JOURNAL OF WOMEN’S HEALTH

Volume 28, Number 9, 2019

ª Mary Ann Liebert, Inc.
DOI: 10.1089/jwh.2018.7383

Characterization and Treatment of Recurrent

Bacterial Vaginosis

Brooke M. Faught, DNP, WHNP-BC, NCMP, IF1 and Sonia Reyes, DNP, FNP-BC2

Abstract

Bacterial vaginosis (BV) is a common but treatable condition, with a number of effective available treatments,
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including oral and intravaginal metronidazole and clindamycin and oral tinidazole. However, as many as 50%
of women with BV experience recurrence within 1 year of treatment for incident disease. Some reasons for
recurrence include the persistence of residual infection, resistance, and possibly reinfection from either male or
female partners. Persistence may occur due to the formation of a biofilm that protects BV-causing bacteria from
antimicrobial therapy. Poor adherence to treatment among patients with genitourinary infections may lead to
resistance. However, the underlying mechanisms of recurrent etiology of BV are not known. Recommended
treatment for recurrent BV consists of an extended course of metronidazole treatment (500 mg twice daily for
10–14 days); if ineffective, metronidazole vaginal gel 0.75% for 10 days, followed by two times per week for 3–
6 months, is an alternate treatment regimen. Past studies of clindamycin and tinidazole in the treatment of
recurrent BV have focused on patients with evidence of metronidazole resistance. Secnidazole may be an
attractive new option due to one-time dosing. Initial studies on biofilm disruption, use of probiotics and
prebiotics, and botanical treatments have shown some promise, but must be studied further before use in the
clinic. Despite limitations, antimicrobial therapy will remain the mainstay of treatment for recurrent BV for
the foreseeable future.

Keywords: bacterial vaginosis, clindamycin, metronidazole, recurrence, secnidazole

Introduction their unrestrained increase in number, often reaching cell

acterial vaginosis (BV) affects *30% of women in
B the United States.1 Although symptoms of BV may be
mild and not bothersome for most women, those with re-
current BV report a moderate-to-severe impact on their self-
esteem, sex life, and overall quality of life.2 The healthy
microbiota of the lower genital tract in women predominantly
consists of Lactobacillus spp., providing a key line of defense
against potential pathogens.3 BV is characterized by a shift in
the vaginal microbiota from aerobic lactobacilli to anaerobic
bacteria, including Gardnerella vaginalis, Atopobium vaginae,
Mobiluncus spp., Bacteroides spp., and Prevotella spp.4–6
Previously, G. vaginalis was considered to be the sole bac-
terium causing BV, but its presence in many women without
BV suggests that the presence of G. vaginalis alone is not
sufficient to warrant treatment. However, some evidence sug-
gests that a polymicrobial biofilm dominated by G. vaginalis
may contribute to the etiology of BV.5 Ultimately, BV is not
caused by the mere presence of these bacteria, but rather by
counts that are 100- to 1,000-fold above the normal bacterial
levels of the vagina.3
Amsel’s criteria are widely used to diagnose BV. A diag-
nosis of BV is considered when at least three out of four of the
following criteria are present7,8: (1) a homogeneous, milk-
like vaginal discharge that coats the vaginal walls; (2) vaginal
pH >4.5; (3) a fishy odor released with the addition of 10%
potassium hydroxide (KOH) to a sample of the discharge
(KOH whiff test); and (4) presence of clue cells (epithelial
cells coated with bacteria such that they appear heavily
stippled with indistinct borders). The Nugent score is a
standardized Gram-stain laboratory test for assessment of
vaginal smears that can also be used for diagnosis.9 Often
employed in research settings, the Nugent score is also used
in the interpretation of vaginal swab test results in the clinic
and for reporting of these results.10
The most recent Centers for Disease Control and Preven-
tion (CDC) guidelines recommend treatment of BV with
oral metronidazole, vaginal metronidazole gel, or vaginal

1
Division of Urology Associates, Women’s Institute for Sexual Health (WISH), Nashville, Tennessee.
2
San Francisco Department of Public Health, San Francisco, California.

