Vaginal candida infections

Vaginal candida infections (VCI) such as vaginal (occurring inside the vagina) or vulvovaginal (occurring on the vulva) candidiasis, are common infections affecting an estimated 75% of sexually active women at least once in their lifetime. Physical symptoms include but are not limited to vaginal itching, dyspareunia, a burning sensation, and a thick lumpy white discharge1 2. VCI represent a heavy negative emotional and sexual burden for patients2, especially as approximately 50% of women will develop a second episode, and 5% of those women will suffer from further recurrences2.

Risk factors for VCIs include antibiotic use3, use of hormonal (and other) contraconceptives4 5, sexual intercourse6, use of vaginal lubricants7, vaginal douching8, menstruation9 10 11 12, pregnancy13, and stress14 15 16. The common feature of these risk factors is that they can cause an imbalance or dysbiosis in the vagina. If the natural vaginal microbiome is out of balance, it cannot prevent overgrowth of pathogens2 17, thus women with a dysbiotic vaginal microbiome are likely at higher risk of developing various symptomatic infections18.

Fungi are important microorganism of the vaginal ecosystem in healthy women19 20 21 and Candida spp. colonize approximately from 20% to 65% of women without causing any symptoms19. However, the transition from normal vaginal resident to symptomatic infection is poorly understood and usually involves the combination of host inflammation, microbiome dysbiosis, and Candida spp. virulence factors.

Anatomy of the vulva
Figure 1: Anatomy of the vulva

The Vaginal Microbiome and Fungal Dysbiosis

The human vagina is inhabited by over 50 different inter-kingdom species22 23, including anaerobic bacteria (mostly Lactobacillus spp.), viruses, and fungi19 21. One of the key functions of this microbiome is to maintain a low pH and thus prevent various pathogenic microorganisms from dominating the niche. It is thought that vaginal microorganisms originate in general from the GI tract24 25 by migrating across the perineum26, which acts as an extra-vaginal reservoir, further explaining the co-morbidities between GI complaints and urogenital infections noted in some patients27. In general, vaginal microbiome research in humans focuses on identification of bacterial and viral microborganisms with very little emphasis on exploring the natural fungal population19 20 21. Thus a majority of vaginal mycobiome studies are still limited to the pathology context and not to understanding how they contribute to health.

The Candida spp. present in a healthy vaginal microbiome include Candida albicans, Candida glabrata, Candida krusei, or Saccharomyces spp.19 21 and it is thought that in VCI, they outcompete the other vaginal microbiome residents to dominate the vaginal niche. The findings of Guo et al. (2012) demonstrated an increase in vaginal funcal diversity in patients with recurrent VCI compared to health volunteers. This subsequent dysbiosis characterized by an increased proportion of C. albicans was also correlated with a reduced proportion of Saccharomyces spp. and other uncultured fungi. This implies that Candida spp. are in fact pathobionts, able to live peacefully in the vagina or able to become virulent pathogens and cause infections.

Candida forms: Yeast, pseudo and hyphae, hyphae
Figure 2: Candida forms: Yeast, pseudo and hyphae, hyphae

Interestingly enough, the pathology of VCI can be partly explained by the three main cellular forms or morphologies of Candida: yeast, pseudohyphae, and hyphae. The last form is the most virulent, while yeast and pseudohyphae are the reproductive and intermediate transitional forms, respectively. It should be noted that each morphology is genetically, metabolically, and physically different and that Candida spp. have evolved so that they can easily switch between forms29 30. The symptoms associated with VCIs are thought to be caused by an overgrowth of the hyphal morphology which causes inflammation31, forms biofilms32 and penetrates deep into vaginal epithelial tissue1 2. When viewed in a wet mount slide, vaginal discharge from a VC patient reveals budding yeast cells and psuedohyphae alongside mature hyphae and activated immune cells33.

