YU.V. GARIFULLOVA, L.I. MALTSEVA

 Kazan State Medical Academy — Branch Campus of the FSBEI FPE RMACPE MOH Russia, Kazan

 Contact details:

Garifullova Yu.V. — Ph. D. (Medicine), Associate Professor of the Department of Obstetrics and Gynecology

Address: 36 Butlerova St., Kazan, Russian Federation, 420012, tel.: +7 (843) 236-68-92, e-mail: gamil.garifullov@yandex.ru

The article provides review data on bacterial vaginosis as the most common reason for the vaginal microbiota disorders; the latter result in replacement of lactobacilli with opportunistic anaerobic bacterial microflora and formation of a bacterial film. Emphasis is placed on the role of such dysbiosis in the development of urinary tract infections and cervical intraepithelial dysplasia. The difficulties of bacterial vaginosis therapy are highlighted, which are due to the development of resistance to the standard treatment regimen; possible ways of overcoming it are described.

Key words: bacterial vaginosis, biofilm, complications, therapy.

REFERENCES

1. Neal C.M., Kus L.H., Eckert L.O., Peipert J.F. Noncandidal vaginitis: a comprehensive approach to diagnosis and management. Am. J. Obstet. Gynecol, 2020, vol. 222 (2), pp. 114–122. DOI: 10.1016/j.ajog.2019.09.001
2. Amabebe E., Anumba D.O.C. The vaginal microenvironment: the physiologic role of lactobacilli. Front. Med. (Lausanne), 2018, vol. 5, p. 181. DOI: 10.3389/fmed.2018.0018
3. Atashili J., Poole C., Ndumbe P.M., Adimora A.A., Smith J.S. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS, 2008, vol. 22 (12), pp. 1493–1501. DOI: 10.1097/QAD.0b013e3283021a37
4. Jolley J.A., Kim S., Wing D.A. Acute pyelonephritis and associated complications during pregnancy in 2006 in US hospitals. J. Matern. Fetal. Neonatal. Med, 2012, vol. 25 (12), pp. 2494–2498.
5. Haarh T., Jensen J.S., Thomsen L., Duus L., Rygaard K., Humaidan P. Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients. Hum. Reprod, 2016, vol. 31 (4), pp. 795–803. DOI: 10.1093/humrep/dew026
6. John E., Delzell M.L. Lefevre Urinary tract infections during pregnancy. Am. Fam. Physician, 2000, vol. 61 (3), pp. 713–720.
7. Klinicheskie rekomendatsii MZRF “Infektsiya mochevykh putey pri beremennosti” [Clinical recommendations of the Ministry of Health of the Russian Federation “Urinary tract infection during pregnancy”], 2021.
8. Kline K.A., Lewis A.L. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol. Spectr, 2016, vol. 4 (2). DOI: 10.1128/microbiolspec.UTI-0012-2012
9. Ciara Kenneally, Craig P. Murphy, Roy D. Sleator, Eamonn P. Culligan. The urinary microbiome and biological therapeutics: Novel therapies for urinary tract infections. Microbiol. Res, 2022, vol. 259, p. 127010. DOI: 10.1016/j.micres.2022.127010
10. Wojciuk B., Salabura A., Grygorcewicz B., Kędzierska K., Ciechanowski K., Dołęgowska B. Urobiome: In Sickness and in Health Microorganisms, 2019, vol. 7 (11), p. 548.
11. Miller-Ensminger T., Garretto A., Brenner J., Thomas-White K., Zambom A., Wolfe A.J., Putonti C. Bacteriophages of the Urinary Microbiome. J. Bacteriol, 2018, vol. 200 (7), p. e00738-17.
12. Zandbergen L.E., Halverson T., Brons J.K., Wolfe A.J., de Vos M.G.J. The Good and the Bad: Ecological Interaction Measurements Between the Urinary Microbiota and Uropathogens. MG J. Front. Microbiol, 2021, vol. 12, p. 659450.
13. Komesu Y.M., Dinwiddie D.L., Richter H.E., Lukacz E.S., Sung V.W., Siddiqui N.Y. et al. Defining the relationship between vaginal and urinary microbiomes. Am. J. Obstet. Gynecol, 2020, vol. 222 (2), pp. 154.e1–154.e10. DOI: 10.1016/j.ajog.2019.08.011
