1887

Abstract

Echinocandins are recommended as first-line agents against invasive fungal infections caused by , which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against . To address this possibility, we performed and experiments with caspofungin against four WT clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandin-resistant strains with known mutations. MIC values for the clinical isolates in RPMI 1640 were ≤ 0.03 mg l but increased to 0.125–0.25 mg l in RPMI 1640+50 % serum. In RPMI 1640+50 % serum, the replication of was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l (paradoxically decreased killing activity). In RPMI 1640+50 % serum, caspofungin at ≥ 1 mg l was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg daily) decreased the fungal tissue burdens significantly ( < 0.05–0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 10 cells (g tissue).The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.

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2015-09-01
2020-09-23
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References

  1. Alexander B. D., Johnson M. D., Pfeiffer C. D., Jiménez-Ortigosa C., Catania J., Booker R., Castanheira M., Messer S. A., Perlin D. S., Pfaller M. A. 2013; Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56:1724–1732 [CrossRef][PubMed]
    [Google Scholar]
  2. Andes D., Diekema D. J., Pfaller M. A., Bohrmuller J., Marchillo K., Lepak A. 2010; In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother 54:2497–2506 [CrossRef][PubMed]
    [Google Scholar]
  3. Ben-Ami R., Garcia-Effron G., Lewis R. E., Gamarra S., Leventakos K., Perlin D. S., Kontoyiannis D. P. 2011; Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. J Infect Dis 204:626–635 [CrossRef][PubMed]
    [Google Scholar]
  4. Berényi R., Kovács R., Domán M., Gesztelyi R., Kardos G., Juhász B., Perlin D., Majoros L. 2014; Efficacy of single large doses of caspofungin in a neutropenic murine model against the “psilosis” group. New Microbiol 37:355–362
    [Google Scholar]
  5. Betts R. F., Nucci M., Talwar D., Gareca M., Queiroz-Telles F., Bedimo R. J., Herbrecht R., Ruiz-Palacios G., Young J. A., other authors. 2009; A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis 48:1676–1684 [CrossRef][PubMed]
    [Google Scholar]
  6. Beyda N. D., John J., Kilic A., Alam M. J., Lasco T. M., Garey K. W. 2014; FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis 59:819–825 [CrossRef][PubMed]
    [Google Scholar]
  7. Borghi E., Andreoni S., Cirasola D., Ricucci V., Sciota R., Morace G. 2014; Antifungal resistance does not necessarily affect Candida glabrata fitness. J Chemother 26:32–36 [CrossRef][PubMed]
    [Google Scholar]
  8. Cantón E., Pemán J., Valentín A., Espinel-Ingroff A., Gobernado M. 2009; In vitro activities of echinocandins against Candida krusei determined by three methods: MIC and minimal fungicidal concentration measurements and time-kill studies. Antimicrob Agents Chemother 53:3108–3111 [CrossRef][PubMed]
    [Google Scholar]
  9. Cantón E., Espinel-Ingroff A., Pemán J., del Castillo L. 2010; In vitro fungicidal activities of echinocandins against Candida metapsilosis, C. orthopsilosis, and C. parapsilosis evaluated by time-kill studies. Antimicrob Agents Chemother 54:2194–2197 [CrossRef][PubMed]
    [Google Scholar]
  10. Chen S. C., Slavin M. A., Sorrell T. C. 2011; Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 71:11–41 [CrossRef][PubMed]
    [Google Scholar]
  11. CLSI 2008 Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts 3rd edn. Approved standard M27-A3 Wayne, PA: Clinical and Laboratory Standards Institute;
    [Google Scholar]
  12. Colombo A. L., Guimarães T., Sukienik T., Pasqualotto A. C., Andreotti R., Queiroz-Telles F., Nouér S. A., Nucci M. 2014; Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a 9-year period. Intensive Care Med 40:1489–1498 [CrossRef][PubMed]
    [Google Scholar]
