jofinЖурнал инфектологииJournal Infectology2072-6732IPO “АIDSSPbR"10.22625/2072-6732-2015-7-3-91-102jofin-427Research ArticleОригинальные исследованияOriginal ResearchОпределение резистентности Candida spp. к антифунгальным препаратам системного действия эпсилометрическим методом (Е-тест) с учетом видо-специфических особенностей кандидDetermination of resistance Candida spp. to antifungal agents with systemic action epsilometric method (E-test) with the species-specific characteristics of CandidaБагироваН. С.BagirovaN. S.

ведущий научный сотрудник лаборатории микробиологической диагностики и лечения инфекций в онкологии Российского онкологического научного центра им. Н.Н. Блохина, д.м.н.; тел.: +7-916-247-17-69

nbagirova@mail.ruДмитриеваН. В.DmitrievaN. V.

заведующая лабораторией микробиологической диагностики и лечения инфекций в онкологии Российского онкологического научного центра им. Н.Н. Блохина, д.м.н., профессор; тел. +7-985-070-75-44

prof.ndmitrieva@mail.ruРоссийский онкологический научный центр им. Н.Н. Блохина, Москва, РоссияРоссияRussian Cancer Research Center named N.N. Blokhin, Moscow, RussiaRussian Federation2015011120157391102Copyright © Багирова Н.С., Дмитриева Н.В., 20152015Багирова Н.С., Дмитриева Н.В.Bagirova N.S., Dmitrieva N.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.niidi.ru/jofin/article/view/427

Оценка чувствительности антифунгальных препаратов системного действия к Candida spp. в последние годы была стандартизирована и уточнена с учетом видо-специфических особенностей кандид. В дополнение к новым значениям клинических ключевых точек было введено новое понятие – эпидемиологическое пороговое значение. Его величина может служить надежным  аркером потенциальной резистентности кандид к антимикотикам. В нашем исследовании была протестирована резистентность эпсилометрическим методом (Е-тест) к флуконазолу, вориконазолу, позаконазолу анидулафунгину, каспофунгину, микафунгину для 294 клинических штаммов Candida spp. (2012–2014 гг.), полученных от онкологических больных. Резистентность к азолам в среднем наблюдалась в 47,4% случаях, к эхинокандинам – в 4,2% случаях.

Evaluation of susceptibility of systemic antifungal agents against Candida spp. in recent years has been standardized and refined based on species-specific characteristics of Candida. In addition to new values clinical breakpoints were introduced epidemiological cutoff value. This value can serve as a sensitive marker of reduced susceptibility to the systemic antifungal agents. In our study was tested the resistance of fluconazole, voriconazole, posaconazole, anidulafungin, caspofungin, micafungin for 294 clinical strains of Candida spp. (2012–2014) from specimens of cancer patients. Definition of MIC was performed by epsilometric method (Е-test). The resistance to azoles in the average observed in 47.4%, to echinocandins – in 4.2%.

