Recommended treatment options for BV include oral and intravaginal
antibiotics, such as metronidazole and clindamycin.
4 5 6
The treatment of BV with antibiotics is not always effective due to
resistance of the pathogens.
7 Given the challenges of the
current recommended treatment options, several studies have proposed
the potential of ingested probiotics to aid in the treatment and prevent
recurrence of BV.
8 Topical
9 and intravaginal
administration of probiotics in the form of vaginal tablets
10
or vaginal suppositories
11 have been previously used to
restore the normal vaginal flora. Ingested lactobacilli can potentially
repopulate the vagina
12 by passing through the intestines,
and colonizing the rectum before ascending to the vagina.
13
Probiotics are expected to replenish the depleted lactobacilli
that produce lactic acid and hydrogen peroxide, in order to maintain
the vaginal pH, protect the vagina from opportunistic bacteria and
prevent recurrence of infection.
7 Several studies
reported better cure rates and lesser recurrence of infection among
patients with BV who were given probiotic supplements.
5 14 15
We did the study because we wanted to know the effectiveness and
safety of metronidazole plus a particular probiotic capsule
preparation available in the market versus metronidazole alone
in treating patients with BV and in preventing recurrence of the disease.
We did an open-label randomized controlled trial from
October 2012 to March 2013 among women diagnosed to have
BV at the Outpatient Gynecology Clinic at Southern Philippines
Medical Center (SPMC), a tertiary hopsital in Davao City,
Philippines. The clinic caters to an average of 10,400 patients
with gynecologic complaints per year.
Patients 18-49 years old diagnosed with BV by Nugent's
criteria were eligible to participate in this study. The Nugent's
criteria makes use of a scoring system that relies on findings of
Gram staining of a cervico-vaginal smear.
16 Three
bacterial morphotypes are examined, counted and scored from
the smear that is viewed under the microscope at a fixed
magnification:
Lactobacillus morphotype (large Gram-positive rods;
scored 0 to 4; the lower the count, the higher the score),
Gardnerella morphotype (small Gram-variable rods; scored 0 to 4;
the higher the count, the higher the score), and
Mobiluncus spp.
morphotype (curved Gram-variable rods; scored 0 to 2; the higher
the count, the higher the score).
17 The individual
morphotype scores are then added, and the total score (Nugent score)
is interpreted against the following criteria: 0 to 3 (normal vaginal
microflora), 4 to 6 (intermediate vaginal microflora), and 7 to 10
(bacterial vaginosis).
18 In order to be eligible for this study,
a patient must have a baseline Nugent score of 7-10.
|
|
Figure 1
Screening, randomization, follow-up, and analysis of patients in the study.
|
Interventions and randomization
We randomly assigned patients to one of two treatment arms.
The first group received metronidazole 500 mg alone, one tablet
twice a day for seven days. The second group received metronidazole
500 mg one tablet twice a day for seven days, followed by oral
probiotics, one capsule once a day for the next seven days. For the
oral probiotics in this study, we used a commercially available
preparation in capsule form. The capsule contains seven live bacteria,
namely, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus
acidophilus, Lactobacillus bulgaricus, Streptococcus thermophilus,
Bifidobacterium longum, and Bifidobacterium breve. The total
viable count per capsule is 100 million CFU.
Data collection
We collected baseline sociodemographic and clinical chracteristics
from the participants who were eventually included in our study.
For sociodemographic data, we gathered information on patients' age,
highest educational attainment, employment status, and household income.
For clinical characteristics, we asked for the patients' parity,
gravidity, past medical history, concomitant diseases, and signs and
symptoms, and we noted the characteristics of their vaginal discharge
on physical examination. We also recorded the patients' Nugent scores
upon enrolment into the study.
