# Vaginal Microbiota and the Use of Probiotics

Authors: Sarah Cribby; Michelle Taylor; Gregor Reid
Journal: Interdisciplinary Perspectives on Infectious Diseases
 (2008)

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## Abstract

The human vagina is inhabited by a range of microbes from a pool of over 50 species. Lactobacilli are the most common, particularly in healthy women. The microbiota can change composition rapidly, for reasons that are not fully clear. This can lead to infection or to a state in which organisms with pathogenic potential coexist with other commensals. The most common urogenital infection in premenopausal women is bacterial vaginosis (BV), a condition characterized by a depletion of lactobacilli population and the presence of Gram-negative anaerobes, or in some cases Gram-positive cocci, and aerobic pathogens. Treatment of BV traditionally involves the antibiotics metronidazole or clindamycin, however, the recurrence rate remains high, and this treatment is not designed to restore the lactobacilli. In vitro studies have shown thatLactobacillus strains can disrupt BV and yeast biofilms and inhibit the growth of urogenital pathogens. The use of probiotics to populate the vagina and prevent or treat infection has been considered for some time, but only quite recently have data emerged to show efficacy, including supplementation of antimicrobial treatment to improve cure rates and prevent recurrences.


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## Body

## 1. The Microbiota of the Vagina

The microbial species that inhabit the vaginal tract play
an important role in the maintenance of health, and prevention of infection.
Over 50 microbial species have been recovered from the vaginal tract [1–3]. These species
do not exist independently, and studies in
vitro and in humans have shown that a multispecies microbiota, usually
associated with bacterial vaginosis (BV), are present in dense biofilms [4–7], while a
lactobacilli dominant microbiota can be sparsely distributed on the epithelium
[4, 5, 8]. In comparison, the gut is
populated with more than 800 species of microbes, the majority of which are
excreted in feces, and a number of which are well equipped to be pathogenic.
Despite the close proximity of the vagina to the anus, the diversity of
microbes present in the vagina is much lower than in the gut. The reason for
this lower diversity is still unclear, but may involve poor receptivity of the
vagina, different nutrient availability compared to the gut, and competition
with indigenous organisms. Some species found in the gut, such as E. coli and Streptococcus, can also be found in the vagina, indicating the
proper receptors, nutrients, and oxygen tension are present for these organisms
to grow.Different methodologies
are being used to identify the composition of the vaginal microbiota. Each has
its strengths and weaknesses. Culture-based methods allow strains to be
identified and used for further experimentation. However, as there remains a
major defect in our ability to grow many bacterial species, we must rely on
nonculture methods to identify the breadth of vaginal microbiota. This has been
achieved by analyzing their ribosomal DNA sequences [3, 9], using a combination
of PCR and denaturing gel gradient electrophoresis (DGGE) [2, 5, 10–12], and by using
degenerate, universal polymerase chain reaction primers to amplify an
approximately 555 base-pair regions of the universal chaperonin-60 gene [13].The species that are present in the vaginal mucosa
vary between premenopausal woman and those who have gone through menopause. The
microbiota of healthy premenopausal woman is generally dominated byLactobacillus species, the most common
of which are L. iners, L. crispatus, L. gasseri, L. jenesenii, followed
by L. acidophilus, L. fermentum, L.
plantarum, L. brevis, L. casei, L. vaginalis, L. delbrueckii, L. salivarius, L.
reuteri, and L. rhamnosus [2, 5, 9–16]. As more
studies are performed on the vaginal organisms in healthy women, it is possible
