Chapter 43
Management of Disease and Disorders
by Prebiotics and Probiotic Therapy:
Probiotics in Bacterial Vaginosis
B. Vitali*, A. Abruzzo* and P. Mastromarino**
*Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; **Department of Public Health and Infectious Diseases,
Sapienza University, Rome, Italy
INTRODUCTION
The human body harbors an enormous number of micro-
organisms that inhabit surfaces and cavities exposed or
connected to the external environment [1]. As one of these
human-microbe habitats, the female genital tract is colo-
nized by bacterial communities that are known to confer an-
timicrobial protection to the vagina and play a crucial role
in health [2,3]. This ecosystem is dynamic with changes in
structure and composition being influenced by stage of life
cycle, hormone levels, immune responses, nutritional status
and disease states. The vaginal microbiota can also be al-
tered by external factors, such as environmental exposures,
microbial interspecies competition or commensalism, and
hygiene behaviors [4].
In healthy women, the vaginal ecosystem is dominated
by Lactobacillus species. Five distinct vaginal bacterial
biotypes, characterized by the dominance of Lactobacil-
lus crispatus, Lactobacillus gasseri, Lactobacillus iners,
Lactobacillus jensenii, or an increased proportion of other
strictly anaerobic bacteria, were described [5]. The vaginal
vault is colonized within 24 h of a female child’s birth and
remains colonized until death. Lactobacilli become the pre-
dominant inhabitants of the vagina at the time of puberty,
because of the effect of estrogens on the glycogen content
of vaginal epithelial cells. Menopause is marked by a dra-
matic reduction in estrogen production, resulting in a drop
of glycogen content in the vaginal epithelium. This leads to
depletion of lactobacilli with a subsequent rise in vaginal
pH, since glucose is not converted to lactic acid. High pH
values promote growth of opportunistic pathogens, particu-
larly colonization by enteric bacteria. Therefore, the vaginal
microbiota suffers significant structural changes at various
The Microbiota in Gastrointestinal Pathophysiology
Copyright © 2017 Elsevier Inc. All rights reserved.
stages in a woman’s life that are closely associated to the
level of estrogens in the body [4].
Lactobacilli form a critical line of defense against po-
tential pathogens through different mechanisms, such as the
production of various antibacterial compounds (lactic acid,
hydrogen peroxide, and bacteriocins), coaggregation, com-
petitive exclusion, and immunomodulation [6,7]. Altera-
tions in the types and relative proportions of the microbial
species in the vagina can be associated with the develop-
ment of infectious conditions, such as bacterial vaginosis
(BV), aerobic vaginitis, candidiasis, and sexually transmit-
ted infections [8,9].
BACTERIAL VAGINOSIS
BV, largely defined as a dysbiosis of the vaginal microbi-
ome, is the most common and enigmatic vaginal condition
in reproductive-age women with unknown etiology and
poorly understood pathogenesis [10,11].
BV represents an imbalance in the ecology of the nor-
mal vaginal microbiota, characterized by a decrease in the
prevalence and concentration of Lactobacillus species, and
an increase in the prevalence and concentration of several
pathogenic bacteria, mainly anaerobes [12]. Conventional
culture-dependent analysis of the vaginal microbiota of
women with BV identified a typical spectrum of anaer-
obes, including Gardnerella vaginalis, Atopobium vaginae,
­Mobiluncus mulieris, Prevotella bivia, Fusobacterium nu-
cleatum, Ureaplasma urealyticum, and Mycoplasma homi-
nis [13]. In recent years, culture-independent techniques
based on the analysis of rRNA gene sequences have been
developed, providing powerful tools to reveal the phylo-
genetic diversity of the microorganisms found within the
399
400 PART | E Management of Disease and Disorders by Prebiotics and Probiotic Therapy
vaginal ecosystem and to understand community dynam-
ics [8,14–16]. These molecular studies indicate that the
vaginal bacterial communities are dramatically different
between women with and without BV. BV is associated
with increased taxonomic richness and diversity. The mi-
crobiota composition is highly variable among subjects at
a fine taxonomic scale (species or genus level), but, at the
phylum level, Actinobacteria and Bacteroidetes are strongly
associated with BV, while higher proportions of Firmicutes
are found in healthy subjects. With the advances in mo-
lecular techniques, the spectrum of anaerobes detected in
BV-affected women was greatly expanded with the addi-
tion of Eggerthella, Megasphaera, Leptotrichia, Dialister,
and Sneathia [17]. Also, the Vaginal Human Microbiome
Project has detected several newly described bacteria in the
Clostridiales order, which are currently designated BVAB1,
BVAB2, and BVAB3 [18]. All these organisms are of rela-
tively low virulence. Therefore, BV is not caused by the
mere presence of the potential pathogens but rather by their
unrestrained increase in number, reaching cell counts that
are 100- to 1000-fold above the normal bacterial levels in
healthy vagina [19].