  13. Cornely O. A., Vehreschild J. J., Vehreschild M. J., Würthwein G., Arenz D., Schwartz S., Heussel C. P., Silling G., Mahne M., other authors. 2011; Phase II dose escalation study of caspofungin for invasive Aspergillosis. Antimicrob Agents Chemother 55:5798–5803 [CrossRef][PubMed]
    [Google Scholar]
  14. Dudiuk C., Gamarra S., Jimenez-Ortigosa C., Leonardelli F., Macedo D., Perlin D. S., Garcia-Effron G. 2015; Quick detection of FKS1 mutations responsible for clinical echinocandin resistance in Candida albicans. J Clin Microbiol 53:2037–2041 [CrossRef][PubMed]
    [Google Scholar]
  15. Farmakiotis D., Tarrand J. J., Kontoyiannis D. P. 2014; Drug-resistant Candida glabrata infection in cancer patients. Emerg Infect Dis 20:1833–1840 [CrossRef][PubMed]
    [Google Scholar]
  16. Farmakiotis D., Kyvernitakis A., Tarrand J. J., Kontoyiannis D. P. 2015; Early initiation of appropriate treatment is associated with increased survival in cancer patients with Candida glabrata fungaemia: a potential benefit from infectious disease consultation. Clin Microbiol Infect 21:79–86 [CrossRef][PubMed]
    [Google Scholar]
  17. Fernández-Silva F., Lackner M., Capilla J., Mayayo E., Sutton D., Castanheira M., Fothergill A. W., Lass-Flörl C., Guarro J. 2014; In vitro antifungal susceptibility of Candida glabrata to caspofungin and the presence of FKS mutations correlate with treatment response in an immunocompromised murine model of invasive infection. Antimicrob Agents Chemother 58:3646–3649 [CrossRef][PubMed]
    [Google Scholar]
  18. Flattery A. M., Hickey E., Gill C. J., Powles M. A., Misura A. S., Galgoci A. M., Ellis J. D., Zhang R., Sandhu P., other authors. 2011; Efficacy of caspofungin in a juvenile mouse model of central nervous system candidiasis. Antimicrob Agents Chemother 55:3491–3497 [CrossRef][PubMed]
    [Google Scholar]
  19. Földi R., Szilágyi J., Kardos G., Berényi R., Kovács R., Majoros L. 2012a; Effect of 50% human serum on the killing activity of micafungin against eight Candida species using time-kill methodology. Diagn Microbiol Infect Dis 73:338–342 [CrossRef][PubMed]
    [Google Scholar]
  20. Földi R., Kovács R., Gesztelyi R., Kardos G., Berényi R., Juhász B., Szilágyi J., Mózes J., Majoros L. 2012b; Comparison of in vitro and in vivo efficacy of caspofungin against Candida parapsilosis, C. orthopsilosis, C. metapsilosis and C. albicans. Mycopathologia 174:311–318 [CrossRef][PubMed]
    [Google Scholar]
  21. Garcia-Effron G., Park S., Perlin D. S. 2011; Improved detection of Candida sp. fks hot spot mutants by using the method of the CLSI M27-A3 document with the addition of bovine serum albumin. Antimicrob Agents Chemother 55:2245–2255 [CrossRef][PubMed]
    [Google Scholar]
  22. Gil-Alonso S., Jauregizar N., Cantón E., Eraso E., Quindós G. 2015; In vitro fungicidal activities of anidulafungin, caspofungin and micafungin against Candida glabrata, Candida bracarensis and Candida nivariensis evaluated by time-kill studies. Antimicrob Agents Chemother 59:3615–3618 [CrossRef][PubMed]
    [Google Scholar]
  23. Howard S. J., Livermore J., Sharp A., Goodwin J., Gregson L., Alastruey-Izquierdo A., Perlin D. S., Warn P. A., Hope W. W. 2011; Pharmacodynamics of echinocandins against Candida glabrata: requirement for dosage escalation to achieve maximal antifungal activity in neutropenic hosts. Antimicrob Agents Chemother 55:4880–4887 [CrossRef][PubMed]
    [Google Scholar]
  24. Kovács R., Gesztelyi R., Berényi R., Domán M., Kardos G., Juhász B., Majoros L. 2014a; Killing rates exerted by caspofungin in 50 % serum and its correlation with in vivo efficacy in a neutropenic murine model against Candida krusei and Candida inconspicua. J Med Microbiol 63:186–194 [CrossRef][PubMed]
    [Google Scholar]
  25. Kovács R., Gesztelyi R., Perlin D. S., Kardos G., Domán M., Berényi R., Majoros L. 2014b; Killing rates for caspofungin against Candida albicans after brief and continuous caspofungin exposure in the presence and absence of serum. Mycopathologia 178:197–206 [CrossRef][PubMed]
    [Google Scholar]
  26. Lepak A., Castanheira M., Diekema D., Pfaller M., Andes D. 2012; Optimizing Echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations. Antimicrob Agents Chemother 56:5875–5882 [CrossRef][PubMed]
