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1.
Adapting to survive: How Candida overcomes host-imposed constraints during human colonization.
Alves, R, Barata-Antunes, C, Casal, M, Brown, AJP, Van Dijck, P, Paiva, S
PLoS pathogens. 2020;(5):e1008478
Abstract
Successful human colonizers such as Candida pathogens have evolved distinct strategies to survive and proliferate within the human host. These include sophisticated mechanisms to evade immune surveillance and adapt to constantly changing host microenvironments where nutrient limitation, pH fluctuations, oxygen deprivation, changes in temperature, or exposure to oxidative, nitrosative, and cationic stresses may occur. Here, we review the current knowledge and recent findings highlighting the remarkable ability of medically important Candida species to overcome a broad range of host-imposed constraints and how this directly affects their physiology and pathogenicity. We also consider the impact of these adaptation mechanisms on immune recognition, biofilm formation, and antifungal drug resistance, as these pathogens often exploit specific host constraints to establish a successful infection. Recent studies of adaptive responses to physiological niches have improved our understanding of the mechanisms established by fungal pathogens to evade the immune system and colonize the host, which may facilitate the design of innovative diagnostic tests and therapeutic approaches for Candida infections.
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2.
Medication association and immunomodulation: An approach in fungal diseases and in particular in the treatment of paracoccidioidomycosis.
Santos, LA, Grisolia, JC, Malaquias, LCC, Paula, FBA, Dias, ALT, Burger, E
Acta tropica. 2020;:105412
Abstract
Fungal infections have been increasing in recent decades, mainly affecting immunocompromised individuals, although certain mycoses, such as paracoccidioidomycosis (PCM), infect immunologically competent individuals. The major problems observed regarding fungal diseases are inadequate diagnosis, prolonged treatment time, the reduced number of drugs available for treatment, in addition to the fact that there are no vaccines for clinical use. Drug combination in order to immunomodulate the immune response is a new strategy used for the treatment of mycoses, since it is difficult to develop new antifungal drugs. The aim of this study is to present and analyze strategies recently suggested for the treatment of fungi of medical interest, in particular for PCM, such as the utilization of combinations of protein fractions or dead microorganisms, as vaccinal antigens, and cellular immunotherapy. We will also propose new therapeutic alternatives, such as lipids, vitamins, synthetic or natural products as well as the use of low intensity LASER therapy (LLLT) to modulate the immune response of the host, enhancing the efficiency of the existing treatments of mycoses of medical interest and in particular of PCM.
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3.
The pathogenicity of Aspergillus fumigatus, drug resistance, and nanoparticle delivery.
Szalewski, DA, Hinrichs, VS, Zinniel, DK, Barletta, RG
Canadian journal of microbiology. 2018;(7):439-453
Abstract
The genus Aspergillus includes fungal species that cause major health issues of significant economic importance. These microorganisms are also the culprit for production of carcinogenic aflatoxins in grain storages, contaminating crops, and economically straining the production process. Aspergillus fumigatus is a very important pathogenic species, being responsible for high human morbidity and mortality on a global basis. The prevalence of these infections in immunosuppressed individuals is on the rise, and physicians struggle with the diagnosis of these deadly pathogens. Several virulence determinants facilitate fungal invasion and evasion of the host immune response. Metabolic functions are also important for virulence and drug resistance, since they allow fungi to obtain nutrients for their own survival and growth. Following a positive diagnostic identification, mortality rates remain high due, in part, to emerging resistance to frequently used antifungal drugs. In this review, we discuss the role of the main virulence, drug target, and drug resistance determinants. We conclude with the review of new technologies being developed to treat aspergillosis. In particular, microsphere and nanoparticle delivery systems are discussed in the context of improving drug bioavailability. Aspergillus will likely continue to cause problematic infections in immunocompromised patients, so it is imperative to improve treatment options.
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4.
A computational model for regulation of nanoscale glucan exposure in Candida albicans.
