of developing ocular surface infection and inflammation, and in severe cases, the infection can result in loss of vision. Antimicrobial peptide-coated contact lenses have been made to help reduce the incidence of infection and inflammation. This paper reviews the research progress from conception, through the laboratory and preclinical tests to the latest information on clinical testing of an antimicrobial contact lens. We provide insights into the pathways followed and pitfalls that have been encountered. The journey has not always been linear or smooth, but has resulted in some of the first published clinical testing of antimicrobial peptide-coated contact lenses in humans. We hope this may help lead to the development and commercialisation of antimicrobial contact lenses in the future.

Therapeutic Potential of Medicinal Plant Proteins: Present Status and Future Perspectives.

Biologically active molecules obtained from plant sources, mostly including secondary metabolites, have been considered to be of immense value with respect to the treatment of various human diseases. However, some inevitable limitations associated with these secondary metabolites like high cytotoxicity, low bioavailability, poor absorption, low abundance, improper metabolism, etc., have forced the scientific community to explore medicinal plants for alternate biologically active molecules. In this context, therapeutically active proteins/peptides from medicinal plants have been promoted as a promising therapeutic intervention for various human diseases. A large number of proteins isolated from the medicinal plants have been shown to exhibit anti-microbial, anti-oxidant, anti-HIV, anticancerous, ribosome-inactivating and neuro-modulatory activities. Moreover, with advanced technological developments in the medicinal plant research, medicinal plant proteins such as Bowman-Birk protease inhibitor and Mistletoe Lectin-I are presently under clinical trials against prostate cancer, oral carcinomas and malignant melanoma. Despite these developments and proteins being potential drug candidates, to date, not a single systematic review article has documented the therapeutical potential of the available biologically active medicinal plant proteome. The present article was therefore designed to describe the current status of the therapeutically active medicinal plant proteins/peptides vis-à-vis their potential as future protein-based drugs for various human diseases. Future insights in this direction have also been highlighted.

Fungal infection models: Current progress of ex vivo methods.

Experimental alternative ex vivo models that simulate infectious processes in vivo are of fundamental importance for the evaluation of new drugs, since in some cases, their execution does not depend on the approval of an ethics committee in research. Although studies using alternative infectious models to evaluate the efficacy of antifungal molecules have been increasingly described and reported, there is no critical consensus that establishes the most appropriate ones regarding the type of infection. Numerous studies contemplate ex vivo protocols of fungal infections on nails, corneas, dentinal tubules and skin and reveal counterpoints and concordances not yet finely confronted. In this minireview, we propose a critical analysis of the main ex vivo models of fungal infections for the evaluation of new antifungal candidates for both topical and systemic use, as opposed to the advantages and disadvantages of the traditional in vivo models employed in preclinical research.

Scedosporium apiospermum Otitis Complicated by a Temporomandibular Arthritis: A Case Report and Mini-Review.

Scedosporium apiospermum is an ubiquitous fungus responsible for various infections in immunocompromised and immunocompetent patients. Ear infections are infrequent. We report an exceptional case of S. apiospermum external otitis complicated by temporomandibular joint arthritis. After 6 months of antibiotherapy, diagnosis was established by mycological analysis of external auditory canal and infratemporal fossae needle sampling. A satisfactory outcome was obtained after 2 months of voriconazole alone. We have reviewed 15 cases of S. apiospermum otitis. Seven of these patients were immunocompromised. Most common clinical presentation included a chronic external otitis lasting months or years before complication stage. Most common clinical features included recurrent unilateral otalgia (11/15) and purulent otorrhea (13/15). Diagnosis was often made at later stage (12/15) with local extension to bones and/or soft tissues (9/15) or cerebral lethal dissemination (3/15).The extremely low incidence of S. apiospermum otomycosis and its non-specific presentation results in a frequent diagnosis delay. A mycological investigation should be performed in case of persistent external otitis and/or osteolysis despite prolonged antibiotic treatment to prevent further extension of the disease.

Safety and efficacy of low-dose liposomal amphotericin B as empirical antifungal therapy for patients with prolonged neutropenia.

BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

[The agent Latrodectus and canine paecilomycotic eclampsia as a laboratory model in the survey of treatment for mycoses and parasitic diseases].

The extragent used to prepare a Latrodectus mactans hydrocarbon extract is a multicomponent system composed of alkanes, alkenes, and arenes. More than 100 compounds were identified in the hydrocarbon extract (petroleum). The petroleum matrix of Latrodectus mactans was first obtained to manufacture homeopathic remedies. The authors could prepare the first Russian homeopathic medicine from Latrodectus mactans, which proved to be effective in treating canine eclampsia. Canine experiments provide a rationale for the authors' choice as the only homeopathic remedy among thousand known drugs to treat female eclampsia. It is Latrodectus mactans that is in the list of homeopathic medicines permitted for use in accordance with Order No. 335 (Supplement 2) of the Ministry of Health and Medical Industry of Russia, issued on November 29, 1995. It is manufactured from Latrodectus mactans living in the USA.

