Article Type : Research Article
Authors : Espit ia De La Hoz FJ
Keywords : Vaginosis; Bacterial; Vaginitis; Postmenopause; Drug effects; Leukorrhea
Introduction: Bacterial vaginosis, or vaginal dysbiosis, is
one of the most common vaginal conditions, characterized by a pathological
change in the vaginal microbiota.
Objective: To establish the effect of the nifuratel -
nystatin combination to treat bacterial vaginosis in postmenopausal women.
Materials and methods: Cohort study in 57 sexually active
postmenopausal women, who consulted for vaginal discharge syndrome, in which
the diagnosis of bacterial vaginosis was made; between 2013 and 2016. In a
private clinic in Armenia (Colombia). The effect was evaluated by observing the
disappearance of symptoms in the first follow-up (seven days after initiating
the treatment) and with the Amsel criteria and the Nugent score one month after
the end of therapy. The dose used was nifuratel 500 mg - nystatin 200,000 IU
intravaginally daily for six days. Convenience sampling was conducted.
Descriptive statistics were used.
Results: The mean age of the women was 57.36 ± 4.28 years.
The most frequent symptom was white-grayish vaginal discharge in 91.22% of the
participants, followed by bad odor in 85.96%. In the seven-day follow-up, the
symptoms disappeared in 94.73% of the patients. In the month's follow-up,
89.47% of the women reported absence of symptoms; which was confirmed with the
Amsel criteria and a median Nugent score of 3. Therapeutic failure, at one
month, was 10.52% (n = 6/57). In none of the patients there were adverse reactions.
Conclusions: The nifuratel - nystatin combination reports a
notable effect to treat bacterial vaginosis in postmenopausal women; being well
tolerated and without adverse reactions. Randomized controlled clinical trials
of its efficacy and safety in larger populations are required in order to
establish recurrence rates.
Vaginal discharge syndrome characterizes an inflammatory/ infectious process of the vulva and vagina, which is associated with three pathologies: Bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and vaginal trichomonas’s (VT); which is accompanied by various signs and symptoms (vaginal discharge, vaginal and/or vulvar erythema, vaginal and/or vulvar burning and / or itching, irritation, dysuria and dyspareunia, depending on the present condition); It occurs secondary to the invasion and multiplication of microorganisms, as a result of the environmental imbalance in the vaginal microbiota [1]. Bacterial vaginosis (BV), or vaginal dysbiosis, is characterized by a change in the vaginal microbiota dominated by Lactobacillus spp. (producers of lactic acid and hydrogen peroxide), generating an imbalance in the vaginal ecosystem, moving towards the colonization of anaerobic bacteria (Gardenella vaginalis, Mycoplasma hominis, Mobiluncus, Prevotella spp, Atopobium vaginae, among others) [1,2]. BV is a condition that affects between 30% and 60% of women worldwide [1,3]. It represents a public health problem among women of reproductive age, for their offspring and their partners; since it is associated with adverse reproductive health outcomes such as: pelvic inflammatory disease (PID), spontaneous abortion, threatened preterm labor, premature delivery and increased risk of acquisition and transmission of the human immunodeficiency virus (HIV) [4-6]. It is known that between 50% and 80% of women can be asymptomatic for BV, with an adherent greyish-white discharge, bad odor, burning, irritation, vaginal itching and dysuria standing out in the symptoms [2,7]. The diagnosis of BV can be made clinically, through the Amsel criteria (Annex 1) and the Nugent score (Annex 2); considered as the “gold standard” throughout the world, for almost three decades, despite its limitations [8-11].
