Special Issue "Treatments for Fungal Infections"

A special issue of Journal of Fungi (ISSN 2309-608X).

Deadline for manuscript submissions: closed (31 July 2018)

Special Issue Editors

Guest Editor
Prof. Esther Segal

Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Website | E-Mail
Interests: fungal virulence factors and pathogenesis of fungal infections; therapy of fungal infections; prevention of infection by intervention with the pathogenic process
Guest Editor
Prof. Daniel Elad

Department of Veterinary Clinical Bacteriology and Mycolgy, The Kimron Veterinary Institute, Bet Dagan, Israel
Website | E-Mail
Interests: diagnostic methods; epidemiology of antimicrobial resistance; emerging diseases in Israel; paratuberculosis

Special Issue Information

Dear Colleagues, 

Antimycotic therapy, until the 1980s, was a rather mundane affair. Many cutaneous and mucous infections were treated topically. When systemic administration of antimycotic drugs was deemed necessary, dermatophytoses, by far the most common fungal infections, were treated with griseofulvin and other mycoses were treated with amphotericin B, with or without 5 fluorocytosine (5FC). Resistance, except for 5FC, was not considered a problem. Subsequently, all this changed.

Immunosuppression, whether pathological (AIDS) or iatrogenic (organ transplants and malignancy treatments) brought about a significant increase in the incidence of fungal infections. Moreover, the etiology, commonly opportunistic fungi that rarely caused infections before, became important and often lethal pathogens. Thus, it became necessary to treat various new fungi, sometimes with different susceptibility profiles. This led to an insurgence of new antimycotic compounds for systemic administration, by improving drugs from existing molecule groups, such as the azoles, and introducing the triazoles, or by discovering new groups, such as the echinocandins. Hence, the drive behind the development of antimycotic drugs was at that stage a necessity to treat new pathogens and not aimed to overcome resistance problems, which are aroused in fungal infections later. In addition, since amphotericin B was still the reference to which other drugs were compared due to its broad spectrum, efforts were made to mitigate its significant toxicity by incorporating it into a variety of molecules. Thus, while the number of new antibacterial drug groups dwindled, that of their antimycotic counterpart flourished.

Since there is now a larger variety of antimycotic drugs, each having its own spectrum of activity, susceptibility testing has become necessary. This was emphasized by the fact that innate resistance was reported for some fungi in regard to certain drugs (i.e., resistance of Candida glabrata to fluconazole) and acquired resistance was becoming a problem as well. Seemingly, the use of azoles in agriculture may prove to be one of the driving forces behind this phenomenon. As a result, susceptibility testing was standardized, first for yeasts, for which the inoculum is easier to quantify, and subsequently for molds. While the predictive value of these tests has been improving continuously, further progress is necessary before they can be universally adopted.

This Special Issue of the Journal of Fungi is aimed at presenting the state-of-the-art for the above-mentioned topics.

Prof. Esther Segal
Prof. Daniel Elad
Guest Editors

Manuscript Submission Information

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Keywords

  • Fungal infections 
  • Antimycotic therapy
  • Antifungal drug susceptibility testing
  • Antifungal drug resistance

Published Papers (14 papers)

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Editorial

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Open AccessEditorial
Special Issue: Treatments for Fungal Infections
J. Fungi 2018, 4(4), 135; https://doi.org/10.3390/jof4040135
Received: 11 December 2018 / Accepted: 11 December 2018 / Published: 12 December 2018
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Abstract
Antifungal therapy is complicated compared to antibacterial treatments by the fact that fungi and their hosts are both eukaryotic organisms, resulting in fewer targets for selective activity. [...] Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)

