Mecanismos de resistencia a fluconazol expresados por Candida glabrata: una situación para considerar en la terapéutica

Leidy Yurani Cárdenas Parra; Jorge Enrique Pérez Cárdenas

Leidy Yurani Cárdenas Parra Universidad de Caldas y Universidad Católica de Manizales (Colombia)
Jorge Enrique Pérez Cárdenas Universidad de Caldas (Colombia)

Palabras clave: Candida glabrata, Candida, resistencia, azoles, fluconazol

Key-words: Candida glabrata, Candida, resistance, azoles, fluconazole

Palavras chave: Candida glabrata, Candida, resistência, azóis, fluconazol

Resumen

Introducción: Los esfuerzos terapéuticos orientados a atender las micosis por Candidaspp. se han enfocado en el empleo de azoles; sin embargo, en la literatura científica se discute su beneficio, por los amplios y descritos mecanismos de resistencia. Objetivo: Describir los mecanismos de resistencia al fluconazol expresados por la especie Candida glabrata, con la intención de que sean considerados dentro de las variables de elegibilidad para la intervención. Método: Se realizó una revisión integrativa utilizando la pregunta orientadora: ¿cuáles son los mecanismos de resistencia al fluconazol expresados por la especie Candida glabrata? Veintinueve estudios obtenidos de la base de datos PubMed cumplieron los criterios del análisis crítico propuesto por el instrumento PRISMA, utilizado para la selección de los artículos incluidos para su revisión en este manuscrito. Las categorías bajo las cuales se organizaron los elementos de análisis fueron: sobrexpresión de bombas de eflujo y modificaciones en la enzima lanosterol 14-alfa-desmetilasa. Resultados: Los mecanismos de resistencia al fluconazol expresados por Candida glabrata están determinados principalmente por la regulación a la alza de bombas de adenosina-trifosfato Binding Cassette (ABC) y por la modificación del punto de unión con su blanco farmacológico: la enzima lanosterol 14-alfa-desmetilasa. Conclusión: Los mecanismos de resistencia expresados por Candida glabrata se asocian con la modificación estructural de la diana farmacológica y la sobreexpresión de bombas de eflujo de manera diferencial a otras especies. Se sugiere que Candida glabrata es intrínsecamente menos susceptible al fluconazol

Abstract

Introduction: Therapeutic efforts aimed at treating mycosis caused by Candida spp. have focused on the use of azoles; however, their benefits have been subject to discussion in scientific literature, due to the extensive and well-described resistance mechanisms. Objective: To describe the resistance mechanisms to fluconazole expressed by the Candida glabrata species, so they are considered within the variables of eligibility for intervention. Method: An integrative review was carried out using the guiding question: what are the fluconazole resistance mechanisms expressed by the Candida glabrata species? Twenty-nine studies obtained from the PubMed database met the criteria for the critical analysis proposed by the PRISMA instrument, which was used for the selection of articles for review included in this paper. The analysis elements were organized in the following categories: overexpression of efflux pumps and modifications in the enzyme lanosterol 14-alpha-demethylase. Results: The resistance mechanisms to fluconazole expressed by Candida glabrata are mainly determined by the upregulation of Adenosine triphosphate Binding Cassette (ABC) pumps and by the modification of the point of attachment with its pharmacological target: the enzyme lanosterol 14-alpha-demethylase. Conclusion: The resistance mechanisms expressed by Candida glabrata are associated with the structural modification of the pharmacological target and the overexpression of efflux pumps, in a way different to other species. It is suggested that Candida glabrata is intrinsically less susceptible to fluconazole

Resumo

Introdução: Os esforços terapêuticos voltados ao tratamento de micose por Candida spp. se focaram no uso de azóis; no entanto, na literatura científica discute-se seu benefício devido aos extensos e descritos mecanismos de resistência. Objetivo: Descrever os mecanismos de resistência ao fluconazol expressos pela espécie Candida glabrata, com a intenção de serem considerados dentro das variáveis de elegibilidade para a intervenção. Método: Uma revisão integrativa foi realizada utilizando a questão norteadora: quais os mecanismos de resistência ao fluconazol expressos pela espécie Candida glabrata? Vinte e nove estudos obtidos da base de dados PubMed atenderam os critérios de análise crítica proposta pelo instrumento PRISMA, utilizado para a seleção dos artigos incluídos para revisão neste manuscrito. As categorias sob as quais se organizaram os elementos de análise foram: superexpressão de bombas de efluxo e modificações na enzima lanosterol 14-alfa-desmetilase. Resultados: Os mecanismos de resistência ao fluconazol expressos por Candida glabrata são determinados principalmente pela regulação positiva das bombas de adenosina-trifosfato Binding Cassette (ABC) e pela modificação do ponto de fixação com seu alvo farmacológico: a enzima lanosterol 14-alfa-desmetilasa. Conclusão: Os mecanismos de resistência expressos por Candida glabrata são associados à modificação estrutural da Diana farmacológica e a superexpressão de bombas de efluxo de maneira diferencial a outras espécies. Sugere-se que Candida glabrata é intrinsecamente menos susceptível ao fluconazol