that some women will be identified, who do not have a lactobacilli-dominated
microbiota [17]. However, until we know more about the dynamics of such a
population, and are sure that it does not increase the risk of the disease, lactobacilli will
remain the organisms of most importance to vaginal health.Factors such as hormonal changes (particularly
estrogen), vaginal pH, and glycogen content can all affect the ability of
lactobacilli to adhere to epithelial cells and colonize the vagina [16]. The
menstrual cycle can also cause changes in the vaginal microbiota, with high
concentrations of estrogen increasing adherence of lactobacilli to vaginal
epithelial cells [18]. With the decrease in estrogen levels associated with
menopause, there is also a decrease in lactobacilli present in the vaginal
tract of postmenopausal women [5, 11, 12, 19]. Postmenopausal women are also more
susceptible to urogenital infections, supporting the theory that colonization
of the vagina by commensal lactobacilli serves as a protection from these
pathogens [19, 20]. Although the methods by which these organisms do this are still unclear, it
appears to involve an ability to adhere to and to populate the vaginal epithelium and mucin layer, to
inhibit pathogens from taking over [21–24], to reduce pathogen
virulence [25, 26], and to modulate host defenses [27].Hormone replacement therapy (HRT) alters the
bacterial profile of the vaginal tract of postmenopausal women, and restores a
lactobacilli-dominated state, as well as reduces the incidence of urinary tract
infections (UTI) [19]. In a study of women taking combination conjugated equine
estrogen and progesterone HRT, only 1 to 3 species of bacteria, mainly Lactobacillus, were detected in the vaginal
mucosa of 87% of the women [5]. In postmenopausal women not receiving HRT,
almost all subjects had vaginal mucosa populated with more than 1 organism,
many of which had pathogenic potential such as Bacteroides, Prevotella, and Gardnerella,
associated with bacterial vaginosis (BV), and E. coli and Enterococcus, associated
with UTI [5].While a vaginal
tract dominated by lactobacilli appears to protect the host against some
vaginal infections, it does not fully prevent colonization by other species.
Pathogens are still able to coexist with these commensal organisms, as shown by
Burton and Reid [10], where G.
vaginalis, a pathogen associated with BV, was detected in a vaginal sample
which also contained a species of Lactobacillus.
Interestingly, G. vaginalis was
displaced beyond detectable limits for 21 days, following a single intravaginal
instillation of probiotic lactobacilli [11]. As more and more studies are
uncovering the diversity microbiota of the vagina, it seems apparent that the
balance between a healthy and diseased state involves some sort of equilibrium
or see-saw effect, which can swing in either direction depending on a number of
factors, such as hormone levels, douching, sexual practices, as well bacterial
interactions and host defenses [20, 21].Witkin et al. [28] have proposed that innate immunity plays an important
role in the switch to BV from a healthy state. The mechanism they propose is through
microbial-induced inhibition of Toll-like receptor expression and/or activity
blocking proinflammatory immunity, as well as a lack of 70-kDa heat-shock
protein production, and a deficit in vaginal mannose-binding lectin
concentrations decreasing the capacity for microbial killing. Three recent
studies have provided further insight into the host’s role. In a study of women
susceptible to UTI, it was discovered that immunological defects in peripheral blood coexisted with a persistently
aberrant microbiota (Kirjavainen et al. [29]). In postmenopausal women, BV
was associated with apparent
reduced expression of host antimicrobial factors [30]. When probiotic L. rhamnosus GR-1 was administered to the vagina of premenopausal women, it resulted in 3 536 gene expression changes and increased
expression levels of some antimicrobial defenses [31].


