Tag Archives: fungi

Rising fungal infections, Future Antifungal therapy and WHO recommendations

With the sudden worldwide spike in hospital acquired secondary fungal infections, a search is on for prevention and cure of fungal diseases, especially antifungals against the deadly fungal diseases.  How can you help? Your assistance in spreading the 10 steps WHO recommends to be taken (click here to read) for making safer antifungal therapy for invasive fungal infections more widely available, in addtion to stopping the practice of unnecessary antifungal prescription would be invaluable.  Fungal diseases of humans have been around for a long time but only recently have they become a reason for public health concern.  Although the first fungal diseases were described in 1840s, they began to be studied intensively since 1940s, when United States soldiers returned from the South Pacific humid tropical warzone. To read a wonderful historical account of the Fungi as human  disease agents by University of Hawaii researchers click here.

Prescription sales of antifungal drugs show a major increase since late 1980s, say scientists from the Center for Infectious Diseases and Travel Medicine, University Hospital, Freiburg, Germany.  They summarized here in 2005 that cancer units are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased.  Role of corticosteroids, immunotherapy and antifungal drugs have also been studied in allergic fungal rhinosinusitis (AFRS) in an individual who is hypersensitive to fungi (Read more). A variety of fungi can be found in such allergic sinuses.

Antifungal drug resistance
Unexpectedly high mortality rate associated with resistant fungal infections indicates that innovative new antifungal drugs are needed. Sustained efforts are now advised to urgently disseminate and implement World Health Organization (WHO) treatment guidelines. WHO recommends increased access to antifungal drugs that can lower mortality rates in subsaharan Africa from crytococcal meningitis and 20% of AIDS related mortality in low and middle income countries (Read more).

Alternative uses of current drugs
One research method is to find alternative uses of current drugs as an antifungal. Zoloft, an antidepressant can also act against Cryptococcus sp., a fungal causal agent of meningitis with the added benefit of being able to penetrate the blood brain barrier. The mode of action was revealed in 2012 by a team at Texas A&M University to be blocking protein synthesis ability of the the fungus at the translation level. You may read the published research by clicking here.

It is a challenge to find antifungals that can penetrate the blood – brain barrier.  The fact that Zoloft can penetrate the blood – brain barrier and act against a fungus that causal a neural infection such as meningitis will help antifungal discovery scientists. Unfortunately, this antidepressant is very selective in its antifungal activity and has no action against other fungi tested.

Fungi enter a host cell using penetration structures called Haustoria

Fungi enter a host cell using penetration structures called Haustoria

Current advances in antifungal drug development
As drug resistance in fungi have been increasing we find ourselves in need of truly novel future approaches to combat fungi. Researchers are following different paths:
1) Virulence factors of fungi and their inhibitors – discovery and characterization. The fungus Candida albicans secretes a virulent factor, aspartic proteinase, and it would be particularly rewarding for many when it’s inhibitor is discovered (Read more).
2) Echinocandins are a new class of antifungal agents with a novel mechanism of action (interference with fungal cell wall synthesis). Caspofungin (Cancidas), Caspofungin MSD) is the first echinocandin to be approved and is administered intravenously against candidiasis and aspergilliosis(Read more).
3) A lipid-associated formulation – Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B.  In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue.  Read more.
4) Adjunctive immune therapy with cytokines – since patients with invasive fungal infection often have a weakened immune system, for example during cancer chemotherapy. The role played by pattern recognition receptors and the induction of proinflammatory cytokines during the early phases of fungal infection are being investigated (Read more).
5) Combination therapy – cryptococcal meningitis patients showed a survival benefit with combination antifungal therapy (Read more).
6) Inhibitors of Beta Glucan synthesis – and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi (Read more).

Related Articles:

In recent years one of the groups most active in drug discovery has been Merck – Antifungal Drug Discovery: Something Old Something New

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Aspergillus and Exserohilum: what turned them deadly?

The recent outbreak of Meningitis (July – October 2012) has been deadly. Of the approximately 13000 individuals exposed to tainted steroid back pain injection (click here for details) 18 had died until October 8, 2012. Fortunately, the average healthy individual is able to fight off the causal agents of this outbreak – two fungi. Well, lets get to know these fungi better.  The two fungi are Aspergillus and Exserohilum.  Here, we cover Exserohilum.

First described by Leonard and Suggs and subsequently reviewed by Sivanesan (see 11)

Exserohilum rostratum conidiophores
Fungal colonies are grey to blackish – brown
Source: Mycology, Adelaide University

Exserohilum sp. conidia
Note the strongly defined protruding truncate “exserted” hilum
Hilum is defined as the scar on the conidia at the point of attachment to conidiophore
Source: Mycology, Adelaide University

More commonly known as an invader of grasses (see 1;2), Exserohilum has rarely caused a disease in humans. While meningitis is known to have a fungal causal agent (see 5), it has never been by the genus Exserohilum (see 7,8). It is an emerging human pathogen and needs to be better understood (8). This genus while found to cause leaf spots and leaf stripes on certain plants (see 10), does not even invade healthy grasses, let alone healthy humans. Sivanesan described 20 species of Exserohilum in 1987 and is the established published source (see 11) on the illustrated biology, pathogenicity, toxin production and distribution of Exserohilum. Robert Leahy has added information on Exserohilum sp. leaf spots of Bromeliads (see 2). Bromeliads in their natural setting are fungus free. Since Bromeliads became increasingly desirable they are now cultivated under conditions where they are susceptible to destructive leaf streaks by this fungus. Hence, the study on how to recognize the symptoms and control them.

What turned the fungus deadly?

Very few scientists study human diseases caused by Exserohilum simply because they are so rare. They do cause  sinusitis (see 9). It has never been located in meningitis disease samples to date (see 8). Meningitis causing fungi are more commonly Aspergillus, Cryptoccocus and Candida (see 5), and Prof Robert Cramer’s laboratory is among the few who are studying the destructive process of human invasion by Aspergillus(see 5).

Certain types of Exserohilum are known to produce toxins, which could perhaps weaken or destroy/kill a weakened host like a plant or a human. A list of some of the toxins it produces are: Glyceolin, Cynodontin, Exserohilone, Monocerin, Monocerin, Ophiobolin A, and Ravenelin (see 10). The first two are produced by E. rostratum, the most commonly studied.

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