Annex 1. Amsel criteria | |
1 |
pH
of vaginal discharge > 4.5 [8] |
2 |
Smell
"fishy" when adding KOH10% to vaginal discharge |
3 |
Presence
of clue cells (guide) |
4 |
Grayish-white
discharge, homogeneous, thin and attached to the vaginal walls |
The
diagnosis of bacterial vaginosis is made with 3 of the 4 criteria. |
Annex 2. Nugent scoring
system | |||
Punctuation |
Lactobacillus
spp (Gram positive rods) |
Gardnerella
vaginalis and Bacteroides spp. (Gram negative rods and cocci) [9] |
Mobiluncus
spp. (Curved Gram negative rods) |
0 |
4+ |
0 |
0 |
1 |
3+ |
1+ |
|
2 |
2+ |
2+ |
1+
o 2+ |
3 |
1+ |
3+ |
3+
o 4+ |
4 |
0 |
4+ |
|
0)
No morphotypes present; 1+) less than 1 morphotype present; 2+) 1-4
morphotypes present; 3+) 5 to 30 morphotypes present; 4+) 30 or more
morphotypes present. The
diagnosis of Bacterial Vaginosis is made when the score is ? 7. |
In the treatment of BV, oral metronidazole has been the drug of choice for several decades; however, all regimens have high recurrence rates (69% to 80%) in 12 months; which has led to the search for alternatives other than metronidazole [12-16]. Post menopause characterizes hypoestrogenism, resulting in the genitourinary syndrome of menopause [17]. Due to the decrease in estrogens, the glycogen content in the vaginal epithelium also decreases, leading to the depletion of lactobacilli spp. (Lactobacilli present during the reproductive period are reduced 10 to 100 times in the vaginal microbiota); This decrease leads to an increase in vaginal pH, because glucose is not converted to lactic acid [18,19]. The high pH promotes the growth of pathogenic bacteria, especially the colonization of Enterobacteriaceae [20]. At present, neither the diagnosis nor the treatment of BV in postmenopausal women are standardized; and knowing that postmenopausal women present twice more BV than women of childbearing age, it is necessary to opt for different alternatives to traditional treatments [21,22]. Nifuratel (a synthetic derivative of nitrofurans) shows strong antiprotozoal (trichomonacidal) and antibacterial activity, with a certain fungicidal effect, without being active against the physiological flora of lactobacilli spp; whose safety and therapeutic efficacy have been evaluated in more than 12,000 patients [23]. Extensive clinical experience confirms that nifuratel is effective and safe for the treatment of bacterial vaginosis, vulvovaginal candidiasis, and vaginal trichomoniasis, especially in women with mixed vaginitis [24]. As there are gaps in knowledge regarding the treatment of BV in postmenopausal women; and since there is not enough research in Colombia about other treatment options beyond metronidazole and clindamycin, a descriptive study was proposed whose objective was to establish the effect of the nifuratel-nystatin combination to treat bacterial vaginosis in postmenopausal women.
Design and population Cohort study
Sexually
active women in natural post menopause, residents of Quindío (Colombia), who
consulted for vaginal discharge syndrome were included; in which the diagnosis
of bacterial vaginosis (BV) was made using the Amsel criteria and confirmed
with the Nugent score (Annex 1 and 2), in a private clinic, of third level of
complexity, reference center in the department from Quindío, and that serves
the population belonging to the contributory regime and the one subsidized by
the State in the social security system in Colombia; between May 1, 2013 and
April 30, 2016. Women who had received antibiotics during the last two weeks,
those who used a vaginal douche or referred sexual intercourse during the 24
hours prior to the check-up, not having received hormone replacement therapy in
the last six months, and data loss greater than 10% were excluded. A
consecutive sampling was done and all women who met the inclusion and exclusion
criteria were considered. Procedure Patients with a diagnosis of BV were
selected, based on the identification of the following codes of the
international classification of diseases (ICD10): N76.0-Acute vaginitis or
N76.1-Subacute vaginitis, in which the Amsel criteria and Nugent score for BV
were met. For women who met the selection criteria and agreed to participate in
the study, the study objectives were explained to them, and after signing the
informed consent, an Excel® 14.0 form was filled out, where the
sociodemographic characteristics were recorded, clinical symptoms and clinical
examination data. All the participants were evaluated by the main investigator;
Speculoscopy was also performed, in order to evaluate flow characteristics
(quantity, color, consistency and smell), and the presence of vulvovaginal signs
(vulva, vaginal walls and cervix), among others. The nature of their clinical
condition was explained to each patient, and intravaginal ovules of the
combination nifuratel 500 mg - nystatin 200,000 IU were offered as a
therapeutic option (every night at bedtime), for six (6) days, following the
scheme, who state that the combination of nifuratel 500 mg + nystatin 200,000
IU once a day is the best dose (in terms of risk / benefit ratio) [25].