## 2. Nonsexually Transmitted Infections of the Vaginal Tract and Interference by Lactobacilli

Pathogenic
organisms are able to infect the vagina, with BV, yeast vaginitis, and UTIs
causing an estimated one billion or more cases per year [32–35]. While there
is some evidence that the causative organisms can be transmitted by sexual
partners, these conditions will be discussed here as nonsexually transmitted.
Other reviews adequately cover sexually transmitted infections [36, 37].Yeast vaginitis is
characterized by white discharge, local itching, and irritation. The majority
of cases are caused byCandida albicans,
but C. glabrata, C. krusei, and C. tropicalis can be problematic [35]. It is diagnosed by microscopic detection of dense
numbers of yeast cells on a vaginal smear, and by physical examination and the
presence of a white, mucous-like yeast discharge. Of note, lactobacilli are
often found in patients with yeast vaginitis, therefore, the induction of
infection does not appear to require the yeast displacing or killing off the
lactobacilli.Urinary tract infections
occur when pathogenic bacteria ascend from the vagina and replicate on, and
sometimes within, the bladder urothelium [32, 38, 39]. These infections are frequent
among women, with an estimated 50% suffering at some time in their life. Symptoms
and signs include suprapubic pain, dysuria, pyuria, frequency and painful micturition,
and occasionally hematuria. Asymptomatic bacteriuria is also a common
occurrence, particularly amongst the elderly. The most frequent pathogen is E. coli, followed by Enterococcus faecalis, and Staphylococcus saprophyticus [39]. Diagnosis
can be achieved by presence of symptoms and signs, and urine samples containing
over 103 organisms/mL of the pathogens. In a portion of patients, the E. coli invade the bladder epithelium and
form dense biofilms that are recalcitrant to antibiotics [40]. In women with no
history of UTI, their vagina and perineum is most commonly colonized by
lactobacilli [20], while in women with recurrent UTI there is an inverse
association between lactobacilli and E.
coli [41], suggesting that lactobacilli play a role in preventing
infection.The most common
urogenital disorder in women of reproductive age is BV, a condition discussed
above. The vaginal microbiota of BV patients typically contains a broader range
of species than found under healthy conditions, withAtopobium vaginae, Bacteroides spp., Gardnerella vaginalis, Mobiluncus, Megasphera, Mycoplasma
hominis, Peptostreptococcus, and Prevotella being particularly prevalent [3, 42–46]. BV is
associated with multiple species of bacteria that occur in 90% of the cases, and essentially
consists of an elevated vaginal pH (>4.5) and depletion of lactobacilli. It affects
women of all age groups, and is often asymptomatic [47]. When symptoms and
signs do occur, they include fishy odor, discharge, and vaginal pH above 4.5 [48].
Indeed, this formed the basis of the often-used Amsel criteria for BV diagnosis:
presence of at least 3 of the following criteria: (1) release of an amine or
fishy odor upon addition of 10% potassium hydroxide, (2) a vaginal pH higher than
4.5, (3) detection of at least 20% of clue cells (which are vaginal cells
colonized by Gram-negative rods), and (4) a milky homogeneous vaginal discharge
[48].  A Gram-staining method called the
Nugent score has also been used [8]. It comprises a scoring system based on the
morphology of bacteria present in vaginal swab samples. A normal score is given
to samples showing predominantly Gram-positive rods indicative of lactobacilli,
while the presence of predominantly small and curved shaped Gram-negative rods
and Gram-positive cocci, along with the absence of lactobacilli, is indicative
of BV. The BVBlue test is another kit used to diagnose BV, and works by
detecting sialidase produced by pathogens associated with the condition [49, 50].  Of note, aerobic vaginitis has also been
described in which the vagina is colonized by organisms such as E. coli and enterococci [51]. During
pregnancy, BV can increase the risk of preterm labor and low birth weight [52, 53].
Other problems associated with BV include pelvic inflammatory disease, UTI, and
increased susceptibility to sexually transmitted diseases, including HIV [54–57].The organisms associated with BV form dense biofilms on
the vaginal epithelium, and these are associated with increased resistance to lactobacilli-produced
lactic acid and hydrogen peroxide (H2O2) which are
normally antagonistic to planktonic organisms [58]. The biofilms are also able
to induce host expression of certain inflammatory factors, such as IL-1 and
IL-8 [59]. It is not currently known whether the production of H2O2 by lactobacilli has a clinically protective role against BV. The increased
prevalence of H2O2-peroxide producing vaginal
lactobacilli in healthy women has been given as a reason to believe that it is
a protective factor [60], however, those studies used culture to recover the
lactobacilli, and arguably had they used nonculture methods, L. iners would have been the most
commonly isolated and it does not appear to produce H2O2.
It is possible to isolate L. iners by
culture, but it requires selective media and extensive incubation. The same
group found that women with the H2O2-producing vaginal L.crispatus or L.jensenii had a
significantly lower incidence of BV than women with a different vaginal flora
[14]. However, Alvarez-Olmos et al.
[61] and Rosenstein et al. [62]
found H2O2-producing lactobacilli in 85% and 91.7%, respectively, of women
with BV. It could be argued that the high prevalence of H2O2-producing
lactobacilli shows that this compound is not protective [32]. Either way, it is
difficult to make a definitive conclusion.McLean
and McGroarty [63] conducted an in vitro study showing that increasing culture pH
reduced the bacteriostatic effects of L. acidophilus on G. vaginalis NCTC 11292 by 60%; a 30% reduction in bacteriostatic effects was seen when
catalase was introduced to degrade H2O2. Klebanoff et al. [64]
found that the toxicity of H2O2-producing lactobacilli was inhibited by
the presence of catalase but lactobacilli that do not produce H2O2 were not affected.
High concentration of H2O2-producing lactobacilli inhibits the
growth of both G. vaginalis and Bacteroides bivius. However, low
concentrations of H2O2-producing lactobacilli must be combined
with myeloperoxidase and chloride in vaginal mucus, to be toxic toward G. vaginalis, with a maximum toxicity in a pH range of 5 to 6. A pH of ≤4.5 inhibited the growth of G. vaginalis on its own and this effect
increased with the addition of the above combination. Suffice to say, H2O2 is likely one of
several factors involved in competition with other organisms in the vagina.