14. Stapleton A.E. The vaginal microbiota and urinary tract infection. Microbiol. Spectr, 2016, vol. 4 (6). DOI: 10.1128/microbiolspec.UTI-0025-2016
15. Malki K., Shapiro J.W., Price T.K., Hilt E.E., Thomas-White K., Sircar T. et al. Genomes of Gardnerella strains reveal an abundance of prophages within the bladder microbiome. PLoS One, 2016, vol. 11 (11), p. e0166757.
16. Putonti C., Thomas-White K., Crum E., Hilt E.E., Price T.K., Wolfe A.J. Genome investigation of urinary Gardnerella strains and their relationship to isolates of the vaginal microbiota. mSphere, 2021, vol. 6 (3), p. e00154-21. DOI: 10.1128/mSphere.00154-21
17. Kesic V., Carcopino X., Preti M., Vieira-Baptista P., Bevilacqua F., Bornstein J. et al. The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the management of vaginal intraepithelial neoplasia. Int. J. Gynecol. Cancer, 2023, vol. 33 (4), pp. 446–461. DOI: 10.1136/ijgc-2022-004213
18. Nieves-Ramírez M.E., Partida-Rodríguez O., Moran P., Serrano-Vázquez A., Pérez-Juárez H., Pérez-Rodríguez M.E. et al. Cervical squamous intraepithelial lesions are associated with differences in the vaginal microbiota of Mexican women. Microbiol. Spectr, 2021, vol. 9 (2), p. e0014321. DOI: 10.1128/Spectrum.00143-21
19. Medina-Contreras O., Luvián-Morales J., Valdez-Palomares F., Flores-Cisneros L., Sánchez-López M. S., Soto-Lugo J. H., et al. Immunonutrition in cervical cancer: immune response modulation by diet. Rev. Invest. Clin, 2020, vol. 72 (4), pp. 219–230. DOI: 10.24875/ric.20000062
20. Ntuli L., Mtshali A., Mzobe G., Liebenberg L.J., Ngcapu S. Role of immunity and vaginal microbiome in clearance and persistence of human papillomavirus infection. Front. Cell Infect. Microbiol, 2022, vol. 12, pp. 927131. DOI: 10.3389/fcimb.2022.927131
21. Champer M., Wong A.M., Champer J., Brito I.L., Messer P.W., Hou J.Y., et al. The role of the vaginal microbiome in gynaecological cancer. BJOG, 2018, vol. 125 (3), pp. 309–315. DOI: 10.1111/1471-0528.14631
22. Pourmollaei S., Barzegari A., Farshbaf-Khalili A., Nouri M., Fattahi A., Shahnazi M. et al. Anticancer effect of bacteria on cervical cancer: Molecular aspects and therapeutic implications. Life Sci, 2020, vol. 246, pp. 117413. DOI: 10.1016/j.lfs.2020.117413
23. Wang H., Ma Y., Li R., Chen X., Wan L., Zhao W. Associations of cervicovaginal lactobacilli with high-risk human papillomavirus infection, cervical intraepithelial neoplasia, and cancer: A systematic review and meta-analysis. J. Infect. Dis, 2019, vol. 220 (8), pp. 1243–1254. DOI: 10.1093/infdis/jiz325
24. Zhou Z., Feng Y., Xie L., Ma S., Cai Z., Ma Y. Alterations in gut and genital microbiota associated with gynecological diseases: a systematic review and meta-analysis. Reprod. Biol. Endocrinol, 2024, vol. 22 (1), p. 13.
25. Carvalho N.S., Silva R.J.C.D., Val I.C.D., Bazzo M.L., Silveira M.F.D. Brazilian protocol for sexually transmitted infections 2020: human papillomavirus (HPV) infection. Rev. Soc. Bras. Med. Trop, 2021, vol. 54 (suppl 1), p. e2020790. DOI: 10.1590/0037-8682-790-2020
26. Rosendo-Chalma P., Antonio-Véjar V., Ortiz Tejedor J.G., Ortiz Segarra J., Vega Crespo B., Bigoni-Ordóñez G.D. The Hallmarks of cervical cancer: molecular mechanisms induced by human papillomavirus. Biology (Basel), 2024, vol. 13 (2), p. 77. DOI: 10.3390/biology13020077