1
 2 FAUGHT AND REYES
clindamycin cream; alternative antibacterial treatments are
also noted (Table 1).8,11 Clinical cure rates in pivotal clinical
trials (defined as return to normal vaginal discharge and res-
olution of Amsel’s criteria) with these recommended treat-
ments range from 36% to 61%.12,13 The CDC guidelines were
last updated in 2015 and do not yet include the recently ap-
proved secnidazole, which is administered as a single dose of
2 g oral granules. Beyond treatment with antimicrobials, it is
recommended that women refrain from sexual activity during
treatment or use condoms consistently and correctly, and to
refrain from douching since douching may increase the risk of
relapse.8
Of note, cure has been defined in multiple ways, including
clinical cure and bacteriological cure, with assessment at dif-
ferent time points after the treatment. This is especially true in
older studies conducted before the U.S. Food and Drug Ad-
ministration (FDA) issued guidances to standardize BV tri-
als.14,15 Thus, reported cure rates (including in this review) may
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be based on different assessments across studies.14,15 Despite
the availability of these treatments, more than half of women
experience recurrence of symptoms and/or reemergence of
abnormal vaginal flora usually within 1 year of treatment.16,17
In addition, poor understanding of the etiology of BV recur-
rence makes treatment of recurrent BV challenging.18,19
Epidemiology and Consequences of Recurrent BV
The National Health and Nutrition Examination Survey
data from 2001 to 2004 identified a number of risk factors for
BV, including education less than high school level, income
below the poverty line, African American or Mexican Ameri-
can ethnicity, and douching.1 In addition, other risk factors are
associated with recurrent BV, including poor adherence to
treatment, trichomoniasis, longer duration of the menstrual
cycle, less than 3 days of menstruation, dysmenorrhea, incon-
sistent condom use, and intrauterine device use.20–24 Ethnic
differences in the vaginal microbiome may explain the preva-
lence of BV in African American women that is as high as
50%.25 Douching is associated with both BV and recurrent
Table 1. Recommendations for Treatment
of Bacterial Vaginosis8,11
Recommended treatments
Metronidazole 500 mg orally bid for 7 days
Metronidazole gel 0.75% intravaginally qd for 5 days
Clindamycin cream 2% intravaginally for 7 days
Alternative treatments
Metronidazole 2 g orally as a single dose or two doses
separated by 48 hours
Clindamycin 300 mg orally bid for 7 days
Tinidazole 1 g orally qd for 5 days
Tinidazole 2 g orally qd for 2 days
Clindamycin 100 mg ovules intravaginally at bedtime for
3 days
Secnidazole 2 g single dose orallya
a
Secnidazole has been approved by the FDA for the treatment of
BV, but has not yet been incorporated into CDC guidelines.
bid, twice daily; BV, bacterial vaginosis; CDC, Centers for Disease
Control and Prevention; FDA, U.S. Food and Drug Administration;
qd, once daily.
BV,26–29 suggesting that the disruption of vaginal microbial
populations may be a causative factor. Use of hormonal con-
traceptives appears to be protective against BV.16,30–32 A de-
crease in the frequency of withdrawal bleeding associated with
some hormonal contraceptives may lead to a reduction in
volume and presence of hemoglobin in the genital tract.32 In
addition, estrogen-containing contraceptives may increase the
glycogen content of epithelial cells in the vagina.32 Glycogen is
metabolized to lactic acid by both epithelial cells and Lacto-
bacillus, resulting in acidification of the vagina. Finally, es-
trogen and progesterone act as immune modulators in the
genital tract and regulate immunoglobulins, secretory leuko-
cyte protease inhibitors, cytokines, and defensins, and help in
the recruitment of immune cells.32 However, to date, no ran-
domized clinical trials have investigated the effectiveness of
oral contraceptives in the prevention of recurrent BV.
