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Echinocandin Resistance in Candida Species: a Review of Recent Developments

Current Infectious Disease Reports volume 18, Article number: 42 (2016) Cite this article

Abstract

The echinocandins are important agents for the treatment of invasive fungal infections, especially those caused by Candida species. However, as with other antimicrobial agents, microbiologic resistance to this class of antifungal agents has emerged and can result in clinical failure. Several studies have recently reported an increase in echinocandin resistance in Candida glabrata isolates at various medical centers in different geographic regions of the USA. Recent studies have also reported that many of these isolates may also be fluconazole resistant, leaving few treatment options available for clinicians to use in patients with invasive candidiasis caused by this species. Our understanding of the clinical relevance of specific point mutations within the FKS genes that cause echinocandin resistance and risk factors for the development of microbiologic resistance and clinical failure have also increased. The purpose of this review is to discuss echinocandin resistance in Candida species and recent reports that have increased our understanding of this growing clinical problem.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of great importance

  1. Messer SA, Diekema DJ, Boyken L, Tendolkar S, Hollis RJ, Pfaller MA. Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp. J Clin Microbiol. 2006;44:324–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43:5425–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020–9.

    CAS  Article  PubMed  Google Scholar 

  4. Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007;45:883–93.

    CAS  Article  PubMed  Google Scholar 

  5. Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:2472–82.

    CAS  Article  PubMed  Google Scholar 

  6. Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007;369:1519–27.

    CAS  Article  PubMed  Google Scholar 

  7. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 2016;62:e1–50.

    Article  PubMed  Google Scholar 

  8. Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012;18 Suppl 7:19–37.

    CAS  Article  PubMed  Google Scholar 

  9. Hope WW, Castagnola E, Groll AH, Roilides E, Akova M, Arendrup MC, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect. 2012;18 Suppl 7:38–52.

    CAS  Article  PubMed  Google Scholar 

  10. Lortholary O, Petrikkos G, Akova M, Arendrup MC, Arikan-Akdagli S, Bassetti M, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS. Clin Microbiol Infect. 2012;18 Suppl 7:68–77.

    CAS  Article  PubMed  Google Scholar 

  11. 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.

    CAS  Article  PubMed  Google Scholar 

  12. Bowman JC, Hicks PS, Kurtz MB, Rosen H, Schmatz DM, Liberator PA, et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother. 2002;46:3001–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Douglas CM, D’Ippolito JA, Shei GJ, Meinz M, Onishi J, Marrinan JA, et al. Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother. 1997;41:2471–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wiederhold NP, Lewis RE. The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy. Expert Opin Investig Drugs. 2003;12:1313–33.

    CAS  Article  PubMed  Google Scholar 

  15. Laverdiere M, Lalonde RG, Baril JG, Sheppard DC, Park S, Perlin DS. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J Antimicrob Chemother. 2006;57:705–8.

    CAS  Article  PubMed  Google Scholar 

  16. Hernandez S, Lopez-Ribot JL, Najvar LK, McCarthy DI, Bocanegra R, Graybill JR. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother. 2004;48:1382–3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Baixench MT, Aoun N, Desnos-Ollivier M, Garcia-Hermoso D, Bretagne S, Ramires S, et al. Acquired resistance to echinocandins in Candida albicans: case report and review. J Antimicrob Chemother. 2007;59:1076–83.

    CAS  Article  PubMed  Google Scholar 

  18. Thompson 3rd GR, Wiederhold NP, Vallor AC, Villareal NC, Lewis 2nd JS, Patterson TF. Development of caspofungin resistance following prolonged therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob Agents Chemother. 2008;52:3783–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 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;49:767–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. • 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;56:1724–32. Study that reported increased rates of echinocandin resistance in C. glabrata at a large transplant center in the U.S. Also reported patient outcomes based on type of FKS mutation.

    Article  PubMed  PubMed Central  Google Scholar 

  21. • Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW. FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 2014;59:819–25. Recent study that reported risk factors for development of echinocandin resistance in C. glabrata. Also reported patient outcomes based on type of FKS mutation.