Caption

The presence of multiple simultaneous morphologies make it extremely difficult to eradicate this organism especially because therapies often only target one morphology34. Another challenge is when Candida spp. reside in a biofilm; Candida biofilms show uniform resistance to a wide spectrum of the currently available antimycotics35. This could be explained in part because the physical biofilm matrix slows down the penetration and diffusion of drugs and thus only the top few biofilm layers are targeted, leaving the remaining biofilm to persist, regrow, and dominate. These particular hallmark virulence factors of Candida endow it with a number of mechanisms by which it can evade the immune system and antimycotic treatment. With high recurrence rates, high treatment failure rates, and the adverse effect on quality of life, there is a need to develop adjuncts and alternative treatments for VCI.

Probiotics and VCI

Studies have shown that probiotics can increase the effectiveness of anti-fungal therapy2 40, that they are safe and have minimal-to-no side effects2 37 38 39. The evidence suggesting that VCI is a result of, or causes, a disruption of the vaginal microbiome, cites research that targets VCI infections or prophylaxis using microbiome management options such as probiotics2. Pre-clinical data show that probiotics can increase the effectiveness of anti-fungal therapy2 39 and inhibit the growth and virulence of urogenital pathogens23. The efficacy of probiotics to populate the vagina and prevent or treat infection has been shown for multiple endpoints, including adjuncts together with antimicrobial treatment to improve cure rates and prevent recurrences23. An huge advantage for patients is that vaginal probiotics have no reported adverse side effects23 38 39, present minimal discomfort37 [Antonio 2009], and can be self-administered23.

Ecologic® FEMI+ Medical Device, for improving the disbalance in the vaginal microbiome

Winclove has developed a probiotic Medical Device for vaginal use: Ecologic® FEMI+. This vaginal capsule aims to improve the natural vaginal microbiome by preventing or improving the disbalance in the microbiome, inhibiting the growing of pathogens and/or preventing the recurrence of vaginal infections.

Selection of strains of Ecologic® FEMI+

The research formulation of the medical device Ecologic® FEMI+ contains a combination of six different bacteria and lactoferrin, an iron-binding protein well known for its anti-candida activity. Pre-clinical data demonstrate that the bacterial strains in Ecologic® FEMI+ are able to produce hydrogen peroxide, D- and L-lactic acid, inhibit the growth of urogenital pathogens, including C. albicans and Candida glabrata, and can survive high concentrations of common antimicrobial and antimycotic drugs.

The selected strain combination from the Ecologic® Femi+ formulation:

  • Bifidobacterium bifidum   W28
  • Lactobacillus acidophilus  W70
  • Lactobacilus helveticus     W74
  • Lactobacillus plantarum    W21
  • Lactobacillus brevis           W63
  • Lactobacillus salivarius      W24

Preclinical and clinical evidence

The bacterial strains in Ecologic® FEMI+ are able to produce hydrogen peroxide, D- and L-lactic acid, inhibit the growth of urogenital pathogens, including C. albicans and Candida glabrata, and can survive high concentrations of common antimicrobial and antimycotic drugs. Furthermore, the bacterial strains in Ecologic® FEMI+ were also shown to adhere strongly to and prevent C. albicans from forming the virulent hyphae morphology in addition to reducing the number of pre-formed hyphae. Equally important, a reduction in the number of adhering hyphae was noted in the presence of compounds produced by the probiotics and this also prevented C. albicans biofilm formation. From the preclinical data, it can be concluded that Ecologic® FEMI+ shows promising evidence regarding mechanisms that can be effective against certain important C. albicans virulence factors.

Winclove Probiotics is further exploring options for a clinical trial in VCI patients. Additionally, Ecologic® FEMI+ is currently being tested in pilot clinical trial in 60 bacterial vaginosis patients.

The research formulation of the medical device Ecologic® FEMI+ is not sold as a consumer product. However our worldwide business partners offer the formulation of the medical device Ecologic® FEMI+ as their own branded product. Thus the specific bacterial composition can be found in different products around the world.

