Recurrent Infectious Vaginitis: A Practical Approach for the Primary Care Clinician.

Recurrent infectious vaginitis can lead to significant morbidity, patient frustration, and health care costs. The most common causes are bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC); however, other infectious and noninfectious etiologies should be considered in patients with recurrent symptoms. A detailed history and physical examination with appropriate testing at the time of symptoms is critical to establishing a correct diagnosis. Management options for recurrent BV and VVC are limited. Complex cases including those with atypical symptoms, negative testing for common causes, refractory symptoms despite appropriate therapy or recurrences during suppressive therapy will require referral to specialist care.

Bacterial Vaginosis and Vulvovaginal Candidiasis Pathophysiologic Interrelationship.

Among the infectious causes of vulvovaginal symptoms, bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) dominate. Apart from infrequent mixed infections, both are considered independent and caused by unrelated pathogenic mechanisms. Clinical experience, however, is strongly suggestive that in some populations these infections are linked with recurrent BV (RBV) serving as the dominant etiopathogenic trigger for development of recurrent VVC (RVVC) with profound clinical and therapeutic consequences. The biologic basis for this critical interrelationship is discussed and suggests that as a consequence of BV dysbiosis, and not necessarily because of antibiotics prescribed, immune defenses are compromised, neutralizing vaginal yeast tolerance. The consequent BV-induced vaginal proinflammatory environment predisposes to mixed infection or consecutive episodes of post-treatment VVC. Recurrent BV and repeated antimicrobial drug exposure also predispose to acquired fluconazole resistance in C. albicans isolates, contributing to refractory vulvovaginal candidiasis.

Understanding and Preventing Recurring Bacterial Vaginosis: Important Considerations for Clinicians.

Bacterial vaginosis (BV) is the most common vaginal infection worldwide. It is associated with an increased risk of acquisition of HIV and other sexually transmitted infections (STIs) as well as pelvic inflammatory disease and adverse birth outcomes. During BV, a polymicrobial biofilm forms on the surface of the vaginal mucosa. However, the exact etiology of BV remains controversial which has impeded significant advances in diagnosis, treatment, and prevention. Despite 30-day cure rates approaching 80% in BV-infected women treated with 7 days of oral metronidazole, recurrence within 12 months is common. This article provides a current review of the epidemiology, pathogenesis, diagnosis, and treatment of recurrent BV for practicing clinicians who commonly see women with this recurrent vaginal infection. Regarding management, we focus primarily on antimicrobial measures that may be effective. Future areas of research in this field are also discussed.

State of the Art for Diagnosis of Bacterial Vaginosis.

Bacterial vaginosis (BV) is the most common cause of vaginal discharge among reproductive-age women. It is associated with multiple adverse health outcomes, including increased risk of acquisition of HIV and other sexually transmitted infections (STIs), in addition to adverse birth outcomes. While it is known that BV is a vaginal dysbiosis characterized by a shift in the vaginal microbiota from protective Lactobacillus species to an increase in facultative and strict anaerobic bacteria, its exact etiology remains unknown. The purpose of this minireview is to provide an updated overview of the range of tests currently used for the diagnosis of BV in both clinical and research settings. This article is divided into two primary sections: traditional BV diagnostics and molecular diagnostics. Molecular diagnostic assays, particularly 16S rRNA gene sequencing, shotgun metagenomic sequencing, and fluorescence in situ hybridization (FISH), are specifically highlighted, in addition to multiplex nucleic acid amplification tests (NAATs), given their increasing use in clinical practice (NAATs) and research studies (16S rRNA gene sequencing, shotgun metagenomic sequencing, and FISH) regarding the vaginal microbiota and BV pathogenesis. We also provide a discussion of the strengths and weaknesses of current BV diagnostic tests and discuss future challenges in this field of research.

A longitudinal study on fluconazole resistance in Candida albicans vaginal isolates.

