Although research on probiotics for the female urogenital tract has been ongoing for over 20 years, only recently have others recognized that probiotic applications go beyond consumption of foods. Evidence from a 64-patient randomized, placebo-controlled trial (114
) indicates that daily oral intake of 109
to 1010 L. rhamnosus
GR-1 and L. fermentum
RC-14 leads to transfer of the organisms from the rectum to the vagina as well as an overall depletion of coliforms and yeasts in the vagina (109
). In these studies of over 100 reportedly healthy women, a significant number presented with an abnormal vaginal microbiota indicative of bacterial vaginosis. This agrees with the findings of others and shows clearly that the vaginal microbiota is often abnormal during the menstrual cycle and postmenopause even when the subject is asymptomatic (68
Questions have been raised as to how abnormal is defined, given that subjects are not ill. The vaginal microbiota is often in a state of flux, as shown by Nugent score analysis, culture, and molecular tracking (17
). The Nugent score (94
) is determined by microscopic analysis of vaginal cells collected from the vagina. When the field of view is dominated by lactobacillus morphotypes, the score is low (0 to 3), and when it is dominated solely by gram-negative rods (indicative of anaerobes like Gardnerella vaginalis
or uropathogens like Escherichia coli
) or gram-positive cocci like group B streptococci or enterococci, the score is high (8 to 10). Intermediate values indicate the presence of pathogens and lactobacilli in a sort of transition state. The factors that contribute to the transition from asymptomatic to symptomatic infection or a return to one that is healthy remain to be determined.
Nevertheless, the incidence of urinary tract infection, bacterial vaginosis, and yeast vaginitis, estimated to affect one billion women each year (the rate for urinary tract infection alone is 0.5 cases per person per year), means that the likelihood of infection is high. Indeed, the presence of pathogens dominating the vagina increases severalfold the likelihood that a woman will develop a symptomatic infection. In short, an abnormal microbiota may indeed lead to a symptomatic vaginal or bladder infection.
The concept of restoring the Lactobacillus
content of the vaginal microbiota as a barrier to prevent infection was first conceived by Canadian urologist Andrew Bruce in the early 1970s. Extensive research since then has shown that certain Lactobacillus
strains are able to colonize the vagina following vaginal suppository use (18
) and reduce the risk of urinary tract infection, yeast vaginitis (108
), and bacterial vaginosis (112
). Strain selection at that time, and even recently, has been based upon in vitro tests and source of the strains (17
), but human studies provide the definitive answer to whether or not strains can function as probiotics.
A study on the prevention of urinary tract infection entailed once-weekly vaginal administration of a suppository containing 109 L. rhamnosus
GR-1 and L. fermentum
B-54 for 1 year and comparing the rate of urinary tract infection occurrence with that in the previous year in 25 women (108
). There was a significant reduction in urinary tract infection during lactobacillus use (from an average of six episodes per year to 1.6 episodes per year [30%]; P
< 0.0001). No side effects were reported. This compares favorably with two studies that used daily antibiotic therapy to prevent urinary tract infection. The first was a randomized study of 64 patients with a history of recurrent urinary tract infections given trimethoprim (100 mg) at night for 1 year or methenamine hippurate (1,000 mg) every 12 h or asked to cleanse the perineum (especially the periurethral area) twice daily with povidone-iodine solution (15
). In this study, the urinary tract infection recurrence rates fell from 6 in the previous year to 2.1, 2.0, and 2.2, respectively, for the three groups.
The second study was an 18-year assessment of 219 women given one of three nitrofurantoin regimens daily for 1 year (14
). The mean incidence of urinary tract infection fell from 6.9 per year to 1.3 per year. Notably, 14% of patients were allergic to the antibiotic, and 40% reported at least one adverse side effect, with nausea, gastrointestinal, genitourinary, and skin effects being the most common. In addition, 25.6% of 43 patients taking 50 mg of microcrystalline nitrofurantoin stopped prematurely as a result of an adverse event. Even the use of another antibiotic, cefaclor, 250 mg daily, in 37 patients resulted in an average of 2.4 breakthrough infections per year; 12.8% reported a side effect, and 7.7% stopped taking the drug (16
). In short, Lactobacillus
therapy taken once per week with no side effects resulted in as low a rate of urinary tract infection as several daily antibiotic regimens with numerous side effects. While a larger phase three trial has not been performed with Lactobacillus
strains GR-1 and B-54, the phase two findings are worthy of note.