Bibliografía

1. Falagas ME, Roussos N, Vardakas KZ. Relative frequency of albicans and the various non-albicans Candida spp. among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis. 2010;14(11):e954-66. https://doi.org/10.1016/j.ijid.2010.04.006

2. Yeşilkaya A, Azap Ö, Aydın M, Akçil Ok M. Epidemiology, species distribution, clinical characteristics and mortality of candidaemia in a tertiary care university hospital in Turkey, 2007-2014. Mycoses. 2017;60(7):433-9. https://doi.org/10.1111/myc.12618

3. Savastano C, de Oliveira Silva E, Gonçalves LL, Nery JM, Silva NC, Dias ALT. Candida glabrata among Candida spp. from environmental health practitioners of a Brazilian Hospital. Braz J Microbiol Publ Braz Soc Microbiol. 2016;47(2):367-72. https://doi.org/10.1016/j.bjm.2015.05.001

4. Goemaere B, Becker P, Van Wijngaerden E, Maertens J, Spriet I, Hendrickx M, et al. Increasing candidaemia incidence from 2004 to 2015 with a shift in epidemiology in patients preexposed to antifungals. Mycoses. 2018;61(2):127-33. https://doi.org/10.1111/myc.12714

5. Sasso M, Roger C, Sasso M, Poujol H, Barbar S, Lefrant J-Y, et al. Changes in the distribution of colonising and infecting Candida spp. isolates, antifungal drug consumption and susceptibility in a French intensive care unit: A 10-year study. Mycoses. 2017;60(12):770-80. https://doi.org/10.1111/myc.12661

6. de Bedout C, Gómez BL. Candida and candidiasis: the challenge continues for an early diagnosis. Infectio. 2010;14:s159-71.

7. Valle GMM del. Candida glabrata: un patógeno emergente. Biociencias. 2016;10(1):89-102. https://doi.org/10.18041/2390-0512/bioc..1.2859

8. Rodríguez AZ, Gómez C de B, Restrepo CAA, Parra HH, Arteaga MA, Moreno AR, et al. [Susceptibility to fluconazole and voriconazole of Candida species isolated from intensive care units patients in Medellin, Colombia (2001-2007)]. Rev Iberoam Micol. 2010;27(3):125-9. https://doi.org/10.1016/j.riam.2010.04.001

9. Magalhães YC, Bomfim MRQ, Melônio LC, Ribeiro PCS, Cosme LM, Rhoden CR, et al. Clinical significance of the isolation of Candida species from hospitalized patients. Braz J Microbiol Publ Braz Soc Microbiol. 2015;46(1):117-23. https://doi.org/10.1590/S1517-838246120120296

10. Tapia P C. Candida glabrata. Rev Chil Infectol. 2008;25(4):293-293. http://dx.doi.org/10.4067/S0716-10182008000400009

11. Olaechea P, Lerma FA, Martínez MP, Ordeñana JI, López-Pueyo MJ, Betolaza IS, et al. Evolución del consumo de antifúngicos en pacientes críticos. Estudio multicéntrico observacional, 2006-2010. Enferm Infecc Microbiol Clin. 2012;30(8):435-40. https://doi.org/10.1016/j.eimc.2012.02.006

12. Sanguinetti M, Posteraro B, Lass-Flörl C. Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses. 2015;58 Suppl 2:2-13. https://doi.org/10.1111/myc.12330

13. Florez J, Armijo JA, De Cost MA. Reacciones adversas a los medicamentos y farmacovigilancia. En: Flórez J, Armijo JA, editores. Farmacología humana. 5.. ed. Barcelona: Masson; 2008. p. 129-46.