The primary outcomes for this study were cure rate and recurrence
rate. To determine cure status, we repeated the cervico-vaginal specimen
collections and Nugent score measurements among all the patients who
returned for follow-up at 2 weeks after start of treatment. Among those
who were cured, we also repeated the specimen collections and Nugent
score measurements on the 2nd and 10th weeks after
being cured in order to determine recurrence status. Cure was considered
when Nugent score 2 weeks after start of treatment was recorded
to be ≤6. Among those who were cured, we considered recurrence
when Nugent score was recorded to be 7 to 10 anytime within 10 weeks
after being cured. We also instructed the patients to report possible
side effects of the interventions, such as symptoms of hypersensitivity,
metallic taste, and gastrointestinal upset.
Statistical analysis
The primary analysis for this study was performed according to
the intention-to-treat principle. The intention-to-treat population
for the cure outcome included all patients who were randomized to
either of the treatment arms. For the recurrence outcome, the
intention-to-treat population included patients who were cured at
2 weeks. Per-protocol analyses were done by excluding patients
who were lost to follow-up and considering only patients who were
actually assessed for cure or recurrence. To assess the robustness of
the main results, we also did several sensitivity analyses by assuming
different scenarios for the outcomes of patients who were lost to
follow-up. We summarized continuous data using means ± standard
deviations and compared them using t-test. We summarized categorical
data using frequencies and percentages and compared them using chi-square
test. A two-tailed p-value of <0.05 was considered significant. All
statistical tests were done using Epi Info 7.1.4.0.
Results
The 60 patients who were recruited into this trial were randomized
either to the metronidazole alone (MA) group (n=30) or to the
metronidazole plus probiotic (MP) group (n=30). The sociodemographic
and clinical characteristics of the patients at baseline are shown in
Table 1. The two treatment groups were comparable in terms of age,
educational attainment, employment status, household income, obstetrical
history, past medical history, concomitant diseases, signs and symptoms,
and vaginal discharge characteristics at the start of the study.
|
Table 1
Baseline demographic and clinical characteristics |
| Characteristics |
Metronidazole alone (n=30) |
Metronidazole + probiotics (n=30) |
p-value |
| Mean age ± SD, years |
33.0 ± 8.1 |
31.6 ± 10.6 |
0.5582 |
| Mean gravidity ± SD |
2 ± 2 |
2 ± 2 |
0.5160 |
| Mean parity ± SD |
2 ± 2 |
2 ± 2 |
0.5380 |
| Educational attainment, frequency (%)
| |
|
0.7807 |
| Elementary |
4 (13.33) |
4 (13.33) |
|
| High school |
4 (13.33) |
20 (66.67) |
|
| College |
22 (73.33) |
6 (20.00) |
|
| Employed, frequency (%) |
15 (50.00) |
8 (29.63) |
0.1175 |
| Mean household income ± SD, Philippine pesos |
7,933.33 ± 5,421 |
7,550.00 ± 8,335.00 |
0.8335 |
| Past medical history, frequency (%) |
|
|
|
| Genital warts |
1 (3.33) |
1 (3.33) |
1.0000 |
| Herpes simplex |
0 |
2 (6.67) |
0.1503 |
| Gonorrhea |
2 (6.67) |
2 (6.67) |
1.0000 |
| Chlamydia infection |
0 |
1 (3.33) |
0.3132 |
| Bacterial vaginosis |
1 (3.33) |
0 |
0.3132 |
| Vulvovaginal candidiasis |
2 (6.67) |
3 (10.00) |
0.6404 |
| Concomitant disease, frequency (%) |
|
|
|
| Diabetes mellitus |
0 |
1 (3.33) |
0.3132 |
| Asthma |
5 (16.67) |
8 (26.67) |
0.5537 |
| Adnexal mass |
2 (6.67) |
2 (6.67) |