Antimicrobial activity of alcohols from Musca domestica.

Information on the stimulatory and inhibitory effects of cuticular alcohols on growth and virulence of insecticidal fungi is unavailable. Therefore, we set out to describe the content of cuticular and internal alcohols in the body of housefly larvae, pupae, males and females. The total cuticular alcohols in larvae, males and females of Musca domestica were detected in comparable amounts (4.59, 3.95 and 4.03 µg g(-1) insect body, respectively), but occurred in smaller quantities in pupae (2.16 µg g(-1)). The major free alcohol in M. domestica larvae was C(12:0) (70.4%). Internal alcohols of M. domestica larvae were not found. Among cuticular pupae alcohols, C(12:0) (31.0%) was the most abundant. In the internal lipids of pupae, only five alcohols were identified in trace amounts. The most abundant alcohol in males was C(24:0) (57.5%). The percentage content of cuticular C(24:0) in males and females (57.5 and 36.5%, respectively) was significantly higher than that of cuticular lipids in larvae and pupae (0.9 and 5.6%, respectively). Only two alcohols were present in the internal lipids of males in trace amounts (C(18:0) and C(20:0)). The most abundant cuticular alcohols in females were C(24:0) (36.5%) and C(12:0) (26.8%); only two alcohols (C(18:0) and C(20:0)) were detected in comparable amounts in internal lipids (3.61±0.32 and 5.01±0.42 µg g(-1), respectively). For isolated alcohols, antimicrobial activity against 10 reference strains of bacteria and fungi was determined. Individual alcohols showed approximately equal activity against fungal strains. C(14:0) was effective against gram-positive bacteria, whereas gram-negative bacteria were resistant to all tested alcohols. Mixtures of alcohols found in cuticular lipids of larvae, pupae, males and females of M. domestica generally presented higher antimicrobial activity than individual alcohols. In contrast, crude extracts containing both cuticular and internal lipids showed no antifungal activity against the entomopathogenic fungus Conidiobolus coronatus, which efficiently kills adult house flies.

Preparation and evaluation of dermal delivery system of griseofulvin containing vitamin E-TPGS as penetration enhancer.

Griseofulvin, an antifungal agent, is a BCS class II drug slowly, erratically, and incompletely absorbed from the gastrointestinal tract in humans. The clinical failure of the conventional oral therapy of griseofulvin is most likely attributed to its poor solubility and appreciable inter- and intra-subject variation in bioavailability from different commercial products. Moreover, the conventional oral therapy is associated with numerous adverse effects and interactions with other drugs. The purpose of the study was to formulate a topical application of griseofulvin which would deliver the drug locally in a therapeutically effective concentration. Griseofulvin was solubilized in ethanol, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and combinations of ethanol with varying amounts of TPGS; then, it was incorporated in the Carbopol (980 NF) base. The formulations were characterized and evaluated ex vivo using Laca mice skin, microbiologically against Microsporum gypseum and Microsporum canis and clinically in a small group of patients. The current study suggested that TPGS and ethanol synergistically enhanced the drug permeation and drug retention in the skin. The selected formulation F VII was found to be effective against M. gypseum and M. canis, non-sensitizing, histopathologically safe, stable at 4°C, 25°C, and 40°C with respect to percent drug content, permeation characteristics, pH, transparency, feel, viscosity, and clinically effective in a small group of subjects. The proposed topical formulation of griseofulvin may be an effective and convenient alternative to the currently available oral therapy for the treatment of superficial fungal infections.

Fungal malignant external otitis.

OBJECTIVE: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO). METHODS: The files of 60 patients treated for MEO in 1990-2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection. RESULTS: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p = 0.01) and had more facial nerve palsies (55% vs. 14%, p = 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p = 0.02), and higher rates of surgery (78% vs. 18%, p = 0.0008) and hyperbaric treatment (78% vs. 4%, p = 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p = 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p = 0.0001). There was no significant between-group difference in survival. CONCLUSION: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered.

A rare complication of ear piercing: a case of subcutaneous phaeohyphomycosis caused by Veronaea botryosa in China.

We present the third case of phaeohyphomycosis caused by Veronaea botryosa in China and the tenth case worldwide. A 16-year-old Chinese girl developed crusted, verrucous lesions, initially on the left ear and later on the left buttock, within 2-5 months of receiving an ear piercing. Histopathological examination of biopsy specimens confirmed diagnosis of subcutaneous phaeohyphomycosis. Microscopic examination of the colonies recovered in culture from a portion of the biopsy specimen resulted in the identification of Veronaea botryosa based primarily on the presence of two-celled, brownish pigmented, cylindrical conidia produced sympodially from erect conidiogenous cells. The lesions significantly improved with daily oral treatment with itraconazole 400 mg and adjuvant thermotherapy for 6 months. A maintenance therapy with low dose itraconazole was prescribed in order to achieve clinical and mycological cure. A two-year follow-up didn't reveal any recurrence of infection. Our case is the first report of V. botryosa infection associated with a cosmetic procedure, which suggests that skin piercing could precipitate V. botryosa or other dematiaceous, as well as opportunistic fungal infections.

