Antimicrobial Resistance Series Part 2: Antifungal Resistance

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Antimicrobial Resistance Series Part 2 Antifungal Resistance

A Review of Microbes and Antimicrobial Resistance

Microbes are:

  • Bacteria
  • Fungi
  • Viruses
  • Parasites

Antimicrobial drugs are:

  • Antibiotics for bacterial infections
  • Antifungals for fungal infections
  • Antivirals for viral infections
  • Antiparasitics for parasitic infections

Antifungal Resistance in Context

First identified in 2009 in Japan from a man’s earwax, the fungus, Candida auris, has quickly spread around the globe and become one of the most antifungal resistant and deadliest fungi known.

A man, who was admitted for abdominal surgery, contracted the fungus at Mt. Sinai Hospital in NY City and died after 90 days. The hospital found out that every single surface – walls, ceiling tiles, medical equipment, mattress, basically everything in his room was covered with C. auris. They had to use special equipment to help eradicate it.

How did this C. auris go unnoticed for so long? Researchers believe it is a newly emerged drug-resistant fungal strain that arose from the use of fungicides on crops.

C. auris mainly afflicts severely immunocompromised individuals. But, don’t feel complacent.

Vaginal yeast infections. Nail infections. Athlete’s foot. Jock itch. Ringworm.

These conditions are common, treatable and – for the most part – benign. They, too, are susceptible to potentially becoming resistant to antifungal drugs. Then, we would be forced to live with these conditions assaulting our bodies. You can roll your eyes at this proclamation, but…

Let’s look at vaginal yeast infections:

Three out of four females will experience a vaginal yeast infection at some point in their lifetime. Yeast infections can vary from the uncomplicated to complicated. Sometimes, an uncomplicated vaginal yeast infection can clear up on its own within a few days. Other times, it may need a little bit of help with an antifungal topical or oral medication.

What causes a yeast infection? An excess growth of the common fungus, Candida albicans. The second most prevalent species is C. glabrata (10-30%). We all have been exposed to these ubiquitous forms of Candida sp. Plus, we have heard a lot about how to reduce Candida in and on the body such as reducing our intake of alcohol, grains and sugars.

Let’s say something happens that – no matter what you did to reduce Candida – you still get a yeast infection because of some sort of change in your body. The most frequent causes of yeast infections in women (and pets) occur because they:

  • Are pregnant
  • Take hormonal contraceptives (for example, birth control pills)
  • Have diabetes
  • Have a weakened immune system (for example, due to HIV and other infections, hormonal imbalances like hypothyroidism and Cushing’s syndrome, or take medicines that weaken the immune system, such as steroids and chemotherapy)
  • Are taking or have recently taken antibiotics

In fact, 30% of vaginal yeast infection cases are attributed to antibiotic use. The reason is that the antibiotics not only kill the ‘bad’ bacteria causing a bacterial infection, but also kill the ‘good’ bacteria. The good bacteria fight to suppress the Candida, but once they are depleted, the Candida yeastcan take over.

Researchers are noticing a minor uptick in C. albicans resistance to the currently preferred treatment option. Antifungal resistance is also becoming common among isolates of C. glabrata.

So, not only are we making the bacteria more antibiotic resistant, but we are compounding the situation with antifungal resistance if we have to resort to an antifungal to control a bad vaginal yeast infection.

Examples of Fungal Infections

  • Ringworm (fungus: Tinea)
  • Nail infection
  • Athlete’s foot (fungus: Tinea)
  • Jock itch (fungus: Tinea)
  • Vaginal yeast infection (fungus: Candida)
  • Thrush (Candida of the mouth, throat and esophagus)
  • Valley Fever (fungus: Coccidioides)
  • Blastomycosis (fungus: Blastomyces)
  • Histoplasmosis (fungus: Histoplasma)
  • Aspergillosis (fungus: Aspergillus)

Fungi Are Not Only Superficial

Fungi exist not only on the body, but also inside the body.

Candida species can cause superficial infections of the oral and vaginal mucosa as well as disseminated infections of the bloodstream and deep-tissues.