Wester, MJ, Lin, J, Neumann, AK
PloS one. 2017;(12):e0188599
Abstract
Candida albicans is a virulent human opportunistic pathogen. It evades innate immune surveillance by masking an immunogenic cell wall polysaccharide, β-glucan, from recognition by the immunoreceptor Dectin-1. Glucan unmasking by the antifungal drug caspofungin leads to changes in the nanostructure of glucan exposure accessible to Dectin-1. The physical mechanism that regulates glucan exposure is poorly understood, but it controls the nanobiology of fungal pathogen recognition. We created computational models to simulate hypothetical physical processes of unmasking glucan in a biologically realistic distribution of cell wall glucan fibrils. We tested the predicted glucan exposure nanostructural features arising from these models against experimentally measured values. A completely spatially random unmasking process, reflective of random environmental damage to the cell wall, cannot account for experimental observations of glucan unmasking. However, the introduction of partially edge biased unmasking processes, consistent with an unmasking contribution from active, local remodeling at glucan exposure sites, produces markedly more accurate predictions of experimentally observed glucan nanoexposures in untreated and caspofungin-treated yeast. These findings suggest a model of glucan unmasking wherein cell wall remodeling processes in the local nanoscale neighborhood of glucan exposure sites are an important contributor to the physical process of drug-induced glucan unmasking in C. albicans.
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5.
Systemic antifungal therapy for tinea capitis in children.
Chen, X, Jiang, X, Yang, M, González, U, Lin, X, Hua, X, Xue, S, Zhang, M, Bennett, C
The Cochrane database of systematic reviews. 2016;(5):CD004685
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Abstract
BACKGROUND Tinea capitis is a common contagious fungal infection of the scalp in children. Systemic therapy is required for treatment and to prevent spread. This is an update of the original Cochrane review. OBJECTIVES To assess the effects of systemic antifungal drugs for tinea capitis in children. SEARCH METHODS We updated our searches of the following databases to November 2015: the Cochrane Skin Group Specialised Register, CENTRAL (2015, Issue 10), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and CINAHL (from 1981). We searched five trial registers and checked the reference lists of studies for references to relevant randomised controlled trials (RCTs). We obtained unpublished, ongoing trials and grey literature via correspondence with experts in the field and from pharmaceutical companies. SELECTION CRITERIA RCTs of systemic antifungal therapy in children with normal immunity under the age of 18 with tinea capitis confirmed by microscopy, growth of fungi (dermatophytes) in culture or both. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included 25 studies (N = 4449); 4 studies (N = 2637) were new to this update.Terbinafine for four weeks and griseofulvin for eight weeks showed similar efficacy for the primary outcome of complete (i.e. clinical and mycological) cure in three studies involving 328 participants with Trichophyton species infections (84.2% versus 79.0%; risk ratio (RR) 1.06, 95% confidence interval (CI) 0.98 to 1.15; low quality evidence).Complete cure with itraconazole (two to six weeks) and griseofulvin (six weeks) was similar in two studies (83.6% versus 91.0%; RR 0.92, 95% CI 0.81 to 1.05; N = 134; very low quality evidence). In two studies, there was no difference between itraconazole and terbinafine for two to three weeks treatment (73.8% versus 78.8%; RR 0.93, 95% CI 0.72 to 1.19; N = 160; low quality evidence). In three studies, there was a similar proportion achieving complete cured with two to four weeks of fluconazole or six weeks of griseofulvin (41.4% versus 52.7%; RR 0.92, 95% CI 0.81 to 1.05; N = 615; moderate quality evidence). Current evidence for ketoconazole versus griseofulvin was limited. One study favoured griseofulvin (12 weeks) because