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Clinical Considerations in Conducting Antifungal Susceptibility Testing

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Strategic Alliance Partners | <b>Society of Infectious Diseases Pharmacists</b>

Access to antifungal susceptibility testing (AFST) remains limited in the United States. Therefore, providers must recognize clinical situations where AFST will provide its greatest value. In the latest article from SIDP, infectious disease pharmacists offers some insights on this subject.

Individuals at risk for invasive fungal infections (IFI) have increased due to the growing population of immunodeficient individuals.1 Worldwide emergence of resistant fungus coupled with widespread use of antifungals has resulted in increased selective pressure.1 Unfortunately, access to antifungal susceptibility testing (AFST) remains limited in the U.S. with only 30% of acute care hospitals offering AFST in their own or an affiliated laboratory.2 In light of this, clinicians must recognize scenarios where AFST will provide greatest value.

Selection of antifungal therapy

Ideally, AFST should be performed on isolates from normally sterile (i.e. blood, CSF, etc.) sites. Though the 2016 IDSA guideline for candidiasis recommended AFST for all Candida spp. isolated from blood, echinocandin and fluconazole susceptibility were performed in only 40% and 54% of patients with candidemia, respectively.3-4 Notably, echinocandin susceptibility was performed in less than 50% of C glabrata or C parapsilosis isolates.4 Transition from an echinocandin to fluconazole is recommended for susceptible isolates, but 40% of patients were changed to fluconazole without AFST.4

Both IDSA and ESCMID do not recommend routine AFST for all Aspergillus spp. isolates since many species exhibit variable susceptibility to antifungal therapies.5-6 However, the prevalence of cross-resistance to azole antifungals identified in A. fumigatus isolates is increasing worldwide leading to poor patient outcomes.7 As a result, AFST is recommended when A. fumigatus is isolated, especially in areas with greater than 10% azole resistance.8

While not recommended for isolates with known intrinsic resistance (e.g., C krusei and fluconazole), AFST should be performed in patients not responding to antifungal therapy or suspected to have a resistant isolate.1

Alternatively, the clinical significance of AFST for Cryptococcus neoformans remains unknown. Smaller studies identified an association between susceptibility and outcomes in cryptococcal meningoencephalitis, but the findings were unable to be replicated using a larger cohort.9

While antifungal susceptibility may be predicted in many fungal species, the above findings, along with reports of C auris, echinocandin-non-susceptible C glabrata, and azole-resistant A fumigatus infections, emphasize the importance of when AFST should be considered.7,10-11 If AFST is unavailable on-site, references labs may be utilized in non-responders, those with prior echinocandin exposure, and in species in which resistance is rising (C parapsilosis, C glabrata).3 Epidemiological data through the CDC and other surveillance programs may be useful in resource-limited settings.

Monitoring antifungal resistance rates

Recent data indicate the proportion of fluconazole-non-susceptible Candida isolates has remained constant for the last 20 years, but echinocandin resistance among C glabrata has increased to approximately 3%.12 For emerging pathogens, such as C auris, approximately 90%, 30%, and 3% isolates collected have been resistant to fluconazole, amphotericin B, and echinocandins, respectively.13 These data suggest the importance of monitoring antifungal resistance rates.

Fortunately, several surveillance programs exist to monitor antifungal resistance rates worldwide. For example, SENTRY Antimicrobial Surveillance Program through JMI labs has several sites across the world.14 Nationally, the Centers for Disease Control and Prevention (CDC) is engaged in surveillance via the 2020 US National Action Plan.13 In addition, resource-limited institutions are encouraged to form relationships with reference labs to obtain local susceptibility data when necessary.1 Collection of surveillance data via several means will guide therapeutic choices and alert clinicians to novel resistance patterns.

Ultimately, selection of antifungal therapy and monitoring of resistance rates are scenarios of particular interest where ASFT may provide most value, especially in resource-limited settings.

Aiman Bandali is an infectious diseases clinical pharmacist at Atlantic Health System at the Overlook Medical Center in Summit, NJ.

Daniel Chastain is a clinical associate professor at the University of Georgia College of Pharmacy on the Southwest Georgia Clinical Campus and serves as the infectious diseases pharmacist for Phoebe Putney Memorial Hospital in Albany, Georgia.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References

  1. Weiderhold NP. Antifungal Susceptibility Testing: A Primer for Clinicians. Open Forum Infect Dis.2021 Sep;8(11):ofab444. doi: 10.1093/ofid/ofab444.
  2. Vallabhaneni S, Sapiano M, Weiner LM,et al. Antifungal Susceptibility Testing Practices at Acute Care Hospitals Enrolled in the National Healthcare Safety Network, United States, 2011-2015. Open Forum Infect Dis.2017 Aug;4(4):ofx175.
  3. 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. Clin Infect Dis.2016 Feb;62(4):e1-50.
  4. Gold JAW, Seagle EE, Nadle J, et al. Treatment Practices for Adults With Candidemia at 9 Active Surveillance Sites-United States, 2017-2018.Clin Infect Dis.2021 Nov;73(9):1609-1616.
  5. 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 Aug;63(4):e1-e60. doi: 10.1093/cid/ciw326.
  6. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018 May;24 Suppl 1:e1-e38.
  7. Verweij PE, Chowdhary A, Melchers WJ, et al. Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin Infect Dis. 2016 Feb;62(3):362-8.
  8. Verweij PE, Ananda-Rajah M, Andes D, et al. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist Updat. 2015 Jul-Aug;21-22:30-40.
  9. O'Connor L, Van Anh D, Chau TTH, et al. Antifungal Susceptibility Does Not Correlate With Fungal Clearance or Survival in AIDS-Associated Cryptococcal Meningitis.Clin Infect Dis. 2021 Oct 5;73(7):e2338-e2341.
  10. Vallabhaneni S, Cleveland AA, Farley MM, 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 Dis. 2015 Dec;2(4):ofv163.
  11. Du H, Bing J, Hu T, Ennis CL, et al. Candida auris: Epidemiology, biology, antifungal resistance, and virulence.PLoS Pathog.2020 Oct 22;16(10):e1008921.
  12. Centers for Disease Control and Prevention. Invasive Candidiasis Statistics. Reviewed August 24, 2021. Available at: Statistics | Invasive Candidiasis | Candidiasis | Types of Diseases | Fungal Diseases | CDC.
  13. Centers for Disease Control and Prevention. Antifungal Susceptibility Testing and Interpretation. Reviewed May 29, 2020. Available at: Antifungal Susceptibility Testing and Interpretation | Candida auris | Fungal Diseases | CDC.
  14. JMI Laboratories. SENTRY Antimicrobial Surveillance Program. Available at: SENTRY Antimicrobial Surveillance Program - JMI Laboratories (jmilabs.com).