Mechanisms of Developing Antifungal Drug Resistance of Candida spp. in Reccurent Urogenital Candidiasis

Abstract

Urogenital candidiasis is an infectious disease caused by Candida sp., a long recurrent course of which can reduce human reproductive health. Its frequent recurrence is associated with constant influence of provoking factors, noncompliance with treatment regimens, treatment without determining the sensitivity of individual antifungal drugs, local immunity disorders, and increasing antifungal drug resistance. Major drugs for genital candidiasis treatment are azole drugs, but at present there is a tendency toward growing antifungal drug resistance of Candida spp. This review describes antifungal drug resistance mechanisms that are currently under study: the ability of Candida spp. to form biofilms, changes in lipid composition of the fungal cell wall, and genetic mutations of Candida spp. The bulk of the accumulated material concerns the structure and role of the ERG11 gene encoding the sterol-14α-demethylase enzyme, the efflux pump genes CDR1 and CDR2, and the membrane transporter gene MDR1, which are associated with azole drug resistance. These genes are suggested for laboratory diagnostics as molecular genetic markers of antifungal resistance in order to select effective antimycotic therapy. For this review, we used sources from the Scopus, CyberLeninka, MedLine, and Russian Science Citation Index databases.

This is a preview of subscription content, log in to check access.

REFERENCES

  1. 1

    Moreva, Zh.G., Mironov, A.Yu., Sashchenko, V.P., and Vasil’ev, M.M., Recurrent urogenital candidiasis as a marker of hormonal disorders in women with infertility (clinical case), Usp. Med. Mikol., 2017, vol. 17, pp. 182–185.

    Google Scholar 

  2. 2

    Tapil’skaya, N.I. and Gaidukov, S.N., Mechanisms of resistance formation for candidal vulvovaginitis therapy: ways of coping and prevention of recurrence, Lechashchii Vrach, 2016, no. 6, p. 71. https://www.lvrach.ru/ 2016/06/15436499/.

  3. 3

    Federal’nye klinicheskie rekomendatsii. Dermatovene-rologiya 2015: Bolezni kozhi. Infektsii, peredavaemye polovym putem (Federal Clinical Recommendations. Dermatovenereology 2015: Skin Diseases. Sexually Transmitted Diseases), Kubanova, A.A., Ed., Moscow: Delovoi Ekspress, 2016.

    Google Scholar 

  4. 4

    Sobel, J.D., Faro, S., Force, R.W., Foxman, B., Ledger, W.J., Nyirjesy, P.R., Reed, B.D., and Summers, P.R., Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations, Am. J. Obstet. Gynecol., 1998, vol. 178, no. 2, pp. 203–210. https://doi.org/10.1016/s0002-93789880001-x

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Omarov, T.R. and Omarova, L.A., Mycotic lesions of the gastrointestinal tract, Russ. Med. Zh., 2016, no. 11, pp. 687–691. https://www.rmj.ru/articles/gastroenterologiya/Gribkovye_poragheniya_gheludochno-kishechnogo_trakta/.

  6. 6

    Burova, S.A., A contemporary view of mycotic pathology of the digestive tract, Lechashchii Vrach, 2005, no. 6. https://www.lvrach.ru/2005/06/4532660/.

  7. 7

    Korobtsova, I.P. and Sergeev, V.Yu., Skin candidiasis in 2016: What’s new?, in Uspekhi meditsinskoi mikologii. Trudy 4-ogo s’ezda mikologov Rossii, Moskva, aprel’ 12–14,2017 (Advances in Medical Mycology. Proc. 4th Convention of Mycologists of Russia), Moscow, April 12–14, 2017, pp. 314–319. https://search.rsl.ru/ru/record/ 01008875405.

  8. 8

    Kuznetsova, Yu.A., Microbiological characteristics of chronic recurrent vulvovaginal candidiasis in women of the Irkutsk region, Cand. Sci. Med. Dissertation, Novosibirsk, 2016. https://search.rsl.ru/ru/record/01006652857.

  9. 9

    Savicheva, A.M. and Shipitsyna, E.V., Recurrent urogenital candidiasis: features of diagnosis and treatment, Med. Sov., 2015, no. 9, pp. 15–17.

  10. 10

    Zarochentseva, N.V. and Belaya, Yu.M., The problem on urogenital candidiasis in women in the modern world, Russ. Med. Zh., 2016, no. 15, pp. 976–980. https://www.rmj.ru/articles/ginekologiya/Problema_ urogenitalynogo_kandidoza_u_ghenschin_v_sovremennom_mire/.