ketoconazole (12 weeks) appeared less effective for complete cure (RR 0.76, 95% CI 0.62 to 0.94; low quality evidence). However, their effects appeared to be similar when the treatment lasted 26 weeks (RR 0.95, 95% CI 0.83 to 1.07; low quality evidence). Another study indicated that complete cure was similar for ketoconazole (12 weeks) and griseofulvin (12 weeks) (RR 0.89, 95% CI 0.57 to 1.39; low quality evidence). For one trial, there was no significant difference for complete cure between fluconazole (for two to three weeks) and terbinafine (for two to three weeks) (82.0% versus 94.0%; RR 0.87, 95% CI 0.75 to 1.01; N = 100; low quality evidence). For complete cure, we did not find a significant difference between fluconazole (for two to three weeks) and itraconazole (for two to three weeks) (82.0% versus 82.0%; RR 1.00, 95% CI 0.83 to 1.20; low quality evidence).This update provides new data: in children with Microsporum infections, a meta-analysis of two studies found that the complete cure was lower for terbinafine (6 weeks) than for griseofulvin (6-12 weeks) (34.7% versus 50.9%; RR 0.68, 95% CI 0.53 to 0.86; N = 334; moderate quality evidence). In the original review, there was no significant difference in complete cure between terbinafine (four weeks) and griseofulvin (eight weeks) in children with Microsporum infections in one small study (27.2% versus 60.0%; RR 0.45, 95% CI 0.15 to 1.35; N = 21; low quality evidence).One study provides new evidence that terbinafine and griseofulvin for six weeks show similar efficacy (49.5% versus 37.8%; RR 1.18, 95% CI 0.74 to 1.88; N = 1006; low quality evidence). However, in children infected with T. tonsurans, terbinafine was better than griseofulvin (52.1% versus 35.4%; RR 1.47, 95% CI 1.22 to 1.77; moderate quality evidence). For children infected with T. violaceum, these two regimens have similar effects (41.3% versus 45.1%; RR 0.91, 95% CI 0.68 to 1.24; low quality evidence). Additionally, three weeks of fluconazole was similar to six weeks of fluconazole in one study in 491 participants infected with T. tonsurans and M. canis (30.2% versus 34.1%; RR 0.88, 95% CI 0.68 to 1.14; low quality evidence).The frequency of adverse events attributed to the study drugs was similar for terbinafine and griseofulvin (9.2% versus 8.3%; RR 1.11, 95% CI 0.79 to 1.57; moderate quality evidence), and severe adverse events were rare (0.6% versus 0.6%; RR 0.97, 95% CI 0.24 to 3.88; moderate quality evidence). Adverse events for terbinafine, griseofulvin, itraconazole, ketoconazole, and fluconazole were all mild and reversible.All of the included studies were at either high or unclear risk of bias in at least one domain. Using GRADE to rate the overall quality of the evidence, lower quality evidence resulted in lower confidence in the estimate of effect. AUTHORS' CONCLUSIONS Newer treatments including terbinafine, itraconazole and fluconazole are at least similar to griseofulvin in children with tinea capitis caused by Trichophyton species. Limited evidence suggests that terbinafine, itraconazole and fluconazole have similar effects, whereas ketoconazole may be less effective than griseofulvin in children infected with Trichophyton. With some interventions the proportion achieving complete clinical cure was in excess of 90% (e.g. one study of terbinafine or griseofulvin for Trichophyton infections), but in many of the comparisons tested, the proportion cured was much lower.New evidence from this update suggests that terbinafine is more effective than griseofulvin in children with T. tonsurans infection.However, in children with Microsporum infections, new evidence suggests that the effect of griseofulvin is better than terbinafine. We did not find any evidence to support a difference in terms of adherence between four weeks of terbinafine versus eight weeks of griseofulvin. Not all treatments for tinea capitis are available in paediatric formulations but all have reasonable safety profiles.
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6.
Human monoclonal antibody-based therapy in the treatment of invasive candidiasis.
