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Drugs Oct 2021The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased... (Review)
Review
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Topics: Animals; Antifungal Agents; Drug Development; Drug Interactions; Drug Resistance, Fungal; Fungi; Humans; Invasive Fungal Infections
PubMed: 34626339
DOI: 10.1007/s40265-021-01611-0 -
F1000Research 2021Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed... (Review)
Review
Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We discuss three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.
Topics: Antifungal Agents; Drug Resistance, Fungal; Fungi; Immunocompromised Host
PubMed: 35136573
DOI: 10.12688/f1000research.28327.2 -
Revista Chilena de Pediatria Oct 2020Tinea capitis (TC) is a dermatophyte infection with a high prevalence in the pediatric population. Its epidemiology has changed in recent decades due to increasing... (Review)
Review
Tinea capitis (TC) is a dermatophyte infection with a high prevalence in the pediatric population. Its epidemiology has changed in recent decades due to increasing population migration worldwide. Environmental and host-specific risk factors have been identified which are with the development of this infection. The clinical manifestations are variable and depend on the causal agent. Dermatosco- py and Wood's lamp are useful tools for the diagnostic approach; however, the confirmation of in fection is based on mycological tests. The identification of the causal agent allows guiding the appro priate antifungal treatment, which is specific and safe in the pediatric population. Treatment focuses on systemic antifungal therapy combined with local measures. The objective of this paper is to carry out an updated review of the clinical and therapeutic approach to TC in the pediatric population.
Topics: Antifungal Agents; Child; Child, Preschool; Dermoscopy; Diagnosis, Differential; Global Health; Humans; Prevalence; Tinea Capitis
PubMed: 33399644
DOI: 10.32641/rchped.vi91i5.1345 -
Revista Iberoamericana de Micologia 2021Invasive fungal infections have increased over the last decades and the therapeutic choices to treat them are limited. The antifungal agents currently available are...
Invasive fungal infections have increased over the last decades and the therapeutic choices to treat them are limited. The antifungal agents currently available are useful and have optimal in vitro activity; however, their activity can be lowered due to the development of fungal resistance. The increase in primary or secondary resistance to some antifungal drugs has led to the search of alternatives such as the combination of drugs or the development of new antifungals. In this paper, the activity of the main families of antifungal drugs, polyenes, azoles, echinocandins, 5-fluorocytosine and other new antifungal drugs, are reviewed. The main resistance mechanisms developed by fungi are also described.
Topics: Antifungal Agents; Azoles; Echinocandins; Humans; Mycoses; Pharmaceutical Preparations
PubMed: 34294519
DOI: 10.1016/j.riam.2021.04.004 -
Current Opinion in Microbiology Oct 2022Fungi have a profound impact on human health, leading to billions of infections and millions of deaths worldwide each year. Exacerbating the public health burden is the... (Review)
Review
Fungi have a profound impact on human health, leading to billions of infections and millions of deaths worldwide each year. Exacerbating the public health burden is the continued emergence of drug-resistant fungal pathogens coupled with a dearth of treatment options to combat serious infections. Despite this health threat, scientific advances in chemistry, genetics, and biochemistry methodologies have enabled novel antifungal compounds to be discovered. Here, we describe current approaches for the discovery and characterization of novel antifungals, focusing on the identification of novel chemical matter and elucidation of the cellular target of bioactive compounds, followed by a review of the most promising emerging therapies in the antifungal-development pipeline.
Topics: Antifungal Agents; Drug Resistance, Fungal; Fungi; Humans
PubMed: 36037637
DOI: 10.1016/j.mib.2022.102198 -
JAMA Network Open Oct 2020Several antifungal drugs are available for antifungal prophylaxis in patients with hematological disease or who are undergoing hematopoietic stem cell transplantation... (Comparative Study)
Comparative Study Meta-Analysis
Comparison of Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Network Meta-analysis.
IMPORTANCE
Several antifungal drugs are available for antifungal prophylaxis in patients with hematological disease or who are undergoing hematopoietic stem cell transplantation (HSCT).
OBJECTIVE
To summarize the evidence on the efficacy and adverse effects of antifungal agents using an integrated comparison.
DATA SOURCES
Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched to collect all relevant evidence published in randomized clinical trials that assessed antifungal prophylaxis in patients with hematological disease. Sources were search from inception up to October 2019.
STUDY SELECTION
Studies that compared any antifungal agent with a placebo, no antifungal agent, or another antifungal agent among patients with hematological disease or undergoing HSCT were included. Of 39 709 studies identified, 69 met the criteria for inclusion.
DATA EXTRACTION AND SYNTHESIS
The outcome from each study was estimated using the relative risk (RR) with 95% CIs. The Mantel-Haenszel random-effects model was used. The reliability and validity of the networks were estimated by addressing inconsistencies in the evidence from comparative studies of different treatments. Data were analyzed from December 2019 to February 2020. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) guideline.
