Mitigation of Human-Pathogenic Fungi That Exhibit Resistance to Medical Agents: Can Clinical Antifungal Stewardship Help?

Claire M Hull; Nicola J Purdy; Suzy C Moody

Future Microbiol. 2014;9(3):307-325.

Abstract

Reducing indiscriminate antimicrobial usage to combat the expansion of multidrug-resistant human-pathogenic bacteria is fundamental to clinical antibiotic stewardship. In contrast to bacteria, fungal resistance traits are not understood to be propagated via mobile genetic elements, and it has been proposed that a global explosion of resistance to medical antifungals is therefore unlikely. Clinical antifungal stewardship has focused instead on reducing the drug toxicity and high costs associated with medical agents. Mitigating the problem of human-pathogenic fungi that exhibit resistance to antimicrobials is an emergent issue. This article addresses the extent to which clinical antifungal stewardship could influence the scale and epidemiology of resistance to medical antifungals both now and in the future. The importance of uncharted selection pressure exerted by agents outside the clinical setting (agricultural pesticides, industrial xenobiotics, biocides, pharmaceutical waste and others) on environmentally ubiquitous spore-forming molds that are lesserstudied but increasingly responsible for drug-refractory infections is considered.

1 2 3 4 5 6 7 8 9 10 11

Next Section

Table 1. Contemporary medical antifungal agents.
Target	Antifungal class (example)	Mode of action	Resistance mechanism(s)
Intracellular	Pyrimidine analogs and thymidylate synthase inhibitors (flucytosine/5-FC)	Impairment of nucleic acid biosynthesis via formation of toxic fluorinated antimetabolites	Decreased drug uptake Decreased antimetabolite formation Defect in cytosine permease
Intracellular	Mitotic inhibitors (griseofulvin)	Bind tubulin and disrupt microtubule and spindle formation	–
Cell wall/membrane	Allylamines (terbinafine)	Inhibition of squalene epoxidase (ERG1)	Mutations in target enzyme
	Morpholines (amorolfine)	Inhibition of sterol reductase (ERG4 and ERG24) and sterol isomerase (ERG2) proteins	Mutations in target enzyme(s)
	Azoles (topical: clotrimazole) (systemic: fluconazole)	Inhibition of sterol 14α-demethylase (ERG11), an essential ergosterol biosynthetic enzyme Notes: ergosterol maintains the integrity and fluidity of the fungal membrane and thus cell viability Sterol 14α-demethylase is a is CYP450 enzyme, also termed CYP51	Azole efflux mediated by transporter proteins Mutations in ERG11 which preserve sterol 14α-demethylase function Alterations in activity of sterol biosynthetic proteins/fungal sterol composition (e.g., suppressor mutation(s) in ERG3) Uptake of exogenous 'rescue' sterols (e.g., host cholesterol)
	Polyenes (topical: nystatin; systemic: amphotericin B)	Bind to cell membrane ergosterol causing membrane perturbation and leakage of cellular ions	Mutations in genes encoding sterol biosynthetic proteins (to include ERG2, ERG3, ERG5, ERG6 and ERG11) and an absence or reduction of cellular ergosterol
	Echinocandins (caspofungin)	Inhibition of 1,3-β glucan synthase and synthesis of cell-wall glucan	Mutations in FKS1/FKS2 that encode putative subunits of 1,3-β glucan synthase