Recently, attention has been directed not only to the
microbiome associated with BV, but also to the charac-
terization of the vaginal proteome and metabolome. It
has been demonstrated that BV is marked by profound
changes in the proteome of vaginal fluids, mainly regard-
ing the abundance of proteins involved in the innate im-
mune response [20]. Studies investigating the metabolites
produced by lactobacilli-dominated microbiota and poly-
microbial BV have shown a striking loss of lactic acid and
a shift toward mixed short-chain fatty acids production
during BV state [21–23].
Clinical presentation of BV is typical. Women have
an unpleasant, “fishy-smelling” discharge that is more
noticeable after unprotected intercourse. The discharge is
off-white, thin, and homogeneous. Erythema and inflamma-
tion are usually absent, and most patients are asymptom-
atic [24]. The overgrowth of vaginal anaerobes determines
an increased production of amines (putrescine, cadaver-
ine, and trimethylamine) that become volatile at alkaline
pH, that is, after sexual intercourse and during menstrual
cycle, and contribute to the typical malodour of the vaginal
discharge [25].
The diagnosis of BV is based on clinical criteria (Am-
sel method) or Gram staining (Nugent method). Amsel
method [26] implies the presence of at least three of the
following criteria: (1) thin, homogeneous, milky vaginal
discharge; (2) vaginal pH higher than 4.5; (3) “fishy”
odor of vaginal fluid after addition of 10% KOH (whiff
test); and (4) presence of “clue cells” on microscopic
evaluation, that are vaginal epithelial cells heavily coated
with bacteria of saline wet preparations. Amsel’s crite-
ria, although widely accepted as the best available means
to diagnose BV in the clinical setting, may fail to iden-
tify women with asymptomatic BV. The second method,
the Gram staining score of vaginal smears according to
­Nugent [27], involves the microscopic quantitation of
bacterial morphotypes yielding a score between 0 and 10
(normal microflora: score ≤ 3; intermediate microflora:
score 4–6; BV: score ≥ 7). Nugent score system is gener-
ally preferred in the scientific community [28].
A large body of literature confirms that BV may lead
to potentially severe complications and sequelae. Sev-
eral studies have demonstrated an increased risk of abor-
tion in the first trimester of pregnancy, premature ruptures
of the membranes, chorioamnionitis, and preterm birth in
women with BV [29–31]. A causal relationship has been
established also between BV, pelvic inflammatory disease
[32,33] and cervicitis [34]. Moreover, alterations in the vag-
inal microenvironment have been associated with urinary
tract infections [35]. Increasing data also indicates that BV
facilitates the acquisition of sexually transmitted diseases,
such as N ­ eisseria gonorrhoeae, Chlamydia trachomatis,
HIV, and Herpes simplex virus type-2 infection (HSV-2)
[36–42]. In vitro experiments using immortalized vaginal
epithelial cells cocultured with common vaginal bacterial
species offered some insight into the host–microbe interac-
tions and mucosal immune response to BV. These studies
suggest that BV-associated bacteria can induce an innate
immune response from the genital epithelium characterized
by upregulation of cytokines associated with increased risk
of HIV-1 transmission, while commensal lactobacilli exert
an antiinflammatory influence [43].