14. Isaza G, Fuentes J, Marulanda T, Buriticá O, Machado J, Moncada J. Generalidades de farmacología. En: Isaza G, Fuentes J, Marulanda T, et al., editores. Fundamentos de farmacología en terapéutica. 6.. ed. Bogotá: Celsus; 2014. p. 27-31.

15. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 21 de julio de 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097

16. Deorukhkar SC, Saini S. Virulence factors attributed to pathogenicity of non albicans Candida species isolated from Human Immunodeficiency virus infected patients with oropharyngeal candidiasis. Ann Pathol Lab Med. 2015;2(2):A62-66. https://doi.org/10.1155/2014/456878

17. Ahmad KM, Kokošar J, Guo X, Gu Z, Ishchuk OP, Piškur J. Genome structure and dynamics of the yeast pathogen Candida glabrata. FEMS Yeast Res. 2014;14(4):529-35. https://doi.org/10.1111/1567-1364.12145

18. Muller H, Hennequin C, Gallaud J, Dujon B, Fairhead C. The asexual yeast Candida glabrata maintains distinct a and alpha haploid mating types. Eukaryot Cell. 2008;7(5):848-58. https://doi.org/10.1128/EC.00456-07

19. Bairwa G, Rasheed M, Taigwal R, Sahoo R, Kaur R. GPI (glycosylphosphatidylinositol)-linked aspartyl proteases regulate vacuole homoeostasis in Candida glabrata. Biochem J. 2014;458(2):323-34. https://doi.org/10.1042/BJ20130757

20. Lesage G, Bussey H. Cell Wall Assembly in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2006;70(2):317-43. https://doi.org/10.1128/MMBR.00038-05

21. Pontón J. La pared celular de los hongos y el mecanismo de acción de la anidulafungina. Rev Iberoam Micol. 2008;25(2):78-82. https://doi.org/10.1016/S1130-1406(08)70024-X

22. Chaffin WL, López-Ribot JL, Casanova M, Gozalbo D, Martínez JP. Cell wall and secreted proteins of Candida albicans: identification, function, and expression. Microbiol Mol Biol Rev MMBR. 1998;62(1):130-80

23. Okada H, Abe M, Asakawa-Minemura M, Hirata A, Qadota H, Morishita K, et al. Multiple functional domains of the yeast l,3-beta-glucan synthase subunit Fks1p revealed by quantitative phenotypic analysis of temperature-sensitive mutants. Genetics. 2010;184(4):1013-24. https://doi.org/10.1534/genetics.109.109892

24. Spanova M, Czabany T, Zellnig G, Leitner E, Hapala I, Daum G. Effect of lipid particle biogenesis on the subcellular distribution of squalene in the yeast Saccharomyces cerevisiae. J Biol Chem. 2010;285(9):6127-33. https://doi.org/10.1074/jbc.M109.074229

25. Base de datos en farmacología Drugbank. Fluconazole [Internet]. Washington: FDA. 2018 [citado 2018 oct 7]. Disponible en: https://www.drugbank.ca/drugs/DB00196

26. Tuck SF, Patel H, Safi E, Robinson CH. Lanosterol 14 alpha-demethylase (P45014DM): effects of P45014DM inhibitors on sterol biosynthesis downstream of lanosterol. J Lipid Res. 1991;32(6):893-902.

27. Fonseca E, Silva S, Rodrigues CF, Alves CT, Azeredo J, Henriques M. Effects of fluconazole on Candida glabrata biofilms and its relationship with ABC transporter gene expression. Biofouling. 2014;30(4):447-57. https://doi.org/10.1080/08927014.2014.886108

28. Castanheira M, Messer SA, Jones RN, Farrell DJ, Pfaller MA. Activity of echinocandins and triazoles against a contemporary (2012) worldwide collection of yeast and moulds collected from invasive infections. Int J Antimicrob Agents. 2014;44(4):320-6. https://doi.org/10.1016/j.ijantimicag.2014.06.007

29. Roetzer A, Gratz N, Kovarik P, Schüller C. Autophagy supports Candida glabrata survival during phagocytosis. Cell Microbiol. 2010;12(2):199-216. https://doi.org/10.1111/j.1462-5822.2009.01391

30. Chelsea M, Armstrong A, Armstrong E. Principios de quimioterapia. En: Brunton L, Chabner B, Knollman B, editores. Bases fisiopatológicas del tratamiento farmacológico. 4.. ed. Barcelona: Lippincott Williams and Wilkins; 2017. p. 661-74.