Collection and transport of samples
Vaginal pH was measured in each participant
using a test strip (MQuant®), the amine test was performed with the application
of 10% potassium hydroxide drops (10% KOH) to a sample of vaginal discharge; A
sample of the vaginal discharge was taken with a cotton swab from the anterior
cul-de-sac and lateral walls of the vagina, which was spread on a microscope
slide with Gram stain in order to evaluate the presence of clue cells (guide)
and the Nugent score.
Intervention [9]
The ovule with the combination of nifuratel
500 mg + nystatin 200,000 IU was applied at night, at bedtime, for 6 days. The
treatment was delivered to each participant by a professional nurse in charge
for this purpose, without the intervention of the researcher. A group of three
nursing assistants were in charge of daily monitoring of each patient to ensure
that the drug was applied in the indicated way, while at the same time
investigating the presence of adverse reactions. Two (2) follow-ups were
conducted: one week (seven days after the therapy started), and one month
(thirty days after the therapy ended). In the first control, the absence or
presence of symptoms was evaluated, and the appearance of adverse reactions was
also investigated to assess safety. In the month's follow-up, the absence or
presence of symptoms was taken into consideration to evaluate the therapeutic
effect, as well as the Amsel criteria and the Nugent score in order to
establish the presence of recurrences. The findings of each of the women were
recorded in each control. The follow-up program was complemented with a
communication telephone line, through which the group of nursing assistants
monitored the application of the therapy on a daily basis and inquired about
the presence of any adverse reaction. The procedures for data collection, completion
and storage of information were standardized by training the nursing staff who
supported the study by the main investigator. Adverse reactions were evaluated
through the application of a survey, to each patient, in each of the controls;
survey prepared by the research team; where the class, frequency and severity
of each adverse reaction and the etiological role of the treatment were
questioned.
Variables measured
Sociodemographic (age, ethnicity, level of
education, marital status, socio-economic stratum, occupation, affiliation to
the general health social security system, religion, area of residence),
weight, height, BMI; time spent with a partner, age of menopause, evolution of
time of menopause; habits (alcohol intake, smoking, sedentary lifestyle),
medical history, sexual behavior variables (masturbation, oral sex, intercourse
–vaginal or anal–, use of erotic toys, frequency of monthly sexual relations);
history of bacterial vaginosis in the last year, incomplete treatment in
episodes of previous bacterial vaginosis; presence or absence of the symptoms
of bacterial vaginosis and adverse reactions. The Amsel criteria and the Nugent
score were also evaluated.
Statistical analysis
Absolute and relative frequencies were
calculated for the qualitative variables; in the quantitative variables,
measures of central tendency (mean, median) and dispersion (standard deviation,
percentiles, minimum value, maximum value and range) were used. The statistical
analysis was done with the Epi Info® 7.2 programs. And Stata® 15.1.
Ethical aspects
The study was approved by the Ethics Committee
of the participating institution. The requirements for medical research on
human beings established in the Declaration of Helsinki and with Resolution
8430 of 1993 were met, which establishes the scientific, technical and
administrative standards for health research. All participants signed the
informed consent to enter the study. The confidentiality of the information was
guaranteed.
Results
During the follow-up period, 3,157 women with bacterial vaginosis were treated at the institution, of which 429 (13.58%) met the inclusion criteria; 147 (34.26%) were excluded for having received antibiotics in the last two weeks, 135 (31.46%) for having used a vaginal douche, 49 (11.42%) because they reported sexual intercourse during the previous 24 hours and 41 (9.55%) for data loss greater than 10%. In the end, a sample of 57 patients was obtained. The mean age of the participants was 57.36 ± 4.28 years. 87.71% were of urban origin, 89.47% belonged to the contributory insurance scheme and 92.98% were Catholic. Table 1 describes the sociodemographic characteristics of the population (Table 1).
Table 1: Sociodemographic characteristics of women with bacterial vaginosis, in Quindío, 2013-2016.