Research

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Open AccessArticle
Itraconazole, Voriconazole, and Posaconazole CLSI MIC Distributions for Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates
J. Fungi 2018, 4(3), 103; https://doi.org/10.3390/jof4030103
Received: 31 July 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 29 August 2018
Cited by 1 | PDF Full-text (569 KB) | HTML Full-text | XML Full-text
Abstract
Azole resistance in Aspergillus fumigatus is most frequently conferred by mutations in the cyp51A gene encoding 14α-sterol demethylases. TR34/L98H and TR46/Y121F/T289A are the two most common mutations associated with environmental resistance selection. We studied the minimal inhibitory concentration (MIC) [...] Read more.
Azole resistance in Aspergillus fumigatus is most frequently conferred by mutations in the cyp51A gene encoding 14α-sterol demethylases. TR34/L98H and TR46/Y121F/T289A are the two most common mutations associated with environmental resistance selection. We studied the minimal inhibitory concentration (MIC) distribution of clinical A. fumigatus isolates to characterize the Clinical and Laboratory Standards Institute (CLSI) susceptibility profiles of isolates with the wild-type (WT) cyp51A genotype, and isolates with the TR34/L98H and TR46/Y121F/T289A cyp51A mutations. Susceptibility testing was performed according to CLSI M38-A2. The MICs of 363 A. fumigatus isolates were used in this study. Based on the CLSI epidemiological cut-off values (ECVs), 141 isolates were phenotypically non-WT and 222 isolates had a phenotypically WT susceptibility. All isolates with the TR34/L98H mutation had an itraconazole MIC > 1 mg/L which is above the CLSI ECV. Eighty-six of 89 (97%) isolates with the TR34/L98H mutation had voriconazole and posaconazole MICs above the CLSI ECV, i.e., MICs of 1 and 0.25 mg/L, respectively. The isolates with a TR46/Y121F/T289A mutation showed a different phenotype. All 37 isolates with a TR46/Y121F/T289A mutation had a voriconazole MIC above the CLSI ECV, while 28/37 (76%) isolates had an itraconazole MIC > 1 mg/L. Interestingly, only 13 of 37 (35%) isolates had a posaconazole MIC > 0.25 mg/L. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Review

