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Probiotics for the Treatment of Vulvovaginal Candidiasis
By Donald Brown, ND, Director of Natural Product Research Consultants, Seattle, WA. Dr. Brown is a consultant to the dietary supplement industry. He reports no relevant financial relationships to any of the probiotic strains discussed in this article.
Vulvovaginal candidiasis (VVC) is a common infection that afflicts an estimated 75% of sexually active women at least once in their life,1 and of these, approximately 50% will develop a second episode, with 5% suffering recurrent VVC (defined as four or more episodes within a 1-year period).2 A 2000 survey in the United States found that 6.5% and 8% of women older than 18 years reported one and four episodes of VVC during the 2 months and 1 year prior to the survey, respectively.3 VVC is the second most common cause of vaginal infections after bacterial vaginosis (BV). In a 1995 U.S. report, VVC diagnosis and treatment, together with lost productivity, resulted in an estimated cost of $1.8 billion.1
VVC is diagnosed by the presence of a thick, white vaginal discharge in association with vulvar itching, burning, and/or dysuria, in addition to normal vaginal pH (< 4.5), presence of hyphae, pseudohyphae, or budding yeasts visualized under optical microscopy in wet mount preparations with 10% potassium hydroxide, visualization of fungi constituents after Gram-staining the vaginal sample, and growth of the micro-organism in selective culture media.4,5 Even though treatment of VVC with a range of oral and intravaginal antifungal drugs is often effective, recurrence rates remain high. One issue related to recurrence is the finding that vaginitis induced by non-albicans species is clinically indistinguishable from that caused by Candida albicans, and these former species are often more resistant to standard drug treatment.6
Vaginal Microbiota and VVC
In a previous review article in this publication, an overview of the Lactobacilli species that dominate the vaginal mircoflora of healthy premenopausal women (principally dominated by Lactobacilli species, especially Lactobacillus crispatus, L. gasseri, L. jensenii, and L. iners) was provided.7 Also noted in that article was the fact that there appears to be an inverse correlation between the presence of H2O2-producing Lactobacilli spp and risk of BV. It is interesting to note that this has not been clearly established in women with VVC. One study found that Lactobacilli were the dominant vaginal microorganisms in 90% of 20 healthy premenopausal women and 96% of 24 premenopausal women with acute exacerbations of recurrent VVC.8 However, the vaginal microbiota was more commonly dominated by L. salivarius in healthy women while L. catenaforme was isolated more frequently in women with VVC. A study with 7,918 pregnant women found that VVC was associated either with normal vaginal microbiota (predominance of Lactobacilli) or a decrease in Lactobacilli.9 Other studies have suggested that pregnant10 or post-term women11 whose vaginas were colonized with H2O2-producing Lactobacilli were less likely to have symptomatic VVC than those colonized with Lactobacilli spp that did not produce H2O2.
Probiotics for the Prevention and Treatment of VVC
A survey published in 2003 reported on 1117 women, ages 18-70 years, with self-reported VVC, found that Lactobacillus supplements were used by 40% and 43% of these women for prevention and treatment of post-antibiotic VVC, respectively.12 The published clinical data to date have focused primarily on the use of probiotics for the prevention of VVC following antibiotics or in at-risk groups (e.g., HIV-positive) and women with a history of recurrent VVC. While this review will be more selective and focus primarily on two studies (one prevention and the other treatment), readers may want to review a meta-analysis published in 2006 by Falaga et al that focuses on prevention of recurrent VVC with probiotics.13 The studies reviewed were published from 1992 to 2004 and include intravaginal and oral (including yogurt) administration of probiotics. The review suffers somewhat by the inclusion of studies that combine women with recurrent VVC and those with other types of recurrent urogenital infections. The authors conclude that many of the relevant studies have methodological problems (e.g., small sample size, no control group) and that the evidence for probiotics in prevention of recurrent VVC is limited. However, they add, "the empirical use of probiotics may be considered in women with frequent recurrence of VVC (more than three episodes per year), especially for those who have had adverse effects from or contraindications for the use of antifungal agents, since adverse effects of probiotics are very rare."