  11. 11

    Abdieva, D.Kh., Valieva, M.S., and Dyrda, N.I., Experience of using the drug “Exagin” for treatment of urogenital candidiasis, Usp. Med. Mikol., 2017, vol. 17, pp. 212–214. https://elibrary.ru/contents.asp?id=34534103.

    Google Scholar 

  12. 12

    Rahmatulina, M.R. and Tsoi, E.G., Current indicators of antifungal resistance of candida species, Farmateka, 2017, vol. 1, no. 17, pp. 22–24. https://pharmateca.ru/ru/archive/article/34548.

  13. 13

    Zheltikova, T.M., Monitoring the resistance of clinical strains of Candida yeast to fluconazole a brief literature review, Med. Sov., 2017, no. 2, pp. 70–74. https://doi.org/10.21518/2079-701X-2017-2-70-74.

  14. 14

    Prosovetskaya, A.L., Modern features of the etiological structure, clinical course, diagnostics of local immunity indicators, and treatment of patients with vulvovaginal candidiasis, Cand. Sci. Med. Dissertation, Moscow, 2007.

  15. 15

    Karaev, Z.O. and Mamedov, L.R., The effect of drugs onto formation of Candida albicans biofilms, Probl. Med. Mikol., 2010, vol. 12, no. 3, pp. 10–12. https://elibrary.ru/contents.asp?id=33657689.

  16. 16

    Mirzabalaeva, A.K. and Zhorzh, O.N., Hormonal disorders in gynecological diseases—a risk factor for chronic relapsing course of genitalia candidiasis, Probl. Med. Mikol., 2012, vol. 14, no. 2, pp. 25–29. https://elibrary.ru/item.asp?id=9571718.

  17. 17

    Nurmatova, Z.I., Nurmatov, A.A., and Ibragimova, N.I., The effect of vaginal candidiasis onto pregnancy, Nauchno-Prakt. Zh. Tadzh. Inst. Poslediplomnoi Podgot. Med. Kadrov, 2013, no. 2, pp. 26–29. https://elibrary.ru/item.asp?id=20540424.

  18. 18

    Baranovskaya, E.I. and Plyushchai, V.V., Vulvovaginal candidiasis in pregnant women, Klin. Med., 2012, no. 3, pp. 6–10. http://elib.gsmu.by/handle/GomSMU/1802.

  19. 19

    Krupeichenko, V.V., Etiopathogenesis of vulvovaginal candidiasis in pregnant women (literature review), Probl. Zdorov’ya Ekol., 2009, vol. 1, no. 19, pp. 9–93. https://cyberleninka.ru/article/n/16051615.

  20. 20

    Lesovoi, V.S., Lipnickii, A.V., and Ochkurova, O.M., Mycoses of the digestive tract (review), Probl. Med. Mikol., 2004, vol. 6, no. 2, pp. 19–23. http://www.rusmedserv.com/mycology/html/labora22.htm.

  21. 21

    Zhukova, N.V. and Krivosheeva, I.M., “Pharaoh’s curse” or mycotic infection of the lungs (pneumomycosis), Krym. Ter. Zh., 2010, no. 2, pp. 16–26. https:// docplayer.ru/42602659-Proklyatie-faraonov-ili-gribkovye-infekcii-legkih-pnevmomikozy-n-v-zhukova-i-m-krivosheeva.html.

  22. 22

    Veselov, A.V. and Kozlov, R.S., Invasive candidiasis: modern aspects of epidemiology, diagnostics, treatment, and prevention for different categories of patients, Klin. Mikrobiol. Antimikrobn. Khimioter., 2016, vol. 18, no. 2, p. 20. https://elibrary.ru/item.asp?id=27025705.

  23. 23

    Karpun, N.A., Burova, S.A., Evdokimov, E.A., and Chaus, N.I., Invasive candidiasis in intensive care units, Med. Alfavit, 2014, vol. 2, pp. 22–25. https://elibrary.ru/item.asp?id=21616816.

    Google Scholar 

  24. 24

    Vasil’eva, N.V., Klimko, N.N., and Tsinzerling, V.A., Diagnostics and treatment of invasive mycoses: current recommendations, Vestn. S.-Peterb. Med. Akad. Poslediplomnogo Obraz., 2010, vol. 8, pp. 5–18. https://mycology.szgmu.ru/files/St_%20from_Vestnik_MAPO_ No_04_10.pdf.

