## Identify common fungal parasites and pathogens

Parasitism describes a symbiotic relationship in which one member of the association benefits at the expense of the other. Both parasites and pathogens harm the host; however, the pathogen causes a disease, whereas the parasite usually does not. Commensalism occurs when one member benefits without affecting the other. Fungi engage in both these types of relationships with other organisms, but as parasites are responsible for economic and environmental damage, as well as some human diseases.

### Learning Objectives

• Describe fungal parasites and pathogens of plants
• Describe the different types of fungal infections in humans
• Explain why antifungal therapy is becoming less successful in public health

## Infections in Plants

The production of sufficient good-quality crops is essential to human existence. Plant diseases have ruined crops, bringing widespread famine. Many plant pathogens are fungi that cause tissue decay and eventual death of the host (Figure 1). In addition to destroying plant tissue directly, some plant pathogens spoil crops by producing potent toxins. Fungi are also responsible for food spoilage and the rotting of stored crops. For example, the fungus Claviceps purpurea causes ergot, a disease of cereal crops (especially of rye). Although the fungus reduces the yield of cereals, the effects of the ergot’s alkaloid toxins on humans and animals are of much greater significance. In animals, the disease is referred to as ergotism. The most common signs and symptoms are convulsions, hallucination, gangrene, and loss of milk in cattle. The active ingredient of ergot is lysergic acid, which is a precursor of the drug LSD. Smuts, rusts, and powdery or downy mildew are other examples of common fungal pathogens that affect crops.

Figure 1. Some fungal pathogens include (a) green mold on grapefruit, (b) powdery mildew on a zinnia, (c) stem rust on a sheaf of barley, and (d) grey rot on grapes. In wet conditions Botrytis cinerea, the fungus that causes grey rot, can destroy a grape crop. However, controlled infection of grapes by Botrytis results in noble rot, a condition that produces strong and much-prized dessert wines. (credit a: modification of work by Scott Bauer, USDA-ARS; credit b: modification of work by Stephen Ausmus, USDA-ARS; credit c: modification of work by David Marshall, USDA-ARS; credit d: modification of work by Joseph Smilanick, USDA-ARS)

Aflatoxins are toxic, carcinogenic compounds released by fungi of the genus Aspergillus. Periodically, harvests of nuts and grains are tainted by aflatoxins, leading to massive recall of produce. This sometimes ruins producers and causes food shortages in developing countries.

### Dutch Elm Disease

Question: Do trees resistant to Dutch elm disease secrete antifungal compounds?

Hypothesis: Construct a hypothesis that addresses this question.

Background: Dutch elm disease is a fungal infestation that affects many species of elm (Ulmus) in North America. The fungus infects the vascular system of the tree, which blocks water flow within the plant and mimics drought stress. Accidently introduced to the United States in the early 1930s, it decimated shade trees across the continent. It is caused by the fungus Ophiostoma ulmi. The elm bark beetle acts as a vector and transmits the disease from tree to tree. Many European and Asiatic elms are less susceptible to the disease than are American elms.

Test the hypothesis: A researcher testing this hypothesis might do the following. Inoculate several Petri plates containing a medium that supports the growth of fungi with fragments of Ophiostoma mycelium. Cut (with a metal punch) several disks from the vascular tissue of susceptible varieties of American elms and resistant European and Asiatic elms. Include control Petri plates inoculated with mycelia without plant tissue to verify that the medium and incubation conditions do not interfere with fungal growth. As a positive control, add paper disks impregnated with a known fungicide to Petri plates inoculated with the mycelium.

Incubate the plates for a set number of days to allow fungal growth and spreading of the mycelium over the surface of the plate. Record the diameter of the zone of clearing, if any, around the tissue samples and the fungicide control disk.

Record your observations in the following table.

Results of Antifungal Testing of Vascular Tissue from Different Species of Elm
Disk Zone of Inhibition (mm)
Distilled Water
Fungicide
Tissue from Susceptible Elm #1
Tissue from Susceptible Elm #2
Tissue from Resistant Elm #1
Tissue from Resistant Elm #2

Analyze the data and report the results. Compare the effect of distilled water to the fungicide. These are negative and positive controls that validate the experimental set up. The fungicide should be surrounded by a clear zone where the fungus growth was inhibited. Is there a difference among different species of elm?

Draw a conclusion: Was there antifungal activity as expected from the fungicide? Did the results support the hypothesis? If not, how can this be explained? There are several possible explanations for resistance to a pathogen. Active deterrence of infection is only one of them.

## Infections in Humans

Fungi can affect animals, including humans, in several ways. A mycosis is a fungal disease that results from infection and direct damage. Fungi attack animals directly by colonizing and destroying tissues. Mycotoxicosis is the poisoning of humans (and other animals) by foods contaminated by fungal toxins (mycotoxins). Mycetismus describes the ingestion of preformed toxins in poisonous mushrooms. In addition, individuals who display hypersensitivity to molds and spores develop strong and dangerous allergic reactions. Fungal infections are generally very difficult to treat because, unlike bacteria, fungi are eukaryotes. Antibiotics only target prokaryotic cells, whereas compounds that kill fungi also harm the eukaryotic animal host.