For instance, the condition candidemia is the presence of Candida yeast that leaked out of the intestines into the bloodstream, causing a potentially life-threatening whole-body infection.

C. auris, mentioned previously, causes bloodstream infections.

The fungal spores of Valley Fever, blastomycosis and histoplasmosis are inhaled and can cause flu-like and more severe systemic symptoms.

Overview of Antifungal Treatment Issues

  • A limited number of antifungal medications are available, although new antifungal treatment options are in development.
  • The classes of antifungals are: polyenes, azoles, allylamines, flucytosine, and echinocandins.
  • Amphotericin B, the first antifungal drug developed, is associated with significant renal toxicity.
  • The symptoms of invasive fungal infections can present like bacterial infections. So, a patient may be prescribed antibiotics instead of an antifungal. Since good and bad bacteria are usually destroyed by the antibiotic, a fungal infection can run rampant throughout the body.
  • Even if a bacterial infection is correctly treated, a fungal infection can still take over, particularly in immunocompromised patients.

Fluconazole Resistance

  • Fluconazole was developed in the 1990’s and is a member of the azole class of antifungals.
  • Azoles can be used to treat many fungal infections like Valley Fever, blastomycosis and Candida infections.
  • In the United States, C. albicans has a low incidence of resistance to fluconazole, approximately 0.5–2%.
  • C. tropicalis is worldwide, but is primarily in tropical and subtropical climates. It can have a resistance rate of 4-9%.
  • C. parapsilos is universal and resistance is around 2-6%.
  • C. glabrata is second most common in the U.S. and has a resistance rate of 11-13%.
  • C. auris can exhibit a rate of resistance to fluconazole as high as 93%.
  • C. krusei is innately resistant to fluconazole.
  • Resistance to fluconazole may increase the resistance to other azoles, such as ketoconazole and itraconazole. These drugs are commonly used in veterinary medicine.

Echinocandin Resistance

  • Echinocandins were introduced in 2001. Soon after, resistance started occurring.
  • Echinocandins are the recommended course of treatment for immunocompromised patients and those who have had prior azole exposure.
  • At this time, resistance to echinocandins remains low.
  • C. glabrata is of particular concern with echinocandin treatment. While clinical failure rates vary depending on the institution (hospital) analyzed, one study of Duke Hospital in North Carolina documented that C. glabrata resistance to echinocandins increased from 4.9% to 12.3% from 2001-2010.
  • 11% of fluconazole resistant bloodstream infections were also resistant to an echinocandin.

References

“About Antimicrobial Resistance”. Centers for Disease Control and Prevention, 10 Sept. 2018, http://www.cdc.gov/drugresistance/about.html.

Alexander, Barbara D et al. “Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations.” Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America vol. 56,12 (2013): 1724-32. doi:10.1093/cid/cit136, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658363/.

Berkow, Elizabeth L, and Shawn R Lockhart. “Fluconazole resistance in Candida species: a current perspective.” Infection and Drug Resistance vol. 10 237-245. 31 Jul. 2017, doi:10.2147/IDR.S118892, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546770/.

Gygax, Scott, et al. “Antifungal Resistance of Candida Glabrata Vaginal Isolates and Development of a Quantitative Reverse Transcription-PCR-Based Azole Susceptibility Assay.” Antimicrobial Agents and Chemotherapy, vol. 52, no. 9, Aug. 2008, pp. 3424–3426., doi:10.1128/AAC.00462-08, https://aac.asm.org/content/52/9/3424.

Sobel, Jack. “Vulvovaginal Candidosis.” The Lancet, vol. 369, no. 9577, 9 Jan. 2007, pp. 1961–1971, doi:10.1016/S0140-6736(07)60917-9, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60917-9/fulltext.

Wiederhold, Nathan P. “Antifungal resistance: current trends and future strategies to combat.” Infection and Drug Resistance vol. 10 249-259. 29 Aug. 2017, doi:10.2147/IDR.S124918, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587015/.

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