Abstract
It was previously demonstrated that brief (≤1 h) exposures to echinocandins are as effective to kill Candida albicans cells as continuous 24-h exposure. However, killing rates after continuous and short (1 h) echinocandin exposures to C. albicans have not yet been evaluated in RPMI-1640 with and without 50 % serum. We evaluated four echinocandin susceptible C. albicans bloodstream isolates, ATCC 10231 type strain and an echinocandin-resistant isolate (DPL20, FKS F645P). Caspofungin MICs, time-kill and postantifungal effect (PAFE) tests were performed in RPMI-1640 with and without 50 % serum. Killing rates (k values) in time-kill and PAFE experiments were determined for each strain and concentration. In time-kill experiments, colony count decreases were isolate- and concentration-dependent at 0.25, 1, 4, 8, 16 and 32 mg/L in RPMI-1640, but concentration-independent at 1, 4, 8, 16 and 32 mg/L in 50 % serum. One-hour caspofungin exposure at 4, 16 and 32 mg/L resulted in CFU decreases comparable with the results obtained in time-kill experiments in RPMI-1640, but 50 % serum at 4, 16 and 32 mg/L allowed growth of all isolates (k values were negative) (P < 0.05–0.001). PAFE in 50 % serum decreased markedly at 4, 16 and 32 mg/L. Killing rates remained high and concentration-independent in 50 % serum in case of continuous but not in case of brief caspofungin exposure. As only a short growth inhibition without killing was observed in 50 % serum, clinical relevance of caspofungin PAFE in vivo is questionable.
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References
Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54:2497–506.
Clancy CJ, Huang H, Cheng S, Derendorf H, Nguyen MH. Characterizing the effects of caspofungin on Candida albicans, Candida parapsilosis, and Candida glabrata isolates by simultaneous time-kill and postantifungal-effect experiments. Antimicrob Agents Chemother. 2006;50:2569–72.
Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, et al. Characterising the post-antifungal effects of micafungin against Candida albicans, Candida glabrata, Candida parapsilosis and Candida krusei isolates. Int J Antimicrob Agents. 2010;35:80–4.
Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, et al. Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis and C. krusei isolates. Antimicrob Agents Chemother. 2009;53:3347–52.
Shields RK, Nguyen MH, Du C, Press E, Cheng S, Clancy CJ. Paradoxical effect of caspofungin against Candida bloodstream isolates is mediated by multiple pathways, but eliminated in human serum. Antimicrob Agents Chemother. 2011;55:2641–7.
Kovács R, Gesztelyi R, Berényi R, Domán M, Kardos G, Juhász B, et al. 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. 2014;63:186–94.
Földi R, Kovács R, Gesztelyi R, Kardos G, Berényi R, Juhász B, et al. Comparison of in vitro and in vivo efficacy of caspofungin against Candida parapsilosis, C. orthopsilosis, C. metapsilosis and C. albicans. Mycopathol. 2012;174:311–8.
Nasar A, Ryan L, Frei CR, Cota JM, Wiederhold NP. Influence of serum and albumin on echinocandin in vitro potency and pharmacodynamics. Curr Fungal Infect Rep. 2013;7:89–95.
Szabó Z, Tóth B, Kovács M, Kardos G, Maráz A, Rozgonyi F, et al. Evaluation of the new Micronaut-Candida system compared to the API ID32C method for yeast identification. J Clin Microbiol. 2008;46:1824–5.
Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard, 3rd ed. M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA (2008).
Cornely OA, Vehreschild JJ, Vehreschild MJ, Würthwein G, Arenz D, Schwartz S, et al. Phase II dose escalation study of caspofungin for invasive Aspergillosis. Antimicrob Agents Chemother. 2011;55:5798–803.
Cantón E, Pemán J, Valentin A, Espinel-Ingroff A, Gobernado M. 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. 2009;53:3108–11.
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 Updat. 2011;14:164–76.
Walker LA, Gow NA, Munro CA. Elevated chitin content reduces the susceptibility of Candida species to caspofungin. Antimicrob Agents Chemother. 2013;57:146–54.
Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother. 2005;49:5058–68.
Acknowledgments
R. Kovács was supported by the TÁMOP 4.2.4. A/2-11-1-2012-0001 “National excellence Program-Elaborating and operating an inland student and researcher personal support system.” The project was subsidized by European Union and co-financed by the European Social Fund.
Conflict of interest
L. Majoros received conference travel grants from MSD, Astellas and Pfizer.
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Kovács, R., Gesztelyi, R., Perlin, D.S. et al. Killing Rates for Caspofungin Against Candida albicans After Brief and Continuous Caspofungin Exposure in the Presence and Absence of Serum. Mycopathologia 178, 197–206 (2014). https://doi.org/10.1007/s11046-014-9799-4
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DOI: https://doi.org/10.1007/s11046-014-9799-4