 

 

 

References

  • 1. a. b. van Schalkwyk J, Yudin MH; Infectious Disease Committee, Yudin MH, Allen V, Bouchard C, Boucher M, Boucoiran I, Caddy S, Castillo E, Kennedy VL, Money DM, Murphy K, Ogilvie G, Paquet C, van Schalkwy JK; Society of Obstetricians and Gynaecologists of Canada. Vulvovaginitis: Screening for and Management of Trichomoniasis, Vulvovaginal Candidiasis, and Bacterial Vaginosis. J Obstet Gynaecol Can. 2015 Mar;37(3):266-76.
  • 2. a. b. c. d. e. f. g. h. i. Martinez RCR, Improved treatment of vulvovaginal candidiasis with fluconazole plus probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, The Society for Applied Microbiology, Letters in Applied Microbiology 48 (2009) 269–274 269.
  • 3. Stokholm J, et al. Antibiotic use during pregnancy alters the commensal vaginal microbiota. Clin Microbiol Infect. 2014 Jul;20(7):629-35.
  • 4. Kazi YF, et al. Investigation of vaginal microbiota in sexually active women using hormonal contraceptives in Pakistan. BMC Urol. 2012 Aug 18;12:22. doi: 10.1186/1471-2490-12-22.
  • 5. Achilles SL, et al. The complexity of contraceptives: understanding their impact on genital immune cells and vaginal microbiota. AIDS. 2013 Oct;27 Suppl 1:S5-15.
  • 6. Marrazzo JM. Interpreting the epidemiology and natural history of bacterial vaginosis: are we still confused? Anaerobe. 2011 Aug;17(4):186-90.
  • 7. Fashemi B et al. Effects of feminine hygiene products on the vaginal mucosal biome. Microb Ecol Health Dis. 2013 Feb 25;24.
  • 8. Arbour M, et al. Douching patterns in women related to socioeconomic and racial/ethnic characteristics. J Obstet Gynecol Neonatal Nurs. 2009 Sep-Oct;38(5):577-85.
  • 9. Eschenbach DA, et al. Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora. Clinical Infectious Diseases. 2000;30:901–907.
  • 10. Smith CB, et al. Bacterial flora of the vagina during the menstrual cycle:findings in users of tampons, napkins, and sea sponges. Ann Intern Med.1982; 96:948–951.
  • 11. Onderdonk AB, et al. Quantitative assessment of vaginal microflora during use of tampons of various compositions. Applied and Environmental Microbiology. 1987; 53:2774–2778.
  • 12. Shiraishi T, et al. Influence of menstruation on the microbiota of healthy women’s labia minora as analyzed using a 16S rRNA gene-based clone library method. Japanese Journal of Infectious Diseases. 2011; 64:76–80.
  • 13. Verstraelen H, et al. Longitudinal analysis of the vaginal microflora in pregnancy suggests that L. crispatus promotes the stability of the normal vaginal microflora and that L. gasseri and/or L. iners are more conducive to the occurrence of abnormal vaginal microflora. BMC Microbiology. 2009; 9:116.
  • 14. Culhane JF, et al. Stress, bacterial vaginosis, and the role of immune processes. Current Infectious Disease Reports. 2006; 8:459–464.
  • 15. Nansel TR, et al. The association of psychosocial stress and bacterial vaginosis in a longitudinal cohort. Am J Obstet Gynecol. 2006; 194:381–386.
  • 16. Culhane J. Exposure to chronic stress and ethnic differences in rates of bacterial vaginosis among pregnant women. Am J Obstet Gynecol. 2002;187:1272–1276.
  • 17. David M. Underhill and Iliyan D. Iliev. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol. 2014 Jun; 14(6): 405–416.
  • 18. Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D, Poehner R, Bruce AW. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003;35(2):131-4. 2003.
