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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