Prevention of VVC in HIV-Positive Women
A three-arm, multicenter, randomized, double-blind, placebo-controlled trial compared the ability of intra-vaginal L. acidophilus and clotrimazole to prevent VVC in HIV-positive women.14 The study enrolled 164 women (ages 25-59 years old) who were HIV seropositive that were not pregnant or taking any antifungal medications. Subjects were randomized to one of three groups: 1) intravaginal L. acidophilus (2 x 109 cfu; Gynatren, Natren, Inc.); 2) clotrimazole powder (100 mg); or 3) placebo powder. Both active treatments were supplied in refrigerated capsules and women were instructed to insert one capsule vaginally once per week for 21 months.
During the 21 months of the study, 34 cases of VVC were diagnosed clinically and microbiologically. Compared to the control group, the relative risk for developing VVC was 0.54 (95% confidence interval [CI], 0.26 to 1.13) for the probiotic group and 0.49 (95% CI, 0.22 to 1.09) for the clotrimazole group. The estimated median time to first episode VVC was longer for clotrimazole group (P = 0.03, log rank test) and the probiotic group (P = 0.09, log rank test) compared with the placebo group.
A detailed analysis of this study questions the significance of the clinical effect found for both treatment groups in the study.15 They also criticize the study design for not confirming the presence of viable Lactobacilli spp in the vaginas of women in the probiotic group to confirm compliance, proper storage, and viability.
Adjunctive Use of Probiotics in Treatment of VVC
In a randomized, double-blind, placebo-controlled trial, 55 women (16-46 years old) with VVC were treated with a single dose of oral fluconazole (150 mg) and then randomized to receive either two capsules containing L. rhamnosus GR-1 and L. reuteri RC-14 (each capsule contained 1 x 109 cfu of each probiotic strain; Chr. Hansen, Horsholm, Denmark) or placebo orally in the morning for 28 days starting on the day of fluconazole use.16
At 4 weeks, the probiotic group exhibited cure of VVC as determined by having no vaginal discharge, itching and/or burning, dyspareunia and/or dysuria, and negative culture (P < 0.05). The probiotic treated group showed significantly less vaginal discharge (10.3% vs 34.6%; P = 0.03) and lower presence of yeast detected by culture (10.3% vs 38.5%; P = 0.014) compared with the placebo group. No significant adverse events were reported in either group.
Albert Döderlein first described the role of "bacillus" in the health of the female genitourinary tract in 1892. Long referred to as "Döderlein bacillus," we now know that the healthy vaginal flora is made up primarily of members of the Lactobacillus family. However, as opposed to the role of healthy vaginal flora in reducing the risk of BV, their role in the prevention of VVC is less clear.
The data on the use of probiotics for the prevention of VVC to date are equivocal; larger and better-designed clinical trials with established probiotic strains are needed to more clearly assess the potential efficacy of probiotics in women with recurrent VVC.
Although there is only the one published clinical trial to date that was reviewed above, the oral probiotic combination of L. rhamnosus GR-1 and L. reuteri RC-14 appears to be an interesting candidate for future clinical trials in women with VVC. As was the case with two trials in women with BV, the use of this combination appears to improve treatment outcomes in women taking standard antimicrobial therapy. Future studies should also follow women for a longer period of time to determine whether this probiotic therapy may also reduce recurrence rates.
Women being treated for VVC with antimicrobial therapy should be informed about the potential benefits of adjunctive use of probiotics to help improve treatment outcomes and to re-establish healthy vaginal flora. Women interested in using probiotics for the prevention of VVC recurrences should be counseled about the equivocal clinical data to date. Despite these shortcomings and questions, the use of probiotics seems a low-risk, practical consideration for this patient population.
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