Many fungal infections are superficial; that is, they occur on the animal’s skin. Termed cutaneous (“skin”) mycoses, they can have devastating effects. For example, the decline of the world’s frog population in recent years may be caused by the chytrid fungus Batrachochytrium dendrobatidis, which infects the skin of frogs and presumably interferes with gaseous exchange. Similarly, more than a million bats in the United States have been killed by white-nose syndrome, which appears as a white ring around the mouth of the bat. It is caused by the cold-loving fungus Pseudogymnoascus destructans, which disseminates its deadly spores in caves where bats hibernate. Mycologists are researching the transmission, mechanism, and control of P. destructans to stop its spread.

Fungi that cause the superficial mycoses of the epidermis, hair, and nails rarely spread to the underlying tissue (Figure 2). These fungi are often misnamed “dermatophytes,” from the Greek words dermis meaning skin and phyte meaning plant, although they are not plants. Dermatophytes are also called “ringworms” because of the red ring they cause on skin. They secrete extracellular enzymes that break down keratin (a protein found in hair, skin, and nails), causing conditions such as athlete’s foot and jock itch. These conditions are usually treated with over-the-counter topical creams and powders, and are easily cleared. More persistent superficial mycoses may require prescription oral medications.

Figure 2. (a) Ringworm presents as a red ring on skin; (b) Trichophyton violaceum, shown in this bright field light micrograph, causes superficial mycoses on the scalp; (c) Histoplasma capsulatum is an ascomycete that infects airways and causes symptoms similar to influenza. (credit a: modification of work by Dr. Lucille K. Georg, CDC; credit b: modification of work by Dr. Lucille K. Georg, CDC; credit c: modification of work by M. Renz, CDC; scale-bar data from Matt Russell)

Systemic mycoses spread to internal organs, most commonly entering the body through the respiratory system. For example, coccidioidomycosis (valley fever) is commonly found in the southwestern United States, where the fungus resides in the dust. Once inhaled, the spores develop in the lungs and cause symptoms similar to those of tuberculosis. Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. It also causes pulmonary infections, and in rarer cases, swelling of the membranes of the brain and spinal cord. Treatment of these and many other fungal diseases requires the use of antifungal medications that have serious side effects.

Opportunistic mycoses are fungal infections that are either common in all environments, or part of the normal biota. They mainly affect individuals who have a compromised immune system. Patients in the late stages of AIDS suffer from opportunistic mycoses that can be life threatening. The yeast Candida sp., a common member of the natural biota, can grow unchecked and infect the vagina or mouth (oral thrush) if the pH of the surrounding environment, the person’s immune defenses, or the normal population of bacteria are altered.

Mycetismus can occur when poisonous mushrooms are eaten. It causes a number of human fatalities during mushroom-picking season. Many edible fruiting bodies of fungi resemble highly poisonous relatives, and amateur mushroom hunters are cautioned to carefully inspect their harvest and avoid eating mushrooms of doubtful origin. The adage “there are bold mushroom pickers and old mushroom pickers, but are there no old, bold mushroom pickers” is unfortunately true.

## Antifungal Therapy

Just like antibiotics cure bacterial infections, antifungal medications save lives by curing dangerous fungal infections. And just like some bacterial infections are resistant to antibiotics, some fungi no longer respond to the antifungal medications that are designed to cure them. This emerging phenomenon is known as antifungal resistance, and it’s primarily a concern for invasive infections with the fungus Candida.

Although antibiotic-resistant bacterial infections are a widely-recognized public health threat, less is known about the effects of antifungal resistance and the burden of drug-resistant fungal infections. This highlights the need for an improved understanding of the reasons for their emergence, heightened awareness among medical and public health communities about these infections, and greater attention to methods that can be used to prevent and control them.

### The Problem

Figure 3. Medical illustration of fluconazole-resistant Candida

Invasive fungal infections cause substantial morbidity and mortality and are a costly, common problem in healthcare settings. The fungus Candida is the most common cause of healthcare-associated bloodstream infections in the United States.[1] Each case of Candida bloodstream infection (also known as candidemia) is estimated to result in an additional 3 to 13 days of hospitalization and $6,000 to$29,000 in healthcare costs.[2]

What’s also concerning is that some types of Candida are becoming increasingly resistant to first-line and second-line antifungal medications, namely, fluconazole and echinocandins (anidulafungin, caspofungin, and micafungin). Approximately 7% of all Candida bloodstream isolates tested at CDC are resistant to fluconazole, most of which are Candida glabrata.[3], [4] CDC’s surveillance data indicate that the proportion of Candida isolates that are resistant to fluconazole has remained fairly constant over the past twenty years.[5], [6], [7] Echinocandin resistance, however, appears to be on the rise, especially among Candida glabrata. CDC’s surveillance data indicate that up to 8% of Candida glabrata isolates in 2014 may not be susceptible to echinocandins; this proportion nearly doubled from 4% in 2008. This is especially concerning as echinocandins are the mainstay of treatment for Candida glabrata, which already has high levels of resistance to fluconazole.[8]

