Skip to main content

Advertisement

SpringerLink
Log in

Exploring the In Vitro Resistance of Candida parapsilosis to Echinocandins

  • Published:
Mycopathologia Aims and scope Submit manuscript

Abstract

The naturally high minimum inhibitory concentration exhibited by echinocandins against Candida parapsilosis has been known since the first introduction of these antifungal agents. Despite this awareness, clinical failures have not been reported; consequently, the resistance of C. parapsilosis to echinocandins remains unexplored. We exposed 30 isolates of C. parapsilosis to echinocandins (caspofungin, micafungin, and anidulafungin) in vitro and studied the effects of this exposure. After 60 exposures, 80, 67, and 60 % of the isolates changed from susceptible to non-susceptible to caspofungin, micafungin, and anidulafungin, respectively. In addition, four strains exhibited cross-resistance to all three echinocandins. Based on the M27-A3 (CLSI, 2008) and M27-S4 (CLSI, 2012) techniques, the susceptibility of the resistant strains to other antifungal agents was assayed. All of the tested echinocandin-resistant strains were susceptible to amphotericin B, and the resistance rate to fluconazole, voriconazole, and flucytosine was 73.3, 43.3, and 20 %, respectively. The exposure of C. parapsilosis to the three echinocandins generated cross-resistant strains and an unexpected in vitro resistance to azoles and flucytosine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Peman J, Canton E, Linares-Sicilia MJ, Rosello EM, Borrell N, Ruiz-Perez-de-Pipaon MT, et al. Epidemiology and antifungal susceptibility of bloodstream fungal isolates in pediatric patients: a Spanish multicenter prospective survey. J Clin Microbiol. 2011;49(12):4158–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Trofa D, Gacser A, Nosanchuk JD. Candida parapsilosis, an emerging fungal pathogen. Clin Microbiol Rev. 2008;21(4):606–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Doi AM, Pignatari AC, Edmond MB, Marra AR, Camargo LF, Siqueira RA, et al. Epidemiology and microbiologic characterization of nosocomial candidemia from a Brazilian National surveillance program. PLoS ONE. 2016;11(1):e0146909.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ullmann AJ, Akova M, Herbrecht R, Viscoli C, Arendrup MC, Arikan-Akdagli S, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin Microbiol Infect. 2012;18(Suppl 7):53–67.

    Article  CAS  PubMed  Google Scholar 

  5. Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, et al. The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci USA. 1994;91(26):12907–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kartsonis NA, Nielsen J, Douglas CM. Caspofungin: the first in a new class of antifungal agents. Drug Resist Updates. 2003;6(4):197–218.

    Article  CAS  Google Scholar 

  7. Arendrup MC. Update on antifungal resistance in Aspergillus and Candida. Clin Microbiol Infect. 2014;20(Suppl 6):42–8.

    Article  CAS  PubMed  Google Scholar 

  8. Forrest GN, Weekes E, Johnson JK. Increasing incidence of Candida parapsilosis candidemia with caspofungin usage. J Infect. 2008;56(2):126–9.

    Article  PubMed  Google Scholar 

  9. Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36(1):1–53.

    Article  PubMed  Google Scholar 

  10. Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724–32.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pfaller MA, Diekema DJ, Ostrosky-Zeichner L, Rex JH, Alexander BD, Andes D, et al. Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol. 2008;46(8):2620–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sipsas NV, Lewis RE, Tarrand J, Hachem R, Rolston KV, Raad II, et al. Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001–2007): stable incidence but changing epidemiology of a still frequently lethal infection. Cancer. 2009;115(20):4745–52.

    Article  CAS  PubMed  Google Scholar 

  13. Perlin DS. Echinocandin resistance, susceptibility testing and prophylaxis: implications for patient management. Drugs. 2014;74(14):1573–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kurtzman C, Fell JW. The yeasts: a taxonomic study. 4th ed. Amsterdam: Elsevier; 1998.