27. Wohlmuth C., Ghorab Z., Shier M., Tinmouth J., Salit I.E., Covens A. et al. Cytology-based screening for anal intraepithelial neoplasia in women with a history of cervical intraepithelial neoplasia or cancer. Cancer Cytopathol, 2021, vol. 129 (2), pp. 140–147. DOI: 10.1002/cncy.22360.
28. Batman S., Messick C.A., Milbourne A., Guo M., Munsell M.F., Fokom-Domgue J. et al. A Cross-sectional study of the prevalence of anal dysplasia among women with high-grade cervical, vaginal, and vulvar dysplasia or cancer: the PANDA study. Cancer Epidemiol. Biomarkers Prev, 2022, vol. 31 (12), pp. 2185–2191. DOI: 10.1158/1055-9965.EPI-22-0548
29. Brzeziński M., Stukan M. Anal cancer and anal intraepithelial neoplasia risk among patients treated for HPV-related gynecological diseases-a systematic review. J. Clin. Med, 2023, vol. 12 (13), pp. 4216. DOI: 10.3390/jcm12134216
30. Bostwick D.G., Woody J., Hunt C., Budd W. Antimicrobial resistance genes and modelling of treatment failure in bacterial vaginosis: Clinical study of 289 symptomatic women. J. Med. Microbiol, 2016, vol. 65, pp. 377–386. DOI: 10.1099/jmm.0.000236
31. Christina A. Muzny, Jack D. Sobel. The role of antimicrobial resistance in refractory and recurrent bacterial vaginosis and current recommendations for treatment. Antibiotics, 2022, vol. 11 (4), p. 500. DOI: 10.3390/antibiotics11040500
32. Mammen-Tobin A., Wilson J.D. Management of metronidazole-resistant Trichomonas vaginalis — a new approach. Int. J. STD AIDS, 2005, vol. 16 (7), pp. 488–490. DOI: 10.1258/0956462054308422
33. Henien M., Nyirjesy P., Smith K. Metronidazole-resistant trichomoniasis: beneficial pharmacodynamic relationship with high-dose oral tinidazole and vaginal paromomycin combination therapy. Sex. Transm. Dis, 2019, vol. 46 (1), pp. e1–e2. DOI: 10.1097/OLQ.0000000000000903
34. Petrina M.A.B., Cosentino L.A., Rabe L.K., Hillier S.L. Susceptibility of bacterial vaginosis (BV)-associated bacteria to secnidazole compared to metronidazole, tinidazole and clindamycin. Anaerobe, 2017, vol. 47, pp. 115–119.
35. Bradshaw C.S., Tabrizi S.N., Fairley C.K., Morton A.N., Rudland E. Garland S.M. The Association of Atopobium vaginae and Gardnerella vaginalis with bacterial vaginosis and recurrence after oral metronidazole therapy. J. Infect. Dis, 2006, vol. 194 (6), pp. 828–836. DOI: 10.1086/506621
36. Rosca A.S., Castro J., Sousa L.G.V., França A., Vaneechoutte M. Cerca N. In vitro interactions within a biofilm containing three species found in bacterial vaginosis (BV) support the higher antimicrobial tolerance associated with BV recurrence. J. Antimicrob. Chemother, 2022, vol. 77 (8), pp. 2183–2190. DOI: 10.1093/jac/dkac155
37. Toh E., Xing Y., Gao X., Jordan S.J., Batteiger T.A., Batteiger B.E. Sexual behavior shapes male genitourinary microbiome composition. Cell Rep. Med, 2023, vol. 4 (3), p. 100981. DOI: 10.1016/j.xcrm.2023.100981
38. Zozaya M., Ferris M.J., Siren J.D., Lillis R., Myers L., Nsuami M.J. et al. Bacterial communities in penile skin, male urethra, and vaginas of heterosexual couples with and without bacterial vaginosis. Microbiome, 2016, vol. 4, p. 16. DOI: 10.1186/s40168-016-0161-6
39. Schwebke J.R., Desmond R.A. A randomized trial of the duration of therapy with metronidazole plus or minus azithromycin for treatment of symptomatic bacterial vaginosis. Clin. Inf. Dis, 2007, vol. 44, pp. 213–219.
40. Turner E., Sobel J.D., Akins R.A. Prognosis of recurrent bacterial vaginosis based on longitudinal changes in abundance of Lactobacillus and specific species of Gardnerella. PLoS One, 2021, vol. 16 (8), p. e0256445. DOI: 10.1371/journal.pone.0256445
