Fungi and Anti-fungal Agents

OVERVIEW

Fungi are a kingdom of eukaryotic organisms distinct from plants and animals that are characterised by thick carbohydrate cellular walls containing glucans and chitin.

• There are over 100,000 known species of fungi (probably more than a million that are unknown), with over 300 known species that are pathogenic (either obligatory or opportunistic)
• Candida and the dermatophytes transmit human-to-human (or animal-to-human), others are acquired from the environment (e.g. by inhalation, penetrating injury, or invasive devices)
• Mycosis is the term for fungal disease – serious mycoses typically occur in the context of immunosuppression and hospital-acquired infection.
• Mycosis can be treated by a variety of different anti-fungal agents

CLASSIFICATION OF FUNGI BY GROWTH FORM

Yeasts

• Yeasts are microscopic eukaryotic, single-celled microorganisms
• Yeast reproduce by budding, and pseudohyphae form when buds remain attached
• May survive and multiply within host phagocytic cells as well as extracellularly
• E.g. Candida, Cryptococcus, Pneumocystis 

Molds

• microscopic multicellular organisms typically arranged into filaments called hyphae
• A mass of hyphae is termed a micellium
• Spores, which may cause disease through inhalation, are released from sacs known as sporangia and are produced by asexual reproduction
• E.g. Aspergillus, Zygomycetes (Mucor, Rhizopus), Other (Scedosporium, Fusarium)

Dimorphic fungi exist in both yeast and mold forms (e.g. Candida can form hyphae in the body)

Mushrooms

• the macroscopic fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source.
• Not usually pathogenic, but may be toxic!

CLASSIFICATION OF FUNGI BY TYPE OF INFECTION

• Superficial mycoses (e.g. oral thrush, tinea) – fungi grow on body surfaces
• subcutaneous infections (e.g. mycetoma, sporotrichosis) – involve nails or deeper layers of the skin
• Systemic or deep mycoses – involve internal body organs and include:
  • endemic mycoses (e.g. histoplasmosis, blastomycosis, coccidioidomycosis) – infect immunocompetent people
  • opportunistic mycoses (e.g. systemic candidiasis, aspergillosis, Pneumocystis) – infect immunocompromised people (most important category in critical care); organisms may be part of the normal body flora
• Diseases caused by free living fungi that produce toxins (e.g. aflatoxin) or spores (e.g. acute bronchopulmonary aspergillosis (ABPA))

ANTI-FUNGAL AGENTS

Anti-fungals

• Neutrophils play a major role in the host response to mycosis
• The distinctive nature of the fungal cell wall and the predominance of ergosterol – rather than cholesterol – in fungal cell membranes are important targets for anti-fungal action
• Limitations of anti-fungals include:
  • Fungal selectivity of anti-microbial agents is more difficult to achieve than for antimicrobials targeting prokaryotes
  • Stability, solubility, and toxicity of some agents (especially amphotericin B)
  • Resistance to azoles is becoming more widespread and resistance to flucytosine means it should not be used as monotherapy

Mechanisms of resistance against anti-fungal agents include:

• Enzyme modification (e.g. destruction of drug)
• Target modification
• Reduced permeability/ entry of drug into pathogen
• Active efflux pumps
• Failure to activate antifungal agents

Brief overview of common therapies for fungal infections that are important in critical care:

Aspergillosis	voriconazole Liposomal amphotericin B
Candidiasis	Superficial Clotrimazole Miconazole Nystatin Fluconazole Systemic  Echinocandins: Caspofungin, micafungin, anidulafungin Liposomal amphotericin Ocular or CNS infection Liposomal amphotericin and flucytosine
Cryptococcosis	Liposomal amphotericin B and flucytosine
Histoplasmosis	Liposomal amphotericin B then itraconazole
Mucormycosis	Liposomal amphotericin B Surgery often required
Pneumocystis pneumonia	co-trimoxazole  Pentamidine, dapsone (second line agents)

CLASSIFICATION OF ANTIFUNGAL AGENTS

There are five main classes of antifungal agents.

