Consultant in Anaesthesia and Critical Care Medicine, James Watts discusses the growing field of fungal infections
Introduction
Fungal organisms are ubiquitous in the human population, but are an increasing problem for the vulnerable and immunosuppressed. There are millions of known fungal species, of which approximately 500 are associated with human; with less than 100 specifically associated with infection in the immunocompetent.
It is estimated that at any one time a billion people may have minor skin, nail and hair fungal infections; that tens of millions will have mucosal thrush; and that over 150 million may have a systemic disease which is serious or even fatal. Overall mortality globally is similar to that of TB, and greater than that attributable to malaria. [1-4]
To cause disease, fungi must also be able to invade the host, cause tissue lysis and resist natural and acquired immunity. However, the main barrier to serious fungal infection is the current inability of most fungi to survive at normal human body temperature. There is unfortunately increasing evidence that some fungi are adapting to live and reproduce at higher temperature ranges [5-8].
In addition, there is growing evidence of multi-drug resistance emerging in various fungal species. Candida auris seems to be particularly prevalent in this regard [9].
There are such serious concerns that the World Health Organisation (WHO) has produced a Fungal Pathogen Priority List to guide further research [10].
This article will attempt to briefly update the reader in this growing field.
Summary of Antifungal disease mechanisms, resistance
Antifungal resistance is not related to plasmid transmission. It is acquired within an infected individual by DNA mutation or protein synthesis drift; or by producing increased proteins at times of stress; or from selection from the increasing use of azoles and other chemicals in the environment [11].
Many fungi will form biofilms, which will make elimination from environments difficult, and which also help protect them from destruction by chemical agents. In addition, spores may remain in the environment for some time.
Systemic human infection is often associated with immunocompromise or indwelling devices. Infection may result in tissue lysis, severe sepsis or unfettered spread from immune underactivity.
The main pathogens in the UK are candida species, aspergillosis (haemato-oncology), and pneumocystis (particularly in those with HIV or organ transplants. Fungal infections can manifest up to 5 years following chemotherapy treatment [12].
Detection of infection may be difficult as the symptoms may be masked or attributed to other problems, and false negative cultures are common, partially because specimen preparation may actually destroy fungi.
Sampling should occur from the site assumed to be most seriously infected. Microscopy remains the most effective diagnostic test. Beta D Glucan tests can be falsely positive due to the presence of BDG in foods, haemofilters etc. [13] Galactomannan (used to diagnose aspergillus) is also present in food stuffs [14].
If a fungal infection is suspected, it may be prudent to start treatment until an infection can be disproved. Fluconazole remains the only antifungal that can penetrate the urine, although amphotericin B and flucytosine have also been used in this regard. [15, 16]
Antifungal treatments [17]
Azoles interfere with the manufacture of fungal cell membranes. Imidazoles, such as ketoconazole, are used for cutaneous and membrane infections. Triazoles are used for systemic infections. Examples include fluconazole (for candida) and itraconazole (for aspergillus infection).
Allylamines also affect cell membrane manufacture and are used to treat surface infections.
Echinocardins also inhibit cell wall manufacture. Anidulafungin and micafungin are particularly effective against candida; whilst caspofungin is also effective against aspergillus.
Polyenes make fungal cell walls porous. Examples include nystatin and amphotericin B (which is effective in aspergillosis, blastomycosis, cryptococcosis, histoplasmosis; mucosal or invasive Candida infections; and coccidioidomycosis).
Flucytosine prevents the manufacture of nucleic acids and proteins and is used particularly in the treatment of candida and cryptococcus. Griseofulvin prevents cell division and is used in cutaneous and nail infections.
Fosmanogepix, ibrexafungerp, olorofim, rezafungin, and opelconazole are newer antifungal agents that are being investigated for effectiveness. Opelconazole can be delivered by inhalation. [18]
Specific fungal organisms
Candida auris [19, 20]
C. auris can produce an invasive candidiasis which is associated with a high mortality (29-53%). Due to its increasing resistance profile, it has already produced several hospital outbreaks. It is intrinsically resistant to most available antifungals (eg 87-100% resistance to fluconazole) and some strains are pan-resistant. However, it remains susceptible to amphotericin B (8-35% resistance) and echinocandins (8% resistance).
Preventive measures are not well established as it is generally thermoresistant and also partially resistant to commonly use disinfectants. It may resist elimination from clinical environments by forming biofilms
Candida albicans [21, 22]
Although Candida albicans is a common fungal pathogen which can be part of the healthy human microbiome, it is associated wit