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Open AccessReview
Therapy and Management of Pneumocystis jirovecii Infection
J. Fungi 2018, 4(4), 127; https://doi.org/10.3390/jof4040127
Received: 10 October 2018 / Revised: 8 November 2018 / Accepted: 11 November 2018 / Published: 22 November 2018
Cited by 2 | PDF Full-text (697 KB) | HTML Full-text | XML Full-text
Abstract
The rates of Pneumocystis pneumonia (PcP) are increasing in the HIV-negative susceptible population. Guidance for the prophylaxis and treatment of PcP in HIV, haematology, and solid-organ transplant (SOT) recipients is available, although for many other populations (e.g., auto-immune disorders) there remains an urgent [...] Read more.
The rates of Pneumocystis pneumonia (PcP) are increasing in the HIV-negative susceptible population. Guidance for the prophylaxis and treatment of PcP in HIV, haematology, and solid-organ transplant (SOT) recipients is available, although for many other populations (e.g., auto-immune disorders) there remains an urgent need for recommendations. The main drug for both prophylaxis and treatment of PcP is trimethoprim/sulfamethoxazole, but resistance to this therapy is emerging, placing further emphasis on the need to make a mycological diagnosis using molecular based methods. Outbreaks in SOT recipients, particularly renal transplants, are increasingly described, and likely caused by human-to-human spread, highlighting the need for efficient infection control policies and sensitive diagnostic assays. Widespread prophylaxis is the best measure to gain control of outbreak situations. This review will summarize diagnostic options, cover prophylactic and therapeutic management in the main at risk populations, while also covering aspects of managing resistant disease, outbreak situations, and paediatric PcP. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Therapy of Non-Dermatophytic Mycoses in Animals
J. Fungi 2018, 4(4), 120; https://doi.org/10.3390/jof4040120
Received: 2 September 2018 / Revised: 21 October 2018 / Accepted: 29 October 2018 / Published: 30 October 2018
Cited by 1 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text
Abstract
This review focuses on aspects of antimycotic therapy specific to veterinary medicine. In the first part, drug availability, limited mostly by economic consideration but also by clinical applicability and specific adverse effects, is described for polyenes, 5 fluorocytosine, azoles, echinocandins and terbinafine. In [...] Read more.
This review focuses on aspects of antimycotic therapy specific to veterinary medicine. In the first part, drug availability, limited mostly by economic consideration but also by clinical applicability and specific adverse effects, is described for polyenes, 5 fluorocytosine, azoles, echinocandins and terbinafine. In the second part, current knowledge and experience in the treatment of selected fungal infections are overviewed. These mycoses include disseminated mold infections in small animals (dogs and cats) and avian species, upper respiratory tract infections of small animals (sino-nasal and sino-orbital aspergillosis) and horses (guttural pouch mycosis), eumycetoma, infections caused by dimorphic fungi, (blastomycosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis and sporothrichosis) and by yeasts and yeast-like microorganism (Cryptococcus spp. and Malassezia pachydermatis). Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview
Advances in the Treatment of Mycoses in Pediatric Patients
J. Fungi 2018, 4(4), 115; https://doi.org/10.3390/jof4040115
Received: 18 September 2018 / Revised: 5 October 2018 / Accepted: 7 October 2018 / Published: 11 October 2018
Cited by 2 | PDF Full-text (382 KB) | HTML Full-text | XML Full-text
Abstract
The main indications for antifungal drug administration in pediatrics are reviewed as well as an update of the data of antifungal agents and antifungal policies performed. Specifically, antifungal therapy in three main areas is updated as follows: (a) Prophylaxis of premature neonates against [...] Read more.
The main indications for antifungal drug administration in pediatrics are reviewed as well as an update of the data of antifungal agents and antifungal policies performed. Specifically, antifungal therapy in three main areas is updated as follows: (a) Prophylaxis of premature neonates against invasive candidiasis; (b) management of candidemia and meningoencephalitis in neonates; and (c) prophylaxis, empiric therapy, and targeted antifungal therapy in children with primary or secondary immunodeficiencies. Fluconazole remains the most frequent antifungal prophylactic agent given to high-risk neonates and children. However, the emergence of fluconazole resistance, particularly in non-albicans Candida species, should be considered during preventive or empiric therapy. In very-low birth-weight neonates, although fluconazole is used as antifungal prophylaxis in neonatal intensive care units (NICU’s) with relatively high incidence of invasive candidiasis (IC), its role is under continuous debate. Amphotericin B, primarily in its liposomal formulation, remains the mainstay of therapy for treating neonatal and pediatric yeast and mold infections. Voriconazole is indicated for mold infections except for mucormycosis in children >2 years. Newer triazoles-such as posaconazole and isavuconazole-as well as echinocandins, are either licensed or under study for first-line or salvage therapy, whereas combination therapy is kept for refractory cases. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview
Susceptibility Testing of Fungi to Antifungal Drugs
J. Fungi 2018, 4(3), 110; https://doi.org/10.3390/jof4030110
Received: 15 July 2018 / Revised: 11 August 2018 / Accepted: 13 August 2018 / Published: 15 September 2018
Cited by 1 | PDF Full-text (1234 KB) | HTML Full-text | XML Full-text
Abstract
Susceptibility testing of fungi against antifungal drugs commonly used for therapy is a key component of the care of patients with invasive fungal infections. Antifungal susceptibility testing (AFST) has progressed in recent decades to finally become standardized and available as both Clinical and [...] Read more.
Susceptibility testing of fungi against antifungal drugs commonly used for therapy is a key component of the care of patients with invasive fungal infections. Antifungal susceptibility testing (AFST) has progressed in recent decades to finally become standardized and available as both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference methods and in commercial manual/automated phenotypic methods. In clinical practice, the Sensititre YeastOne and Etest methods are widely used for AFST, particularly for sterile site isolates of Candida. Nevertheless, AFST is moving toward new phenotypic methods, such as matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), that are capable of providing rapid, and potentially more actionable, results for the treating clinician. Our objective is to summarize updated data on phenotypic methods for AFST of Candida and Aspergillus species and to assess their significance in view of opposing, but emerging, molecular genotypic methods. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata
J. Fungi 2018, 4(3), 105; https://doi.org/10.3390/jof4030105
Received: 16 August 2018 / Revised: 28 August 2018 / Accepted: 30 August 2018 / Published: 1 September 2018
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Abstract
Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug [...] Read more.
Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable “genetic escape”. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata is highlighted. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Therapy of Skin, Hair and Nail Fungal Infections
J. Fungi 2018, 4(3), 99; https://doi.org/10.3390/jof4030099
Received: 25 June 2018 / Revised: 10 August 2018 / Accepted: 10 August 2018 / Published: 20 August 2018
Cited by 2 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Treatment of superficial fungal infections has come a long way. This has, in part, been through the development and evaluation of new drugs. However, utilising new strategies, such as identifying variation between different species in responsiveness, e.g., in tinea capitis, as well as [...] Read more.
Treatment of superficial fungal infections has come a long way. This has, in part, been through the development and evaluation of new drugs. However, utilising new strategies, such as identifying variation between different species in responsiveness, e.g., in tinea capitis, as well as seeking better ways of ensuring adequate concentrations of drug in the skin or nail, and combining different treatment methods, have played equally important roles in ensuring steady improvements in the results of treatment. Yet there are still areas where we look for improvement, such as better remission and cure rates in fungal nail disease, and the development of effective community treatment programmes to address endemic scalp ringworm. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview
Treatment of Aspergillosis
J. Fungi 2018, 4(3), 98; https://doi.org/10.3390/jof4030098
Received: 24 July 2018 / Revised: 12 August 2018 / Accepted: 15 August 2018 / Published: 19 August 2018
Cited by 2 | PDF Full-text (316 KB) | HTML Full-text | XML Full-text
Abstract
Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to [...] Read more.
Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to diagnose due to low sensitivities of mycological tests for IA. IA is also increasingly observed in other non-neutropenic patient groups, where clinical presentation is atypical and diagnosis remains challenging. Early and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals. Recent guidelines recommend voriconazole and/or isavuconazole for the primary treatment of IA, with liposomal amphotericin B being the first alternative, and posaconazole, as well as echinocandins, primarily recommended for salvage treatment. Few studies have evaluated treatment options for chronic pulmonary aspergillosis (CPA), where long-term oral itraconazole or voriconazole remain the treatment of choice. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview
Treatment of Invasive Candidiasis: A Narrative Review
J. Fungi 2018, 4(3), 97; https://doi.org/10.3390/jof4030097
Received: 25 July 2018 / Revised: 8 August 2018 / Accepted: 12 August 2018 / Published: 16 August 2018
Cited by 5 | PDF Full-text (780 KB) | HTML Full-text | XML Full-text
Abstract
Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, [...] Read more.
Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Therapy of Mucormycosis
J. Fungi 2018, 4(3), 90; https://doi.org/10.3390/jof4030090
Received: 15 July 2018 / Revised: 28 July 2018 / Accepted: 30 July 2018 / Published: 31 July 2018
Cited by 5 | PDF Full-text (408 KB) | HTML Full-text | XML Full-text
Abstract
Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to [...] Read more.
Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to guide therapy. In this mini-review, we present the current status of treatment options. In view of the heterogeneity of the disease (different types of affected hosts, sites of infection, and infecting Mucorales), mucormycosis management requires an individualized management plan that takes into account the net state of immunosuppression of the host, including comorbidities, certainty of diagnosis, site of infection, and antifungal pharmacological properties. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Treatment of Infections Due to Aspergillus terreus Species Complex
J. Fungi 2018, 4(3), 83; https://doi.org/10.3390/jof4030083
Received: 14 June 2018 / Revised: 3 July 2018 / Accepted: 6 July 2018 / Published: 9 July 2018
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Abstract
The Aspergillus terreus species complex is found in a wide variety of habitats, and the spectrum of diseases caused covers allergic bronchopulmonary aspergillosis, Aspergillus bronchitis and/or tracheobronchitis, and invasive and disseminated aspergillosis. Invasive infections are a significant cause of morbidity and mortality mainly [...] Read more.
The Aspergillus terreus species complex is found in a wide variety of habitats, and the spectrum of diseases caused covers allergic bronchopulmonary aspergillosis, Aspergillus bronchitis and/or tracheobronchitis, and invasive and disseminated aspergillosis. Invasive infections are a significant cause of morbidity and mortality mainly in patients with hematological malignancy. The section Terrei covers a total of 16 accepted species of which most are amphotericin B resistant. Triazoles are the preferred agents for treatment and prevention of invasive aspergillosis. Poor prognosis in patients with invasive A. terreus infections seems to be independent of anti-Aspergillus azole-based treatment. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview
Present and Future Therapy of Cryptococcus Infections
J. Fungi 2018, 4(3), 79; https://doi.org/10.3390/jof4030079
Received: 19 May 2018 / Revised: 25 June 2018 / Accepted: 26 June 2018 / Published: 3 July 2018
Cited by 5 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Cryptococcal infections burden the immunocompromised population with unacceptably high morbidity and mortality. This population includes HIV-infected individuals and those undergoing organ transplants, as well as seemingly immunocompetent patients (non-HIV, non-transplant). These groups are difficult to manage with the current therapeutic options and strategies, [...] Read more.
Cryptococcal infections burden the immunocompromised population with unacceptably high morbidity and mortality. This population includes HIV-infected individuals and those undergoing organ transplants, as well as seemingly immunocompetent patients (non-HIV, non-transplant). These groups are difficult to manage with the current therapeutic options and strategies, particularly in resource-limited settings. New trials aimed at providing the best treatment strategies for resource-limited countries that will reduce costs and adverse reactions have focused on decreasing the length of therapy and using more readily accessible antifungal agents such as fluconazole. Furthermore, the emergence of antifungal resistance poses another challenge for successful treatment and may require the development of new agents for improved management. This review will discuss the principles of management, current and future antifungal agents, as well as emerging techniques and future directions of care for this deadly infection. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview
Recent Advances in the Treatment of Scedosporiosis and Fusariosis
J. Fungi 2018, 4(2), 73; https://doi.org/10.3390/jof4020073
Received: 26 April 2018 / Revised: 13 June 2018 / Accepted: 16 June 2018 / Published: 18 June 2018
Cited by 1 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
Species of Scedosporium and Fusarium are considered emerging opportunistic pathogens, causing invasive fungal diseases in humans that are known as scedosporiosis and fusariosis, respectively. These mold infections typically affect patients with immune impairment; however, cases have been reported in otherwise healthy individuals. Clinical [...] Read more.
Species of Scedosporium and Fusarium are considered emerging opportunistic pathogens, causing invasive fungal diseases in humans that are known as scedosporiosis and fusariosis, respectively. These mold infections typically affect patients with immune impairment; however, cases have been reported in otherwise healthy individuals. Clinical manifestations vary considerably, ranging from isolated superficial infection to deep-seated invasive infection—affecting multiple organs—which is often lethal. While there have been a number of advances in the detection of these infections, including the use of polymerase chain reaction (PCR) and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS), diagnosis is often delayed, leading to substantial morbidity and mortality. Although the optimal therapy is controversial, there have also been notable advances in the treatment of these diseases, which often depend on a combination of antifungal therapy, reversal of immunosuppression, and in some cases, surgical resection. In this paper, we review these advances and examine how the management of scedosporiosis and fusariosis may change in the near future. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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