Antifungal Resistance

Fungal infections that are resistant to treatment are a public health challenge. We all have a role in preventing these infections and reducing antifungal resistance.

The problem

Medical illustration of fluconazole-resistant Candida

Medical illustration of fluconazole-resistant Candida

Antifungal drugs save lives by treating dangerous fungal infections, just like antibacterial drugs (antibiotics) are used to treat bacterial infections. Unfortunately, germs like bacteria and fungi can develop the ability to defeat the drugs designed to kill them. This is known as antimicrobial resistance. That means the germs are not killed and continue to grow. When this occurs with fungi that no longer respond to antifungal drugs, it is called antifungal resistance. This is especially a concern for patients with invasive infections like those caused by the fungus Candida, a yeast, which can cause serious health problems, including disability and death.

More information is needed about the risk antifungal resistance poses on human health and how many people are sickened by drug-resistant fungal infections each year. CDC and its partners are working to:

  • Better understand why and how antifungal resistance emerges.
  • Increase awareness among medical and public health communities about these infections.
  • Develop better methods to prevent and control drug-resistant fungal infections.

Fungal infections are a serious problem in healthcare settings

Invasive fungal infections can cause disability and death. Patients can get fungal infections while receiving care for something else in a healthcare facility. For example, the fungus Candida is a leading cause of healthcare-associated bloodstream infections in US hospitals.1 These infections are also costly for patients and healthcare facilities. 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 when we find antifungal resistance in some types of Candida, which makes them harder to treat.

Antifungal resistance makes infections harder to treat

Antifungal resistance is a particular problem with Candida infections. Some types of Candida are increasingly resistant to the first-line and second-line antifungal medications, such as fluconazole and the echinocandins (anidulafungin, caspofungin, and micafungin). About 7% of all Candida bloodstream isolates (pure samples of a germ) tested at CDC are resistant to fluconazole. More than 70% of these resistant isolates are the species Candida glabrata or Candida krusei.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 20 years.4-6 Echinocandin resistance, however, appears to be emerging, especially among Candida glabrata isolates. CDC’s surveillance data indicate that approximately 3% of Candida glabrata isolates are resistant to echinocandins. This is especially concerning as echinocandins are the first-line treatment for Candida glabrata, which already has high levels of resistance to fluconazole.3

Multidrug-resistant Candida infections (those that are resistant to both fluconazole and an echinocandin) have very few remaining treatment options. The primary treatment option is Amphotericin B, a drug that 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 are less likely to survive than patients who have candidemia that can be treated by antifungal medications.7,8  We must act to prevent further resistance from developing and to prevent the spread of these infections. Emerging antifungal resistance has been identified in species like Candida auris.9 Isolates of C. auris sent to CDC are almost all resistant to fluconazole, and up to one-third are resistant to amphotericin B, usually reserved as a last-resort treatment.10 Most C. auris isolates are susceptible to echinocandins. However, echinocandin resistance can develop while the patient is being treated. C. auris is also a concerning public health issue because it is difficult to identify with standard laboratory methods and because it spreads easily in healthcare settings, such as hospitals and long-term care facilities.

Antifungal resistance in Aspergillus

Microscopy of Aspergillus Fumigatus

Microscopic view of Aspergillus

Although the most common antifungal resistance occurs in Candida species, resistance in other types of less common fungi is also a problem. In Aspergillus (a mold) infections, emerging resistance to the first-line treatment threatens the effectiveness of life-saving medications.