Complement and fungal pathogens: an update.

Fungal infections are a serious complication in immunocompromised patients such as human immunodeficiency virus-infected individuals, patients with organ transplantations or with haematological neoplasia. The lethality of opportunistic fungal infection is high despite a growing arsenal of antimycotic drugs, implying the urgent need for supportive immunological therapies to strengthen the current inefficient antimicrobial defences of the immunocompromised host. Therefore, increasing effort has been directed to investigating the interplay between fungi and the host immunity and thus to find starting points for additional therapeutic approaches. In this article, we review the actual state of the art concerning the role of complement in the pathogenesis of fungal infections. Important aspects include the activation of the complement system by the fungal pathogen, the efficiency of the complement-associated antimicrobial functions and the arsenal of immune evasion strategies applied by the fungi. The twin functions of complement as an interactive player of the innate immunity and at the same time as a modulator of the adaptive immunity make this defence weapon a particularly interesting therapeutic candidate to mobilise a more effective immune response and to strengthen in one fell swoop a broad spectrum of different immune reactions. However, we also mention the 'Yin-Yang' nature of the complement system in fungal infections, as growing evidence assigns to complement a contributory part in the pathogenesis of fungus-induced allergic manifestations.

Quantifying fungal infection of plant leaves by digital image analysis using Scion Image software.

A digital image analysis method previously used to evaluate leaf color changes due to nutritional changes was modified to measure the severity of several foliar fungal diseases. Images captured with a flatbed scanner or digital camera were analyzed with a freely available software package, Scion Image, to measure changes in leaf color caused by fungal sporulation or tissue damage. High correlations were observed between the percent diseased leaf area estimated by Scion Image analysis and the percent diseased leaf area from leaf drawings. These drawings of various foliar diseases came from a disease key previously developed to aid in visual estimation of disease severity. For leaves of Nicotiana benthamiana inoculated with different spore concentrations of the anthracnose fungus Colletotrichum destructivum, a high correlation was found between the percent diseased tissue measured by Scion Image analysis and the number of leaf spots. The method was adapted to quantify percent diseased leaf area ranging from 0 to 90% for anthracnose of lily-of-the-valley, apple scab, powdery mildew of phlox and rust of golden rod. In some cases, the brightness and contrast of the images were adjusted and other modifications were made, but these were standardized for each disease. Detached leaves were used with the flatbed scanner, but a method using attached leaves with a digital camera was also developed to make serial measurements of individual leaves to quantify symptom progression. This was successfully applied to monitor anthracnose on N. benthamiana leaves. Digital image analysis using Scion Image software is a useful tool for quantifying a wide variety of fungal interactions with plant leaves.

Truffle's revenge: a pig-eating fungus.

A 77-year-old female initially presented with symptomatic mitral valve stenosis involving a bioprosthesis that had been implanted 8 months earlier for myxomatous mitral valve disease and severe valvular regurgitation. The patient was taken for a second mitral valve replacement due to stenosis. Intraoperatively, the bioprosthetic mitral valve was noted to have an unusual clot-like mass on the atrial side. Initial fungal smears were positive for yeast stains, and pathology revealed extensive colonization by thick filamentous fungus with apparent true hyphae, pseudohyphae, and yeast forms. The fungus was identified as Hormographiella aspergillata, the asexual form of Coprinus cinereus, a common inky cap mushroom that grows in the lawn. She was treated with 6 weeks of liposomal amphotericin B and then switched to voriconazole for long-term (lifelong) suppressive therapy in the setting of a new mechanical mitral valve. The only other reported case of infective endocarditis caused by a Coprinus species occurred in a 53-year-old man who had developed native aortic valve fungal endocarditis and died [J Med Microbiol (1971);4(3):370-4]. The valve isolate was identified as probable C. cinereus.

Voriconazole : a review of its use in the management of invasive fungal infections.

Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis. In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.

An overview of antifungal drugs and their use for treatment of deep and superficial mycoses in animals.

Fungal infections are often challenging to manage, given the limited numbers of therapeutics and a general lack of applicable clinical literature for their use in a given animal species. This article reviews some of the underlying principles that can affect the therapeutic outcome for a given antifungal, and provides specific information from the literature that is intended to highlight the distinctive properties of the most commonly used antifungals in veterinary medicine to better facilitate their successful application in clinical practice.

Manifestaciones orales de patologías tropicales / Oral manifestations of tropical diseases

El presente trabajo expone las características clínias e histopatológicas de las pricnipales patologías tropicales (micóticas, parasitarias y virales) que presentan manifestaciones bucales, poniendo énfasis en la paracoccidioidomicosis, histoplasmosis, critpcocosis, dengue, leishmaniasis e infección micótica (AU)