    CAS  Article  PubMed  Google Scholar 

  22. •• Vallabhaneni S, Cleveland AA, Farley MM, Harrison LH, Schaffner W, Beldavs ZG, 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;2:ofv163. Large surveillance study showing increased rates of echinocandin resistance in C. glabrata in different metropolitan areas in the U.S. Also reported high rate of fluconazole resistance in these isolates.

    Article  PubMed  PubMed Central  Google Scholar 

  23. • Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol. 2012;50:1199–203. Surveillance study that first reported an increase in the number of C. glabrata isolates with resistance to both the echinocandins and fluconazole.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Balashov SV, Park S, Perlin DS. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother. 2006;50:2058–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Park S, Kelly R, Kahn JN, Robles J, Hsu MJ, Register E, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother. 2005;49:3264–73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Garcia-Effron G, Park S, Perlin DS. Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother. 2009;53:112–22.

    CAS  Article  PubMed  Google Scholar 

  27. Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother. 2009;53:3690–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS. A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother. 2008;52:2305–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. •• Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis. 2014;27:484–92. Comprehensive review of echinocandin resistance in Candida species.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Kartsonis N, Killar J, Mixson L, Hoe CM, Sable C, Bartizal K, et al. Caspofungin susceptibility testing of isolates from patients with esophageal candidiasis or invasive candidiasis: relationship of MIC to treatment outcome. Antimicrob Agents Chemother. 2005;49:3616–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts; fourth informational supplement. CLSI document M27-S4. Wayne, PA: Clinical and Laboratory Standards Institute; 2012.

    Google Scholar 

  32. Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ. Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob Agents Chemother. 2013;57:3528–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Jensen RH, Johansen HK, Arendrup MC. Stepwise development of a homozygous S80P substitution in Fks1p, conferring echinocandin resistance in Candida tropicalis. Antimicrob Agents Chemother. 2013;57:614–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Jensen RH, Justesen US, Rewes A, Perlin DS, Arendrup MC. Echinocandin failure case due to a previously unreported FKS1 mutation in Candida krusei. Antimicrob Agents Chemother. 2014;58:3550–2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Dannaoui E, Desnos-Ollivier M, Garcia-Hermoso D, Grenouillet F, Cassaing S, Baixench MT, et al. Candida spp. with acquired echinocandin resistance, France, 2004-2010. Emerg Infect Dis. 2012;18:86–90.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. • Fekkar A, Meyer I, Brossas JY, Dannaoui E, Palous M, Uzunov M, et al. Rapid emergence of echinocandin resistance during Candida kefyr fungemia treatment with caspofungin. Antimicrob Agents Chemother. 2013;57:2380–2. Case report that demonstrated that the rapid development of echinocandin resistance can occur.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. • Lewis JS, 2nd, Wiederhold NP, Wickes BL, Patterson TF, Jorgensen JH. 2013. Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. Antimicrob Agents Chemother 57:4559-4561.Case report that demonstrated that the rapid development of echinocandin resistance in C. glabrata can occur.

  38. Malani A, Hmoud J, Chiu L, Carver PL, Bielaczyc A, Kauffman CA. Candida glabrata fungemia: experience in a tertiary care center. Clin Infect Dis. 2005;41:975–81.

    Article  PubMed  Google Scholar 

  39. Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37:634–43.

    Article  PubMed  Google Scholar 

  40. • Shields RK, Nguyen MH, Press EG, Clancy CJ. Abdominal candidiasis is a hidden reservoir of echinocandin resistance. Antimicrob Agents Chemother. 2014;58:7601–5. Study that highlighted the importance of the abdominal cavity as a potential reservoir for resistant C. glabrata isolates.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shields RK, Nguyen MH, Press EG, Kwa AL, Cheng S, Du C, et al. The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata. Antimicrob Agents Chemother. 2012;56:4862–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ. Anidulafungin and micafungin MIC breakpoints are superior to that of caspofungin for identifying FKS mutant Candida glabrata strains and Echinocandin resistance. Antimicrob Agents Chemother. 2013;57:6361–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. •• Jensen RH, Johansen HK, Soes LM, Lemming LE, Rosenvinge FS, Nielsen L, et al. Posttreatment antifungal resistance among Colonizing Candida Isolates in Candidemia patients: results from a systematic multicenter study. Antimicrob Agents Chemother. 2016;60:1500–8. Study that highlighted the presence of echinocandin resistant isolates colonizing the oral mucosa following treatment of candidemia with an echinocandin.