## 3. Probiotics to Prevent and Treat Urogenital Infections

As antimicrobial treatment of urogenital infections is not always
effective, and problems remain due to bacterial and yeast resistance, recurrent
infections [65, 66], as well as side effects, it is no surprise that
alternative remedies are of interest to patients and their caregivers. It is
assumed that recurrences are due to antimicrobials failing to eradicate the
pathogens, perhaps because of biofilm resistance, or that the virulent
organisms come back from their source (the person’s gut, or a sex partner) and
attack a host whose defenses are suboptimal. Young girls who suffer from UTI
are more likely to have repeated episodes in adulthood, and overall many UTI,
BV, and yeast vaginitis patients will have a recurrence [21, 67]. Recurrent
infection may also be due to the elimination of the commensal organisms in the vagina
by the antimicrobial, thereby increasing susceptibility to recolonization by
pathogens [68, 69]. This is one of the main reasons for considering the use of
probiotics, to replenish the commensal microbes as a way to lower the risk of
reinfection. In a study of 120 children with persistent primary
vesicoureteral reflux, L. acidophilus treatment daily was as effective as trimethoprim/sulfamethoxazole in reducing
the rate of UTI (P=.926), suggesting that probiotics could provide a
prophylactic option [70].The route of delivery of probiotic lactobacilli has
intuitively been via direct instillation into the vagina. For example, the
weekly application ofL. rhamnosus GR-1 and L. fermentum B-54 was shown
to reduce UTI recurrences from an average of 6 to 1.6 per year [71]. The ability
of a given strain of lactobacilli to adhere to vaginal cells was considered an
advantage in temporarily populating the vaginal [71, 72] and creating an
environment conducive to the restoration of the host’s indigenous lactobacilli
rather than a return of pathogens. The adhesion of lactobacilli to the
uroepithelium varies among species and strains, as shown by in vitro studies [72], and may be
mediated by glycoprotein and carbohydrate adhesins binding to glycolipid receptors [73].
Still, it is unclear the extent to which a difference in in vitro adhesion, say of 10 per
cell, means that an organism will succeed or fail to protect the host if
instilled into the vagina. Thus, adhesion per se is not the definitive criteria
to predict success. Once administered in a viable count of one billion or more, L. rhamnosus GR-1 and L. reuteri (formerly fermentum) RC-14 have been found to be detectable for three weeks
or more, depending on the host [74, 75]. This implies a correlation between in
vitro adherence and in vivo presence.The concept of delivering lactobacilli orally to repopulate
the vagina was first reported in 2001 [76], and based upon the question “if
urogenital pathogens can do this, why cannot lactobacilli”? The organisms were
delivered in a milk base and shown to be recovered from the rectum [77]; therefore
supporting the concept that ingested strains could pass through the intestine,
reach the rectum, and potentially ascend to the vagina. This was confirmed
independently by others [78].In order to conduct clinical studies with the view of providing more women
with access to these strains, a two-year shelf life capsule formulation was
then developed and used successfully in a number of studies. An oral dose of
over one billion organisms per day was found to maintain a lactobacilli-dominated
vaginal presence [79]. The time for this intervention to affect the vaginal
tract is obviously longer than direct vaginal instillation, and will depend on
viability of the strains as they pass through the stomach and gut [78]. In
addition, the load of lactobacilli that can be delivered this way is clearly lower
than via vaginal administration. However, an advantage of the oral approach may
be the ability of the lactobacilli to reduce the transfer of yeast and pathogenic
bacteria from the rectum to the vagina [80], which could potentially lower the
risk of infection. In that randomized, placebo-controlled trial of 64 healthy
women, 37% of the patients in the L. rhamnosus GR-1 and L. reuteri RC-14 probiotic group had a lactobacilli-dominated
normal vaginal microbiota restored from a BV vaginal flora compared to 13% in
the placebo group (P=.02). At both the 28-day and 60-day test points,
women in the lactobacilli treatment group had a greater number of vaginal lactobacilli
than women in the control group (P=.08 and P=.05, resp.) as shown
by microscopy and culture. The ability of this oral probiotic therapy to create
a lactobacilli normal flora and convert some subjects from a BV status to