    Google Scholar 

  15. White PL, Barton R, Guiver M, Linton CJ, Wilson S, Smith M, et al. A consensus on fungal polymerase chain reaction diagnosis? A United Kingdom Ireland evaluation of polymerase chain reaction methods for detection of systemic fungal infections. J Mol Diagn. 2006;8(3):376–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. White PL. Detection of seven Candida species using the Light-Cycler system. J Med Microbiol. 2003;52(3):229–38.

    Article  PubMed  Google Scholar 

  17. Mirhendi H, Makimura K, Khoramizadeh M, Yamaguchi H. A one-enzyme PCR-RFLP assay for identification of six medically important Candida species. Jpn J Med Mycol. 2006;47(3):225–9.

    Article  CAS  Google Scholar 

  18. Mirhendi H, Diba K, Rezaei A, Jalalizand N, Hosseinpur L, Khodadadi H. Colony-PCR is a rapid and sensitive method for DNA amplification in yeasts. Iran J Public Health. 2007;36(1):40–4.

    CAS  Google Scholar 

  19. Tavanti A, Davidson AD, Gow NA, Maiden MC, Odds FC. Candida orthopsilosis and Candida metapsilosis spp. nov. to replace Candida parapsilosis groups II and III. J Clin Microbiol. 2005;43(1):284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tavanti A, Hensgens LA, Ghelardi E, Campa M, Senesi S. Genotyping of Candida orthopsilosis clinical isolates by amplification fragment length polymorphism reveals genetic diversity among independent isolates and strain maintenance within patients. J Clin Microbiol. 2007;45(5):1455–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard. 3rd ed. CLSI document M27-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

  22. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of yeasts, 4th informational supplement. CLSI document M27–S4. Wayne, PA: Clinical and Laboratory Standards Institute; 2012.

  23. Fekete-Forgacs K, Gyure L, Lenkey B. Changes of virulence factors accompanying the phenomenon of induced fluconazole resistance in Candida albicans. Mycoses. 2000;43(7–8):273–9.

    Article  CAS  PubMed  Google Scholar 

  24. Pfaller MA, Diekema DJ. Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol. 2012;50(9):2846–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.

    Article  CAS  PubMed  Google Scholar 

  26. Glockner A. Treatment and prophylaxis of invasive candidiasis with anidulafungin, caspofungin and micafungin: review of the literature. Eur J Med Res. 2011;16(4):167–79.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kale-Pradhan PB, Morgan G, Wilhelm SM, Johnson LB. Comparative efficacy of echinocandins and nonechinocandins for the treatment of Candida parapsilosis Infections: a meta-analysis. Pharmacotherapy. 2010;30(12):1207–13.

    Article  CAS  PubMed  Google Scholar 

  28. Moudgal V, Little T, Boikov D, Vazquez JA. Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis. Antimicrob Agents Chemother. 2005;49(2):767–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kabbara N, Lacroix C. Peffault de Latour R, Socie G, Ghannoum M, Ribaud P. Breakthrough C. parapsilosis and C. guilliermondii blood stream infections in allogeneic hematopoietic stem cell transplant recipients receiving long-term caspofungin therapy. Haematologica. 2008;93(4):639–40.

    Article  CAS  PubMed  Google Scholar 

  30. Pfeiffer CD, Garcia-Effron G, Zaas AK, Perfect JR, Perlin DS, Alexander BD. Breakthrough invasive candidiasis in patients on micafungin. J Clin Microbiol. 2010;48(7):2373–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheung C, Guo Y, Gialanella P, Feldmesser M. Development of candidemia on caspofungin therapy: a case report. Infection. 2006;34(6):345–8.

    Article  CAS  PubMed  Google Scholar 

  32. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, et al. Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updates. 2011;14(3):164–76.

    Article  CAS  Google Scholar 

  33. Pfaller MA, Messer SA, Diekema DJ, Jones RN, Castanheiraa M. Use of micafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 3,764 clinical isolates of Candida by Use of CLSI methods and interpretive criteria. J Clin Microbiol. 2014;52(1):114.