Table 2. Clinical summary for selected spore-forming, environmentally ubiquitous human-pathogenic fungi.
Species	Disease(s) (to include)	Typical antifungal treatment choice(s)
Species	Disease(s) (to include)	Pyrimidine analogs	Echinocandins	Polyenes	Allylamines	Azoles
Aspergillus spp.	Allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis	^†	^†	^‡,§	^¶	^‡,¶,§
Basidiobolus ranarum	Subcutaneous chronic zygomycosis	^¶		^¶		^‡,¶,§
Blastomyces dermatitidis	Cutaneous and systemic (disseminated) blastomycosis			^‡		^‡
Cladosporium spp.	Infections of the skin and toenails, as well as sinusitis and pulmonary infections			^‡		^‡
Coccidioides immitis	Valley fever; influenza-like illness with fever, cough, headaches, rash, myalgia and arthralgia			^‡		^‡,¶
Conidiobolus coronatus	Rhinofacial zygomycosis, subcutaneous infection of nasal mucosa and maxillofacial tissues			^¶		^‡,¶
Cryptococcus spp.	Pneumonia-like illness. Symptoms include shortness of breath, cough and fever	^†	^¶	^†,§		^‡,¶,§
Exserohilum rostratum	Keratitis, subcutaneous phaeohyphomycosis, endocarditis, osteomyelitis and sinusitis		^‡	^‡		^‡
Fusarium spp.	Onychomycosis, superficial suppurative thrombophlebitis; asthma, allergic rhinitis and hypersensitivity pneumonitis			^‡,¶	^¶	^¶,‡
Geotrichum spp.	Pulmonary, bronchial, oral, vaginal, cutaneous and alimentary infections; allergic and asthmatic reactions	^‡	^†	^‡		^‡,†
Histoplasma capsulatum	Often asymptomatic. Nonspecific respiratory symptoms, cough/flu-like resembling tuberculosis. Ocular histoplasmosis			^‡		^‡
Lichtheimia corymbifera	Subcutaneous mycosis and opportunistic pulmonary, rhinocerebral, disseminated, CNS or cutaneous infection			^‡	^¶	^‡
Paecilomyces spp.	Peritonitis, endophthalmitis following lens implantation, endocarditis, pyelonephritis, sinusitis and cutaneous lesions	^¶		^‡	^‡	^‡,¶
Paracoccidioides brasiliensis	Systemic mycosis; primary pulmonary infection often inapparent, disseminates to buccal, nasal and gastrointestinal mucosa			^‡		^‡
Penicillium marneffei	Systemic infection (penicilliosis) with fever and anemia similar to disseminated cryptococcosis			^‡	^‡	^‡
Pseudallescheria boydii	To include: sinusitis, keratitis, lymphadenitis, endophthalmitis, meningoencephalitis, brain abscess, endocarditis and pneumonia, lung abscess, pulmonary fungus ball, allergic bronchopulmonary fungal disease, bursitis, arthritis, osteomyelitis, urethritis and disseminated infections			^‡,¶		^¶,‡
Rhizopus spp.	Rhinocerebral and craniofacial mucormycosis			^‡,¶	^¶	^‡,¶
Scopulariopsis spp.	Onychomycosis, skin lesions, mycetoma, sinusitis, keratitis, endophthalmitis, pulmonary infections, endocarditis, brain abscess and disseminated infections	^¶		^‡,¶	^¶,†	^‡,†,¶
Sporothrix schenckii	Subcutaneous and disseminated mycosis. Gardeners, landscapers and foresters at heightened risk			^‡		^‡,¶
Trichosporon spp.	White piedra, superficial infections and invasive trichosporonosis affecting lungs, kidneys, spleen, CNS, cornea and peritoneum		^¶	^¶	^†	^‡,¶,†

^†Effective combination therapy; ^‡Antifungal activity; ^§Acquired resistance documented; ^¶Intrinsic resistance to certain agents.