1.0000 |
| Uterine mass |
3 (10.00) |
6 (20.00) |
0.2781 |
| Signs and symptoms, frequency (%) |
|
|
|
| Burning sensation |
5 (16.67) |
4 (13.33) |
0.7177 |
| Vulvar pruritus |
5 (16.67) |
8 (26.67) |
0.3472 |
| Dyspareunia |
6 (20.00) |
11 (36.67) |
0.1520 |
| Foul-smelling vaginal discharge |
13 (13.33) |
20 (66.67) |
0.0693 |
| Vulvar edema |
1 (3.33) |
0 |
0.3132 |
| Vulvar excoriations |
1 (3.33) |
4 (13.33) |
0.7177 |
| Vulvar fissures |
1 (3.33) |
1 (3.33) |
1.0000 |
| Vulvar spotting |
4 (13.33) |
4 (13.33) |
1.0000 |
| Pelvic tenderness |
2 (6.67) |
0 |
0.1503 |
| Vaginal discharge charactersitics, frequency (%) |
|
|
0.0762 |
| Grayish |
23 (76.67) |
17 (56.67) |
|
| Yellowish |
7 (23.33) |
9 (30.00) |
|
| No discharge |
0 |
4 (13.33) |
|
Table 2 shows the cure rates and recurrence rates between
the treatment arms and according to the type of analysis. There
were 27 patients from the MA group and another 27 patients from
the MP group who returned for assessment of cure status two weeks
after starting treatment. On intention-to-treat analysis, there was
no significant difference between the cure rates in the MA group
(22/30; 73.33%) and the MP group (20/30; 66.67%) (p=0.8071).
|
Table 2
Clinical outcomes |
| Outcome |
Metronidazole alone |
Metronidazole + probiotics |
p-value |
| Cure, frequency (%)† |
|
|
|
| Intention-to-treat analysis |
22/30 (73.33) |
20/30 (66.67) |
0.8071 |
| Per-protocol analysis |
22/27 (81.48) |
20/27 (74.07) |
0.5127 |
| Recurrence, frequency (%)‡ |
|
|
|
| Intention-to-treat analysis |
5/22 (22.73) |
4/20(20.00) |
0.8297 |
| Per-protocol analysis |
5/19 (26.32) |
4/19 (21.05) |
0.7028 |
†Measured at two weeks after start of treatment;
‡measured within 10 weeks after being cured |
Among the patients who were cured, there were 19 patients from
the MA group and another 19 patients from the MP group who could be
assessed for BV recurrence within the subsequent 10 weeks after the
cure assessment. On intention-to-treat analysis, the recurrence rates
were 5/22 (22.73%) in the MA group and 4/20 (20.00%) in the MP group
(p=0.8297).
After doing per-protocol analyses and several sensitivity analyses,
the cure and recurrence rates remained comparable between the two
treatment groups.
One patient in the MP group developed pruritic rashes after taking
metronidazole, hence, the antibiotic was discontinued on
the 5th day, and the patient was given cetirizine 10 mg
once a day for 5 days. The patient took the oral probiotics as scheduled.
No other side effects of the interventions were noted in either of the
groups.
Discussion
Key results
We did this study in order to find out whether adding a
7-day course of oral probiotics to metronidazole treatment for
BV would affect cure and recurrence rates. Both outcomes did not
significantly differ between the metronidazole alone group and the
metronidazole plus probiotics group.
Strengths and limitations
We were able to demonstrate that adding oral probiotics at a
dose of 100 million CFU per day for 7 days to a metronidazole treatment
regimen does not change cure and recurrence rates of BV. Follow-up rate
was high among the study participants, and the study population had been
adequate up to the last assessment of the outcomes. Our findings also
remained unchanged across different analytical approaches
(intention-to-treat, per-protocol, and sensitivity analyses).
There were some limitations in this study. We did not account
for or monitor some factors that could possibly affect the outcomes
that we measured, such as personal hygiene practices and vaginal pH.