normal [79] goes beyond the proof-of-concept stage and provides a method for
women to help maintain vaginal health. Failure of L. rhamnosus GG to be effective, at least in one small study [79], emphasizes the strain-specific
aspects of probiotic use. Thus, one cannot and should not utilize the data from
one strain to infer that another untested strain will provide the same
benefits.The mechanisms whereby lactobacilli function as anti-infective defenses
are still not fully understood. As discussed above, this may involve production
of antimicrobial factors [81], and maintenance of a
vaginal pH of ≤4.5. It could also be due to biosurfactants
which alter the surrounding surface tension and reduce the ability of a wide
range of pathogens to adhere [82, 83]. This might explain the relatively sparse
coverage of epithelial cells noted in healthy women [8].  In addition, lactobacilli have been shown to bind (coaggregate)
some pathogens and this may be a means to block their adhesion, kill them
through production of antimicrobials, and prevent their spread to other areas
of the vagina and bladder [84]. Among 10 strains of lactobacilli being
evaluated for use in a probiotics tablet, Mastromarino et al. [85] found,
in vitro, that Lactobacillus
gasseri 335 and Lactobacillus salivarius FV2 were able to coaggregate
with G. vaginalis. When these strains of lactobacilli were combined with Lactobacillus brevis CD2 in a vaginal tablet, adhesion of G.
vaginalis was reduced by 57.7%, and 60.8% of adherent cells were displaced.
Boris et al.found that the adherent properties G. vaginalis were similarly affected by Lactobacillus acidophilus [73].It
has been known for some time thatLactobacilllus produce bacteriocins that can inhibit the
growth of pathogens, including some associated with BV, such as G. vaginalis [86]. Only relatively recently has a study shown in animals that bacteriocin
production might have an effect in vivo. A stable mutant of Lactobacillus salivarius UCC118 that did
not produce a specific bacteriocin was unable to protect mice against Listeria intestinal infection, while the
wild type did, thereby leading the authors to conclude that bacteriocin
production can be a primary mediator of anti-infective defense [87].Relatively
few studies have attempted to prevent urogenital infection using probiotics. Shalev
et al. [88] assessed 46 premenopausal
women with ≥4 episodes of BV and/or vaginal
candidiasis in the previous year, to compare the recurrence of BV using a probiotic
yoghurt versus one that was pasteurized. Patients were not receiving long-term
antibiotics or immunosuppressive therapy and had not consumed yoghurt prior to
the commencement of the study. They were randomly assigned to one of two
treatment groups and ingested 150 mL of either pasteurized yoghurt (n=23) or
yoghurt containing L. acidophilus at >1.0×108 colony-forming units (n=23). Yoghurt was consumed
daily for two months followed by two months of no yoghurt. There was a 60%
reduction in BV episodes among patients consuming probiotic yoghurt after one
month while only a 25% reduction occurred in subjects who received pasteurized
yoghurt (P=.004). After two months of yoghurt consumption, the results
were similar; however, 25% of patients from both groups had left the study.
Product integrity was only assessed prior to the study and no adverse effects
were reported.Neri
et al. [89] studied 84 women in the first trimester of pregnancy to
observe the effects of probiotic-containing yoghurt on BV. The subjects were randomized to one of three treatment
groups: inserting a tampon containing 5% acetic acid (n=32), a 10 to 15 mL
vaginal douche containing >1.0×108  colony-forming units/mL of L. acidophilus (n=32), or no treatment
(n=20). Both active treatments were administered twice a day for one week.
Amsel criteria (three of five findings: release of an amine fishy odor;
release of amine odor after the addition of 10% potassium hydroxide; vaginal pH
greater than 4.5; clue cells in the vaginal fluid; milky homogenous vaginal
discharge) were absent in 88%, 38%, and 15% of subjects
who received intravaginal lactobacilli, acetic acid tampons, and placebo,
respectively, after 30 days. There was a significant difference in the cure
rate between probiotic and control groups (P<.005), and lactobacilli
and acetic acid groups (P=.004).Fredricsson et al. [90] conducted an
open-label trial to compare the cure rates of 61 women with BV given one of
four intravaginal products. Patients were diagnosed with BV if ≥3 Amsel criteria were present. Each of the four
treatments that patients were randomized to receive was administered twice a day for