The sequelae of BV can be serious, including increased risk
of sexually transmitted diseases, such as HIV33,34 and pelvic
inflammatory disease (and associated subsequent infertility),
and adverse outcomes of pregnancy, including miscarriage,
preterm delivery, low-birth-weight infants, chorioamnionitis,
and reduced quality of life.2,35–37 Women who reported a
higher number of recurrences tended to report a greater neg-
ative impact of BV on quality of life.2
Etiology of Recurrence
While there is no universally accepted definition of re-
current BV, a few studies have defined it as three or more
confirmed episodes (clinically diagnosed by Amsel’s criteria
or microscopically) in 12 months.18 It is not clear whether BV
becomes recurrent due to residual infection, resistance, or
reinfection.21,34
Residual infection is implicated as a cause of recurrence
due to persistence of infection following treatment. G. va-
ginalis resistance to metronidazole has been demonstrated,38
as has resistance to clindamycin, although there is no direct
relationship between microbiological resistance and clinical
resistance.39 There are a number of possible mechanisms for
antimicrobial resistance, including failure to achieve inhibi-
tory concentrations (most likely due to a lack of adherence),
reduced drug activation, drug inactivation, prevention of
entry or efflux, and altered bacterial DNA repair.40 Of note, a
meta-analysis in 29,291 subjects found that adherence to
antibiotic therapy was only 41% for patients with genitouri-
nary infections, substantially lower than for antibiotic use
overall.41 The presence of different clades of G. vaginalis
could be associated with microbiological resistance and BV
recurrence. G. vaginalis clades 1 and 3 have been associated
with BV but not with normal vaginal microbial populations,
whereas clades 3 and 4 exhibit a high frequency of metro-
nidazole resistance in vitro.38 Furthermore, in a recent study
in women with BV, clade 1 G. vaginalis decreased imme-
diately after high-dose intravaginal metronidazole treatment
and increased posttreatment only in those with recurrent BV,
whereas clade 2 decreased in patients who had a sustained
response but not in those with recurrent BV.42
BV-associated bacteria, primarily G. vaginalis and A. va-
ginae, are associated with the formation of a biofilm in the
vagina.43,44 A biofilm forms when bacteria attach to a surface
and form a slimy extracellular matrix accompanied by an
altered bacterial phenotype and gene transcription.45,46 A
 TREATMENT OF RECURRENT BV
recent study indicated that expression of a gene coding for the
sialidase enzyme may be key for biofilm formation. Siali-
dases facilitate the destruction of the protective mucus layer
on the vaginal wall through hydrolysis of sialic acid on the
glycans of mucous membranes and allow bacteria to adhere
on the epithelium.47 These biofilms can cause a decrease in
susceptibility to antimicrobial agents and facilitate develop-
ment of resistance, as well as provide a safe haven for other
pathogens.19,46,48 Known mechanisms of biofilm resistance
include slow or incomplete penetration of antimicrobials,
physiological changes in the biofilm microenvironment,
phenotypic changes in biofilm cells (similar to spore forma-
tion), cell-to-cell signaling between biofilm microorganisms,
expression of solute pumps that can remove antimicrobials,
and the presence of ‘‘persister’’ cells that can survive anti-
microbial concentrations well above minimal inhibitory
concentrations.49 As a result, the formation of a biofilm may
be a key for recurrent BV, and disruption of biofilms may be
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required for successful treatment.19
The presence and persistence of pathogens is also asso-
ciated with recurrent BV. Most research to date has been
focused on G. vaginalis, but studies have also found asso-
ciations of other bacteria, including A. vaginae, Mobiluncus
spp., Bacteroides spp., Prevotella spp., Clostridiales spp.,
and Leptotrichia/Sneathia spp.4,5,50 A recent study found
that higher concentrations of Megasphaera phylotype 2 and