Current therapy for BV involves oral or intravaginal
administration of metronidazole or clindamycin [44], but
long-term follow-up suggests high recurrence rates [45].
The reasons for recurrence may include the failure to eradi-
cate the offending organisms, due to the formation of a pro-
lific bacterial biofilm adhering to the vaginal epithelium.
The main components of this polymicrobial biofilm are G.
vaginalis and A. vaginae [46]. Using mathematical mod-
els, it has been demonstrated that the human microbiome
is dynamic within a single anatomic niche and can undergo
complete reorganization in less than a day during antibiotic
treatment. Within 24 h of metronidazole treatment initia-
tion, most BV-associated bacteria undergo rapid exponen-
tial depletion. Levels of Lactobacillus species, particularly
L. iners, often surge to fill the transient microbial vacuum.
When treatment is stopped anaerobic species quickly re-
emerge, suggesting a possible role for intermittent prophy-
lactic treatment [47].
The high recurrence rates, which result in repeated ex-
posure to antibiotics and the emergence of drug-resistant
strains, suggest a need for alternative therapeutic tools.
­Novel antibiotic treatments are progressively being stud-
ied, like rifaximin [48], in order to have more options for
switching therapy, combining therapies and long-term

p­ rophylactic use to prevent recurrences. In this panorama,
probiotics are emerging as good candidates to improve the
efficacy of BV therapy as well as to prevent recurrences.
RATIONALE FOR USING PROBIOTICS
IN BACTERIAL VAGINOSIS
Evidence exists of the beneficial functions of the human
microbiota, and prompted the selection of bacterial strains,
recognized as probiotics, with health-promoting activities
for the treatment of conditions in which the microbiota
composition or functionality is perturbed. Probiotics are de-
fined as “live microorganisms which when administered in
adequate amounts confer health benefit on the host” [49],
and therefore can represent an alternative approach for the
prophylaxis and therapy of vaginal infections. Lactoba-
cillus are the commonest bacteria used as probiotics. The
­rationale for the use of probiotics in BV is based on the reg-
ulatory role played by lactobacilli in the vaginal ecosystem
and the need for restoration of the microbial homeostasis
after insult [7].
Probiotics used in the treatment and prevention of BV
may be administered both by oral and vaginal formula-
tions. Orally consumed probiotics are believed to ascend to
the vaginal tract after they are excreted from the rectum;
vaginal administration allows for direct replacement of the
probiotics for unhealthy vaginal microbiota and occupation
of specific adhesion sites at the epithelial surface of the va-
gina, which consequently results in maintenance of a low
pH and production of antimicrobial substances like acids,
hydrogen peroxide, and biosurfactants [50].
The next paragraph reviews the most relevant current lit-
erature and investigations on probiotics’ potential to prevent
and treat BV.
TABLE 43.1 Clinical Trials on Probiotics Use for Treatment of Bacterial Vaginosis (BV)
Type of Study/
Authors No. of patients Duration
Hallén et al. [51] 57 R, DB, PC; 20–40 days
Parent et al. [52] 32 R, PC; 4 weeks
Anukam et al. [53] 40 R, OB, AC; 30 days
Mastromarino et al. [54] 34 R, DB, PC; 3 weeks
AC, Active controlled; CFU, colony forming units; DB, double blind; OB, observer blind; PC, placebo controlled; R, randomized.
Probiotics in Bacterial Vaginosis Chapter | 43 401
CLINICAL TRIALS ON PROBIOTICS USE
IN BACTERIAL VAGINOSIS
Various studies have been carried out to assess the efficacy
of a single strain or a combination of different probiotic
strains in the treatment of BV. The probiotic products con-
tained a range of Lactobacillus species (Lactobacillus aci-
dophilus, Lactobacillus rhamnosus, Lactobacillus reuteri,
Lactobacillus brevis, Lactobacillus salivarius, Lactobacil-
lus. plantarum, L. gasseri) and were administered orally
or intravaginally. Two approaches for the treatment of BV
have been used: treatment with probiotics alone or admin-
istration of probiotics following a conventional antibiotic
therapy (adjuvant therapy).