seven days: 5 mL of fermented milk containing between 5.0×108 and 2.0×109 colony-forming units/mL of L.
acidophilus NCDO 1748 (n=13), 5 mL of acetic jelly (n=15), 5 mL of estrogen
cream (n=16), or 500 mg metronidazole vaginal tablets (n=15). BV was considered
to have been cured if ≤1 Amsel criterion was present at 4 and 8 weeks. After
both 4 and 8 weeks from the initiation of treatment, the cure rates in the
metronidazole, acetic acid, probiotic, and estrogen groups were 93%, 18%, 7%,
and 6%, respectively; no statistical analysis was reported. In this case, the
so-called probiotic was not effective. No information about the strain was provided.The cure rates of BV in 57 women with a mean age of
24 were studied following treatment with either “probiotics” or placebo in a
double-blind trial [91]. Subjects were randomized
to receive either a vaginal suppository containing 1.0×108-9 colony-forming
units of L. acidophilus (n=28) or
placebo (n=29). The vaginal suppositories were administered twice a day for 6
days. Symptom resolution, which was not clearly defined, was used to evaluate
the cure of BV. At 7–10 days after the
commencement of treatment, BV symptoms were absent in 57% of women in the
probiotic group and 0% of women in the placebo group (P<.005). After
20 to 40 from the initiation of treatment, the cure rate in the probiotic group
fell to 21% and remained at 0% in the placebo group (p=NS). This poorly
conceived study is hard to interpret and is insufficient to verify efficacy of
the product.Eriksson et
al. [92] studied how lactobacilli augmented antibiotics in curing BV
through a double-blind, placebo-controlled trial including 187 women with a
median age of 32 over two menstrual periods. Open-label
treatment with 100 mg/d of clindamycin was administered to all patients for 3
days. The subjects were then randomized to one of two treatment groups which
required at least five tampons to be inserted during the next menstrual period.
The treatment groups were placebo tampons (n=96) and tampons impregnated with L. fermentum, L. gasseri, and L. rhamnosus at 1.0×108 colony-forming
units per tampon (n=91). Cure rates of BV were assessed by the absence of Amsel
criteria after the second menstrual period in both the probiotic and placebo groups,
and found to be 56% and 62%, respectively, (p=NS). Infection with Candida was reported in 14.3% of subjects
in the probiotic group and 13.5% of patients in the placebo group. The viable
number of bacteria per tampon diminished to 106 colony-forming units
by the end of the study. In short, this product was not successful. The
rationale for administering lactobacilli during menses could be questioned, as
it exposes the users’ blood stream directly to the organisms, and the flushing
effect of menstruation may be nonconducive to lactobacilli repopulating the
vagina.A comparison of
intravaginal probiotics and metronidazole gel in treating 40 women (ages 18 to
50) with BV was conducted by a single-blind study by Anukam et al. [93]. The presence of ≥3 Amsel
criteria, a Nugent score of ≥7, and a positive sialidase test led to a
diagnosis of BV. Patients were randomized to one of two treatment groups for
five days. They either inserted an intravaginal capsule with L. rhamnosus GR-1 and L. reuteri RC-14 at 1.0×109 colony-forming
units nightly (n=20) or applied a 0.75% metronidazole gel twice daily (n=20). A
Nugent score of ≤3 at 30 days indicated a cure of BV. A BV cure rate of 88% in
the probiotic group and 50% in the metronidazole group was found (p=NS).
Treatment was prematurely discontinued by patients in both the metronidazole
and probiotic groups at 10% and 15%, respectively. This study, albeit small in
size, showed the potential of probiotics to cure BV.The
efficacy of combining probiotics or placebo with oral metronidazole was assessed
in 125 women aged 18 to 44 [94]. Oral
metronidazole was administered at 500 mg twice daily to all patients for 7 days,
and they were randomized to receive twice-daily oral capsules containing either
a placebo (n=60) or L. rhamnosus GR-1
and L. reuteri RC-14 at 1.0×109 colony-forming units (n=65) for a total treatment duration of 30 days. At the
end of 30 days, BV was considered absent if the patient had a negative sialidase
test and a Nugent score of <3. This was the case in 40% of placebo and 88%
of probiotic subjects (P<.001). If an intermediate Nugent score was regarded as “cure of BV”, the cure rate was 100% with metronidazole and probiotics versus 70% with metronidazole and placebo. This study is important as it implies that probiotics can augment the effects of antibiotics in treatment of disease. Further studies have confirmed this effect, but are awaiting publication.