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC), despite its worldwide prevalence, has limited treatment options; and a long-term prophylactic regimen utilising fluconazole is the dominant choice. OBJECTIVES: An increase in fluconazole resistance is reported, and little information is available about the reversibility of resistance status following the withdrawal of fluconazole. METHODS: Repeated antifungal susceptibility tests (ASTs) for fluconazole at a median interval of 3 months between them were evaluated in women with refractory or recurrent VVC patients at the Vaginitis clinic from 2012 to 2021 (10 years) and performed at pH 7 and pH 4.5 using the broth microdilution tests based on the CLSI M27-A4 reference method. RESULTS: Of 38 patients with long-term follow-up with repeat ASTs, 13 patients (13/38, 34.2%) tested at pH 7.0 remained susceptible to fluconazole with MIC ≤2 µg/mL. Nineteen patients (19/38, 50%) remained resistant to fluconazole with MIC ≥8 µg/mL, whereas four (4/38, 10.5%) changed from susceptible to resistant and two (2/38, 5.2%) changed from resistant to susceptible over time. At pH 4.5, among the 37 patients with repeated MIC values, nine (9/37, 24.3%) remained susceptible to fluconazole and 22 (22/37, 59.5%) remained resistant. Three isolates (3/37, 8.1%) changed from susceptible to resistant, while 3 (3/37, 8.1%) changed from resistant to susceptible over time. CONCLUSION: Fluconazole susceptibility in Candida albicans vaginal isolates obtained longitudinally in women with RVVC remains stable with rare reversal of resistance despite azole avoidance.

New Antifungals for Vulvovaginal Candidiasis: What Is Their Role?

New antifungals, ibrexafungerp and oteseconazole, are now available for treatment of vulvovaginal candidiasis. Both have novel antimicrobial and pharmacokinetic properties and advantages over fluconazole, although comparative trials have involved only placebo. In the absence of allergy, intolerance, and resistance, it is unclear whether these antifungals will replace fluconazole.

Vaginal Candida albicans: High Frequency of in Vitro Fluconazole Resistance in a Select Population-A Brief Note.

Among clinician-ordered vaginal cultures positive for Candida albicans , 30% exhibited fluconazole resistance. Resistance did not reliably predict future susceptibility. Prospective studies to verify associations with demographic and clinical factors as well as to correlate in vitro resistance with treatment response and longitudinal resistance patterns are needed.

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.

Association of key species of vaginal bacteria of recurrent bacterial vaginosis patients before and after oral metronidazole therapy with short- and long-term clinical outcomes.

Bacterial vaginosis (BV) is associated with a state of vaginal dysbiosis typically involving depletion of otherwise dominant populations of Lactobacillus. The causes of this microbial succession are not known; there may be multiple causes. Standard treatment includes oral metronidazole, which typically restores Lactobacillus species to dominance. However, recurrence rates are high; recurrent BV patients recur 3-4 times annually and are often refractory to treatment. Our previous qPCR-based study of recurrent BV patients pointed to putatively more virulent species of Gardnerella that were associated with refractory responses to oral metronidazole, and less robust recovery of Lactobacillus species associated with recurrence after an initial period of remission. However, these associations did not account for outcomes in all patients, suggesting that other bacterial species were involved. In this follow-up study, we sequenced the V4 domain of 16S rRNA sequences of 41of these same patients pre- and posttreatment. Overall compositions among pretreatment clinical outcome groups were not different, although alpha diversity significantly decreased: refractory > recurrent > remission. Combinations of key species were associated with and prognostic for outcome. Higher pretreatment abundance of Megasphaera lornae together with lower abundance of Gardnerella Gsp07 and Finegoldia magna predicted long term remission after oral metronidazole. Furthermore, a subset of refractory patients that did not have high levels of Gardnerella Gsp07, instead had elevated levels of alternative species including Atopobium vaginae, Mageeibacillus indolicus (BVAB3), and Prevotella timonensis. Patients who recurred after transient remission had elevated abundance of species including Atopobium vaginae, Gardnerella, and Aerococcus christensenii, compared to long-term remission patients. Core bacterial species among refractory patients did not change in abundance after metronidazole, suggesting resistance or tolerance, in contrast to the loss in abundance of the same species among recurrent or remission patients. These findings have potential prognostic and therapeutic implications.

Clue Cells and Pseudo Clue Cells in Different Morphotypes of Bacterial Vaginosis.

