Bacterial Vaginosis and Urinary Tract Infections
Many women experience a transient, often recurrent, loss of a lactobacilli-dominated vaginal microbiota and reduced vaginal acidity, which is associated with increased risk of urogenital infections as the reduction in lactobacilli makes for a more conducive vaginal environment for the proliferation of many anaerobic bacteria such as Gardnerella vaginalis (G. vaginalis) and Atopobium vaginae (A. vaginae).
Bacterial Vaginosis (BV) and Urinary Tract Infections (UTIs) are common infections, afflicting hundreds of millions of women annually, with BV the most common cause of vaginal symptoms among women.1,2 In the United States, the prevalence of BV (determined by a Nugent score of 7-10) was estimated to be 21.2 million (29.2%) among women aged 14-49 years, based on a nationally representative sample of women who participated in the National Health and Nutrition Examination Survey (NHANES) 2001-2004. BV is a risk factor for acquisition of both bacterial (gonorrhoea, chlamydia, and Trichomonas infection and viral (HIV, herpes simplex virus (HSV), Human Papillomavirus (HPV)) sexually transmitted infections (STIs) as well as adverse obstetric outcomes (e.g., miscarriage, fetal distress syndrome, PROM, pre-term birth).3-6
G.vaginalis and A. vaginae are commonly associated with BV whereas the majority (>80%) of UTIs are caused by uropathogenic E. coli (UPEC) and often associated with Aerobic Vaginitis (AV).7-9 These pathogenic bacteria colonise the vagina via the formation of biofilms, which results in increased tolerance to adverse conditions for better persistence in hostile environments (i.e., protection from the immune system and decreased susceptibility to antibiotics).10-11
Adherent biofilm comprised of mostly G. vaginalis and A. vaginae was observed to persist for three weeks following one-week treatment with orally administered metronidazole in women with BV.8 In the UK, BV is frequently treated with topical clindamycin. The proportion of group B streptococci isolated from neonatal blood cultures that are resistant to clindamycin or erythromycin has risen substantially over recent years in the UK (Health Protection Report 2013, 7:46), most likely as a result of exposure to these antibiotics.
In another randomized, double-blind, placebo-controlled clinical trial, oral supplementation with the selected probiotic strains and yogurt significantly improved cure rate and symptoms of BV compared to control.12 Women with newly diagnosed BV (based on Amsel criteria, diagnostic criteria for BV of which 3 of 4 criteria must be met: pH > 4.5, positive whiff test, presence of discharge, and presence of clue cells in the wet smear) were administered metronidazole (2 x 500 mg/day) for one week and the multi-strain probiotic formulation twice daily in 125 g yogurt (intervention group; n = 17) or acidified yogurt (control group; n = 17), which naturally contained live fermentation starter cultures Lactobacillus delbrueckii subspecies bulgaricus and Streptococcus thermophilus.
After a four-week intervention period, 0/17 women had BV in the intervention group vs. 6/17 (35%) in the control group, a statistically significant and clinically relevant difference in cure rate. Amsel score was significantly decreased in the intervention group by a median value of 4 compared to a median value of only 2 in the control group. Odour and discharge (Amsel 2 and 3) was significantly decreased in the intervention group vs. control group, 2 vs. 1, respectively.
Various common factors are thought to influence the vaginal microbiota and have been associated with dysbiosis / BV (hygiene) / intravaginal practices (douching), sexual activity (e.g. increased frequency and number of partners, lack of male circumcision/condom use), stress, smoking, and use of antibiotics/anti-fungals.4,13 Antimicrobials have been the primary therapeutic intervention utilised for the treatment of urogenital ‘infections” (overgrowth of potentially pathogenic microbes) for more than four decades.
Unfortunately, antimicrobial treatment of urogenital infections is often ineffective, particularly for BV; and there is a high rate of recurrent infections without preventative continuation of antimicrobial therapies. Efficacy is also diminishing with increasing development of antimicrobial resistance. The antimicrobial, metronidazole, is the most commonly used treatment for BV; however, cure rates associated with this treatment are low (as low as 61% one month post-therapy with a high incidence of overgrowth of potentially pathogenic bacteria following treatment.14,15
Antibiotics affect not only pathogenic microorganisms, but many human residential symbiotic and administered probiotic bacterial strains too. Many strains of the most prevalent vaginal lactobacilli species (L. crispatus, L. iners, L. jensenii, and L. gasseri) were all demonstrated to be susceptible to commonly used systemic antibiotics including ampicillin, cefazolin, cefotaxime, and vancomycin, but insensitive to metronidazole and trimethoprim / sulfamethoxazole along with differential sensitivity to others (gentamycin, clindamycin, erythromycin, ciprofloxacin, and tetracycline). For example, treatment with clindamycin was shown to suppress/eradicate L. crispatus and induce the selective accumulation of L. iners and L. gasseri.
REFERENCES 1. Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health and Nutrition Examination Survey data. Obstet Gynecol 2007, 109:114-120. 2. Stamm WE, Norrby SR. Urinary tract infections: disease panorama and challenges. J Infect Dis 2001, 183 Suppl 1:S1-4. 3. Green KA, et al. Gynecologic health and disease in relation to the microbiome of the female reproductive tract. Fertil Steril 2015, 104:1351-1357. 4. Lewis FM, et al. Vaginal Microbiome and Its Relationship to Behavior, Sexual Health, and Sexually Transmitted Diseases. Obstet Gynecol 2017, 129:643-654. 5. Dingens AS, et al. Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study. BMC Pregnancy Childbirth 2016, 16:278. 6. Denney JM, Culhane JF. Bacterial vaginosis: a problematic infection from both a perinatal and neonatal perspective. Semin Fetal Neonatal Med 2009, 14:200-203. 7. Hummelen R, et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS One 2010, 5:e12078. 8. Swidsinski A, et al. An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am J Obstet Gynecol 2008, 198:97 e91-96. 9. Donders GG, et al. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. BJOG 2002, 109:34-43. 10. Danese PN, et al. Biofilm formation as a developmental process. Methods Enzymol 2001, 336:19-26. 55. Hardy L, et al. Bacterial biofilms in the vagina. Res Microbiol 2017. 11. MacPhee RA, et al. Probiotic strategies for the treatment and prevention of bacterial vaginosis. Expert Opin Pharmacother 2010, 11:2985-2995. 12. Vedmedovska N, et al. Preventable maternal risk factors and association of genital infection with fetal growth restriction. Gynecol Obstet Invest 2010, 70:291-298. 13. Mayer BT, et al. Rapid and Profound Shifts in the Vaginal Microbiota Following Antibiotic Treatment for Bacterial Vaginosis. J Infect Dis 2015, 212:793-802. 14. Schmitt C, et al. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992, 79:1020-1023. 15. Reid G, Bruce AW. Urogenital infections in women: can probiotics help? Postgrad Med J 2003, 79:428-432