    Google Scholar 

  25. 25

    CDC. Candida auris: A Drug-Resistant Germ That Spreads in Healthcare Facilities. https://www.cdc.gov/ fungal/candida-auris/c-auris-drug-resistant.html.

  26. 26

    Kul’ko, A.B., Mitrohin, S.D., and Kuz’min, D.E., Candidiasis of the low respiratory tract in patients with tuberculosis, Usp. Med. Mikol., 2003, vol. 2, no. 2, pp. 251–252. https://elibrary.ru/contents.asp?id=34217629.

  27. 27

    Bairamov, G.R., Chronic recurrent vulvovaginal candidiasis and cervical pathology, Ginekologiya, 2007, vol. 9, no. 1, pp. 26–28. https://con-med.ru/magazines/ gynecology/gynecology-01-2007/khronicheskiy_ retsidiviruyushchiy_vulvovaginalnyy_kandidoz_i_patologiya_sheyki_matki/.

  28. 28

    Farr, A., Kiss, H., Holzer, I., Husslein, P., Hagmann, M., and Petricevic, L., Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome, Acta Obstet. Gynecol. Scand., 2015, vol. 94, no. 9, pp. 989–996. https://doi.org/10.1111/aogs.12697

    Article  PubMed  Google Scholar 

  29. 29

    Rahmatulina, M.R., Gushchin, A.E., and Tsoi, E.G., Vaginal candida infection: Clinical features and diagnostic methods, Vestn. Dermatol. Venerol., 2015, vol. 2, pp. 122–129.

    Google Scholar 

  30. 30

    Savochkina, Yu.A., Rumyantseva, T.A., Dolgova, T.I., and Gushchin, A.E., The development of technique of diagnostic of vulvovaginal candidiasis based on quantitative multiplex polymerase chain reaction, Klin. Lab. Diagn., 2015, vol. 60, no. 4, pp. 56–62. https://cyberleninka.ru/article/n/15794732.

    CAS  Google Scholar 

  31. 31

    Ivanova, L.V., Barantsevich, E.P., and Shlyahto, E.V., The resistance of fungi pathogens to antimycotics (review), Probl. Med. Mikol., 2011, vol. 13, no. 1, pp. 14–17. http://www.rusmedserv.com/mycology/html/mapo_1_ 2011.pdf.

  32. 32

    Lysenko, O.V., Study of sensitivity to antimycotic drugs microflora of patients receiving long-term antibacterial therapy, Mezhdunar. Nauchno-Issled. Zh., 2016, vol. 2, no. 44, pp. 60–64. https://doi.org/10.18454/IRJ.2016.44.079.

  33. 33

    Dolgo-Saburova, Yu.V., Mirzabalaeva, A.K. and Klimko, N.N., On the problem on resistance of pathogens of recurrent vulvovaginal candidiasis, Ginekologiya, 2014, vol. 16, no. 1, pp. 110–114.

    Google Scholar 

  34. 34

    Pashinina, O.A., Kartashova, O.L., Pashkova, T.M., and Popova, L.P., Antimycotic resistance of Candida fungi isolated from the reproductive tract of women with inflammatory diseases of the genitalia, Byull. Orenb. Nauchn. Tsentra Ural. Otd. Ross. Akad. Nauk, 2016, vol. 3, pp. 1–8. https://elibrary.ru/item.asp?id=27033078.

    Google Scholar 

  35. 35

    CDC. Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

  36. 36

    Galachiev, O.V., Kuznetsov, R.E., Baraeva, A.A., Murakov, S.V., Makeeva, D.I., and Popkov, S.A., Vulvovaginal candidiasis: the problem of recurrences, Vestn. Poslediplomnogo Med. Obraz., 2017, vol. 1, pp. 51–54. https://elibrary. ru/contents.asp?id=34474139.

    Google Scholar 

  37. 37

    Sheika matki, vlagalishe, vul’va. Fiziologiya, patologiya, kol’poskopiya, esteticheskaya korrektsiya. Rukovodstvo dlya praktikuyushchikh vrachei (Cervix Uteri, Vagina, Vulva. Physiology, Pathology, Colposcopy, Aesthetic Correction. Guideline for Practicing Physicians), Rogovskaya, S.I. and Lipova, E.V., Eds., Moscow: StatusPraesens, 2016

    Google Scholar 

  38. 38

    Mezhevitinova, E.A., Prilepskaya, V.N., Donnikov, A.E., Pogosyan, Sh.M., Abakarova, P.R., and Brovkina, T.V., Molecular genetic markers of recurrent candidiasis, Akush. Ginekol. (Moscow), 2014, no. 9, pp. 16–23.