Treatment of Bacterial Vaginosis Using Only
Probiotics
The relevant randomized controlled trials using the first
type of approach on women affected by BV are reported in
Table 43.1.
The first clinical trials were conducted in the nineties us-
ing various strains of L. acidophilus. A product containing
H2O2-producing L. acidophilus turned out to be ineffective
for treatment of BV assessed according to Amsel criteria
[51]. Nevertheless, it is difficult to evaluate the real effi-
cacy of the product tested in this study since 50% of the pa-
tients in the active group and 86% of the placebo group did
not complete the trial. In comparison, a high BV cure rate
(88%) was observed in a placebo-controlled study using a
pharmaceutical product (containing a H2O2-producing L.
acidophilus strain plus estriol) that included both pregnant
and nonpregnant women [52]. However, the results reported
in this trial may have been biased by the enrolment criteria
Intervention BV Cure Rate
Twice daily vaginal suppository containing 21% compared to
L. acidophilus 108–9 CFU or placebo for 0% control (P = NS)
6 days
1–2 daily vaginal tablet containing 88% compared
L. acidophilus ≥ 107 CFU and 0.03 mg to 22% control
estriol for 6 days (P < 0.05)
Twice daily vaginal capsule containing 65% compared to
L. rhamnosus GR-1 (109 CFU) and 33% metronidazole
L. reuteri RC-14 (109 CFU), or 0.75% (P = 0.056)
metronidazole gel for 5 days
Daily vaginal tablet containing ≥ 109 CFU 50% compared
of L. brevis CD2, L. salivarius FV2, and to 6% control
L. plantarum FV9 for 7 days (P = 0.017)
402 PART | E Management of Disease and Disorders by Prebiotics and Probiotic Therapy
in which only two of the four Amsel criteria were required
for a positive definition of BV status.
Both studies described previously do not use well-
characterized probiotic Lactobacillus strains. Two more
recent clinical trials employing different species of lacto-
bacilli have been performed using well-characterized and
well-selected strains specific for treatment of genitouri-
nary infections [53,54]. Both studies used a combination
of different species of lactobacilli with different biologi-
cal properties on fertile nonpregnant women. L. rham-
nosus GR-1 and Lactobacillus fermentum RC-14 strains
used in the first study [53] adhere to uroepithelial cells,
inhibit pathogen binding [55,56] and can be recovered
from the vagina after oral administration [57]. In addition,
L. ­fermentum RC-14 produces biosurfactants [58] and
significant amounts of hydrogen peroxide [56]. A single-
blind comparison of intravaginal probiotics (L. rhamnosus
GR-1 and L. fermentum RC-14) and metronidazole gel for
the treatment of BV was carried out on a group of Nigerian
women [53]. Cure of BV was based on a Nugent score ≤
3 at 30 days. A BV cure rate of 65% was achieved after
probiotic treatment compared to 33% of the metronidazole
therapy (P = 0.056).
The second study also used a product containing well-
characterized and rationally selected Lactobacillus strains
(L. brevis CD2, L. salivarius FV2, and L. plantarum FV9)
[54]. L. salivarius FV2 and L. plantarum FV9 produce anti-
infective agents, including hydrogen peroxide, and are able
to coaggregate efficiently with vaginal pathogens [59]. L.
plantarum and L. brevis strains are able to adhere at high
levels to human epithelial cells, displacing vaginal patho-
gens [59,60]. The strains are able to temporarily colonize
the human vagina [61], reduce vaginal proinflammatory
cytokines IL-1β and IL-6 [62], and showed inhibitory ac-
tivity toward HSV-2 and C. trachomatis replication in cell
cultures [63–65]. In the double-blind, placebo-controlled
trial [54] both the Amsel criteria and Nugent scores to as-
sess BV cure were utilized as recommended by FDA (US
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and R ­ esearch.
