Vulvovaginal Candidiasis (VVC)

Overview

Vulvovaginal candidiasis (VVC) is a highly prevalent fungal infection predominantly caused by Candida albicans and occasionally by non-albicans species such as C. glabrata and C. krusei. It affects approximately 70-75% of women at least once in their lifetime, with 5-8% experiencing recurrent vulvovaginal candidosis (RVVC), defined as four or more symptomatic episodes per year.^[1] The disease manifests as an acute inflammatory condition of the vulva and vaginal mucosa, characterized by itching, burning, redness, and abnormal vaginal discharge. The pathogenesis is multifactorial, involving complex interactions among the Candida species’ virulence factors, host immune responses, estrogenic environment, and vaginal microbiome, primarily Lactobacilli.^[2] Candida’s ability to switch between yeast and hyphal forms, form biofilms, and secrete toxins such as candidalysin contributes to infection persistence and symptom severity. Diagnosis remains challenging due to the presence of Candida as a commensal in many asymptomatic women.^[3] Treatment mainly relies on azole antifungals, though increasing azole resistance, especially among non-albicans species, complicates management.^[4][5] Long-term maintenance antifungal regimens are often necessary for RVVC but are associated with risks of resistance and relapse. Patient quality of life is significantly affected due to physical discomfort, psychological burden, and impaired sexual health. Advancing diagnostic accuracy, understanding microbiome-host interactions, and developing novel therapeutics are critical needs for improving clinical outcomes.

Associated Conditions

RVVC is linked with several associated conditions that modulate susceptibility and severity. High estrogen states such as pregnancy, use of oral contraceptives, and hormone replacement therapy increase the risk by altering vaginal immunity and microbiome balance.^[6] Diabetes mellitus and immunosuppressive states, including HIV infection, also predispose women to frequent recurrences.^[7][8] Antibiotic usage disrupts the protective Lactobacillus-dominant vaginal microbiota, facilitating Candida overgrowth.^[9] Behavioral factors such as frequent sexual intercourse, use of poorly ventilated clothing, and atopic diseases may contribute to susceptibility. Genetic polymorphisms affecting innate immune signaling pathways have been implicated in impaired fungal clearance and enhanced inflammation. These factors, individually or in combination, create a permissive environment for Candida pathogenicity and chronic infection.

Causal Theories

The etiology of VVC remains incompletely understood and is recognized as multifactorial. The primary causal theory revolves around an imbalance between Candida virulence mechanisms and host immune defenses. Candida albicans employs a polymorphic lifestyle, switching from benign yeast to invasive hyphal forms, secreting enzymes and candidalysin that promote tissue invasion and inflammation. Biofilm formation further shields Candida from antifungal agents.^[10] Host factors impair fungal clearance, including estrogen-driven changes, neutrophil dysfunction, and genetic variants in pattern recognition receptors. The vaginal microbiome, particularly Lactobacilli, usually suppresses Candida growth; disruptions to this ecosystem via antibiotics or other factors remove this inhibition.^[11] Limitations in current causal theories include insufficient understanding of the triggers converting asymptomatic colonization into symptomatic infection and the role of non-cultivable fungal species. Novel hypotheses suggest that immunological hypersensitivity to Candida antigens may drive symptoms independent of fungal load, highlighting the complexity of RVVC pathogenesis.^[12]

Theory	Description
Candida Virulence & Morphogenesis	Candida’s morphological switching and virulence factor secretion lead to tissue damage
Host Immune Dysfunction	Genetic and functional immune defects impair fungal clearance
Microbiome Dysbiosis	Disruption of Lactobacillus-dominated vaginal flora facilitates Candida overgrowth
Hypersensitivity Response	Exaggerated inflammatory reaction to Candida antigens causes symptoms