Variable and categories |
n(%) |
Age: X ± SD years |
57,36 ± 4,28 |
Age of partner: X ± SD years |
59,61 ± 4,38 |
Weight: X ± SD Kg |
67,95 ± 8,24 |
Height: X ± SD Cms |
157,39 ± 4,82 |
BMI: X ± SD |
27,63 ± 5,41 |
Race |
|
White |
37 (64.91%) |
Indigenous |
7 (12.28%) |
Afro Colombian % |
13 (22.8 %) |
Civil Status |
|
Married % |
24 (42.1%) |
Common Law |
14 (24.56%) |
Single |
10 (17.54%) |
Widows |
9 (15.78%) |
Occupation |
|
Housewives |
34 (59.64%) |
Employed |
17 (29.82%) |
Retired |
6 (10.52%) |
Socioeconomic status |
|
High |
15 (26.31%) |
Middle |
36 (63.15%) |
Low |
6 (10.52%) |
Educational level |
|
Primary |
3 (5.26%) |
Secondary |
18 (31.57%) |
Technical |
21 (36.84%) |
Professionals |
15 (26.31%) |
The mean age of menopause was 48.93 ± 5.71 years, with a mean duration of menopause of 8.95 ± 4.73 years. The time of living together as a couple was 16.27 ± 5.92 years. Alcohol intake was present in 68.42% of the women. 19.29% smoked, with a median consumption of 3 cigarettes per day (range between 3 and 9). Sedentary lifestyle was observed in 77.19%. In the medical history, it was observed that 40.35% had hypertension, 36.84% had dyslipidemia, 15.78% hypothyroidism, and 8.25% had type 2 diabetes. 8.77% had a history of breast cancer, and 12.28% had morbid obesity. A history of bacterial vaginosis in the last year was detected in 21.05% (n = 12/57) of the women; of which eight stated that they had not completed the treatment. In relation to the variables of sexual behaviour, masturbation was an experience barely explored by 14.03% of the women. Oral sex was the preferred sexual practice for 84.21%. Vaginal intercourse was practiced by 100%, while anal was reported by 12.28%. The frequency of monthly sexual intercourse yielded a median of 2 (range between 0 and 5). The use of erotic toys was detected in 22.8% of the participants. Upon entry to the study, 100% of the women were symptomatic. The symptoms reported by the patients, in order of frequency, are detailed in Table 2; being the grayish-white adherent discharge (91.22%) the most frequent, followed by bad odor (85.96%) and vaginal burning (75.43%). 75.43% (n = 43/57) presented four or fewer symptoms, 19.29% (n = 11/57) five, and 5.26% (n = 3/57) six or more symptoms; with a median of 4 (range between 3 and> 6) (Table 2).
Table 2: Symptoms of postmenopausal women with bacterial vaginosis, in Quindío, 2013–2016.
Symptoms |
n
(%) |
Bad
vaginal odor |
49
(85.96%) |
Clue
cells (guide) |
34
(59.64%) |
Dysuria |
5
(8.77%) |
Grayish-white
adherent discharge |
52
(91.22%) |
pH
>4,5 |
41
(71.92%) |
Vaginal
burning |
43
(75.43%) |
Vaginal
irritation |
6
(10.52%) |
Vaginal
itching |
14
(24.56%) |
At one week of follow-up, the positive effect
of the combination of nifuratel 500 mg + nystatin 200,000 IU was evident when
the absence of symptoms was observed in 94.73% (n = 54/57) of the participants;
presenting a total of 3 therapeutic failures (n = 3/57 = 5.26%), of which two
were diabetic and one had morbid obesity. At one month of follow-up, 89.47% (n
= 51/57) of the patients reported absence of symptoms, which was demonstrated
with the Amsel criteria and confirmed with a median Nugent score of 3; In 5.26%
there was a recurrence of the infection, which added to 5.26% of therapeutic
failure, finally reported 10.52% (n = 6/57) of therapeutic failure; of which
three were diabetic, two were morbidly obese and one was a sex worker. The
initial median in the Nugent score was 8 (range between 7 and 10), decreasing
to 3 (range between 0 and 7) at one month of follow-up. In none of the patients
there were adverse reactions, therefore, there was no need to discontinue the
medication; there was also no loss to follow up.