## 4. Possible Negative Effects of Probiotic Use

Annually, over one billion doses of probiotics are administered worldwide, and those administered for urogenital health have been well tolerated [11, 75, 93–96]. In addition, the mouth, gastrointestinal tract, and female genitourinary tract are inhabited by Lactobacillus [96]. Yet, endocarditis and bacteremia caused by lactobacilli are extremely rare. Most cases occur in patients with chronic diseases or debilitating conditions that provide direct access to the bloodstream from a leaky gut. Only 1.7% of 241 cases of bacteremia, endocarditis, and localized infections associated with Lactobacillus that were investigated by Cannon et al. were considered to have a
possible link with heavy consumption of dairy products [97]. Only one case had
a Lactobacillus isolate that was indistinguishable from a probiotic strain. There was no connection between the species of Lactobacillus isolated and the type of infection or mortality. A recent study that directly instilled a six-strain bacterial product into the intestine of patients with severe, potentially fatal pancreatitis portrayed probiotics as being dangerous [97]. However, the
product had never been proven to be probiotic, it was administered as a drug unlike 99.9% of probiotics, the randomization process led to patients with multiorgan failure being given large doses of live bacteria, and the authors
failed to provide a rationale for the study in an appropriate animal model. All this led to unwarranted adverse publicity for the field of probiotics [98].Nevertheless, safety of probiotic use must
continually be monitored and considered when doing clinical studies. The
potential for transfer of antibiotic resistance is one factor to consider,
although it remains to be proven that probiotics have contributed in any way to
drug resistance, or disease. Rather, the overuse of antibiotics, especially in
livestock feed and long-term prevention of infection, remains a root cause of
the increasing concerns over drug resistance. Efforts to substitute
prophylactic antibiotics with probiotics, especially in children with recurrent
UTI [70] and perhaps some patients preparing to undergo surgery [99], are
worthy of pursuit.


## 5. Conclusion

Molecular
methodologies are providing a greater understanding of the dynamic microbial
presence, both short and long term, in the vagina. The defenses of the host
which include some of these microbes perform a remarkable function given the
opportunity of pathogens to cause infection. The use of probiotic lactobacilli
to prevent infection has a good rationale, and an excellent safety record, but
so far only a few strains have been clinically proven to be effective, in
particular to prevent BV. It is critically important that strains be
characterized and tested clinically using the delivery system of choice (oral,
vaginal, dried powder, or in suspension). An advantage for women is that they can
self-administer the probiotics. Many more studies are needed to optimize the
defensive properties of the vaginal microbiota, but the potential remains that
the health of many women can be improved by probiotic intervention.



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