Guidance for industry: BV—developing antimicrobial
drugs for treatment 1998). The intravaginal probiotic-­
treated group showed a BV cure rate of 50% compared to
6% in the placebo-treated group with the combined test
methods, whereas 67% versus 12% cure rate was obtained
when considering only the Amsel criteria.
Treatment of Bacterial Vaginosis Using
Probiotics as Adjuvant Therapy
Eight randomized controlled trials used lactobacilli follow-
ing conventional antibiotic treatment (Table 43.2) to evalu-
ate BV cure rate after 1 month [66–68] or BV recurrence
after 2–6 months [69–73].
A trial in Nigeria evaluated augmentation of antimicro-
bial metronidazole therapy for BV by a 30-day oral pro-
biotic treatment (L. rhamnosus GR-1 and L. fermentum
RC-14) compared to placebo-treated control [66]. At the
end of treatment a significantly greater number of wom-
en in the probiotic group compared to the placebo group
were BV-free (Nugent score ≤ 3). The same Lactobacillus
strains were used in a subsequent trial after treatment with a
single dose of tinidazole [68]. Probiotic oral capsules were
­administered for 28 days starting on the first day of anti-
biotic treatment. At the end of the treatment the probiotic
group had a significantly higher cure rate of BV than the
placebo group.
In the study of Petricevic and Witt [67] a 7-day Lactoba-
cillus treatment was performed after clindamycin therapy.
Intravaginal L. casei rhamnosus (Lcr35) was used in the in-
tervention group, whereas women in the control group did
not receive Lcr35. The BV cure rate, evaluated by Nugent
method 4 weeks after the last administration of medication,
showed a significantly higher cure rate in the intervention
group.
The efficacy of Lactobacillus supplementation after
clindamycin or metronidazole treatment on the recurrence
rate of BV has been evaluated in five trials [69–73]. Admin-
istration of tampons impregnated with L. gasseri, L. casei
subsp. rhamnosus and L. fermentum, or placebo tampons
during the menstrual period following clindamycin treat-
ment was exploited [70]. Cure rates assessed by Amsel
criteria after the second menstrual period did not show a
significant difference between the two groups. Possible ex-
planations for the lack of effects could be the low amount
of lactobacilli in tampons at the end of the study (106 CFU,
colony forming units) or the unfavorable period of adminis-
tration, that is, during the menstrual flow.
A 10-day repeated treatment with L. gasseri Lba EB01-
DSM 14869 and L. rhamnosus Lbp PB01-DSM 14870 dur-
ing three menstrual cycles was compared with a placebo
treatment on BV-affected women enrolled according to
Amsel criteria [71]. The cure was evaluated by the Hay/Ison
score [74]. Probiotic use did not improve the efficacy of BV
therapy after the first month of treatment, but it significantly
reduced the recurrence rate of BV at 6 months from initia-
tion of treatment.
Even two studies carried out by the same group [72,73]
indicated that vaginal application of a L. rhamnosus strain
significantly prevented BV recurrence. Thirty days after
the end of a 2 months once weekly treatment with the
probiotic a significantly higher number of women in the
treated group were BV-free in comparison to control
[72]. Consistently, a higher percentage of treated pa-
tients showed no BV recurrences after another 3 months
­compared to controls, although the difference was not sta-
tistically significant (P = 0.07). A similar 6 months pro-
biotic treatment indicated that during the first 6 months
 Probiotics in Bacterial Vaginosis Chapter | 43 403

TABLE 43.2 Clinical Trials on Probiotics Use Combined With Antibiotic Therapy for Treatment of Bacterial
Vaginosis (BV)
No. of Type of Study/
Authors Patients Duration Intervention BV Cure Rate