  • 19. a. b. c. d. e. T. Drell, et al. PLoS One. 2013; 8(1): e54379. Published online 2013 Jan 23.
  • 20. a. b. Guo, R., Zheng, N., Lu, H., Yin, H., Yao, J. and Chen, Y., 2012. Increased Diversity of Fungal Flora in the Vagina of Patients with Recurrent Vaginal Candidias is and Allergic Rhinitis. Microbial Ecology 64: 918-927.
  • 21. a. b. c. d. Zheng, N.N., Guo, X.C., Lv, W., Chen, X.X. and Feng, G-.F., 2013. Characterization of the vaginal fungal flora in pregnant diabetic women by 18S r RNA sequencing. European Journal of Clinical Microbiology and Infectious Diseases 32: 1031-1040.
  • 22. Ravel J, et al. Vaginal microbiome of reproductive-age womenProc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1
  • 23. a. b. c. d. e. Cribby, 2008, Vaginal Microbiota and the Use of Probiotics, Hindawi Publishing Corporation
  • 24. Fede, T. 1983. Vulvovaginitis in children. Clinical and Experimental Obstetrics & Gynecology 10: 118–119.
  • 25. Pierce, A. and Hart, C. 1992. Vulvovaginitis: causes and management. Archives of Disease in Childhood 67: 509–512.
  • 26. Gorbachinsky I, Sherertz R, Russell G, Krane LS, Hodges SJ. Altered perineal microbiome is associated with vulvovaginitis and urinary tract infection in preadolescent girls. Ther Adv Urol. 2014 Dec;6(6):224-9.
  • 27. Cayan, S., Doruk, E., Bozlu, M., Duce, M., Ulusoy, E. and Akbay, E. 2001. The assessment of constipation in monosymptomatic primary nocturnal enuresis. International Urology and Nephrology 33: 513–516.
  • 29. Brown AJ, Brown GD, Netea MG, Gow NA. Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels. Trends Microbiol. 2014 22(11):614-22.
  • 30. van de Wijgert JH, Borgdorff H, Verhelst R, Crucitti T, Francis S, Verstraelen H, Jespers V. The Vaginal Microbiota: What Have We Learned after a Decade of Molecular Characterization? PLoS One. 2014 Aug 22;9(8):e105998.
  • 31. Muzny CA, Schwebke JR. Biofilms: An Underappreciated Mechanism of Treatment Failure and Recurrence in Vaginal Infections. Clin Infect Dis. 2015 Aug 15;61(4):601-6.
  • 32. Engberts MK, et al. Vulvovaginal candidiasis: Diagnostic and therapeutic approaches used by Dutch general practitioners, European Journal of General Practice 2008;14:30-33
  • 33. Jabra-Rizk MA, Falkler WA, Meiller TF. Fungal biofilms and drug resistance.Emerg Infect Dis. 2004 Jan;10(1):14-9.
  • 34. Shahid Z, Sobel JD. Reduced fluconazole susceptibility of Candida albicans isolates in women with recurrent vulvovaginal candidiasis: effects of long-term fluconazole therapy. Diagn Microbiol Infect Dis. 2009 Jul;64(3):354-6.
  • 35. Falagas, Probiotics for Prevention of Recurrent Urinary Tract Infections in Women A Review of the Evidence from Microbiological and Clinical Studies, Drugs 2006; 66 (9): 1253-1261
  • 40. Elias J. Bozzo P, Einarson A. Are probiotics safe for use during pregnancy and lactation? Can Fam Physician. 2011 Mar; 57(3): 299–301.
  • 37. a. b. Falagas ME, Makris GC. Probiotic bacteria and biosurfactants for nosocomial infection control: a hypothesis. J Hosp Infect. 2009 Apr;71(4):301-6
  • 38. a. b. Antonio MA, Meyn LA, Murray PJ, Busse B, Hillier SL. Vaginal colonization by probiotic Lactobacillus crispatus CTV-05 is decreased by sexual activity and endogenous Lactobacilli. J Infect Dis. 2009 May 15;199(10):1506-13.
  • 39. a. b. c. Reid G, Dols J, Miller W. Targeting the vaginal microbiota with probiotics as a means to counteract infections. Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):583-7.