    [Google Scholar]
  27. Li H., Chen Z., Zhang C., Gao Y., Zhang X., Sun S. 2015; Resistance reversal induced by a combination of fluconazole and tacrolimus (FK506) in Candida glabrata. J Med Microbiol 64:44–52 [CrossRef][PubMed]
    [Google Scholar]
  28. Lortholary O., Renaudat C., Sitbon K., Madec Y., Denoeud-Ndam L., Wolff M., Fontanet A., Bretagne S., Dromer F., French Mycosis Study Group. 2014; Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med 40:1303–1312 [CrossRef][PubMed]
    [Google Scholar]
  29. MacCallum D. M., Odds F. C. 2004; Need for early antifungal treatment confirmed in experimental disseminated Candida albicans infection. Antimicrob Agents Chemother 48:4911–4914 [CrossRef][PubMed]
    [Google Scholar]
  30. Migoya E. M., Mistry G. C., Stone J. A., Comisar W., Sun P., Norcross A., Bi S., Winchell G. A., Ghosh K., other authors. 2011; Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants. J Clin Pharmacol 51:202–211 [CrossRef][PubMed]
    [Google Scholar]
  31. Nasar A., Ryan L., Frei C. R., Cota J. M., Wiederhold N. P. 2013; Influence of serum and albumin on echinocandin in vitro potency and pharmacodynamics. Curr Fungal Infect Rep 7:89–95 [CrossRef]
    [Google Scholar]
  32. Pappas P. G., Rotstein C. M. F., Betts R. F., Nucci M., Talwar D., De Waele J. J., Vazquez J. A., Dupont B. F., Horn D. L., other authors. 2007; Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 45:883–893 [CrossRef][PubMed]
    [Google Scholar]
  33. Pappas P. G., Kauffman C. A., Andes D., Benjamin D. K. Jr, Calandra T. F., Edwards J. E. Jr, Filler S. G., Fisher J. F., Kullberg B. J., other authors. 2009; Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535 [CrossRef][PubMed]
    [Google Scholar]
  34. Perlin D. S. 2014; Echinocandin resistance, susceptibility testing and prophylaxis: implications for patient management. Drugs 74:1573–1585 [CrossRef][PubMed]
    [Google Scholar]
  35. Pfaller M. A., Diekema D. J., Andes D., Arendrup M. C., Brown S. D., Lockhart S. R., Motyl M., Perlin D. S., CLSI Subcommittee for Antifungal Testing. 2011; Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14:164–176 [CrossRef][PubMed]
    [Google Scholar]
  36. Pfaller M., Neofytos D., Diekema D., Azie N., Meier-Kriesche H. U., Quan S. P., Horn D. 2012; Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004–2008. Diagn Microbiol Infect Dis 74:323–331 [CrossRef][PubMed]
    [Google Scholar]
  37. Shields R. K., Nguyen M. H., Press E. G., Updike C. L., Clancy C. J. 2013; Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob Agents Chemother 57:3528–3535 [CrossRef][PubMed]
    [Google Scholar]
  38. Spreghini E., Orlando F., Sanguinetti M., Posteraro B., Giannini D., Manso E., Barchiesi F. 2012; Comparative effects of micafungin, caspofungin, and anidulafungin against a difficult-to-treat fungal opportunistic pathogen, Candida glabrata. Antimicrob Agents Chemother 56:1215–1222 [CrossRef][PubMed]
    [Google Scholar]
  39. Stone J. A., Holland S. D., Wickersham P. J., Sterrett A., Schwartz M., Bonfiglio C., Hesney M., Winchell G. A., Deutsch P. J., other authors. 2002; Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother 46:739–745 [CrossRef][PubMed]
    [Google Scholar]
  40. Szilágyi J., Földi R., Bayegan S., Kardos G., Majoros L. 2012; Effect of nikkomycin Z and 50% human serum on the killing activity of high-concentration caspofungin against Candida species using time-kill methodology. J Chemother 24:18–25 [CrossRef][PubMed]
    [Google Scholar]
  41. Wang E., Farmakiotis D., Yang D., McCue D. A., Kantarjian H. M., Kontoyiannis D. P., Mathisen M. S. 2015; 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 [CrossRef][PubMed]
    [Google Scholar]
  42. Wiederhold N. P., Najvar L. K., Bocanegra R., Molina D., Olivo M., Graybill J. R. 2007; In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera. Antimicrob Agents Chemother 51:1616–1620 [CrossRef][PubMed]
    [Google Scholar]
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