Abstract
Background:
Vulvovaginal candidiasis (VVC) is a prevalent form of vaginitis, and most patients show improvement when treated with antifungal medications. However, recurrence may affect a minority. It has been found through previous research that the concomitant utilisation of probiotics during acute VVC leads to early relief of symptoms and signs and offers a preventive measure against recurrences.
Objectives:
This study aimed to assess the efficacy of the combination of oral probiotics with conventional antifungal treatment as compared to conventional antifungal treatment alone.
Methods:
Sixty patients who were newly diagnosed with VVC were enrolled in a randomised controlled trial. They were divided into two groups. Group A included 30 cases treated with conventional antifungal medication (oral fluconazole 150 mg single dose), while Group B included 30 cases treated with conventional antifungal medication (oral fluconazole 150 mg single dose) alongside oral probiotic capsules (Lactobacillus rhamnosus, L. crispatus, L. gasseri, L. jensenii) for 2 months. The clinical and mycological findings were recorded before and after treatment. The relapse rate and side effects were recorded during the period of our study.
Results:
No significant difference between the clinical cure rate, mycological cure, and relapse rate was seen between the two groups. (P < 0.05). However, a larger proportion of patients in Group B (97%) achieved complete remission compared to Group A (90%). No side effects were noted in either of the groups.
Conclusion:
Based on the findings, it can be concluded that the addition of probiotics to conventional antifungal treatment led to better rates of clinical and mycological cure and a lower likelihood of relapse compared to conventional antifungal treatment alone.
KEY WORDS: Antifungals, probiotics, sexual health, vulvovaginal candidiasis
Introduction
Vulvovaginal candidiasis (VVC) is an infection caused by overgrowth of a yeast in vulva and vagina. It affects 75% of sexually active women in their life at least once and out of these, 40–50% approximately develop another episode, with 5% suffering recurrent vulvovaginal candidiasis (RVVC).[1,2] As a result, it has detrimental effects on one’s physical and emotional health, as well as their sexual and marital relationships.[3]
About 85–90% of candidal vaginitis is caused by C. albicans.[4] Other species in order of incidence include C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, and C. guiliermondii.[5] Factors like the use of broad-spectrum antibiotics, estrogen in hormonal replacement therapy, pregnancy, high dose estrogen (50 μg) in oral contraceptive pills (OCPs), douching, or the use of perfumed, feminine hygiene products, immunosuppressed patients, use of sponges and IUCDs, early onset of sexual activity causes the loss of normal microbial flora and facilitates opportunistic infection.[6,7]
VVC is diagnosed clinically by thick, white vaginal discharge, swelling, and redness of the vulva associated with itching, burning, and/or dysuria because of fissuring, with normal vaginal pH (<4.5). If left untreated, complications can occur, such as pelvic inflammatory disease, infertility, ectopic pregnancy, pelvic abscess, spontaneous abortion, and menstrual disorders. Therefore, prevention, early diagnosis, and prompt treatment of VVC, especially among risk groups, are essential to reduce such complications.[8]
Probiotics have been tested for their effectiveness in preventing and treating recurrent bacterial vaginosis (BV), particularly lactobacillus strains such as Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri.[9,10] The mechanism for administering oral lactobacilli to benefit vaginal health is supported by several studies which hypothesise that these bacteria can ascend from the rectum and perineal skin, similar to several pathogens to cause urogenital tract infections. Despite the growing trend of intravaginal probiotics, we selected oral probiotics as a more practical option, given their inclusion of Lactobacillus strains and ease of use.[11] Probiotics can recover and maintain the normal vaginal microbiota, and they also can resist the growth of Candidal organisms and other pathogenic bacteria.[6,7] Many studies have been conducted on probiotics, which are considered safe.[12] However, most of these studies had limitations, and the use of probiotics in the treatment of VVC remains controversial. Therefore, this study was conducted to assess the efficacy of probiotic lactobacilli in patients with VVC.
Materials and Methods
In central India, a hospital-based randomised open-label trial was conducted at a tertiary care hospital Lady Hardinge Medical College in the Department of Dermatology over a span of 16 months. The Institutional Ethics Committee granted ethical approval for the study. The clinical trial is registered with the clinical trial registry, India (CTRI/2021/02/031155). Before the study started, written informed consent was obtained from all patients.
Patient selection
The present study included 60 patients in the age range of 18–50 years who were newly diagnosed cases of VVC by clinical (cottage cheese-like vaginal discharge with minimal odour, pruritus, vaginal soreness, burning sensation, dyspareunia, dysuria) and positive microscopic findings or positive vaginal culture for candida. The exclusion criteria were:
Pregnant and lactating females
Recurrent vulvovaginal candidiasis (RVVC), defined as four or more episodes within the one-year period
Vaginal discharge other than those of candidiasis or mixed infection
Those taking any kind of treatment for VVC/probiotics within the last one month
Other pathologies (immunodeficiency, diabetes). A detailed history including predisposing factors, was taken.