41. Wang F.M., Qian X.D., Xu H., Yu H.Y., Zhonghua Yi, Xue Za Zhi. Efficacy of 5-nitroimidazole derivatives in treatment of bacterial vaginosis, 2008, vol. 88 (31), pp. 2201–2203.
42. Khryanin A.A., Knorring G.Yu. Modern ideas about bacterial vaginosis. Ginekologiya, 2021, no. 23 (1), pp. 37–42 (in Russ.).
43. Guidelines Centers for Disease Control and Prevention, 2021, Guidelines. International Union against Sexually Transmitted Infections. IJ of STD&AIDS, 2018, no. 29, pp. 1258–1272.
44. Klinicheskie rekomendatsii po diagnostike i lecheniyu zabolevaniy, soprovozhdayushchikhsya patologicheskimi vydeleniyami iz polovykh putey zhenshchin (izd. 2) [Clinical recommendations for the diagnosis and treatment of diseases accompanied by pathological discharge from the genital tract of women (ed. 2)]. Moscow: ROAG, 2019.
45. Klinicheskie rekomendatsii “Bakterial’nyy vaginoz”. Obshcherossiyskaya obshchestvennaya organizatsiya “Rossiyskoe obshchestvo dermatovenerologov i kosmetologov”, MZ RF, 2022 [Clinical recommendations “Bacterial vaginosis”. All-Russian public organization «Russian Society of Dermatovenereologists and Cosmetologists», Ministry of Health of the Russian Federation, 2022].
46. Nailor M.D., Sobel J.D. Tinidazole for bacterial vaginosis. Expert Rev Anti Infect Ther, 2007, vol. 5 (3), pp. 343–348. DOI: 10.1586/14787210.5.3.343
47. Livengood C.H. 3rd, Ferris D.G., Wiesenfeld H.C., Hillier S.L., Soper D.E., Nyirjesy P. et al. Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis: a randomized controlled trial. Obstet. Gynecol, 2007, vol. 110 (2 pt 1), pp. 302–309. DOI: 10.1097/01.AOG.0000275282.60506.3d
48. Lefler E., Stevens D.A. Inhibition and killing of Candida albicans in vitro by five imidazoles in clinical use. Antimicrob. Agents Chemother, 1984, vol. 25, pp. 450–454.
49. Torshin I.Yu., Apolikhina I.A., Baranov I.I., Tapil’skaya N.I., Savicheva A.M., Gromova O.A. Efficacy and safety of the combination of tinidazole and tioconazole in the treatment of vaginal infections. AiG, 2020, no. 4, pp. 214–222 (in Russ.). DOI: 10.18565/aig.2020.4.214-222
50. Shikh E.V., Lazareva N.B., Ponomarenko T.M. Short courses of antimicrobial therapy for bacterial vaginosis: possibilities of modern pharmacology. Ginekologiya, 2022, no. 24 (4), pp. 271–276 (in Russ.). DOI: 10.26442/20795696.2022.4.201826
51. Sebastian J., Rathinasamy K. Cytotoxic mechanism of tioconazole involves cell cycle arrest at mitosis through inhibition of microtubule assembly. Cytotechnology, 2022, vol. 74 (1), pp. 141–162. DOI: 10.1007/s10616-021-0516-w
52. Eleutério J.Jr, Campaner A.B., de Carvalho N.S. Diagnosis and treatment of infectious vaginitis: Proposal for a new algorithm. Front. Med. (Lausanne), 2023, vol. 10, pp. 1040072. DOI: 10.3389/fmed.2023.1040072
53. Baylson F.A., Nyirjesy P., Weitz M.V. Treatment of recurrent bacterial vaginosis with tinidazole. Obstet. Gynecol, 2004, vol. 104 (5 pt 1), pp. 931–932. DOI: 10.1097/01.AOG.0000141551.67833.06
54. He Y., Na R., Niu X., Xiao B., Yang H. Lactobacillus rhamnosus and Lactobacillus casei affect various stages of Gardnerella species biofilm formation. Front. Cell Infect. Microbiol, 2021, vol. 11, pp. 568178. DOI: 10.3389/fcimb.2021.568178
55. Afifirad R., Darb Emamie A., Golmoradi Zadeh R., Asadollahi P., Ghanavati R., Darbandi A. Effects of pro/prebiotics alone over pro/prebiotics combined with conventional antibiotic therapy to treat bacterial vaginosis: a systematic review. Int. J. Clin. Pract, 2022, vol. 2022, pp. 4774783. DOI: 10.1155/2022/4774783