Table 2. Tested Treatments for Recurrent Bacterial Vaginosis
Treatment
Metronidazole 500 mg bid for 10–14 days11
Metronidazole vaginal gel (0.75%) for 3–6 months57
Secnidazole 2 g single dose58
Metronidazole 750 mg/miconazole 200 mg for five
nights each month for 12 months59
Dequalinium chloride 10 mg tablets for 6 days60
Clindamycin vaginal cream 2% for 7 days60
Octenidine for 7 days61
Lactic acid vaginal gel 5 g for 7 days62
Acetic acid vaginal gel 0.94% 2.5 g63
Ascorbic acid 250 mg intravaginal tablet for six
nights/month64
Lactobacillus rhamnosus, Lactobacillus acidophilus,
and Streptococcus thermophilus probiotic capsule
for 7 days on, 7 days off, and 7 days on65
Prebiotic gel with APP-1466
Lactobacillus gasseri, Lactobacillus fermentum, and
Lactobacillus plantarum were administered twice
daily for 10 days after 7 days of oral
metronidazole67
Vaginal capsules of Lactobacillus crispatus68
Vitamin D 50,000 IU at weeks 1, 2, 3, 4, 8, 12, 16, 20,
and 24 after metronidazole therapy69
Vaginal gel containing metronidazole 0.75% and
Myrtus communis 2% for five nights70
3
BV-associated bacteria at initial diagnosis, as well as higher
concentrations of G. vaginalis posttreatment, were associated
with recurrent disease.51 A. vaginae is frequently present with
G. vaginalis in patients with recurrent BV, with 83% of pa-
tients with both bacteria reporting recurrent BV, compared
with 38% of those with only G. vaginalis.52 Additionally,
persistence of Mobiluncus curtisii is significantly associated
with BV recurrence.53
Although BV is not considered to be a sexually transmitted
disease, having a regular sexual partner,16,30 having a female
sexual partner with confirmed BV,54 multiple sexual part-
ners,23,54 and inconsistent condom use for penile/vaginal
sex30 are associated with recurrent BV. A trial to determine
the effect of male sexual partner treatment is currently re-
cruiting.55 However, current treatment guidelines do not
recommend treatment of male sex partners based on the re-
sults of six randomized, controlled trials that showed no
consistent benefit.8,56
Treatment of Recurrent BV
Treatments that have been tested in the context of re-
current BV are summarized in Table 2.11,57–70 Although this
is not a systematic review, an extensive literature search was
conducted to identify both antimicrobial and alternative
treatments of recurrent BV; however, we acknowledge the
Outcome
Standard therapy, but not supported by data in recurrent BV
Recurrence rate 25.5% vs. placebo 59.1% ( p = 0.001) after 16
weeks of therapy
53.3% clinical responder rate with secnidazole vs. placebo
19.3% ( p < 0.001) in patients with a mean of three episodes
in prior 12 months
BV observed at 21.2% of follow-up visits with
metronidazole/miconazole vs. placebo 32.5% ( p = 0.005)
Recurrence occurred in 13.5% of patients vs. 9.2% with
clindamycin 2% vaginal cream; 70% of patients had prior
BV
Recurrence occurred in 9.2% vs. dequalinium chloride 10 mg;
70% of patients had prior BV
Relapse occurred in 66.6% (recurrence in 33.4%)
Recurrence rate 6.7% over 56 days vs. 14.3% with
metronidazole 500 mg bid for 7 days and 3.6% with
metronidazole + lactic acid
Recurrence rate 51%
Recurrence rate 16.2% vs. placebo 32.4% ( p < 0.05)
Recurrence rate 15.8% vs. placebo 45.0% ( p < 0.001) after
2 months and 10.6% vs. 27.7% after 11 months ( p = 0.04)
Recurrence rate 11% at day 84 vs. placebo 19%
No significant difference in recurrence vs. metronidazole alone
Recurrence rate 20.5% vs. placebo 41%
Recurrence rate 65% vs. placebo 48%
No recurrence vs. metronidazole gel 0.75% alone 30% at
3 weeks follow-up
 4 FAUGHT AND REYES

potential for bias in such an approach. Key studies, sys- persist in a carrier state.61,76,77 Persistence of biofilms in
tematic reviews, and meta-analyses identified during our otherwise successful antimicrobial treatment appears to be an
review process discussing these treatments are covered in important mechanism of BV recurrence. Hence, biofilm tar-
detail below. geting may be an attractive approach to treat recurrent BV
disease. A study by Reichman et al. suggested that the ad-
Antibacterials dition of daily intravaginal boric acid to weekly metronida-