Sample collection and processing
Vaginal discharge was collected on two sterile swab sticks during patient enrollment. One swab was smeared on two clean slides for KOH and Gram staining to exclude the diagnosis of bacterial vaginosis. The second swab was sent for culture on SDA culture tubes. Colonies from SDA agar were inoculated on CHROM agar for species identification.
Randomisation and treatment protocol
Patients were randomised as per the variable block size randomization (2 or 4) using computer generated randomization sequence by person not involved in the study. For allocation concealment, sealed opaque envelopes containing group codes were prepared. Envelopes were sequentially numbered and kept in order according to their serial number. The envelope was opened at the time of randomisation and the patient was allocated to the respected group. Randomisation technique into two groups: Group A comprising 30 cases receiving only conventional antifungal treatment (oral fluconazole 150 mg single dose) and Group B comprising 30 cases receiving conventional antifungal treatment (oral fluconazole 150 mg single dose) with oral probiotic capsules (containing L. crispatus 1 billion CFU, L. rhamnosus 1 billion CFU, L. gasseri 0.3 billion CFU, and L. jensenii 0.2 billion CFU): Two capsules daily for 2 weeks, after that one capsule weekly till 2 months. The patients were followed up at the end of 2,4 and 8 weeks. The patients were assessed again for the clinical signs and symptoms, and side-effects related to the drug and/or probiotic in all the visits. Microscopic examination and swab were sent at week 2 and were repeated at week 8 only if there was a recurrence of signs and symptoms. Lifestyle modifications, maintaining local hygiene, and avoiding synthetic underwear were other additional factors that were counselled to the patients to prevent recurrence at every follow-up.
Definition of variables used –
Clinical cure is complete resolution of signs and symptoms (itching, redness, vaginal soreness, dyspareunia, white curdy discharge) during the study period.
Mycological cure is negative findings in microscopy (no budding yeast cells or pseudo-hyphae) and culture (absence of yeast colonies).
Relapse rate defined as those in whom symptoms of VVC recur within 2 months of successful treatment.
Statistical analysis
SPSS software version 23 was used for study analysis. Continuous variables were expressed as mean +/−standard deviation according to the distribution of values and categorical variables were expressed as frequencies and percentages, and were analysed using the Chi-square test. All results were significant at a P value of < 0.05.
Results
Patients in both groups typically presented at an age of 30.33 ± 7.24 years. Most of the patients were married (78.3%) and sexually active (81.7%) [Table 1]. Majoirty of the participants in both the groups were multipara (65%), used vaginal washes (61.7%) and vaginal douches (43.3%). Most of the patients used the barrier method of contraception (58%), followed by IUCDs (31%) and OCPs (3.3%). Other findings included were early age at first intercourse (14%), engaging in receptive oro-genital sex (8.3%), and recent use of antibiotics (6.7%).
Table 1.
Baseline clinico-demographic characteristics of study groups
| Variables | Group | |||
|---|---|---|---|---|
|
| ||||
| A (n=30),% | B (n=30),% | |||
| Married | 25 | 83.3% | 22 | 73.3% |
| Sexually active | 28 | 86.7% | 23 | 76.7% |
| Multiparity | 19 | 63.3% | 20 | 66.7% |
| Contraceptive use | 14 | 43.3% | 18 | 60% |
| Barrier | 8 | 26.7% | 10 | 33.3% |
| IUD | 5 | 16.7% | 7 | 23.3% |
| OCP | 1 | 3.3% | 1 | 3.3% |
| Injectables | 0 | 0 | 0 | 0 |
| Use of vaginal washes | 19 | 63.3% | 18 | 60% |
| Vaginal douching | 13 | 43.3% | 13 | 43.3% |
| Receptive oro-genital sex | 1 | 3.3% | 4 | 13.3% |
The most frequently reported clinical complaints in both groups were itching and abnormal vaginal discharge, followed by dysuria and dyspareunia during their initial visit. On clinical evaluation, all the patients (100%) reported vulvovaginal itching. Curdy white discharge was observed in 25 patients (83.3%) in Group A and 28 patients (93.3%) in Group B. Additionally, vulval erythema was seen in 21 patients (70%) in Group A and 22 patients (73.3%) in Group B [Figure 1a and b].
Figure 1.
(a) Pre-treatment clinical picture of Group A (week 0). (b) Group A had persistent VVC signs at week 8
The initial mycological assessment (week 0), showed the presence of Candida in 13 patients (43.3%) and 15 patients (50%) in Groups A and B, respectively, using the KOH method. In Group A, Candidal species was isolated from 27 patients (90%) using the culture method, while in Group B, it was isolated from 29 patients (96.6%). The two groups did not show any statistical significance in chief complaints and mycological assessment before the treatment was administered [Table 2].
Table 2.
