Paradoxical growth effects of the echinocandins caspofungin and micafungin, but not of anidulafungin, on clinical isolates of Candida albicans and C. dubliniensis

  • M. Fleischhacker
  • C. Radecke
  • B. Schulz
  • M. Ruhnke
Article
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Abstract

Objectives To analyze the effects of a high concentration of three antifungal substances, the echinocandins anidulafungin, caspofungin, and micafungin, on the growth of Candida spp. Methods The growth of 127 C. dubliniensis isolates and 103 C. albicans isolates cultured in medium containing anidulafungin, caspofungin, or micafungin was analyzed using a broth microdilution test according to the guidelines of the CLSI M27-A2 [NCCLS (1997), Wayne, PA]. The final concentrations of all three echinocandins ranged from 0.125 to 64 μg/L. Results The different effects of these three antifungal substances on C. albicans cells in comparison to C. dubliniensis cells were quite distinct. When both Candida species were grown in the presence of anidulafungin only a trailing effect was observed. Micafungin induced an Eagle effect in C. dubliniensis only (63%), while caspofungin induced this effect in the majority of C. dubliniensis isolates (90%) and in only a few C. albicans isolates (14%). Conclusions Based on our observations, anidulafungin has effects that are different from the ones produced by micafungin and caspofungin. Whether this different response to high concentrations of echinocandins is based on genetic or phenotypic differences between C. albicans and C. dubliniensis has to be determined in future experiments.