1. Polyenes – selectively bind ergosterol
   • e.g. Amphotericin B, Nystatin
2. Azoles – prevent the synthesis of ergosterol from lanosterol by inhibiting lanosterol-C14-α-demethylase
   • Imidazoles – e.g. clotrimazole, miconazole, ketoconazole
   • Triazoles
     • First generation – e.g. fluconazole, itraconazole
     • Second generation (extended spectrum) – e.g. voriconazole, posaconazole
   • Thiazoles – e.g. abafungin
3. Allylamines – inhibit squalene epoxidase and prevent ergosterol synthesis
   • e.g. Amorolfin, Butenafine, Naftifine, Terbinafine
4. Echinocandins – inhibit glucan synthesis in the fungal cell wall
   • e.g. Anidulafungin, Caspofungin, Micafungin
5. Others –
   • e.g. Griseofulvin (a microtubule inhibitor), Flucytosine (5FC) (inhibits nuceic acid synthesis), Pentamidine 

TISSUE PENETRATION OF ANTI-FUNGALS

Anti-fungal agents must penetrate tissues that are the site of infection and achieve concentrations capable fo eliminating the pathogen to be effective (Felton et al, 2014).

• small polar agents with low protein binding (e.g., fluconazole and 5FC) distribute more evenly and into a wider range of tissues than the larger, more lipophilic (itraconazole) or amphipathic (e.g., amphotericin B and echinocandins) agents.
• more lipophilic or amphipathic agents may have longer residence times within tissues and may accumulate to concentrations that exceed those in the plasma.
• agents with relatively low molecular weights, such as fluconazole, 5FC, and voriconazole, penetrate more readily into tissue beds.
• formulations may have a significant impact on serum and tissue pharmacokinetics.
• the measurable concentration of a drug within a tissue may not be an indication of its biological activity in that compartment.
• marked differences in tissue distribution can occur within a single drug class even with closely related structures (e.g., the triazoles).

References and Links

FOAM and web resources

• LITFL
  • CCC — Aspergillosis
  • CCC — Candidiasis
  • CCC — Cryptococcosis
  • CCC — Mushroom toxicity
  • CCC — Pneumocystis jiroveci
  • CCC — Rhinocerebral Mucormycosis
  • CCC — Amphotericin B (conventional and liposomal)
  • CCC — Caspofungin
  • CCC — Fluconazole
  • CCC — Voriconazole
• EMCrit Internet Book of Critical Care — Anti-fungals (2020)
• ICN Podcast — 69. Janin on Fungal Infections (2012)
• Maryland CC Project — Fungal Invasion of the ICU: A catastrophe waiting to happen (2014)

Journal articles

• Brunton, L., Hilal-Dandan, R., Knollman, B. (2017). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition. United States: McGraw-Hill Education. Ch 61.
• Chatelon J, Cortegiani A, Hammad E, Cassir N, Leone M. Choosing the Right Antifungal Agent in ICU Patients. Adv Ther. 2019 Dec;36(12):3308-3320. doi: 10.1007/s12325-019-01115-0. Epub 2019 Oct 15. PMID: 31617055; PMCID: PMC6860507.
• Dockrell, H., Goering, R., Chiodini, P. L., Zuckerman, M. (2018). Mims’ Medical Microbiology and Immunology. United Kingdom: Elsevier. Ch 4, 34.
• Enoch DA, Ludlam HA, Brown NM. Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006 Jul;55(Pt 7):809-18. PMID: 16772406.
• Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014 Jan;27(1):68-88. doi: 10.1128/CMR.00046-13. PMID: 24396137; PMCID: PMC3910906.
• Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother. 2018 Jan 1;73(suppl_1):i26-i32. doi: 10.1093/jac/dkx446. PMID: 29304209; PMCID: PMC6636388.
• Van Thiel DH, George M, Moore CM. Fungal infections: their diagnosis and treatment in transplant recipients. Int J Hepatol. 2012;2012:106923. PMC3433127.
• Wall G, Lopez-Ribot JL. Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy. Antibiotics (Basel). 2020 Jul 25;9(8):445. doi: 10.3390/antibiotics9080445. PMID: 32722455; PMCID: PMC7460292.