zole for 4 months may reduce recurrence rates.78 However,
In women with documented recurrent BV, extending the
the uncontrolled study design did not allow for the contri-
course of metronidazole treatment (500 mg twice daily for
bution of boric acid to be properly evaluated. A randomized,
10–14 days) may prevent further recurrences.11 Alter-
placebo-controlled study of intravaginal boric acid (600 mg)
natively, metronidazole vaginal gel 0.75% therapy for 10
and metronidazole (10%) intravaginal cream for 10 days is
days followed by two times per week for 3–6 months has also
ongoing and may provide the insight on the effect of boric
been recommended. Recurrence rates with twice-weekly
acid for the treatment of symptomatic BV.79
metronidazole gel therapy for 16 weeks in women with re-
Octenidine, a local antiseptic that has been found to be
current BV were found to be 25.5% versus 59.1% with pla-
effective in treating several biofilm-associated infections, has
cebo ( p = 0.001) at the end of the 16-week treatment period.57
demonstrated initial cure rates as high as 87.5%, but the re-
In 2017, a single oral dose of secnidazole 2 g was approved
lapse rate at 6 months was also high as resistance developed
for the treatment of incident BV after FDA priority review in
in 66.6% of the patients.61 There is also an interest in using
the United States.71 A randomized, phase 2 study of single-
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DNAse, retrocyclin, chitosan gels, subtilosin, and lauramide

dose treatment of secnidazole 1 or 2 g oral granules in 215
arginine ethyl ester to disrupt biofilms, but none of these has
women with BV showed a significantly higher clinical cure
been evaluated in humans.80–83 Overall, the use of antiseptics
rate compared with placebo with both doses (51.6% and
and disinfectants for treatment of BV has been poorly stud-
67.7% vs. 17.7%, respectively, p < 0.001 for each compari-
ied, and there is insufficient evidence to warrant their use.84
son). Microbiological cure rates were also significantly
higher (23.4% [p = 0.007] and 40.3% [p < 0.001] vs. 6.5%,
respectively).72 In a phase 3, randomized, double-blind, Vaginal acidification
placebo-controlled study in 189 women randomized 2:1 to a
BV is characterized by a vaginal pH of more than 4.5.7
single dose of secnidazole 2 g or placebo, secnidazole was
Therefore, it has been proposed that maintenance of an acidic
shown to be superior to placebo, with 53.3% and 19.3% of the
vaginal pH <4.5 to prevent overgrowth of undesired bacteria
patients ( p < 0.001) achieving clinical cure, respectively.58
and allow regrowth of Lactobacillus spp. may be an alter-
This trial included subjects with a history of BV; *30% of
native therapeutic approach. Treatment of women with a
those treated with secnidazole who were clinical responders
lactic acid vaginal gel as an adjunct to metronidazole treat-
reported four or more occurrences of BV in the last 12 months.
ment has been associated with a lower rate of recurrence of
An earlier, ex-U.S. phase 3 clinical study found secnidazole
BV than metronidazole alone.62 In a study of 90 women
was at least as effective as a multiple-dose regimen of met-
randomized to treatment with lactic acid vaginal gel 5 g, oral
ronidazole with respect to clinical and bacteriological cure
metronidazole 500 mg twice daily, or both together for 7
rates at day 28 (60.1% and 59.5%, respectively).73 Other
days, two patients given lactic acid gel, four patients in the
preliminary studies suggested secnidazole efficacy is similar
metronidazole arm, and one patient in the combination arm
to that of metronidazole.58,71,74,75 Oral secnidazole has not
had recurrence of BV within 15–56 days.62 Wilson et al.
been evaluated for the treatment of recurrent BV. However,
evaluated the efficacy of acetic acid vaginal gel in 49 women
the single-dose administration and the lack of an alcohol in-
with frequent recurrence of BV.63 Half of the women had no
teraction make it an attractive therapeutic option, especially
further recurrence. Moreover, acetic acid vaginal gel pro-
for those patients with lower medication adherence.