Bugli, F, Cacaci, M, Martini, C, Torelli, R, Posteraro, B, Sanguinetti, M, Paroni Sterbini, F
Clinical & developmental immunology. 2013;:403121
Abstract
Invasive candidiasis (IC) represents the leading fungal infection of humans causing life-threatening disease in immunosuppressed and neutropenic individuals including also the intensive care unit patients. Despite progress in recent years in drugs development for the treatment of IC, morbidity and mortality rates still remain very high. Historically, cell-mediated immunity and innate immunity are considered to be the most important lines of defense against candidiasis. Nevertheless recent evidence demonstrates that antibodies with defined specificities could act with different degrees showing protection against systemic and mucosal candidiasis. Mycograb is a human recombinant monoclonal antibody against heat shock protein 90 (Hsp90) that was revealed to have synergy when combined with fluconazole, caspofungin, and amphotericin B against a broad spectrum of Candida species. Furthermore, recent studies have established an important role for Hsp90 in mediating Candida resistance to echinocandins, giving to this antibody molecule even more attractive biological properties. In response to the failure of marketing authorization by the CHMP (Committee for Medicinal Products for Human Use) a new formulation of Mycograb, named Mycograb C28Y variant, with an amino acid substitution was developed in recent years. First data on Mycograb C28Y variant indicate that this monoclonal antibody lacked efficacy in a murine candidiasis model.
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7.
Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment.
Wark, P
Respiratory medicine. 2004;(10):915-23
Abstract
BACKGROUND Allergic bronchopulmonary aspergillosis (ABPA) is a complex condition that affects people with asthma and cystic fibrosis (CF). It results from exposure to the fungus Aspergillus fumigatus, which leads to worsening airway inflammation and progressive damage to the lungs. The aim of this review is to outline the pathogenesis of the disorder, diagnostic criteria and to discuss the use of anti-fungal agents in its treatment. METHODS The Cochrane library of systematic reviews and the Cochrane database of controlled trials were searched for controlled trials on ABPA and its treatment in both asthma and CF. In addition, articles included within the reviews were examined separately, and a separate search carried out using Medline. RESULTS A systematic review for the use of azole anti-fungal agents in ABPA was identified for their use in both CF and non-CF-related disease. The review of ABPA alone identified two randomized-controlled trials of itraconazole in chronic disease. These trials demonstrated improvements in symptoms and immune activation, but were short-term trials and failed to show a significant change in lung function. No trials were identified in CF. CONCLUSIONS The use of anti-fungal agents in ABPA seems to be a rational one, with short-term efficacy demonstrated for the use of itraconazole. Further investigations are required to identify individuals who will benefit most from treatment and to establish the correct dose and means of delivering treatment in ABPA. Longer-term studies are required to demonstrate that treatment modifies the progressive decline in lung function seen with the disease.
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8.
Treatment of recurrent vulvovaginal candidiasis.
Ringdahl, EN
American family physician. 2000;(11):3306-12, 3317
Abstract
Vulvovaginal candidiasis is considered recurrent when at least four specific episodes occur in one year or at least three episodes unrelated to antibiotic therapy occur within one year. Although greater than 50 percent of women more than 25 years of age develop vulvovaginal candidiasis at some time, fewer than 5 percent of these women experience recurrences. Clinical evaluation of recurrent episodes is essential. Patients who self-diagnose may miss other causes or concurrent infections. Known etiologies of recurrent vulvovaginal candidiasis include treatment-resistant Candida species other than Candida albicans, frequent antibiotic therapy, contraceptive use, compromise of the immune system, sexual activity and hyperglycemia. If microscopic examination of vaginal secretions in a potassium hydroxide preparation is negative but clinical suspicion is high, fungal cultures should be obtained. After the acute episode has been treated, subsequent prophylaxis (maintenance therapy) is important. Because many patients experience recurrences once prophylaxis is discontinued, long-term therapy may be warranted. Patients are more likely to comply when antifungal therapy is administered orally, but oral treatment carries a greater potential for systemic toxicity and drug interactions.