Eriksson et al. [70] 187 R, DB, PC; Vaginal 100 mg clindamycin ovules for 3 days, then tampons 56% compared
2 menstrual containing 108 CFU of L. gasseri, Lactobacillus casei rhamnosus, to 62% control
periods L. fermentum or placebo tampons during the next menstrual (P = NS)
period
Anukam et al. [66] 125 R, DB, PC; Twice daily oral metronidazole 500 mg for 7 days and twice daily 88% compared
30 days oral capsules containing L. rhamnosus GR-1 (109 CFU), and L. to 40% control
reuteri RC-14 (109 CFU) or placebo for 30 days starting on day 1 (P < 0.001)
of metronidazole treatment
Petricevic and Witt 190 R, OB, PC; Twice daily oral clindamycin 300 mg for 7 days, then vaginal 83% compared
[67] 4 weeks capsules containing 109 CFU of L. casei rhamnosus (Lcr35) for to 35% control
7 days (P < 0.001)
Marcone et al. [72] 84 R; 3–6 months Twice daily oral metronidazole 500 mg for 7 days followed by 88% compared
vaginal tablet containing > 104 CFU freeze-dried L. rhamnosus to 71% control
once a week for 2 months starting 1 week after the last antibiotic (P = 0.05) at 3
administration months
83% compared
to 67% control
(P = 0.07) at 6
months
Larsson et al. [71] 100 R, DB, PC; Daily 2% vaginal clindamycin cream directly followed by vaginal 65% compared
6 menstrual capsules containing L. gasseri Lba EB01-DSM 14869 (108–109 to 46% control
periods CFU) and L. rhamnosus Lbp PB01-DSM 14870 (108–109 CFU) (P = 0.042)
for 10 days, probiotic treatment repeated for 10 days after each
menstruation during three menstrual cycles
Martinez et al. [68] 64 R, DB, PC; Single dose of tinidazole (2 g) followed by two oral capsules 87.5%
28 days containing L. rhamnosus GR-1 (109 CFU) and L. reuteri RC-14 compared to
(109 CFU) or placebo for 28 days starting on the first day 1 of 50% control
tinidazole treatment (P < 0.05)
Marcone et al. [73] 49 R; 12 months Twice-daily oral metronidazole 500 mg for 7 days followed by 91% compared
once-weekly vaginal tablet containing > 104 CFU freeze-dried to 69% control
L. rhamnosus for 6 months. (P < 0.05)
Bradshaw et al. [69] 268 R, DB, PC; Twice daily oral metronidazole 400 mg for 7 days followed by 72% compared
6 months vaginal pessary containing L. acidophilus KS400 ≥ 107 CFU and to 73% control
0.03 mg estriol for 12 days (P = NS)
CFU, Colony forming units; DB, double blind; OB, observer blind; PC, placebo controlled; R, randomized.

of follow-up, a constant percentage (96%) of patients in A recent prospective, randomized, placebo-controlled,

probiotic treated group had a balanced vaginal ecosystem.
Follow-up over 12 months showed no statistically signifi-
cant difference among vaginal ecosystems in patients in
the treated group, while in the control group there was a
significant increase in the number of women with abnor-
mal flora over time [73].
Pessaries containing L. acidophilus KS400 were used
in a recent trial to evaluate the efficacy of probiotics on
the recurrence rate of BV following oral metronidazole
treatment [69]. A 12 days course of probiotic pessary did
not achieve higher cure rates for BV compared with pla-
cebo pessary over 6 months of follow-up as assessed by
Nugent score.
double-blinded study evaluated the efficacy of vaginal
­probiotic capsules for BV prophylaxis in healthy women
with a history of recurrent BV [75]. One hundred twenty
healthy Chinese women with a history of recurrent BV (≥2
BV episodes in the previous year), were assigned randomly
to daily vaginal prophylaxis with 1 capsule that contained
8 × 109 CFU of L. rhamnosus (6.8 × 109 CFU), L. aci-
dophilus (0.4 × 109 CFU), and Streptococcus thermophilus
(0.8 × 109 CFU) or 1 placebo capsule for 7 days on, 7 days
off, and 7 days on. Probiotic prophylaxis resulted in low-
er recurrence rates for BV (15.8% vs. 45.0%; P < 0.001)
through 2 months as assessed according to Amsel criteria.