The stable yet substantial rates of fluconazole resistance and the emergence of echinocandin resistance are concerning because echinocandins are typically used to treat infections caused by C. glabrata, the species that’s most often associated with fluconazole resistance. For multi-drug resistant Candida infections (those that are resistant to both fluconazole and an echinocandin), the few remaining treatment options are expensive and can be toxic for patients who are already very sick. Not surprisingly, there is growing evidence to suggest that patients who have drug-resistant candidemia have poorer outcomes than patients who have candidemia that’s susceptible to antifungal medications.[9], [10] Overall, antifungal resistance is still relatively uncommon, but the problem will likely continue to evolve unless more is done to prevent further resistance from developing and prevent the spread of these infections.

### The Cause

Some species of fungi are naturally resistant to certain types of antifungal medications. Other species may be normally susceptible to a particular type of medication, but develop resistance over time as a result of improper antifungal use—for example, dosages that are too low or treatment courses that aren’t long enough.[11], [12] Some studies have indicated that antibacterial medications may also contribute to antifungal resistance; this could occur for a variety of reasons, one of which is that antibacterials reduce bacteria in the gut and create favorable conditions for Candida growth.[13] It’s not yet known if decreasing the use of all or certain antimicrobial agents can reduce Candida infections, but appropriate use of antibacterial and antifungal agents is one of the most important factors in fighting drug resistance.

### What Can Be Done

Antifungal resistance is becoming increasingly recognized, particularly for Candida. Everyone has a role in preventing Candida infections and reducing antifungal resistance.

• CDC is:
• Tracking trends in antifungal resistance through the Emerging Infections Program by conducting multi-center candidemia surveillance and performing species confirmation and antifungal susceptibility testing on Candida bloodstream isolates.[14], [15]
• Using genetic sequencing and developing new laboratory tests to identify and understand specific mutations associated with antifungal resistance in Candida.
• Hospital executives and infection control staff can:
• Assess antifungal use as part of their antibiotic stewardship programs.
• Ensure adherence to guidelines for hand hygiene, prevention of catheter-associated infections, and environmental infection control.
• Doctors and other hospital staff can:
• Prescribe antifungal medications appropriately.
• Document the dose, duration, and indication for every antifungal prescription.
• Stay aware of local antifungal resistance patterns.
• Participate in and lead efforts within your hospital to improve antifungal prescribing practices.
• Follow hand hygiene and other infection control measures with every patient.
• Hospital patients can:
• Be sure everyone cleans their hands before entering your room.
• If you have a catheter, ask each day if it is necessary.

Answer the question(s) below to see how well you understand the topics covered in the previous section. This short quiz does not count toward your grade in the class, and you can retake it an unlimited number of times.

Use this quiz to check your understanding and decide whether to (1) study the previous section further or (2) move on to the next section.

1. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. The New England journal of medicine 2014;370:1198–208.
2. Morgan J, Meltzer MI, Plikaytis BD, et al. Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infection control and hospital epidemiology 2005;26:540–7.
3. Vallabhaneni S, Cleveland A, Farley M, et al. Epidemiology and Risk Factors for Echinocandin Nonsusceptible Candida glabrata Bloodstream Infections: Data From a Large Multisite Population-Based Candidemia Surveillance Program, 2008–2014. Open Forum Infect Diseases 2015;2(4):ofv163.
4. Lockhart SR, Iqbal N, Cleveland AA, et al. Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011. Journal of clinical microbiology 2012;50:3435–42.
5. Ibid.
6. Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program. Journal of clinical microbiology 2004;42:1519–27.
7. Kao AS, Brandt ME, Pruitt WR, et al. The epidemiology of candidemia in two United States cities: results of a population-based active surveillance. Clinical infectious diseases 1999;29:1164–70.
8. Vallabhaneni S, Cleveland A, Farley M, et al.
9. Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clinical infectious diseases 2013;56:1724–32.
10. Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrobial agents and chemotherapy 2008;52:3022–8.
11. Lortholary O, Desnos-Ollivier M, Sitbon K, et al. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrobial agents and chemotherapy 2011;55:532–8.
12. Shah DN, Yau R, Lasco TM, et al. Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia. Antimicrobial agents and chemotherapy 2012;56:3239–43.
13. Ben-Ami R, Olshtain-Pops K, Krieger M, et al. Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrobial agents and chemotherapy 2012;56:2518–23.
14. Vallabhaneni S, Cleveland A, Farley M, et al.
15. Lockhart SR, Iqbal N, Cleveland AA, et al.