In general, Aspergillus infections are associated with high rates of death, especially in patients with weakened immune systems or underlying disease. Aspergillus is the leading cause of invasive mold infections, with an estimated 300,000 cases worldwide every year.11 Depending on location, up to 12% of Aspergillus infections are estimated to be resistant to antifungal medications.12 In a large US study, antifungal resistance was identified in up to 7% of Aspergillus specimens from patients with stem cell and organ transplants.13-15

Resistant Aspergillus infections can develop in people who have taken certain antifungal medications.16 However, resistant infections are also found in people who have not taken antifungal medications. This demonstrates that antifungal resistance in Aspergillus is likely acquired before entering the healthcare setting and is partially driven by environmental sources. For example, research shows that agricultural use of azole fungicides to treat crop diseases, which are similar to azole medications like fluconazole, can lead to the growth of resistant strains of Aspergillus in soil and other places in the environment.17,18 If people with weakened immune systems breathe in antifungal-resistant Aspergillus spores, then they could develop infections that are difficult to treat. There is a potential for resistant infections if people with weak immune systems breathe in spores.18 More research is needed about how Aspergillus becomes resistant and how to prevent people from getting resistant Aspergillus infections.

What causes antifungal resistance?

Some species of fungi are naturally resistant to treatment with certain types of antifungal medications. Other species can develop resistance over time due to improper antifungal use—for example, dosages too low or treatment courses that are not long enough.19,20

Some studies have indicated that antibacterial medications may also contribute to antifungal resistance. This resistance could occur for a variety of reasons. For example, antibacterial drugs can reduce good and bad bacteria in the gut, which creates favorable conditions for Candida growth.21 It is not yet known if decreasing the use of all or certain antibiotics can reduce Candida infections, but appropriate use of antibacterial and antifungal medications is one of the most important factors in fighting drug resistance.

What you can do

Antifungal resistance is a growing threat. Everyone has a role to play in preventing fungal infections and reducing antifungal resistance.

  • CDC is:
    • Tracking trends in antifungal resistance through the Emerging Infections Program by conducting multicenter candidemia surveillance and performing species confirmation and antifungal susceptibility testing on Candida bloodstream isolates.
    • Using genetic sequencing and developing new laboratory tests to identify and understand specific mutations associated with antifungal resistance in Candida.
    • Summarizing antifungal prescribing patterns across different healthcare facilities to understand opportunities to promote appropriate use of antifungals.
  • Healthcare facility 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.
    • Test for antifungal resistance for patients with invasive disease who are not improving with first-line antifungal medications.22,23
    • Stay aware of resistance patterns, including antifungal resistance, in your facility and community.
    • Document the dose, duration, and indication for every antifungal prescription.
    • Participate in and lead efforts within your hospital to improve antifungal prescribing practices.
    • Follow hand hygiene and other infection prevention and control guidelines with every patient.
  • Hospital patients can:
    • Clean your hands.
    • Be sure everyone cleans their hands before entering your room.
    • If you have a catheter, ask each day if it is necessary.
    • Talk to your healthcare provider about your risk for certain infections, especially if you have a weakened immune system.
    • Learn more about using antibiotics, including when they are needed and when they are not.

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References
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  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. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Satoh K, Makimura K, Hasumi Y, Nishiyama Y, Uchida K, Yamaguchi H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol 2009;53:41-4.
  10. Lockhart SR, Etienne KA, Vallabhaneni S, et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2017;64:134-40.
  11. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med 2012;4:165rv13.
  12. Rivero-Menendez O, Alastruey-Izquierdo A, Mellado E, Cuenca-Estrella M. Triazole Resistance in Aspergillus spp.: A Worldwide Problem? J Fungi (Basel) 2016;2.
  13. Baddley JW, Marr KA, Andes DR, et al. Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network. Journal of clinical microbiology 2009;47:3271-5.
  14. Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clinical Infectious Diseases 2010;50:1091-100.
  15. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clinical Infectious Diseases 2010;50:1101-11.
  16. Howard SJ, Cerar D, Anderson MJ, et al. Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerging infectious diseases 2009;15:1068-76.
  17. Mortensen KL, Mellado E, Lass-Florl C, Rodriguez-Tudela JL, Johansen HK, Arendrup MC. Environmental study of azole-resistant Aspergillus fumigatus and other aspergilli in Austria, Denmark, and Spain. Antimicrobial agents and chemotherapy 2010;54:4545-9.
  18. Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis 2009;9:789-95.
  19. 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.
  20. 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.
  21. 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.
  22. Patterson TF, Thompson GR, 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-e60.
  23. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016;62:e1-50.