Table 3. Ecological information for selected spore-forming, environmentally ubiquitous humanpathogenic fungi.
Species	Distribution	Habitat/ecological niche					Host/vector		Infection route(s)
Species	Distribution	Dust	Soil and compost	Animal feces	Fresh water	Sea water	Plant	Animal(s)	Spore inhalation	Traumatic inoculation	Mucosal surfaces	Ingestion
Aspergillus spp.	Worldwide	^†	^†	^†			^†	^‡, ^§, ^¶	^†	^†
Basidiobolus ranarum	Worldwide; typically Africa, South America and tropical Asia		^†	^†				^#, ^† ^†, ^§, ^‡ ^‡, ^§ ^§, ^¶, ^¶ ^¶		^# ^#		^# ^#
Blastomyces dermatitidis	Endemic in North America. Africa		^†		^# ^#			^§	^†
Cladosporium spp.	Worldwide		^†				^†		^†
Coccidioides immitis	Southwestern USA, Mexico, Central and South America	^†	^†					^§, ^¶	^†	^†
Conidiobolus coronatus	Worldwide; especially Africa, Central America and India		^†	†				^#, ^§, ^§ ^§, ^¶	^†	^†	^†
Cryptococcus spp.	Worldwide		^†	^†				^‡	^†
Exserohilum rostratum	Worldwide; warm and humid climates		^†	^†			^†			^†	^†
Fusarium spp.	Worldwide		^†		^# ^#		^†			^†
Geotrichum spp.	Worldwide		^†	^†			^†		^†
Histoplasma capsulatum	Worldwide. Endemic in eastern and central USA. Africa		^†	^†				^† ^†, ^‡, ^¶	^†
Lichtheimia corymbifera	Worldwide		^†	^†				^¶	^†	^†	^# ^#
Paecilomyces spp.	Worldwide		^†					^‡, ^§, ^§ ^§	^†	^†	^†
Paracoccidioides brasiliensis	Brazil and South America				^# ^#	^# ^#			^†		^# ^#
Penicillium marneffei	Prevalent southeast Asia. Reports from Australia, Europe, Japan, UK and USA		^†	^†				^† ^† ^†	^# ^#			^# ^#
Pseudallescheria boydii	Worldwide		^†	^†	^†			^§, ^¶		^†
Rhizopus spp.	Worldwide; high prevalence in tropical and subtropical regions	^†	^†	^†					^†	^†
Scopulariopsis spp.	Worldwide	^†	^†	^†				^§ ^§	^†	^†
Sporothrix schenckii	Worldwide; often South America		^†	^†				^§		^†
Trichosporon spp.	Worldwide; typically tropical and temperate regions		^†	^†	^†	^†		^† ^†, ^‡, ^§, ^¶		^†	†

^†Typically; ^‡Bird; ^§Domestic pets; ^¶Livestock; ^#Amphibians; ^††Bat; ^‡‡Fish; ^§§Insects; ^¶¶Reptiles; ^##Possibly; ^†††Rats.

Sidebar

Executive Summary

Antifungal stewardship

Contemporary drivers
- Provide cost-efficient care through optimal resource utilization and appropriate antifungal drug choice.
- Reduce indiscriminate use of fungicides and establish evidence-based treatment guidelines.
- Determine and refine antifungal drug doses to minimize toxicity and adverse drug interactions.
Future targets
- Develop rapid, accurate diagnostics for human-pathogenic fungi and improved (including combination or novel) antifungal treatments.
- Establish and monitor the actual scale of antifungal resistant fungi (local and global trends).
- Robust, evidence-based clinical guidelines for efficacious treatment regimens and patient care (personalized medicine).

Resistance to medical antifungal agents: is it really a problem?

Traditional view
- Natural horizontal transfer of genes encoding resistance is not known to occur in fungi; a global explosion of resistance to clinically used antifungals is therefore unlikely.
- Human-pathogenic fungi present in the environment are not exposed to clinically used antifungals, thus selection pressure for resistance is low.
- Enzymatic metabolism/detoxification of currently available medical agents is not understood to occur in fungi.
Evidence for resistance is growing
- Several antifungal resistance mechanisms are now known, including: drug efflux, alterations in drug targets, changes in cell membrane and lipid composition, facultative uptake of 'rescue' sterols.
- Antifungal resistant (and cross-resistant) human-pathogenic fungal isolates documented in hospitals and wider environment.
Problem fungi
- Spore-forming, environmentally ubiquitous molds (e.g., Aspergillus and Rhizopus spp.) that cause opportunistic mucormycoses and disease in humans (immunocompromised and immunocompetent hosts).
- Commensal species that can, and do, cause drug-refractory systemic infections (e.g., Candida glabrata).

Awareness points & emergent issues

There are significant geographical variations in fungal epidemiology and resistance; local trends must be monitored in order to develop guidelines for appropriate antifungal treatment.
Need to characterize resistance traits (acquired and intrinsic) and to develop molecular diagnostics to differentiate between susceptible and resistant isolates.
Factors governing species distributions and dispersal are vast: climatic (including climate change) and geographic variation; wind, fresh water and oceanic transport; animal and plant vectors and/or hosts.
There is a need for fundamental research into fungal biology, including the extent and clinical relevance of cryptic sexuality and sexual reproduction.
There is a need to better-understand the relationship(s) between the biology of the human host and the infecting fungus, and how these might influence the epidemiology of species that exhibit intrinsic antifungal resistance.
Non-antifungal xenobiotics used in medical, industrial, agricultural and domestic settings could exert 'off-target' selection pressure for antifungal resistance traits. Regulation and stewardship of existing and new chemical agents is needed.