Hygeine practices in the vaginal area
20 and vaginal
pH
21 may affect the bacterial flora of the vagina, as well
as the cure and recurrence rates of BV. For this study, we only used
the Nugent's criteria to screen patients for entry into the study and
to measure the study oucomes. Using other diagnostic criteria for BV,
such as the Amsel's criteria,
22 the Spiegel criteria,
23 or the Ison-Hay classification,
24
in lieu of or in combination with Nugent's criteria may yield different outcome
findings for this study.
Interpretation
Several trials on probiotic use among patients with BV demonstrated
different results because of the varied therapeutic approaches employed
in the trials.
14 15 25 26 27 28 29 30
Most of the trials used antibiotic and
probiotic combinations,
14 15 25 26 27 30 but some used probiotics
alone as treatment for bacterial vaginosis.
28 29
As to route of administration of probiotics, some trials used the intravaginal
route,
15 25 26 27 30
while others used the oral route.
28 30 In some trials, the probiotics were administered
together with the antibiotics,
14 15 while in others, the
probiotics were administered after the antibiotic course.
25 26
The doses of the probiotics used in the study also varied from 10
million CFU
27 to 1 billion CFU.
14 25 Durations
of probiotics administration ranged from 7 days
25 or one
menstrual cycle,
26 to 6 months.
30 Finally, the
lactobacilli strains used in the trials varied greatly, but many used
Lactobacillus reuteri,
Lactobacillus rhamnosus,
Lactobacillus gasseri, and
Lactobacillus acidophilus
alone or in different combinations.
14 15 26 27 28 30The probiotic preparation in our study has been marketed for
general use, rather than for specific use in gynecologic conditions.
As such, it contains other good bacteria, including those that belong
to the normal gastrointestinal microflora that were not utilized in
previous studies on BV. The probiotic dose, route of administration,
duration of administration, and the timing of administration of
probiotics that we employed in our study were similar to those used
in other studies. Like some clinical trials done previously,
15 26 27
our study showed that adding probiotics to
the antibiotic treatment regimen for BV does not provide any
beneficial effects in terms of cure or prevention of recurrence.
Generalizability
We did this study among women with diverse sociodemographic
characteristics, and with clinical profiles that cover a wide
range of past and concomitant diseases. The symptoms that our
participants reported at baseline also include the most common
signs and symptoms of BV. Hence, the results of this study can be
applicable to most women diagnosed to have BV by Nugent's criteria.
Our findings do not support the addition of oral probiotics to the
antibiotic treatment regimen for BV. Treatment of BV with a week's
course of oral metronidazole alone can result in a reasonably high
cure rate two weeks after start of treatment and a reasonably low
recurrence rate within 10 weeks of being cured of BV.
Conclusion
Among patients with BV by Nugent's criteria, oral metronidazole
treatment did not significantly differ from oral metronidazole plus
oral probiotics treatment in terms of cure two weeks after treatment
and recurrence within 10 weeks after being cured of BV.
In essence
The management of bacterial vaginosis (BV) includes the administration of appropriate antibiotics and restoration of the normal vaginal microbiota.
In this study, cure rates and recurrence rates among patients with BV did not differ between those who received oral metronidazole alone and those who received oral metronidazole plus oral probiotics.
While ingested probiotics can potentially populate the vagina after colonizing the rectum, findings in this study do not support their addition to the antibiotic treatment of BV.
Acknowledgments
We would like to extend our heartfelt gratitude to Dr Oscar Grageda, Dr Jao Ancheta, the SPMC Laboratory staff, and the SPMC Obstetrics and Gynecology Department Office staff for their generous support during the conduct of this research.
Ethics approval
This study was reviewed and approved by the Department of Health XI Cluster Ethics Review Committee (DOHXI CERC reference P12072601).
Funding
Supported by personal funds of the author
Competing interests
None declared
Access and license
This is an Open Access article licensed under the Creative Commons
AttributionNonCommercial
4.0 International License, which allows
others to share and adapt the work, provided that derivative works
bear appropriate citation to this original work and are not used for
commercial purposes. To view a copy of this license, visit
https://creativecommons.org/licenses/by-nc/4.0/
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