In
this study, it was observed that the therapeutic response of the
nifuratel-nystatin combination, to treat bacterial vaginosis in postmenopausal
women, at one week of follow-up, was present in 94.73% of the participants,
managing to be maintained in 89, 47% at one month of follow-up; results that
align with those, who in a group of 52 women (not pregnant), aged between 20
and 54 years, observed a good clinical and microbiological influence where the
controls reported 89.5% and 84.2% respectively. For its part, another study
concludes that treatment with the combination nifuratel - nystatin, in women
with complaints of vaginal discharge and / or itching, is successful in all
cases [26]. In the Czech Republic, in a participating population of 50 women
with vaginal complaints, published that the therapy with the combination
nifuratel 500 mg - nystatin 200,000 IU intravaginal, over a period of 7 days,
exerts a high effect and a low number of relapses. A Bulgarian article from
1999, a study that included 159 women with vaginal infections (not pregnant)
[28], aged between 15 and 54 years; indicates that the results obtained give
reason to approve that the nifuratel - nystatin combination has a good chance
of influencing mixed forms of vaginal infection, since an effect was found in
88.1% of the participants [29]. In the study in which they evaluated the in
vitro activity of nifuratel on vaginal bacteria, suggesting that it has a
better spectrum of activity against metronidazole and clindamycin, being highly
active against Gardnerella vaginalis and Atopobium vaginae, without affecting
lactobacilli; they also conclude that nifuratel is a potential candidate for
the first-line treatment of BV. Another article, published in Italy in 2012,
suggests that nifuratel is probably the most valid therapeutic agent for the
treatment of BV [30]. In a meta-analysis, which included seven controlled
clinical trials comparing nifuratel and metronidazole, performed in patients
with vulvovaginal infections; in which a total of 1,767 patients participated,
832 of whom were treated with nifuratel and 935 with metronidazole. The results
confirmed the equivalence between nifuratel and metronidazole, the overall
proportion of patients cured in the two groups was 88.5% and 90.0%,
respectively, in the presence of homogeneity between the studies (p = 0.342);
however, some research has shown that the cure rate of nifuratel in patients
with mixed Trichomonas vaginalis + Candida or Trichomonas vaginalis +
infections or with bacterial vaginosis and mixed bacterial flora, is higher
than that of metronidazole, due to the broad spectrum of action of nifuratel
[23]. A systematic review of the literature reports that nifuratel has a strong
trichomonacidal activity equivalent to that of metronidazole; it has a broad
spectrum of antibacterial action, which includes both Gram positive and Gram
negative bacteria; it is active against Chlamydia trachomatis and Mycoplasma
spp. and it also has some degree of activity against Candida spp. Its broad
spectrum of action, confirmed by in vitro and in vivo studies, covers practically
all microorganisms responsible for genitourinary tract infections [31]. Its
toxicological profile makes it very safe, being practically non-toxic, and well
tolerated after repeated intravaginal administrations. The comparison between
past and recent clinical studies confirms that, unlike metronidazole, no
phenomena of resistance to treatment with nifuratel are reported. It can be
used in adolescents, in lactation and during pregnancy, due to the absence of
teratogenic effects. In conclusion, nifuratel shows a very favorable risk /
benefit ratio for the treatment of patients with vulvovaginal infections. Based
on the above and in conjunction with our results, we can assure that the
nifuratel 500 mg - 200,000 IU intravaginal nystatin combination continues to be
effective against bacterial vaginosis (BV) with low recurrence rates and no
adverse reactions; For this reason, we consider that this medicine could be the
replacement of traditional therapies [32,33]. The main strength of this
research consists of being the first study carried out in Colombia, in a
postmenopausal population, with the use of the combination nifuratel 500 mg -
nystatin 200,000 IU intravaginal, as well as the use of endorsed and easily
reproducible clinical criteria (criteria Amsel and Nugent score). Another
strength is the complete follow-up of all participants after 30 days. Among the
weaknesses is the small size of the sample, the fact that it was conducted in a
single institution, in addition to the weaknesses of a prospective cohort study
such as its cost.
The nifuratel-nystatin combination has a
significant effect in treating bacterial vaginosis in postmenopausal women,
being well tolerated and without adverse reactions; retaining itself as an
adequate treatment option, despite its age. Randomized controlled clinical trials
on the efficacy and safety of this combination are required in larger
populations in order to establish the eventuality of recurrence rates. Such
investigations must face the reality that conventional therapies offer
unsatisfactory results, due to high recurrence rates.
We thank Hathor, Clínica Sexologica, for
providing their computer equipment to conduct the statistical process; to Dr.
Adriana Patricia Camero Lascano, for her guidance and collaboration in the
development of this research
This research did not have the financing or
sponsorship of third parties, it is the result of the economic effort of the
author; resources obtained from midwifery shifts.