longed the time to recurrence of the BV disease compared
Other approaches have also been studied in restricted settings
with the time to their previous recurrence (4.8 months vs. 2.1
or have been proposed. In a randomized, placebo-controlled
months, p = 0.003). In an uncontrolled study, 58 women ap-
trial, compounded suppositories containing metronidazole
plied hydrogen peroxide 3% each evening for a week to
750 mg with miconazole 200 mg were used by women for five
normalize pH to <4.5.85 Vaginal pH was normalized in 98%
consecutive nights each month for 12 months. BV was ob-
of participants and normal vaginal flora was restored in 100%
served at 21.2% of the follow-up visits with the metronida-
of the participants; 89% of the primary BV symptoms were
zole/miconazole combination compared with 32.5% with
eliminated within 3 months of the end of treatment. Anae-
placebo ( p = 0.005).59 Recently, an intravaginal ring designed to
robic pathogenic flora and clue cells were also eliminated
release metronidazole over 4–7 days and lactic acid over 28 days
from vaginal smears in 100% of patients. A systematic re-
for prophylaxis and treatment of BV has been proposed.75 Fi-
view, however, found no benefit to hydrogen peroxide dou-
nally, treatment of recurrent BV with the bacteriostatic com-
ches.86 Vitamin C suppositories have also been used to
pound dequalinium chloride as 10 mg vaginal tablets for 6 days
reduce intravaginal pH. In a randomized, double-blind,
was shown to be as effective as clindamycin vaginal cream for 7
placebo-controlled study, women with a history of BV re-
days in a randomized, single-blind study (70% of women had
currence who had been successfully treated with metroni-
recurrent BV at baseline), with similar recurrence rates.60
dazole or clindamycin were randomized to ascorbic acid
tablets 250 mg or placebo.64 One tablet was inserted into the
Biofilm disruption
vagina for six nights per month after menses for 6 months.
While treatment with antimicrobials can effectively elimi- After 6 months, the rate of recurrence was 16.2% in the vi-
nate bacteria, they do not eliminate biofilms in which bacteria tamin C group compared with 32.4% in the placebo group
 TREATMENT OF RECURRENT BV
( p < 0.05). Nevertheless, as there have been studies of vagi-
nal acidification on symptomatic BV with negative or vari-
able results, more well-designed studies of the effect of
vaginal acidification on recurrent BV are needed to better
understand if this is a viable treatment option.44
Prebiotics/probiotics
Since a decrease in the normal vaginal lactobacilli and
proliferation of anaerobic species is observed in BV,4–6 one
approach to prevention and treatment of recurrent BV may be
to restore the normal vaginal microbiota. While some sys-
tematic reviews have suggested a potential benefit to this
approach, these have been based on a relatively small number
of trials with heterogeneity among study designs, and thus
should be interpreted with caution.87–89 A recent meta-
analysis of probiotics in combination with metronidazole
showed no significant benefit compared with metronidazole
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alone for the treatment of BV.90 There is a clear need for
good-quality randomized controlled trials. Some of the most
intriguing trials conducted to date are described below.
McLean and Rosenstein identified strains of lactobacilli
that demonstrated good inhibitory activity against BV-
associated bacterial species in vitro, created a highly acidic
intravaginal pH <4, produced hydrogen peroxide, and were
strongly adherent to vaginal epithelial cells, potentially al-
lowing for disruption of biofilms.91 Although not clinically
tested, two Lactobacillus acidophilus strains were identified
as potential probiotics for vaginal recolonization. Other po-
tential probiotics were also studied clinically. One hundred
and twenty Chinese women with a history of recurrent BV
were randomized to receive daily vaginal prophylaxis with a
capsule containing Lactobacillus rhamnosus, L. acidophilus,
and Streptococcus thermophilus or placebo for 7 days on,
then 7 days off, and lastly 7 days on. BV recurrence rates after
2 months were 15.8% with the probiotic compared with
45.0% for placebo ( p < 0.001), and after 11 months the rates
were 10.6% versus 27.7% ( p = 0.04).65 The incidence of G.
vaginalis colonization was also lower with capsules com-
pared with placebo (3.5% vs. 18.3%, respectively, p = 0.02).
Coste et al. took a slightly different approach to restoring the
normal vaginal biota through the application of a prebiotic
gel that promoted growth of Lactobacillus crispatus, Lacto-
bacillus vaginalis, and Lactobacillus jensenii without pro-
moting growth of Candida albicans, Escherichia coli, or G.
vaginalis.66 All patients in this study who were randomized
to the prebiotic gel had a normal Nugent score after 16 days of
treatment, whereas 24% of those treated with placebo had
scores equal to or greater than intermediate. At follow-up on
day 84, 11% of the treatment group and 19% of the placebo
group experienced a recurrent episode of BV.