31. Nabili M, Abdollahi Gohar A, Badali H, Mohammadi R, Moazeni M. Amino acid substitutions in Erg11p of azole-resistant Candida glabrata: Possible effective substitutions and homology modelling. J Glob Antimicrob Resist. 2016;5:42-6. https://doi.org/10.1016/j.jgar.2016.03.003

32. Morace G, Perdoni F, Borghi E. Antifungal drug resistance in Candida species. J Glob Antimicrob Resist. 2014;2(4):254-9. https://doi.org/10.1016/j.jgar.2014.09.002

33. Morio F, Jensen RH, Le Pape P, Arendrup MC. Molecular basis of antifungal drug resistance in yeasts. Int J Antimicrob Agents. 2017;50(5):599-606. https://doi.org/10.1016/j.ijantimicag.2017.05.012

34. Flórez J, Peralta G, Mediavilla A. Enfermedades infecciosas. En: Flórez J, Armijo JA, editores. Farmacología humana. 5.. ed. Barcelona: Masson; 2008. p. 1301-16.

35. Sheppard D, Lampiris H. Fármacos quimioterapéuticos. En: Katzung BG, Masters SB, Trevor AJ, editores. Farmacología básica y clínica. 12.. ed. México: McGraw-Hill; 2013. p. 849-60.

36. Silva V, Díaz MC, Febré N. Vigilancia de la resistencia de levaduras a antifúngicos. Rev Chil Infectol. 2002;19 (suppl 2):149-56. http://dx.doi.org/10.4067/S0716-10182002019200016

37. Becher R, Wirsel SGR. Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens. Appl Microbiol Biotechnol. 2012;95(4):825-40. https://doi.org/10.1007/s00253-012-4195-9

38. Morace G, Perdoni F, Borghi E. Antifungal drug resistance in Candida species. J Glob Antimicrob Resist. 2014;2(4):254-9. https://doi.org/10.1016/j.jgar.2014.09.002

39. Biswas C, Chen SC-A, Halliday C, Kennedy K, Playford EG, Marriott DJ, et al. Identification of genetic markers of resistance to echinocandins, azoles and 5-fluorocytosine in Candida glabrata by next-generation sequencing: a feasibility study. Clin Microbiol Infect. 2017;23(9):676.e7-676.e10. https://doi.org/10.1016/j.cmi.2017.03.014

40. Morio F, Jensen RH, Le Pape P, Arendrup MC. Molecular basis of antifungal drug resistance in yeasts. Int J Antimicrob Agents. 2017;50(5):599-606. https://doi.org/10.1016/j.ijantimicag.2017.05.012

41. Silva DB dos S, Rodrigues LMC, Almeida AA de, Oliveira KMP de, Grisolia AB. Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species. Mem Inst Oswaldo Cruz. 2016;111(3):192-9. https://doi.org/10.1590/0074-02760150400

42. Puri N, Manoharlal R, Sharma M, Sanglard D, Prasad R. Overcoming the heterologous bias: an in vivo functional analysis of multidrug efflux transporter, CgCdr1p in matched pair clinical isolates of Candida glabrata. Biochem Biophys Res Commun. 2011;404(1):357-63. https://doi.org/10.1016/j.bbrc.2010.11.123

43. Clinical and Laboratory Standards Institute (CLSI). Methods for antifungal disk diffusion susceptibility testing of yeasts; approved guideline-Second Edition; 2009. CLSI Document M44-A2: [Internet]. 2009. Disponible en: https://clsi.org/media/1634/m44a2_sample.pdf

44. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard-Third Edition; 2008. CLSI Document M27-A3 [Internet]. 2008. Disponible en: https://clsi.org/media/1461/m27a3_sample.pdf

45. Clinical and Laboratory Standards Institute (CLSI). reference method for broth dilution antifungal susceptibility testing of yeasts; fourth informational supplement; 2012. CLSI Document M27-S4. [Internet]. 2012. Disponible en: https://clsi.org/media/1897/m27ed4_sample.pdf

46. Clinical and Laboratory Standards Institute (CLSI). Perfomance stands for antifungal susceptibility testing of yeasts; first edition; 2017. CLSI Document M60 [Internet]. 2017. Disponible en: https://clsi.org/standards/products/microbiology/documents/m60/