Diagnosis

Accurate diagnosis of VVC requires confirmation of Candida presence combined with clinical symptoms. Conventional diagnosis relies on clinical examination, microscopy to detect pseudohyphae or blastospores, and culture to identify Candida species.^[13] However, microscopy sensitivity ranges from 50-80%, and culture may be slow or inconclusive. Molecular methods such as PCR enhance detection sensitivity and can identify mixed or resistant strains, but are not widely accessible.^[14] Identification of Candida species is crucial, as non-albicans species often exhibit reduced susceptibility to azoles. Antifungal susceptibility testing is recommended in refractory cases.^[15] Emerging research into microbiome and metabolomic signatures holds promise for non-invasive diagnostics that distinguish colonization from infection and identify treatment-resistant profiles.^[16] Nonetheless, lack of point-of-care rapid testing and inconsistent guideline adherence contribute to delayed or inappropriate treatment, underscoring the need for improved diagnostics integrating microbiome insights.

Primer

VVC cannot be fully understood without considering its relationship with the vaginal microbiome, where beneficial bacteria such as Lactobacillus species maintain an acidic environment that suppresses fungal overgrowth. Beyond microbial interactions, the vaginal environment’s metal content plays a vital role. Essential metals like zinc and copper are tightly controlled by the host through nutritional immunity mechanisms to restrict fungal growth. Meanwhile, Candida has evolved strategies to acquire these metals despite host defenses. This dynamic interplay between the host’s immune system, resident microbes, and metal availability forms a complex network that shapes the course of VVC and offers new directions for diagnosis and treatment.

Metallomic Signatures

The metallomic signature of VVC reflects how Candida albicans interacts with and adapts to metal stress in the host environment. Research shows that C. albicans can tolerate and even sequester high concentrations of toxic metals like chromium, lead, and zinc, using biosorption mechanisms involving its cell wall.[17]^[x] These adaptations not only enhance its survival in hostile environments but may also reinforce its biofilm structure and resistance to antifungal agents. Additionally, differential sensitivity to metals like cadmium and mercury indicates the presence of complex detoxification and efflux pathways, which may overlap with drug resistance mechanisms. From a therapeutic perspective, disrupting Candida’s metal homeostasis, or exploiting its biosorptive capacity, could offer novel treatment strategies, particularly in drug-resistant or recurrent VVC cases. This metallomic insight expands our understanding of the infection beyond microbiome shifts, adding a crucial chemical-ecological layer to host-pathogen interactions.

What is the Metallomic Signature of Vulvovaginal candidiasis?

Zinc (Zn

Zinc is a vital micronutrient that Candida albicans requires for enzymatic functions and virulence.^[18] The host restricts zinc availability through sequestration proteins like calprotectin, which bind zinc to limit fungal growth.^[19] In response, C. albicans expresses zinc scavenging proteins such as PRA1 and the high-affinity transporter ZRT1 to overcome this metal limitation.^[20]

Copper (Cu)

Copper serves dual roles as an essential cofactor and a potential toxin. The host limits copper access to Candida by sequestration, forcing the fungus to adapt by downregulating copper-dependent enzymes like SOD1 and upregulating manganese-dependent alternatives such as SOD3.^[21] Copper also exhibits antimicrobial properties that disrupt fungal respiration and ATP production.^[22]

Lead (Pb)

Lead is a toxic heavy metal to which Candida albicans shows biosorption ability.[23]^[x] Although not essential for fungal growth, lead exposure influences fungal physiology and may affect biofilm formation. The full role of lead in VVC pathogenesis requires further study.

Mercury (Hg) and Silver (Ag)

Both mercury and silver possess potent antifungal effects by inhibiting cellular respiration and enzymatic activity in Candida.^[24][25]^[x] Silver ions, in particular, demonstrate significant antifungal potential and are explored as topical treatments for resistant infections. Candida’s resistance to these metals is limited, highlighting their promise as adjunctive therapies.