Clinical and mycological outcomes of study groups at baseline (week 0)
| Clinical assessment | Group A (%) (n=30) | Group B (%) (n=30) | P |
|---|---|---|---|
| Itching | 30 (100%) | 30 (10%) | − |
| Discharge | 25 (83.3%) | 28 (93.3%) | 0.424 |
| Vulval erythema | 21 (70%) | 22 (73.3%) | 0.774 |
| KOH | 13 (43.3%) | 15 (50% | 0.605 |
| Culture | 27 (90%) | 29 (96.6%) | 0.301 |
At the end of the study (week 8), 27 (90%) patients from Group A and 29 (96.7%) patients from Group B achieved clinical remission on regular follow-up. At the end of this 2-month assessment period, there were 3 (10%) patients in Group A and 1 (3.3%) patient in Group B who had a recurrence of clinical symptoms [Figure 2a and b]. Those patients who had a symptomatic relapse underwent mycological assessment. No fungal elements were seen in any of the samples. However Candida was isolated from one patient (3.3%) in group A and none from patients in group B. The evaluation of both groups showed no significant statistical significance in terms of clinical symptoms, signs, and mycological assessment (P > 0.05) [Table 3].
Figure 2.
(a) Pre-treatment clinical picture of Group B (week 0). (b) No signs of VVC were observed in Group B at week 8 follow-up
Table 3.
Clinical and mycological outcomes of relapsed study groups at the end of follow-up (week 8)
| Clinical assessment | Group A (%) (n=30) | Group B (%) (n=30) | P |
|---|---|---|---|
| Itching | 3 (10%) | 1 (3.3%) | 0.301 |
| Discharge | 3 (10%) | 1 (3.3%) | 0.161 |
| Vulval erythema | 3 (10%) | 1 (3.3%) | 0.301 |
| KOH | 1 (3.3%) | 0 | 0.505 |
| Culture | 1 (3.3%) | 0 | 0.505 |
No adverse effects were observed in either of the groups during the course of the study.
Discussion
With the concerns of RVVC and increased drug resistance among Candida sp., our study suggests that combining probiotic lactobacilli with oral fluconazole for 2 months enhances the effectiveness of VVC treatment, resulting in better clinical and mycological cure rates, although the difference between both the groups was not significant (P > 0.05).
The clinico-demographic data of patients in the two study groups were nearly identical at baseline visits. Certain factors were found to trigger the occurrence of VVC.
In this study, we found itching and vaginal discharge were the most common clinical symptoms, similar to previous studies. Early symptomatic relief was observed in patients of Group B, in contrast to Group A. In a study by Martinez et al.[13] the probiotic-treated group at the end of 28 days showed significantly less vaginal discharge and other symptoms (10.3% vs 34.6%). A similar conclusion was made in a study by Ehrström et al.[14]
All patients in Group B who received both conventional oral antifungal and probiotics achieved mycological cure by week 8, while a patient in Group A who only received conventional oral antifungal remained culture positive. Although probiotic supplementation therapy has a higher mycological cure rate than fluconazole alone, the difference is not statistically significant. In a study by Anukam et al.[10] on day 90, 21% of the patients who received probiotics showed yeast in culture compared to 57% of patients on placebo (P = 0.1490). The study suggested that probiotics did not impact the cure rate by day 7, but later on led to fewer vulvovaginitis recurrences. Martinez et al.[13] observed that after daily administration of probiotics at 4 weeks, the probiotic-treated group showed a decrease in yeast in culture as compared to the placebo-treated group. (10.3% vs 38.5%; P = 0.014).
No adverse events were reported by participants in either treatment group during the study. Similarly, Nouraei et al.[15] and Vujic et al.[16] noted no major side effects in both the treatment groups. While in the fluconazole and probiotic group studied by Martinez et al.,[13] two subjects mentioned increased appetite, one had a headache, and another reported loose stool, although it could not be concluded that these effects were directly caused by the probiotic.
At the end of the study, clinical remission was achieved by more than 90% of patients in both groups. Patients who had clinical relapses underwent a culture analysis, which identified one Candida-positive case in Group A and none in Group B. Despite this, no statistically significant difference was found during the assessment of both groups. In a study conducted by Pendharkar et al.,[17] women who received fluconazole and vaginal EcoVag® capsules had a higher 12-month cure rate compared to those who received fluconazole alone, but the difference was not significant, as in our study. Another similar study by Carriero et al.[18] where vaginal probiotic capsules were given daily for 6 consecutive days for 3 months. At 4 months, the relapse of VVC in the probiotic group was significantly lower than in the control group.
Thus the group who received a single dose of fluconazole with oral probiotics showed a marginally better rate of clinical and mycological cure and had fewer vaginal signs and symptoms, early remission of symptoms, and decrease relapse rate. Our study outcomes do not match the conclusions of most of the referenced studies, which exhibited statistical significance between the two groups. Differences between the results reported here and those of other studies may be attributed to the small sample size, use of vaginal Lactobacilli, and quality of probiotics. Therefore, comparative efficacy by head-to-head comparison of various probiotic preparations could not be determined. In our study, no anti-fungal sensitivity was tested hence we cannot comment on the resistance of Candida species to Fluconazole in our study as this will be a major determinant of both clinical and mycological cure.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
We would like to thank Mr. Lokesh Parashar for all the valuable technical support.
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