47. Branco J, Ola M, Silva RM, Fonseca E, Gomes NC, Martins-Cruz C, et al. Impact of ERG3 mutations and expression of ergosterol genes controlled by UPC2 and NDT80 in Candida parapsilosis azole resistance. Clin Microbiol Infect. 2017;23(8):575.e1-575.e8. https://doi.org/10.1016/j.cmi.2017.02.002

48. Tapia C. Antifúngicos y resistencia. Rev Chil Infectol. 2012;29(3):357-357. http://dx.doi.org/10.4067/S0716-10182012000300020

49. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012;125(1 Suppl):S3-13. https://doi.org/10.1016/j.amjmed.2011.11.001

50. Abbes S, Amouri I, Sellami H, Neji S, Trabelsi H, Cheikhrouhou F, et al. Changes in genotype and fluconazole susceptibility of isolates from patients with Candida glabrata in Tunisia. Thérapie. 2014;69(5):449-55. https://doi.org/10.2515/therapie/2014059

51. López-Ávila K, Dzul-Rosado KR, Lugo-Caballero C, Arias-León JJ, Zavala-Castro JE. Mecanismos de resistencia antifúngica de los azoles en Candida albicans: una revisión. Rev Bioméd. 2016;27(3):127-36. http://dx.doi.org/10.32776/revbiomed.v27i3.541

52. Vermitsky J-P, Edlind TD. Azole Resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-Like transcription factor. Antimicrob Agents Chemother. 2004;48(10):3773-81. https://doi.org/10.1128/AAC.48.10.3773-3781.2004

53. Kanafani ZA, Perfect JR. Resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis. 2008;46(1):120-8. https://doi.org/10.1086/524071

54. 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(4):1199-203. https://doi.org/10.1128/JCM.06112-11

55. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12(4):501-17

56. Balouiri M, Sadiki M, Ibnsouda SK. Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Anal. 2016;6(2):71-9. doi 10.1016/j.jpha.2015.11.005

57. Sakagami T, Kawano T, Yamashita K, Yamada E, Fujino N, Kaeriyama M, et al. Antifungal susceptibility trend and analysis of resistance mechanism for Candida species isolated from bloodstream at a Japanese university hospital. J Infect Chemother. 2019;25(1):34-40. https://doi.org/10.1016/j.jiac.2018.10.007

58. Rocha DAS, Sa LFR de, Pinto ACC, Junqueira M de L, Silva EM da, Borges RM, et al. Characterisation of an ABC transporter of a resistant Candida glabrata clinical isolate. Mem Inst Oswaldo Cruz. 2018;113(4):e170484. https://doi.org/10.1590/0074-02760170484

59. Szweda P, Gucwa K, Romanowska E, Dzierz Anowska-Fangrat K, Naumiuk Ł, Brillowska-Da Browska A, et al. Mechanisms of azole resistance among clinical isolates of Candida glabrata in Poland. J Med Microbiol. 2015;64(6):610-9. https://doi.org/10.1099/jmm.0.000062

60. Holmes AR, Keniya MV, Ivnitski-Steele I, Monk BC, Lamping E, Sklar LA, et al. The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrob Agents Chemother. 2012;56(3):1508-15. https://doi.org/10.1128/AAC.05706-11

61. Salazar SB, Wang C, Münsterkötter M, Okamoto M, Takahashi-Nakaguchi A, Chibana H, et al. Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata. FEMS Yeast Res. 2018;18(1). https://doi.org/10.1093/femsyr/fox079

62. Tsai H-F, Sammons LR, Zhang X, Suffis SD, Su Q, Myers TG, et al. Microarray and molecular analyses of the azole resistance mechanism in Candida glabrata oropharyngeal isolates. Antimicrob Agents Chemother. 2010;54(8):3308-17. https://doi.org/10.1128/AAC.00535-10

63. Hou X, Xiao M, Wang H, Yu S-Y, Zhang G, Zhao Y, et al. Profiling of PDR1 and MSH2 in Candida glabrata bloodstream isolates from a multicenter study in China. Antimicrob Agents Chemother. 2018;62(6). https://doi.org/10.1128/AAC.00153-18

Mecanismos de resistencia a fluconazol expresados por Candida glabrata: una situación para considerar en la terapéutica

Resistance mechanisms to fluconazole expressed by Candida glabrata: a situation to consider in therapy

Mecanismos de resistência a fluconazol expressos por Candida glabrata: uma situação a considerar na terapêutica

Resumen

Abstract

Resumo

Bibliografía