Е-тестCandida spp.инвазивный кандидозрезистентностьклинические ключевые точкиэпидемиологическое пороговое значениеминимальная ингибирующая концентрацияE-testCandida spp.invasive candidiasisresistanceclinical breakpointsepidemiological cutoff valuethe minimum inhibitory concentrationReferencesClinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts—third edition. CLSI document M27-A3. Clinical and Laboratory Standards Institute, Wayne, PAClinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts—third edition. CLSI document M27-A3. Clinical and Laboratory Standards Institute, Wayne, PAClinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts; 3rd informational supplement. CLSI M27-S3. Clinical and Laboratory Standards Institute, Wayne, PAClinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts; 3rd informational supplement. CLSI M27-S3. Clinical and Laboratory Standards Institute, Wayne, PAESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). 2008. EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Clin. Microbiol. Infect. 14:398–405ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). 2008. EUCAST definitive document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Clin. Microbiol. Infect. 14:398–405O. A.Cornely, M. Bassetti, T. Calandra, J. Garbino, B. J. Kullberg,O. Lortholary, W.Meersseman, M.Akova, Arendrup, S. Arikan-Akdagli, J. Bille, Castagnola,M.Cuenca-Estrella, J. P. Donnelly, A. H. Groll, R. Herbrecht, W. W.Hope, H.E. Jensen, C. Lass-Flo¨ rl,G. Petrikkos,M. D. Richardson, E. Roilides, P. E.Verweij, C. Viscoli and A. J. Ullmann for the ESCMID Fungal Infection Study Group (EFISG). ESCMID* guideline for the diagnosis and management of Candida diseases 2012: nonneutropenic adult patients. Clin Microbiol Infect 2012; 18 (7):19–37.O. A.Cornely, M. Bassetti, T. Calandra, J. Garbino, B. J. Kullberg,O. Lortholary, W.Meersseman, M.Akova, Arendrup, S. Arikan-Akdagli, J. Bille, Castagnola,M.Cuenca-Estrella, J. P. Donnelly, A. H. Groll, R. Herbrecht, W. W.Hope, H.E. Jensen, C. Lass-Flo¨ rl,G. Petrikkos,M. D. Richardson, E. Roilides, P. E.Verweij, C. Viscoli and A. J. Ullmann for the ESCMID Fungal Infection Study Group (EFISG). ESCMID* guideline for the diagnosis and management of Candida diseases 2012: nonneutropenic adult patients. Clin Microbiol Infect 2012; 18 (7):19–37.Maiken Cavling Arendrup. Candida and Candidaemia. Susceptibility and Epidemiology. Dan Med J 2013; 60(11):B4698.Maiken Cavling Arendrup. Candida and Candidaemia. Susceptibility and Epidemiology. Dan Med J 2013; 60(11):B4698.Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement, M27-S4. 2012Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement, M27-S4. 2012Pfaller M.A., Shawn A. Messer, Leah N. Woosley, Ronald N. Jones, Mariana Castanheira. Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance. J. Clin. Microbiol. August 2013 . – Vol. 51 № 8: 2571–2581Pfaller M.A., Shawn A. Messer, Leah N. Woosley, Ronald N. Jones, Mariana Castanheira. Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance. J. Clin. Microbiol. August 2013 . – Vol. 51 № 8: 2571–2581Pfaller MA, Andes D, Arendrup MC, Diekema DJ, Espinel- Ingroff A, Alexander BD, Brown SD, Chaturvedi V, Fowler CL, Ghannoum MA, Johnson EM, Knapp CC, Motyl MR, Ostrosky- Zeichner L, Walsh TJ.. Clinical breakpoints for voriconazole and Candida spp. revisited: review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the development of species-specific interpretive criteria. Diagn. Microbiol. Infect. Dis. 2011; 70: 330–343Pfaller MA, Andes D, Arendrup MC, Diekema DJ, Espinel- Ingroff A, Alexander BD, Brown SD, Chaturvedi V, Fowler CL, Ghannoum MA, Johnson EM, Knapp CC, Motyl MR, Ostrosky- Zeichner L, Walsh TJ.. Clinical breakpoints for voriconazole and Candida spp. revisited: review of microbiologic, molecular, pharmacodynamic, and clinical data as they pertain to the development of species-specific interpretive criteria. Diagn. Microbiol. Infect. Dis. 2011; 70: 330–343Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D, CLSI Subcommittee for Antifungal Susceptibility Testing. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug Resist. Updat. 2010; 13:180–195Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D, CLSI Subcommittee for Antifungal Susceptibility Testing. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug Resist. Updat. 2010; 13:180–195Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN. Echinocandin and triazole antifungal susceptibility profiles for Candida spp., Cryptococcus neoformans, and Aspergillus fumigatus: application of new CLSI clinical breakpoints and epidemiologic cutoff values to characterize resistance in the SENTRY Antimicrobial Surveillance Program (2009). Diagn. Microbiol. Infect. Dis. 2011; 69:45–50Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN. Echinocandin and triazole antifungal susceptibility profiles for Candida spp., Cryptococcus neoformans, and Aspergillus fumigatus: application of new CLSI clinical breakpoints and epidemiologic cutoff values to characterize resistance in the SENTRY Antimicrobial Surveillance Program (2009). Diagn. Microbiol. Infect. Dis. 2011; 69:45–50Pfaller 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; 50:2846–2856Pfaller 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; 50:2846–2856Pfaller 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; 50:1199–1203Pfaller 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; 50:1199–1203Pfaller MA, Woosley LN, Messer SA, Jones RN, Castanheira M. Significance of molecular identification and antifungal susceptibility of clinically significant yeasts and moulds in a