  39. 39

    Bouklas, T., Alonso-Crisostomo, L., Székely, T., Jr., Diago-Navarro, E., Orner, E.P., Smith, K., et al., Generational distribution of a Candida glabrata population: resilient old cells prevail, while younger cells dominante in the vulnerable host, PLoS Pathog., 2017, vol. 135, no. 5, p. e1006355. https://doi.org/10.1371/journal.ppat.1006355

    CAS  Article  Google Scholar 

  40. 40

    Guo, H., Xie, S.M., Li, S.X., Song, Y.J., Zhong, X.Y., and Zhang, H., Involvement of mitochondrial aerobic respiratory activity in efflux-mediated resistance of C. albicans to Fluconazole, J. Mycol. Med., 2017, vol. 27, no. 3, pp. 339–344. https://doi.org/10.1016/j.mycmed.2017.04.004

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Shlepotina, N.M., Plotkin, L.L., and Belov, V.V., Microbiological and clinical significance of biofilm infections (literature review), Ural. Med. Zh., 2014, vol. 4, no. 118, pp. 106–112. https://elibrary.ru/contents. asp?issueid=1301848.

  42. 42

    Lisovskaya, S.A. and Khaldeeva, E.V., The way for researching sensitivity clinical strains of Candida albicans as a component of biofilms to antifungal drugs, Usp. Med. Mikol., 2016, vol. 15, pp. 270–272.

    Google Scholar 

  43. 43

    Gladkih, P.G., Importance of microbial biofilms in human infectious pathology (review), Vestn. Nov. Med. Tekhnol., 2015, no. 1.

  44. 44

    Makareva, E.S., Tonko, O.V., and Bobrik, D.I., The biofilm of microorganisms as a factor for forming antibiotic resistance, Uch. Zap. Uchrezhd. Obraz. Vitebsk.Ordena Znak Pocheta Gos. Akad. Vet. Med., 2017, vol. 53, no. 2, pp. 77–78.

    Google Scholar 

  45. 45

    Silva, D.B., Rodrigues, L.M., Almeida, A.A., Oliveira, K.M., and Grisolia, A.B., Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species, Mem. Inst. Oswaldo Cruz, 2016, vol. 111, no. 3, pp. 192–199. https://doi.org/10.1590/0074-02760150400

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Hargrove, T.Y., Friggeri, L., Wawrzak, Z., Qi, A., Hoekstra, W.J., Schotzinger, R.J., York, J.D., Guengerich, F.P., and Lepesheva, G.I., Structural analyses of Candida albicans sterol 14alpha-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis, J. Biol. Chem., 2017, vol. 292, no. 16, pp. 6728–6743.

    CAS  Article  Google Scholar 

  47. 47

    Wei Jia, Haiyun Zhang, Caiyun Li, Gang Li, and Xiaoming Liu, The calcineurin inhibitor cyclosporine a synergistically enhances the susceptibility of Candida albicans biofilms to fluconazole by multiple mechanisms, BMC Microbiol., 2016, vol. 16, p. 113.

    Article  Google Scholar 

  48. 48

    Cowen, L.E., Sanglard, D., Howard, S.J., Rogers, P.D., and Perlin, D.S., Mechanisms of antifungal drug resistance, Cold Spring Harbor Perspect. Med., 2015, vol. 5, no. 7, p. a019 752. https://doi.org/10.1101/cshperspect.a019752

    CAS  Article  Google Scholar 

  49. 49

    Xiaoyuan He, Mingfeng Zhao, Jinyan Chen, Rimao Wu, Jianlei Zhang, Rui Cui, et al., Overexpression of both ERG11 and ABC2 genes might be responsible for itraconazole resistance in clinical isolates of Candida krusei, PLoS One, 2015, vol. 10, no. 8, p. e0 136 185. https://doi.org/10.1016/j.biochi.2

    Article  Google Scholar 

  50. 50

    Caban, M., Strapagiel, D., Dziadek, J., Korycka-Machała, M., and Grzelak, A., Principles of a new protocol for prediction of azole resistance in Candida albicans infections on the basis of ERG11 polymorphisms, Curr. Microbiol., 2016, vol. 73, pp. 172–182. https://scholar.google.ru/citations?user=5mZsUEMAAAAJ&hl=en.