Introduction: Clue cells (epithelial cells heavily covered with adherent bacteria) are an accepted clue to the diagnosis of bacterial vaginosis. However, the exact morphologic criteria of clue cells and bacterial adherence were never elaborated. Materials and Methods: We investigated adhesive and cohesive patterns of main microbiota groups in vaginal discharge using fluorescence in situ hybridization (FISH). Samples from 500 women diagnosed with bacterial vaginosis and positive for clue cells with classic microscopy were collected from 42 gynecologic practices in Berlin and reexamined in our FISH laboratory for the spatial distribution of Bifidobacteriaceae, Gardnerella, Fannyhessea vaginae (Atopobium); low G+C (guanine+cytosine) bacteria, lactobacilli, Lactobacillus iners; Lactobacillus crispatus, Gamma-Proteobacteria; and Enterobacteriaceae, Prevotella-Bacteroides, Veillonella, and Coriobacterium groups. Results: Bacterial taxa present in vaginal smears were not accidentally assembled according to their relative abundance but were built in group-specific distribution patterns, which can be well described by two features: cohesiveness to each other and adherence to epithelial cells. Accordingly, four patterns can be distinguished: dispersed (non-adherent bacteria), dispersed adherent bacteria, cohesive (non-adherent) bacteria, and cohesive adherent bacteria. Direct cohesive adherence to the epithelial cells representing true clue cells was unique for Gardnerella species and observed only in 56% of the investigated samples. In the remaining vaginal samples, the epithelial cells were mechanically entrapped in bacterial masses, and the composition was unrelated to the epithelial cell surface, building non-adherent pseudo clue cells. The proportion of women with true clue cells in their samples from different gynecologic practices varied from 19% to 80%. Discussion: Taxon indifferent imaging is inadequate for the exact analysis of the microbial layer adjacent to the vaginal epithelial cells. Morphologically seen bacterial vaginosis is a mix of at least two different conditions: biofilm vaginosis and bacterial excess vaginosis.

Determining Susceptibility in Candida Vaginal Isolates.

Antifungal drug susceptibility tests (AST) for Candida albicans are increasingly demanded for women with refractory or recurrent Candida vaginitis due to fluconazole resistance. Given reduced activity of azole drugs at pH levels found in women with Candida vaginitis, it is proposed that AST be performed at pH 4.5, since testing at only the recommended pH 7.0 is likely to miss a significant number of clinically relevant azole-resistant C. albicans vaginal isolates.

Ibrexafungerp for the treatment of vulvovaginal candidiasis.

Worldwide, effective management of vulvovaginal candidiasis (VVC) continues to serve as a major therapeutic goal with numerous unmet drug treatment challenges. After 3 decades of azole drug dominance, with few recent new antifungal agents and little progress in VVC management, the first-in-class oral triterpenoid glucan synthase inhibitor agent ibrexafungerp has emerged in the treatment of acute VVC. After reviewing existing treatment standards and unmet needs, the pharmacology, pharmacokinetics, antimicrobial activity and clinical efficacy of ibrexafungerp are reviewed in this article together with phase III clinical trial results and drug safety. The projected role and status of ibrexafungerp are reviewed together with perspectives of its future development and role in the treatment of VVC.

Vulvovaginal Candidiasis: A Review of the Evidence for the 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections Treatment Guidelines.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a common cause of vulvovaginal itching and discharge. This article discusses the latest CDC STI Treatment Guidelines for VVC. METHODS: A literature search of relevant topics was performed, and a team of experts was convened to discuss (1) diagnosis/testing modalities; treatment of (2) uncomplicated VVC , (3) complicated VVC, and (4) VVC caused by non-albicans yeast; (5) alternative treatment regimens; (6) susceptibility testing of yeast; Special Populations: (7) pregnancy and (8) HIV and VVC. RESULTS: Yeast culture remains the gold standard for diagnoses. Newer molecular assays have been developed for the diagnosis of VVC and perform well. Azole antifungals remain the treatment of choice for uncomplicated VVC. Two new drugs, TOL-463 and recently FDA-approved ibrexafungerp, appeared promising in clinical trials. For recurrent VVC, oteseconazole, not yet commercially available, may represent a new option. For non-albicans yeast infections in symptomatic patients, boric acid appears useful. No evidence supports the use of alternative treatments, including probiotics. Fluconazole during pregnancy may be associated with spontaneous abortion and craniofacial and heart defects. In women with HIV infection, lower CD4+ T-cell counts are associated with increased rates of VVC, and VVC is associated with increased viral shedding. Treatment measures in women with HIV infection are identical to those women without HIV infection. CONCLUSIONS: There has been significant new knowledge generated about VVC since the 2015 CDC Guidelines which have led to changing recommendations.

Diagnosis and Management of Bacterial Vaginosis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines.

In preparation for the 2021 Centers for Disease Control and Prevention (CDC) sexually transmitted infections (STIs) treatment guidelines, the CDC convened an advisory group in 2019 to examine recent literature addressing updates in the epidemiology, diagnosis, and management of STIs. This article summarizes recent data in each of these key topic areas as they pertain to bacterial vaginosis (BV), the most common cause of vaginal discharge. The evidence reviewed primarily focused on updates in the global epidemiology of BV, risk factors for BV, data supportive of sexual transmission of BV-associated bacteria, BV molecular diagnostic tests, and novel treatment regimens. Additionally, recent literature on alcohol abstinence in the setting of 5-nitroimidazole use was reviewed.

Vulvovaginal candidiasis: An overview of mycological, clinical, and immunological aspects.