global antifungal surveillance programme. Mycopathologia 2012; 174:259–271Pfaller MA, Woosley LN, Messer SA, Jones RN, Castanheira M. Significance of molecular identification and antifungal susceptibility of clinically significant yeasts and moulds in a global antifungal surveillance programme. Mycopathologia 2012; 174:259–271Pfaller 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, doi:10.1016/j.drup.2011.01.004Pfaller 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, doi:10.1016/j.drup.2011.01.004Bagirova N.S., Dmitrieva N.V, Hachaturova V.A. In vitro aktivnost‘ flukonazola i vorikonazola protiv drozhzhevyh gribov, vydelennyh u onkologicheskih bol‘nyh. Soprovoditel‘naja terapija v onkologii, 2007; № 1-2. C. 73-81Bagirova N.S., Dmitrieva N.V, Hachaturova V.A. In vitro aktivnost‘ flukonazola i vorikonazola protiv drozhzhevyh gribov, vydelennyh u onkologicheskih bol‘nyh. Soprovoditel‘naja terapija v onkologii, 2007; № 1-2. C. 73-81Arendrup M. C., G.Garcia-Effron, C. Lass-FloЁrl, A. Gomez Lopez, J. Luis Rodriguez-Tudela, M. Cuenca-Estrella, and D.S. Perlin. Echinocandin Susceptibility Testing of Candida Species: Comparison of EUCAST EDef 7.1, CLSI M27-A3, Etest, Disk Diffusion, and Agar Dilution Methods with RPMI and IsoSensitest Media. Antimicrob. Aagents and Chemother., Jan. 2010; 54 (1): 426–439Arendrup M. C., G.Garcia-Effron, C. Lass-FloЁrl, A. Gomez Lopez, J. Luis Rodriguez-Tudela, M. Cuenca-Estrella, and D.S. Perlin. Echinocandin Susceptibility Testing of Candida Species: Comparison of EUCAST EDef 7.1, CLSI M27-A3, Etest, Disk Diffusion, and Agar Dilution Methods with RPMI and IsoSensitest Media. Antimicrob. Aagents and Chemother., Jan. 2010; 54 (1): 426–439Cuesta Isabel, Concha Bielza, Manuel Cuenca-Estrella, Pedro Larran aga, and Juan L. Rodr guez-Tudela. Evaluation by Data Mining Techniques of Fluconazole Breakpoints Established by the Clinical and Laboratory Standards Institute (CLSI) and Comparison with Those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Antimicrob. Aagents and Chemother., Apr. 2010; 54(4): 1541–1546Cuesta Isabel, Concha Bielza, Manuel Cuenca-Estrella, Pedro Larran aga, and Juan L. Rodr guez-Tudela. Evaluation by Data Mining Techniques of Fluconazole Breakpoints Established by the Clinical and Laboratory Standards Institute (CLSI) and Comparison with Those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Antimicrob. Aagents and Chemother., Apr. 2010; 54(4): 1541–1546Alexander B.D., Johnson M.D., Pfeiffer C.D., Jimenes-Ortigosa C., Canania J., Booker R., et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutation and elevated minimum inhibitory concentrations. Clin. Infect. Dis. 2013; 56:1724-32Alexander B.D., Johnson M.D., Pfeiffer C.D., Jimenes-Ortigosa C., Canania J., Booker R., et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutation and elevated minimum inhibitory concentrations. Clin. Infect. Dis. 2013; 56:1724-32Cuenca-Estrella M., Verweij P.E., Arendrup M.C., Arikan-Akdagli S., Bille J., Donnelly J.P. et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: diagnosis procedures. Clin. Microbiol. Infect. 2012; 18(7): 9-18Cuenca-Estrella M., Verweij P.E., Arendrup M.C., Arikan-Akdagli S., Bille J., Donnelly J.P. et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: diagnosis procedures. Clin. Microbiol. Infect. 2012; 18(7): 9-18Shields R.K., Nguyen M.N., Press E.G., Updike C.L., Clancy C.J. Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob. Agents Chemother. 2013; 57: 3528-35Shields R.K., Nguyen M.N., Press E.G., Updike C.L., Clancy C.J. Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob. Agents Chemother. 2013; 57: 3528-35Ben-Ami R., Y. Hilerowicz, A. Novikov, M. Giladi. The impact of new epidemiological cutoff values on Candida glabrata resistance rates and concordance between testing methods. Diagnostic Microbiol. And Infect Dis. 2014; 79: 209-213Ben-Ami R., Y. Hilerowicz, A. Novikov, M. Giladi. The impact of new epidemiological cutoff values on Candida glabrata resistance rates and concordance between testing methods. Diagnostic Microbiol. And Infect Dis. 2014; 79: 209-213Cuenca-Estrella M., A. Gomez-Lopez, A. Alastruey-Izquierdo, L. Bernal-Martinez, I. Cuesta, M.J. Buitrago, and J.L. Rodriguez-Tudela. Comparison of the VITEK 2 Antifungal Susceptibility System with the CLSI and the EUCAST Broth Microdilution Reference methods and with the Sensititre Yeast-One and the Etest Techniques for the Detection in Vitro of Antifungal Resistance in Yeasts. J. Clin. Microbiol., May 2010 ; 48 (5): 1782–1786Cuenca-Estrella M., A. Gomez-Lopez, A. Alastruey-Izquierdo, L. Bernal-Martinez, I. Cuesta, M.J. Buitrago, and J.L. Rodriguez-Tudela. Comparison of the VITEK 2 Antifungal Susceptibility System with the CLSI and the EUCAST Broth Microdilution Reference methods and with the Sensititre Yeast-One and the Etest Techniques for the Detection in Vitro of Antifungal Resistance in Yeasts. J. Clin. Microbiol., May 2010 ; 48 (5): 1782–1786Pfaller M.A, L. Boyken, R. J. Hollis, J. Kroeger, S. A. Messer, S. Tendolkar, and D. J. Diekema. Wild-Type MIC Distributions and Epidemiological Cutoff Values for Posaconazole and Voriconazole and Candida spp. as Determined by 24-Hour CLSI Broth Microdilution. J. Clin. Microbiol. 2011; 49(2): 630–637Pfaller M.A, L. Boyken, R. J. Hollis, J. Kroeger, S. A. Messer, S. Tendolkar, and D. J. Diekema. Wild-Type MIC Distributions and Epidemiological Cutoff Values for Posaconazole and Voriconazole and Candida spp. as Determined by 24-Hour CLSI Broth Microdilution. J. Clin. Microbiol. 2011; 49(2): 630–637

The authors declare that there are no conflicts of interest present.