    CAS  Article  Google Scholar 

  51. 51

    Wu, Y., Gao, N., Li, C., Gao, J., and Ying, C., A newly identified amino acid substitution T123I in the 14alpha-demethylase (Erg11p) of Candida albicans confers azole resistance, FEMS Yeast Res., 2017, vol. 17, no. 3. https://doi.org/10.1093/femsyr/fox012

  52. 52

    Alvarez-Rueda, N. and Fleury, A., The amino acid substitution N136Y in Candida albicans sterol 14alpha-demethylase is involved in fluconazole resistance, Med. Mycol., 2016, vol. 54, no. 7, pp. 764–775. https://doi.org/10.1371/journal.pone.0021239

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Dmitriev, K.A., Pchelin, I.M., Vybornova, I.V., and Taraskina, A.E., Structural analysis of the ERG11 gene of resistant strains of Candida albicans to the azoles group drugs, Probl. Med. Mikol., 2016, vol. 18, no. 2, p. 60. https://mycology.szgmu.ru/files/MAPO_2_2016.pdf.

  54. 54

    Wang, B., Huang, L.-X., Zhao, J., Wei, M., Fang, H., Wang, D., et al., ERG11 mutations associated with azole resistance in Candida albicans isolates from vulvovaginal candidosis patients, Asian Pac. J. Trop. Biomed., 2015, vol. 5, no. 11, pp. 909–914.

    CAS  Article  Google Scholar 

  55. 55

    Gołąbek, K., Strzelczyk, J.K., Owczarek, A., Cuber, P., Ślemp-Migiel, A., and Wiczkowski, A., Selected mechanisms of molecular resistance of Candida albicans to azole drugs, Acta Biochim. Pol., 2015, vol. 62, no. 2, pp. 247–251.

    Article  Google Scholar 

  56. 56

    Berkow, E.L. and Lockhart, S.R., Fluconazole resistance in Candida species: A current perspective, Infect. Drug Resist., 2017, vol. 10, pp. 237–245.

    CAS  Article  Google Scholar 

  57. 57a

    Liu, Z. and Myers, L.C., Candida albicans Swi/Snf and mediator complexes differentially regulate Mrr1-induced MDR1 expression and fluconazole resistance, Antimicrob. Agents Chemother., 2017, vol. 61, no. 11, p. e01 344-17.https://doi.org/10.1128/AAC.01344-17

    Article  Google Scholar 

  58. 58a

    Liu, Z. and Myers, L.C., Mediator tail module is required for Tac1 activated CDR1 expression and azole resistance in Candida albicans, Antimicrob. Agents Chemother., 2017, vol. 61, no. 11, p. e01 342-17. https://doi.org/10.1128/AAC.01342-17

    Article  Google Scholar 

  59. 59

    Bhattacharya, S., Sobel, J.D., and White, T.C., A Combination fluorescence assay demonstrates increased efflux pump activity as a resistance mechanism in azole-resistant vaginal Candida albicans isolates, Antimicrob. Agents Chemother., 2016, vol. 60, no. 10, pp. 5858–5866. https://doi.org/10.1128/AAC.02227-17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Rosana, Y., Yasmon, A., and Lestari, D., Overexpression and mutation as a genetic mechanism of fluconazole resistance in Candida albicans isolated from HIV patients in Indonesia, J. Med. Microbiol., 2015, vol. 64, pp. 10 146–1052. https://doi.org/10.1099/jmm.0.000123

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to M. B. Bezhenar or K. I. Plakhova.

Ethics declarations

COMPLIANCE WITH ETHICAL STANDARDS

The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

ADDITIONAL INFORMATION

Corresponding author: M.B. Bezhenar, e-mail: maribeje@mail.ru.

Additional information

Translated by K. Lazarev

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bezhenar, M.B., Plakhova, K.I. Mechanisms of Developing Antifungal Drug Resistance of Candida spp. in Reccurent Urogenital Candidiasis. Mol. Genet. Microbiol. Virol. 35, 14–21 (2020). https://doi.org/10.3103/S0891416820010024

Download citation

Keywords:

  • Candida spp.
  • resistance
  • antifungal drugs
  • gene ERG11
  • gene CDR1
  • gene CDR2
  • gene MDR1
  • 14α-demethylase
  • recurrent candidiasis
  • review