References

  1. 1.
    Cappelletty D, Elselstein-McKltrick K (2007) The echinocandins. Pharmacotherapy 27:369–388PubMedCrossRefGoogle Scholar
  2. 2.
    Morris MI, Villmann M (2006) Echinocandins in the management of invasive fungal infections, part 1. Am J Health Syst Pharm 63:1693–1703PubMedCrossRefGoogle Scholar
  3. 3.
    Stevens DA, Espiritu M, Parmar R (2004) Paradoxical effect of caspofungin: reduced activity against Candida albicans at high drug concentrations. Antimicrob Agents Chemother 48:3407–3411PubMedCrossRefGoogle Scholar
  4. 4.
    Stevens DA, White TC, Perlin DS, Selitrennikoff CP (2005) Studies of the paradoxical effect of caspofungin at high drug concentrations. Diagn Microbiol Infect Dis 51:173–178PubMedCrossRefGoogle Scholar
  5. 5.
    St-Germain G (1990) Effects of pentamidine alone and in combination with ketoconazole or itraconazole on the growth of Candida albicans. Antimicrob Agents Chemother 34:2304–2306PubMedGoogle Scholar
  6. 6.
    Arai R, Sugita T, Nishikawa A (2005) Reassessment of the in vitro synergistic effect of fluconazole with the non-steroidal anti-inflammatory agent ibuprofen against Candida albicans. Mycoses 48:38–41PubMedCrossRefGoogle Scholar
  7. 7.
    Arikan S, Sancak B, Hascelik G (2005) In vitro activity of caspofungin compared to amphotericin B, fluconazole, and itraconazole againstCandida strains isolated in a Turkish University Hospital. Med Mycol 43:171–178PubMedCrossRefGoogle Scholar
  8. 8.
    Torres-Rodriguez JM, Carrillo-Munoz A, Gallach-Bau C, Madrenys N (1989) Susceptibility of Candida species to cilofungin (LY-121019). Mycoses 32:316–318PubMedCrossRefGoogle Scholar
  9. 9.
    Marr KA, Rustad TR, Rex JH, White TC (1999) The trailing end point phenotype in antifungal susceptibility testing is pH dependent. Antimicrob Agents Chemother 43:1383–1386PubMedGoogle Scholar
  10. 10.
    Marchetti O, Moreillon P, Glauser MP, Bille J, Sanglard D (2000) Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans. Antimicrob Agents Chemother 44:2373–2381PubMedCrossRefGoogle Scholar
  11. 11.
    Jacobsen MD, Whyte JA, Odds FC (2007)Candida albicans andCandida dubliniensis respond differently to echinocandin antifungal agents in vitro. Antimicrob Agents Chemother 51:1882–1884PubMedCrossRefGoogle Scholar
  12. 12.
    Ostrosky-Zeichner L, Rex JH, Pappas PG, Hamill RJ, Larsen RA, Horowitz HW, Powderly WG, Hyslop N, Kauffman CA, Cleary J, Mangino JE, Lee J (2003) Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother 47:3149–3154PubMedCrossRefGoogle Scholar
  13. 13.
    Pfaller MA, Diekema DJ, Messer SA, Hollis RJ, Jones RN (2003) In vitro activities of caspofungin compared with those of fluconazole and itraconazole against 3,959 clinical isolates of Candida spp., including 157 fluconazole-resistant isolates. Antimicrob Agents Chemother 47:1068–1071PubMedCrossRefGoogle Scholar
  14. 14.
    Espinel-Ingroff A (2003) In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev Iberoam Micol 20:121–136PubMedGoogle Scholar
  15. 15.
    Ruhnke M, Schmidt-Westhausen A, Engelmann E, Trautmann M (1996) Comparative evaluation of three antifungal susceptibility test methods for Candida albicans isolates and correlation with response to fluconazole therapy. J Clin Microbiol 34:3208–3211PubMedGoogle Scholar
  16. 16.
    National Committee for Clinical Laboratory Standards (NCCLS) (1997) Reference method for broth dilution antigungal susceptibility testing of yeasts: approved standard, 2nd edn. NCCLS Document M27-A. NCCLS, Wayne, PAGoogle Scholar
  17. 17.
    Hall GS, Myles C, Pratt KJ, Washington JA (1988) Cilofungin (LY121019), an antifungal agent with specific activity againstCandida albicans and Candida tropicalis. Antimicrob Agents Chemother 32:1331–1335PubMedGoogle Scholar
  18. 18.
    Iwata K, Yamamoto Y, Yamaguchi H, Hiratani T (1982) In vitro studies of aculeacin A, a new antifungal antibiotic. J Antibiot (Tokyo) 35:203–209Google Scholar
  19. 19.
    Pfaller MA, Wey S, Gerarden T, Houston A, Wenzel RP (1989) Susceptibility of nosocomial isolates of Candida species to LY121019 and other antifungal agents. Diagn Microbiol Infect Dis 12:1–4PubMedCrossRefGoogle Scholar
  20. 20.
    Chamilos G, Lewis RE, Albert N, Kontoyiannis DP (2007) Paradoxical effect of Echinocandins across Candida species in vitro: evidence for echinocandin-specific and Candida species-related differences. Antimicrob Agents Chemother 51:2257–2259PubMedCrossRefGoogle Scholar
  21. 21.
    Uzun O, Arikan S, Kocagoz S, Sancak B, Unal S (2000) Susceptibility testing of voriconazole, fluconazole, itraconazole and amphotericin B against yeast isolates in a Turkish University Hospital and effect of time of reading. Diagn Microbiol Infect Dis 38:101–107PubMedCrossRefGoogle Scholar
  22. 22.
    Clemons KV, Espiritu M, Parmar R, Stevens DA (2006) Assessment of the paradoxical effect of caspofungin in therapy of candidiasis. Antimicrob Agents Chemother 50:1293–1297PubMedCrossRefGoogle Scholar
  23. 23.
    Gumbo T, Drusano GL, Liu W, Kulawy RW, Fregeau C, Hsu V, Louie A (2007) Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia. Antimicrob Agents Chemother 51:968–974PubMedCrossRefGoogle Scholar
  24. 24.
    Sutton DA (2002) Laboratory evaluation of new antifungal agents against rare and refractory mycoses. Curr Opin Infect Dis 15:575–582PubMedGoogle Scholar
  25. 25.
    Espinel-Ingroff A, Barchiesi F, Cuenca-Estrella M, Pfaller MA, Rinaldi M, Rodriguez-Tudela JL, Verweij PE (2005) International and multicenter comparison of EUCAST and CLSI M27-A2 broth microdilution methods for testing susceptibilities of Candida spp. to fluconazole, itraconazole, posaconazole, and voriconazole. J Clin Microbiol 43:3884–3889PubMedCrossRefGoogle Scholar
  26. 26.
    Carrillo-Munoz AJ, Giusiano G, Ezkurra PA, Quindos G (2006) Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter 19:130–139PubMedGoogle Scholar
  27. 27.
    Yamaguchi H, Hiratani T, Iwata K, Yamamoto Y (1982) Studies on the mechanism of antifungal action of aculeacin A. J Antibiot (Tokyo) 35:210–219Google Scholar
  28. 28.
    Ellepola AN, Hurst SF, Elie CM, Morrison CJ (2003) Rapid and unequivocal differentiation of Candida dubliniensis from other Candida species using species-specific DNA probes: comparison with phenotypic identification methods. Oral Microbiol Immunol 18:379–388PubMedCrossRefGoogle Scholar
  29. 29.
    Neppelenbroek KH, Campanha NH, Spolidorio DM, Spolidorio LC, Seo RS, Pavarina AC (2006) Molecular fingerprinting methods for the discrimination between C. albicans and C. dubliniensis. Oral Dis 12:242–253Google Scholar
  30. 30.
    Stevens DA, McCullough MJ, Clemons KV, Martinez MC (2006a) Candida dubliniensis (Cd), a species with an extremely high frequency of paradoxical effect (PE) with caspofungin (CAS). 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, San Francisco Sept 27–30, M-363Google Scholar
  31. 31.
    Stevens DA, Ichinomiya M, Koshi Y, Horiuchi H (2006b) Escape of Candida from caspofungin inhibition at supra-MIC concentrations (“Paradoxical effect”) accomplished by increased cell wall chitin; evidence for beta-1,6-glucan synthesis inhibition by caspofungin. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, San Francisco Sept 27–30, M-1756Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • M. Fleischhacker
    • 1
  • C. Radecke
    • 1
  • B. Schulz
    • 1
  • M. Ruhnke
    • 1
    • 2
  1. 1.Department of Internal Medicine, Div. Oncology and HematologyCharité Universitätsmedizin BerlinBerlinGermany
  2. 2.Med. Klinik m. S. Onkologie u. HämatologieCharité-Universitätsmedizin BerlinBerlinGermany

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