    CAS  Article  PubMed Central  Google Scholar 

  44. Arendrup MC, Perlin DS, Jensen RH, Howard SJ, Goodwin J, Hope W. Differential in vivo activities of anidulafungin, caspofungin, and micafungin against Candida glabrata isolates with and without FKS resistance mutations. Antimicrob Agents Chemother. 2012;56:2435–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Wiederhold NP, Najvar LK, Bocanegra RA, Kirkpatrick WR, Patterson TF. Caspofungin dose escalation for invasive candidiasis due to resistant Candida albicans. Antimicrob Agents Chemother. 2011;55:3254–60.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Ben-Ami R, Garcia-Effron G, Lewis RE, Gamarra S, Leventakos K, Perlin DS, et al. Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. J Infect Dis. 2011;204:626–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 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;56:208–17.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen YL, et al. Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog. 2012;8:e1002718.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Lackner M, Tscherner M, Schaller M, Kuchler K, Mair C, Sartori B, et al. Positions and numbers of FKS mutations in Candida albicans selectively influence in vitro and in vivo susceptibilities to echinocandin treatment. Antimicrob Agents Chemother. 2014;58:3626–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 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;38:65–9.

    CAS  Article  PubMed  Google Scholar 

  51. Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun. 2016;7:11128.

    CAS  Article  PubMed  Google Scholar 

  52. •• 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;57:5836–42. Multicenter study that demonstrated significant interlaboratory variability with caspofungin susceptibility testing against Candida species, especially C. glabrata and C. krusei.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Eschenauer GA, Nguyen MH, Shoham S, Vazquez JA, Morris AJ, Pasculle WA, et al. Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates. Antimicrob Agents Chemother. 2014;58:1897–906.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Arendrup MC, Rodriguez-Tudela JL, Lass-Florl C, Cuenca-Estrella M, Donnelly JP, Hope W, et al. EUCAST technical note on anidulafungin. Clin Microbiol Infect. 2011;17:E18–20.

    CAS  Article  PubMed  Google Scholar 

  55. 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;52:3223–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Pfaller MA, Messer SA, Diekema DJ, Jones RN, Castanheira 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;52:108–14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Arendrup MC, Rodriguez-Tudela JL, Park S, Garcia-Effron G, Delmas G, Cuenca-Estrella M, et al. Echinocandin susceptibility testing of Candida spp. Using EUCAST EDef 7.1 and CLSI M27-A3 standard procedures: analysis of the influence of bovine serum albumin supplementation, storage time, and drug lots. Antimicrob Agents Chemother. 2011;55:1580–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Fothergill AW, McCarthy DI, Albataineh MT, Sanders C, McElmeel M, Wiederhold NP. Effects of treated versus untreated polystyrene on Caspofungin in vitro activity against Candida species. J Clin Microbiol. 2016;54:734–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Zhao Y, Nagasaki Y, Kordalewska M, Press EG, Shields RK, Nguyen MH, Clancy CJ, Perlin DS. Rapid detection of FKS-associated echinocandin resistance in Candida glabrata. Antimicrob Agents Chemother. 2016.

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  1. Department of Pathology, Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Nathan P. Wiederhold

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Dr. Nathan P. Wiederhold declare that he received grant support from Astellas, bioMerieux, Merck, Pfizer, F2G, and Viament, outside the submitted work. Dr. Wiederhold also serves on the scientific advisory boards for Astella, Merck, and Viamet.

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Wiederhold, N.P. Echinocandin Resistance in Candida Species: a Review of Recent Developments. Curr Infect Dis Rep 18, 42 (2016). https://doi.org/10.1007/s11908-016-0549-2

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Keywords

  • Anidulafungin
  • Caspofungin
  • Micafungin
  • Candida
  • Candida glabrata
  • FKS1
  • FKS2
  • Antifungal resistance
  • Echinocandin resistance