In terms of preventing or treating bacterial vaginosis, recent studies have shown that daily ingestion of capsules containing L
GR-1 and L. fermentum
RC-14 by 19 women with a bacterial vaginosis microbiota resulted in a normal microbiota (by Nugent scoring) in 81% of cases, compared to 50% in women given placebo (P
= 0.001) (109
). This is not yet sufficient evidence to use oral probiotics for symptomatic bacterial vaginosis treatment, but it does illustrate the potential to reduce the incidence of recurrent bacterial vaginosis that is common after antibiotic treatment (54
). Another study, the results of which are only available on a web site, show that L. crispatus
CTV05 given vaginally after metronidazole treatment for bacterial vaginosis resulted in a clinical cure at 30 days in subjects colonized by lactobacilli (70%) compared to noncolonized (47%) patients receiving placebo (P
< 0.001). Further studies with vaginal Lactobacillus
treatment of bacterial vaginosis that are more likely to deliver lactobacilli in higher numbers and more quickly than oral ingestion are warranted. Indeed, certain Lactobacillus
strains, including L. crispatus
CTV05, L. rhamnosus
GR-1, and L. fermentum
RC-14, are able to remain in the vagina for several months after insertion (18
The prevention or resolution of bacterial vaginosis is particularly important in women at risk of human immunodeficiency virus (HIV) infection. Studies have shown that women with bacterial vaginosis (no lactobacilli) are at significantly increased risk of HIV (127
). Studies of 94 prostitutes in Madagascar showed bacterial vaginosis prevalence of 85% (9
); a study in Malawi showed an odds ratio of 3.0 (95% confidence interval, 2.4 to 3.8) for an association between bacterial vaginosis and HIV (139
); another Malawi study of 1,196 HIV-seronegative women showed that bacterial vaginosis was significantly associated with antenatal HIV seroconversion (adjusted odds ratio = 3.7) and postnatal HIV seroconversion (adjusted rate ratio = 2.3) (140
); a cross-sectional study of 144 female commercial sex workers in Chiang Mai, Thailand, found a significant association between bacterial vaginosis and seropositivity for HIV (odds ratio, 2.7; 95% confidence interval, I0.3 to 5.0) (27
); and a study of 4,718 women in Uganda showed an adjusted odds ratio of HIV-1 infection and bacterial vaginosis of 2.08 (95% confidence interval, 1.48 to 2.94) (127
The depletion of lactobacilli and the risk of HIV was further illustrated in a study of 657 HIV-1-seronegative women in Kenya, where only 26% were colonized with Lactobacillus
species, and the absence of these organisms was associated with an increased risk of acquiring HIV-1 infection (hazard ratio, 2.0; 95% confidence interval, 1.2 to 3.5) (82
). The authors concluded that treatment of bacterial vaginosis and promotion of vaginal lactobacilli may reduce a woman's risk of acquiring HIV-1, gonorrhea, and trichomoniasis.
Having shown that certain Lactobacillus
strains can colonize the vagina, this raises the questions of whether and how probiotics can reduce the risk of HIV infection (56
). As stated earlier, supernatants from the strains L. rhamnosus
GR-1 and L
RC-14 can inactivate viruses within minutes. It is presumed that a simple acidification of the vagina could affect HIV, but whether other mechanisms such as blocking receptor binding of the virus to CD4+
cells are at work remains to be investigated. Given the failure of current management and interventional steps to halt the AIDS epidemic, use of oral or vaginal lactobacilli appears worthy of consideration, especially given that they can be delivered relatively inexpensively to large numbers of people on the African continent, where drug supplies are often inaccessible or financially prohibitive.
Another potential application is for pregnant women to reduce the risk of bacterial vaginosis infection associated with infant mortality and preterm labor. Oral probiotics would be particularly useful in this case, as they can be administered safely during pregnancy (66
). For reasons not yet known, some lactobacilli, such as L. rhamnosus
GG and L. acidophilus
NCFM, appear to be not well suited for the urogenital tract (18
), while products on the market such as the vaginal suppository Fermalac, comprising L. rhamnosus
and other strains (Rosell, Montreal, Canada), have no peer-reviewed studies proving eradication of bacterial vaginosis. Thus, for clinical practice at present, there are few clinically proven, commercially available options to antibiotic and antifungal therapy for urogenital infections and antiviral drugs for HIV spread.