The efficacy of oral probiotics has also been evaluated in a
few clinical studies. An oral probiotic containing a mixture
of Lactobacillus gasseri, Lactobacillus fermentum, and
Lactobacillus plantarum was administered twice daily for 10
days after 7 days of oral metronidazole in a randomized,
placebo-controlled trial.67 This large study, which included
578 women, found no significant difference in clinical BV
recurrence between arms, but the average time to relapse was
47.3 days in the placebo group compared with 71.4 days
in the probiotic group. Laue et al. assessed oral probiotic
treatment using a yogurt formulated with strains of L. cris-
5
patus, L. gasseri, L. jensenii, and L. rhamnosus isolated from
healthy pregnant women and selected based on their acidi-
fication capacity, production of hydrogen peroxide, glycogen
utilization, bile salt tolerance, and inhibition of pathogens.92
This was a small, single-center, randomized, placebo-controlled
trial of the probiotic taken for 4 weeks along with metroni-
dazole 500 mg twice daily for 7 days. Recovery from BV and
BV symptoms was significantly different in favor of probiotic
treatment as assessed by Amsel’s criteria but not Nugent
criteria at week 4. However, recurrence was not assessed over
a longer period. In another prospective, multicenter, double-
blind, randomized trial of women with at least two docu-
mented episodes of BV in the previous year, Bohbot et al.
compared the effect of vaginal capsules of L. crispatus and
placebo after treatment with metronidazole 1 g/day for 7
days.68 Fewer women treated with L. crispatus reported BV
recurrence compared with placebo (20.5% vs. 41%; p < 0.05),
and time to recurrence was increased by 28% in the L. cris-
patus group (3.75 months) compared with placebo (2.93
months).68 Restoration of normal vaginal flora with prebiotics
and/or probiotics in addition to pharmacotherapy present an
attractive approach to improve response rates and reduce BV
recurrence. However, more clinical evidence is required to
determine correct formulation and dosing.
Vitamin-based treatment
BV has been reported to be associated with vitamin D
insufficiency.69 Inadequate vitamin D levels may also be a
source of racial differences in the incidence of BV. However,
in a 24-week, randomized, double-blind, placebo-controlled
study in 118 women, vitamin D 50,000 IU taken at weeks 1,
2, 3, 4, 8, 12, 16, 20, and 24 after metronidazole therapy
resulted in a higher rate of BV recurrence (65%) compared
with placebo (48%). Hence, vitamin D supplementation did
not reduce BV recurrence.
Herbal treatments
Herbal or botanical treatments have also been used to treat
BV. Myrtus communis is an extract of the common myrtle
with antibacterial and antifungal properties.70 In combination
with metronidazole, M. communis was studied for the pre-
vention of recurrent BV. Recently, Masoudi et al. investi-
gated the effect of an application of a vaginal gel containing
metronidazole 0.75% and M. communis 2% for five nights on
the recurrence of BV in a double-blind, randomized clinical
trial. No recurrence was observed in the metronidazole and
M. communis-treated patients compared with recurrence of
BV in 30% of the patients treated with metronidazole alone in
a relatively short follow-up of 3 weeks.70 Hence, M. com-
munis may be used as an adjunct to metronidazole in the
prevention of BV recurrence. However, further studies with a
longer follow-up period and a larger sample size are needed.
Challenges in the Management of Patients
with Recurrent BV
Currently, effective treatment for recurrent BV is lacking.
Although a few of the approaches discussed in this review
show some promise, a greater understanding of the etiology
of BV and its recurrence is required to further improve out-
comes.19
 6 FAUGHT AND REYES
Women have a high level of dissatisfaction with current
pharmacotherapy for BV. In fact, most of them have resorted
to self-help remedies and lifestyle modifications at some
point to prevent further recurrences, although with little
benefit and increased risk of exacerbating recurrence.93 Self-
help remedies include douching, bathing in cider vinegar
diluted with water, garlic suppositories, over-the-counter pH-
balancing vaginal gel, yogurt, probiotics, and vitamins.