    Article  Google Scholar 

  34. Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis. 2014;27(6):484–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Marti-Carrizosa M, Sanchez-Reus F, March F, Canton E, Coll P. Implication of Candida parapsilosis FKS1 and FKS2 mutations in reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2015;59(6):3570–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee KK, Maccallum DM, Jacobsen MD, Walker LA, Odds FC, Gow NA, et al. Elevated cell wall chitin in Candida albicans confers echinocandin resistance in vivo. Antimicrob Agents Chemother. 2012;56(1):208–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bizerra FC, Melo AS, Katchburian E, Freymuller E, Straus AH, Takahashi HK, et al. Changes in cell wall synthesis and ultrastructure during paradoxical growth effect of caspofungin on four different Candida species. Antimicrob Agents Chemother. 2011;55(1):302–10.

    Article  CAS  PubMed  Google Scholar 

  38. Walker LA, Gow NA, Munro CA. Elevated chitin content reduces the susceptibility of Candida species to caspofungin. Antimicrob Agents Chemother. 2013;57(1):146–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Healey KR, Katiyar SK, Raj S, Edlind TD. CRS-MIS in Candida glabrata: sphingolipids modulate echinocandin-Fks interaction. Mol Microbiol. 2012;86(2):303–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pfaller MA, Diekema DJ, Jones RN, Castanheira M. Use of anidulafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 4,290 clinical isolates of Candida by using CLSI methods and interpretive criteria. J Clin Microbiol. 2014;52(9):3223–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Espinel-Ingroff A, Arendrup MC, Pfaller MA, Bonfietti LX, Bustamante B, Canton E, et al. Interlaboratory variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST methods: should the clinical laboratory be testing this agent? Antimicrob Agents Chemother. 2013;57(12):5836–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M. Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in intensive care unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008–2009). Int J Antimicrob Agents. 2011;38(1):65–9.

    Article  CAS  PubMed  Google Scholar 

  43. Cho EJ, Shin JH, Kim SH, Kim HK, Park JS, Sung H, et al. Emergence of multiple resistance profiles involving azoles, echinocandins and amphotericin B in Candida glabrata isolates from a neutropenia patient with prolonged fungaemia. J Antimicrob Chemother. 2015;70(4):1268–70.

    CAS  PubMed  Google Scholar 

  44. Wang E, Farmakiotis D, Yang D, McCue DA, Kantarjian HM, Kontoyiannis DP, et al. The ever-evolving landscape of candidaemia in patients with acute leukaemia: non-susceptibility to caspofungin and multidrug resistance are associated with increased mortality. J Antimicrob Chemother. 2015;70(8):2362–8.

    Article  CAS  PubMed  Google Scholar 

  45. Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob Agents Chemother. 2010;54(3):1360–2.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the National Council for Scientific and Technological Development—(CNPq; process #470229/2012-8) and by CAPES (Brazil).

Author information

Authors and Affiliations

  1. Health Sciences Centre, Federal University of Santa Maria, Santa Maria, RS, Brazil

    Francieli Chassot, Tarcieli Pozzebon Venturini, Fernanda Baldissera Piasentin, Luana Rossato & Sydney Hartz Alves

  2. Department of Clinical Analysis and Biomedicine, State University of Maringa, Maringa, PR, Brazil

    Adriana Fiorini & Terezinha Inez Estivalet Svidzinski

  3. Departamento de Microbiologia e Parasitologia, Universidade Federal de Santa Maria (UFSM), Av. Roraima n° 1000, Prédio 20, Sala 4139, Santa Maria, RS, CEP 97105-900, Brazil

    Francieli Chassot

Authors
  1. Francieli Chassot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tarcieli Pozzebon Venturini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernanda Baldissera Piasentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luana Rossato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adriana Fiorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Terezinha Inez Estivalet Svidzinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sydney Hartz Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francieli Chassot.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chassot, F., Venturini, T.P., Piasentin, F.B. et al. Exploring the In Vitro Resistance of Candida parapsilosis to Echinocandins. Mycopathologia 181, 663–670 (2016). https://doi.org/10.1007/s11046-016-0028-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11046-016-0028-1

Keywords

Search

Navigation