Between the 2- and 11-month follow-up periods, women
404 PART | E Management of Disease and Disorders by Prebiotics and Probiotic Therapy

who received probiotics reported a lower incidence of BV to cure this dysbiosis. When probiotics were used following
(10.6% vs. 27.7%; P = 0.04). However, a limitation of this antibiotic treatment, BV cure rate was increased and recur-
study was that 11-month outcomes were collected by tele- rence rates were reduced.
phone follow-up interview. The preferred route of delivery for probiotic lactobacilli
is intravaginal. However, some authors delivered lactoba-
FORMULATIONS OF PROBIOTIC BACTERIA cilli orally to repopulate the vagina, based on the observa-
tion that Lactobacillus strains can pass from the gut into the
FOR THE TREATMENT OF BACTERIAL urogenital system and can be recovered from the vagina. It
VAGINOSIS is noteworthy that the capability of the lactobacilli to colo-
A suitable vaginal probiotic delivery system should (1) nize the vagina after oral ingestion is strictly dependent on
ensure the inclusion of a high number of microorganisms, their viability and capability to survive gastric acid and bile
(2) guarantee their viability during the production and the salts. Obviously, the timing of vaginal colonization after
storage period, (3) maintain their ability to produce active oral administration is longer compared to direct administra-
and beneficial substances, (4) modulate their release into tion at the vaginal level. Also, the load of lactobacilli that
the vaginal environment [76]. Thus, the selection of specific can be delivered orally to the vagina is clearly lower than
technological processes, dosage forms, and excipients is a direct vaginal administration. However, the oral administra-
critical point in order to design a functional and successful tion of probiotics has the advantage of producing systemic
probiotic delivery system. In particular, encapsulation and effects, such as promoting intestinal health and modulates
freeze-drying are widely applied methods for preserving the immune response, which may contribute to improving
and protecting probiotic cells against stressing physical-­ the overall clinical picture of the woman.
chemical factors [77–80]. Probiotics have been mainly Anyway, probiotic administration requires the design
formulated in different traditional vaginal forms, such as of a suitable delivery system able to ensure microorganism
douches, gels, ovules, tablets, or capsules [81–83]. Gener- viability and to maintain their beneficial properties during
ally, douches or aqueous solutions are not suitable formula- its preparation and storage period. In particular, the selec-
tions for bacteria viability, due to the high water activity, tion of specific technological processes, dosage forms and
which hinders the bacteria survival. Semisolid formula- excipients represented a key requirement in order to obtain
tions, ovules, tablets, and capsules, able to dissolve in situ a final successful probiotic formulation.
or gelify and characterized by a lower moisture content, are A systematic review conducted in 2009 [87] only based
rapidly removed from the washing action of vaginal fluids, on four studies [52,53,66,70] did not provide conclusive
thus requiring multiple daily doses and consequently lead- evidence that probiotics are superior to or enhance the ef-
ing to poor patient compliance [84]. For this reason, several fectiveness of antibiotics in the treatment of BV. However,
mucoadhesive polymers can be used in order to prolong the a more recent metaanalysis based on 12 clinical trials de-
residence time of the formulation into vaginal cavity [85]. scribed here [51,52,54,66–73,75] concluded that probiotics
Furthermore, prebiotics can be also used thanks to their supplementation can significantly improve the cure rate of
ability to promote probiotic viability and growth [77,86]. BV [88]. Moreover, the pooled results of these trials also
Although different probiotic delivery systems were showed that probiotics were associated with a significant
widely investigated, only a few studies reported the use improvement in the cure rate of BV either in orally inter-
of probiotic-based formulation for BV treatment. Mastro- vention or in vaginal application [88].
marino et al. [59] formulated effervescent vaginal tablets In conclusion, lactobacilli use in BV is supported by
containing different lactobacilli strains. The authors demon- scientific results. However, further clinical trials, including
strated that tablet production did not influence cell viability; larger samples of BV-affected women, in which lactobacilli
moreover, tablets showed a significant bactericidal activity are compared either with placebo or conventional antibiot-
toward G. vaginalis. ics, need to be conducted before drawing definitive conclu-
sions about the actual efficacy of probiotics as a strategy to
treat women with BV.
CONCLUSIONS
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