Lifestyle approaches include changes in sexual practices and
hygiene, changes in clothing choices, and attempts to im-
prove general health and well-being.93 However, some of
these approaches, such as excessive cleansing and use of
douches, are established risk factors that actually exacerbate
BV or may lead to recurrence of BV. Since numerous factors
contribute to the recurrence of BV, it is important to record
patient history (to consider any of the abovementioned
measures) when determining a course of treatment for re-
current BV.
Downloaded by East Carolina University from www.liebertpub.com at 08/19/19. For personal use only.
Development of antimicrobial resistance is a major chal-
lenge in treating any infection. Poor medication adherence is
an important cause of resistance since it may lead to drug
levels that are too low to prevent bacterial replication but
high enough to exert a selection pressure, leading to treatment
failure, emergence of resistant bacteria, and loss of therapeutic
options.94 Reasons for nonadherence to BV treatments include
gastrointestinal complaints, duration of therapy, lifestyle
restrictions (such as refraining from intercourse with in-
travaginal treatments), symptomatic improvement, bad
taste, and messy application.21,93,95,96
The alcohol avoidance required during and immediately
following nitroimidazole (metronidazole and tinidazole)
therapy8 may also be challenging for some women with BV.
A study of BV in adolescent girls (11–18 years of age) who
attended sexually transmitted disease clinics in Baltimore,
Maryland, found high rates of alcohol use in this patient
population, highlighting the need to counsel teens who may
need BV treatment.21 A review of the literature also found a
high prevalence of alcohol use among female sex workers
worldwide. Underlying reasons for high alcohol use among sex
workers may include: dealing with an impoverished lifestyle,
coping with stresses and fears related to work (potential for
arrest, violence, disease, etc.), boosting one’s confidence, al-
lowing for relaxation, and/or overcoming aversion to clients.24
Intravaginal boric acid or hydrogen peroxide may be consid-
ered in such populations to control BV.
Currently available therapy for recurrent BV necessitates
repeated or long-term treatment that may increase health care
costs. Oral metronidazole is an inexpensive generic treatment
in the United States, but this medication may not be suitable
for women with recurrent BV who refuse to avoid alcohol,
have already failed oral metronidazole treatment, or have
experienced side effects. In the United Kingdom, oral met-
ronidazole is the least expensive treatment available, fol-
lowed by intravaginal metronidazole 0.75%, oral tinidazole,
and clindamycin 2% intravaginal cream.97 Over-the-counter
remedies such as prebiotics and herbal treatments are often
cost prohibitive for women of low socioeconomic status, and
evidence for their effectiveness is limited.87–89 Any assess-
ment of the cost implications of recurrent BV should include
effects on loss of work productivity, time off from work for
physician appointments, and decreased access to care, as well
as the direct costs of the medication.
Conclusions
Although BV is a readily treatable condition, it is associ-
ated with a high rate of recurrence. The exact mechanism of
recurrence is not fully understood, but may be related to the
formation of biofilms that protect BV-associated bacteria and
allow them to persist, even with efficacious treatments. To
date, interventional strategies to target BV-associated bac-
teria and biofilms and to restore the normal vaginal micro-
biome are at an early stage. Thus, there is an unmet need for
improved treatment regimens to prevent and treat BV re-
currence. Further research to understand mechanisms of re-
current BV and effective and safe prophylaxis and treatment
is warranted.
Acknowledgments
The authors are responsible for all content and editorial
decisions, and received no honoraria related to the develop-
ment of this article. Both authors contributed to the research,
writing, and reviewing of all drafts of this article and ap-
proved the final version. Editorial support in the preparation
of this article was provided by Phase Five Communications,
funded by Symbiomix Therapeutics, LLC.
Author Disclosure Statement
B.M.F. has received research funding from IPSEN In-
novation and has been a speaker/consultant for AMAG Phar-
maceuticals, Inc., Duchesnay, Lupin Pharmaceuticals, JDS
Therapeutics, and TherapeuticsMD. S.R. has no competing
financial interests to disclose.
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Address correspondence to:
Brooke M. Faught, DNP, WHNP-BC, NCMP, IF
Division of Urology Associates
Women’s Institute for Sexual Health (WISH)
2416 21st Avenue South, Suite 300
Nashville, TN 37212
E-mail: bmfaught@au-pc.com