MAIN OUTCOMES AND MEASURES
The primary outcomes were invasive fungal infections (IFIs) and mortality. The secondary outcomes were fungal infections, proven IFIs, invasive candidiasis, invasive aspergillosis, fungi-related death, and withdrawal owing to adverse effects of the drug.
RESULTS
We identified 69 randomized clinical trials that reported comparisons of 12 treatments with at total of 14 789 patients. Posaconazole was the treatment associated with the best probability of success against IFIs (surface under the cumulative ranking curve, 86.7%; mean rank, 2.5). Posaconazole treatment was associated with a significant reduction in IFIs (RR, 0.57; 95% CI, 0.42-0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15-0.85) compared with placebo. Voriconazole was associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26) compared with placebo. However, posaconazole was associated with a higher incidence of withdrawal because of the adverse effects of the drug (surface under the cumulative ranking curve, 17.5%; mean rank, 9.2). In subgroup analyses considering efficacy and tolerance, voriconazole might be the best choice for patients undergoing HSCT, especially allogenic HSCT; however, posaconazole was ranked as the best choice for patients with acute myeloid leukemia or myelodysplastic syndrome.
CONCLUSIONS AND RELEVANCE
These findings suggest that voriconazole may be the best prophylaxis option for patients undergoing HSCT, and posaconazole may be the best prophylaxis option for patients with acute myeloid leukemia or myelodysplastic syndrome.
Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycoses; Pre-Exposure Prophylaxis; Triazoles; Voriconazole
PubMed: 33030550
DOI: 10.1001/jamanetworkopen.2020.17652 -
International Journal of Molecular... Mar 2022Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the... (Review)
Review
Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals.
Topics: Antifungal Agents; Biofilms; Cell Wall; Drug Resistance, Fungal; Humans; Hyphae; Mycoses
PubMed: 35269898
DOI: 10.3390/ijms23052756 -
Brazilian Journal of Microbiology :... Mar 2021Sporothrix schenckii sensu lato is currently recognized as a species complex with only Sporothrix brasiliensis, Sporothrix schenckii sensu stricto, Sporothrix globosa... (Review)
Review
Sporothrix schenckii sensu lato is currently recognized as a species complex with only Sporothrix brasiliensis, Sporothrix schenckii sensu stricto, Sporothrix globosa and Sporothrix pallida identified to cause disease in the cat. Feline sporotrichosis in Asia is mainly reported from Malaysia where a single clonal strain of clinical clade D, Sporothrix schenckii sensu stricto manifesting low susceptibility to major antifungal classes, has been identified as the agent of the disease. Sporothrix globosa has been identified to cause disease from a single cat in Japan while the specific species of agent has not been identified yet for the disease in Thailand. Despite efforts to elucidate and describe the pathogenicity of the agent and the disease it causes, the paucity of data highlights the need for further molecular epidemiological studies to characterize this fungus and the disease it causes in Asia. Its prognosis remains guarded to poor due to issues pertaining to cost, protracted treatment course, zoonotic potential and low susceptibility of some strains to antifungals.
Topics: Animals; Antifungal Agents; Asia; Cat Diseases; Cats; Sporothrix; Sporotrichosis
PubMed: 32363567
DOI: 10.1007/s42770-020-00274-5 -
Tidsskrift For Den Norske Laegeforening... Apr 2021The diagnosis of intracerebral fungal abscesses may be difficult due to the paucity of laboratory tests and similar radiological appearance to other lesions.
BACKGROUND
The diagnosis of intracerebral fungal abscesses may be difficult due to the paucity of laboratory tests and similar radiological appearance to other lesions.
CASE PRESENTATION
We present an immunocompromised woman in her forties who was admitted with a diagnosis of bacterial meningitis. MRI examination showed findings suggestive of fungal abscesses, and a subsequent lumbar puncture showed PCR positive for non-fumigatus Aspergillus. The patient received antifungal treatment and had satisfactory clinical, biochemical and radiological response. Consecutive MRI examinations over the following weeks showed gradual decrease of abscesses, with almost complete resolution within 12 weeks.
INTERPRETATION
Adequate management of brain abscesses requires correct identification of the causative agent, so that proper treatment can be initiated as soon as possible. MRI plays an important role in distinguishing between pyogenic and fungal brain abscesses. Headaches or focal neurological deficits in immunocompromised patients should cause CNS fungal infection to be considered.
Topics: Antifungal Agents; Aspergillosis; Brain Abscess; Female; Headache; Humans; Magnetic Resonance Imaging
PubMed: 33876620
DOI: 10.4045/tidsskr.20.0825 -
Drugs in R&D Mar 2022On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as... (Review)
Review
On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as vaginal yeast infection. Ibrexafungerp is the first drug approved in a novel antifungal class in more than two decades, and the Food and Drug Administration's decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. The decision was also based on substantial preclinical and clinical work in both the pharmacokinetics and pharmacodynamics of ibrexafungerp. This paper reviews that research and looks ahead to explore how this novel antifungal agent may be used in the future to address the expanding problem of drug-resistant mycotic infections.
Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes; United States
PubMed: 34961907
DOI: 10.1007/s40268-021-00376-x