AIM: To provide an overview of clinical, immunological, and mycological aspects of vulvovaginal candidiasis (VVC). METHODS: A literature search was conducted to find relevant articles about different aspects of VVC. Related data from retrieved articles were summarized in different headings. RESULTS: VVC has a global distribution and Candida albicans is the leading cause of infection except for specific patient groups like postmenopausal, diabetic, or immunocompromised women. VVC has a range of clinical presentations, accordingly, its diagnosis should be based on clinical examination coupled with laboratory investigations. The best therapeutic regimen depends on the patient's conditions and the causative agent. Moreover, factors like drug resistance of the causative agents and different mutations in the immunity-related genes could affect the treatment outcome. CONCLUSION: As a globally distributed disease, VVC needs further attention, especially in areas related to the treatment failure and recurrence of the disease.

The Role of Antimicrobial Resistance in Refractory and Recurrent Bacterial Vaginosis and Current Recommendations for Treatment.

Bacterial vaginosis (BV), the most common cause of vaginal discharge, is characterized by a shift in the vaginal microbiota from Lactobacillus species dominance to a diverse array of facultative and strict anaerobic bacteria which form a multi-species biofilm on vaginal epithelial cells. The rate of BV recurrence after therapy is high, often >60%. The BV biofilm itself likely contributes to recurrent and refractory disease after treatment by reducing antimicrobial penetration. However, antimicrobial resistance in BV-associated bacteria, including those both within the biofilm and the vaginal canal, may be the result of independent, unrelated bacterial properties. In the absence of new, more potent antimicrobial agents to eradicate drug-resistant pathogenic vaginal microbiota, treatment advances in refractory and recurrent BV have employed new strategies incorporating combination therapy. Such strategies include the use of combination antimicrobial regimens as well as alternative approaches such as probiotics and vaginal fluid transfer. Our current recommendations for the treatment of refractory and recurrent BV are provided.

Antimicrobial Susceptibility of Microbiota in Bacterial Vaginosis Using Fluorescence In Situ Hybridization.

BACKGROUND: Testing of antibiotic resistance of intact vaginal microbiota in pure culture is not feasible. METHODS: Metronidazole, antiseptic octenisept®, antimycotic ciclopirox, bacterial probiotic Lactobacillus crispatus, yeast probiotic Saccharomyces boulardii, Gardnerella-phage-endolysin named phagolysin and phagolysin in combination with probiotics were tested for bacteriolytic activity. Included were vaginal swabs from 38 random women with Amsel-confirmed bacterial vaginosis (BV). Test aliquots were incubated by 37° for 2 and 24 h. Gardnerella, low G+C, Atopobium, lactobacilli, Lactobacillus iners and crispatus, Prevotella-Bacteroides, and Gammaproteobacteria microbial groups were quantified using fluorescence in situ hybridization (FISH). RESULTS: The probiotic strain Lactobacillus crispatus demonstrated the weakest bacteriolytical effects, followed by metronidazole. Both had no impact on Gardnerella species, instead lysing Prevotella-Bacteroides, Enterobacteriaceae (by L.crispatus) or LGC, Atopobium and Prevotella-Bacteroides (by metronidazole) groups of the microbiota. Cytolytic activity on Gardnerella was highly pronounced and increased from octenisept to ciclopirox, phagolysin, phagolysin with L.crispatus, being best in the combination of phagolysin with S.boulardii. Universally active ciclopirox and octenisept® suppressed nearly all microbial groups including those which are regarded as beneficial. Phagolysin had no effect on naturally occurring Lactobacillus crispatus. Conclusions: FISH susceptibility testing allows unique efficacy evaluation of individually adjusted topical therapy without microbial isolation facilitating optimal therapy choice.

Lower Genital Tract Microbiome-A Work in Progress.

ABSTRACT: The lower genital tract microbiome is composed of millions upon millions of microbes colonizing this unique anatomical niche reflecting the influence of genetic, biologic, and behavioral factors. Over the last decade, as a result of ever advancing technology and research investment, our knowledge of this complex microbiome ecosystem has grown enormously. All too often such progress remains invisible to practitioners. In this special issue, clinical scientists, in a unique contribution, have bridged the ever-increasing distance between vaginal microbiota science and clinical disease. Approaching a myriad of pathologic entities, authors describe the clinical application of recent molecular laboratory findings encouraging diagnostic, prognostic, and therapeutic advances. Nevertheless, challenges are recognized and the authors outline vulvovaginal disease management opportunities. Above all, exposing the dynamism of vaginal microbiota affords a better understanding of pathogenesis of lower genital tract disease.