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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. ...In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or ...special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Wildfire smoke, a potential infectious agent Kobziar, Leda N; Thompson, 3rd, George R
Science (American Association for the Advancement of Science),
12/2020, Volume:
370, Issue:
6523
Journal Article
Peer reviewed
Bacteria and fungi are transported in wildland fire smoke emissions
Wildfires over the past 3 years have resulted in lengthy episodes of smoke inundation across major metropolitan areas in Australia, ...Brazil, and the United States. In 2020, air quality across the western United States reached and sustained extremely unhealthy to hazardous levels for successive weeks from August through November. Although the pulmonary and cardiovascular consequences of human exposure to smoke particulate matter are extensively researched, there remains little recognition or monitoring of a smoke component with potentially important health repercussions: microbes.
Aspergillus Infections Thompson, George R; Young, Jo-Anne H
The New England journal of medicine,
10/2021, Volume:
385, Issue:
16
Journal Article
Peer reviewed
Aspergillosis is an opportunistic fungal infection that poses a particular risk for patients with neutrophil defects and causes diverse clinical syndromes. This review addresses our current ...understanding of aspergillosis and advances in diagnosis and treatment.
In the United States, endemic mycoses--blastomycosis, coccidioidomycosis, and histoplasmosis--pose considerable clinical and public health challenges. Although the causative fungi typically exist ...within broadly defined geographic areas or ecologic niches, some evidence suggests that cases have occurred in humans and animals not exposed to these areas. We describe cases acquired outside regions of traditionally defined endemicity. These patients often have severe disease, but diagnosis may be delayed because of a low index of suspicion for mycotic disease, and many more cases probably go entirely undetected. Increased awareness of these diseases, with a specific focus on their potential occurrence in unusual areas, is needed. Continued interdisciplinary efforts to reevaluate and better describe areas of true endemicity are warranted, along with a more nuanced view of the notion of endemicity. The term "nonendemic" should be used with care; mycoses in such regions might more accurately be considered "not known to be endemic."
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This case series describes the clinical resolution of systemic symptoms and lesions, along with any adverse events, in patients with monkeypox infection who were treated with tecovirimat on a ...compassionate use basis.
Coccidioidomycosis Stockamp, Nathan W; Thompson, 3rd, George R
Infectious disease clinics of North America,
03/2016, Volume:
30, Issue:
1
Journal Article
Peer reviewed
Coccidioides immitis and C posadasii are pathogenic dimorphic fungi responsible for causing coccidioidomycosis in the Southwestern United States and Central and South America. Antifungal therapy is ...beneficial and entails careful periodic assessment with therapies ranging from none or short courses of therapy to prolonged antifungal therapy. Factors that influence the decision to treat are the duration or severity of infection, radiographic findings, anticomplementary titers, presence of underlying immunosuppression, and comorbidities. Cure for disseminated infection is infrequent with current treatment regimens. This review summarizes the management guidelines for various disease manifestations and reviews data on challenging cases with newer agents.
Case reports have identified invasive fungal diseases in persons who use cannabis, and fungal contamination of cannabis has been described. In a large health insurance claims database, persons who ...used cannabis were 3.5 (95% CI 2.6-4.8) times more likely than persons who did not use cannabis to have a fungal infection in 2016.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat ...(LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.
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