Nutritional Immunity

Nutritional immunity is a key host defense mechanism in VVC, where the body restricts access to essential metals like zinc and copper to limit the growth and virulence of Candida albicans. During infection, immune cells such as neutrophils release calprotectin, a protein that tightly binds these metals, effectively starving the fungus of nutrients it needs to survive.^[26] In response, C. albicans activates specialized metal-scavenging systems, including the zinc-binding protein PRA1 and transporter ZRT1, and shifts its antioxidant defenses to rely on manganese when copper is unavailable.^[27] This ongoing struggle between host and pathogen, essentially a biochemical tug-of-war over micronutrients, plays a critical role in infection severity and persistence. When the vaginal microbiota, particularly protective Lactobacillus species, is disrupted, this defense can weaken, giving Candida a competitive edge.^[28] Understanding nutritional immunity not only sheds light on the pathogenesis of VVC but also suggests new therapeutic directions, including strategies that enhance host metal-binding defenses or target fungal nutrient acquisition systems.

Microbiome Signature: Vulvovaginal Candidiasis (VVC)

Interventions

Our validation method evaluates the efficacy of microbiome-targeted interventions for VVC by correlating their influence on vaginal microbial balance, clinical symptom resolution, and the modulation of pathogenic mechanisms such as Candida overgrowth and biofilm formation. This approach distinguishes interventions that are validated, promising, or experimental based on the strength of evidence connecting changes in the vaginal microbiome with clinical improvement and relevant microbiological signatures.

Intervention	Classification	Mechanism of Action	MBTI Status
Probiotics	Supplement	Replenish beneficial vaginal microbiota, competitively inhibit Candida, acidify vaginal pH, produce antifungal compounds and immunomodulate host response.^[29][30]	Validated
Postbiotics	Supplement	Bioactive compounds released by probiotics, such as bacteriocins, SCFAs, and enzymes that inhibit pathogen growth and modulate inflammation.[31]^[x]	Promising Candidate
Prebiotics/Synbiotics	Supplement	Selectively enhance growth of beneficial microbes, thus indirectly suppressing Candida overgrowth; synbiotics combine prebiotics and probiotics.^[32][33]^[x]	Promising Candidate
Vaginal Microbiome Transplantation (VMT)	Microbiota-based therapy	Transplant healthy donor vaginal microbiota to restore eubiosis and Lactobacillus dominance, reversing dysbiosis linked to VVC.[34]^[x]	Promising Candidate
Short chain fatty acid supplements	Supplement	Modulate vaginal pH, inhibit Candida growth and virulence, support mucosal immunity.[35]^[x]^[36]	Under investigation
Lactoferrin	Supplement	Chelates iron and other metals, impairs Candida growth, modulates inflammation, supports mucosal immunity.^[37][38]	Promising candidate
Dietary Supplementation to maintain optimal calprotectin responses	Diet	Calciprotein binds and withholds essential metals (Zn, Cu), induces nutritional immunity, inhibits Candida growth and virulence gene expression.^[39]	Experimental
Boric acid	Pharmaceutical	Disrupts Candida cell wall integrity, inhibits biofilm formation, restores vaginal acidity, effective against non-albicans and azole-resistant Candida species.^[40]	Validated

FAQs

How does the vaginal microbiome influence susceptibility to recurrent VVC (RVVC)?

The vaginal microbiome is crucial in determining whether a woman will experience recurrent vulvovaginal candidiasis (RVVC). A healthy microbiome, dominated by Lactobacillus species, produces lactic acid, which helps maintain an acidic vaginal pH of around 4.5, an environment that inhibits Candida overgrowth. In women with RVVC, the vaginal microbiome often shows a reduced abundance of Lactobacillus species, with an overgrowth of other bacteria or fungi, allowing Candida to thrive. Additionally, factors like immune system dysfunction, such as neutrophil dysfunction, can impair the body’s ability to clear Candida effectively. Disruption of the microbiome can also lead to biofilm formation by Candida, which further shields the pathogen from antifungal treatments and immune responses, leading to persistent or recurrent infections. This imbalance in the vaginal microbiome plays a pivotal role in the recurrence of VVC, making its restoration through probiotics and other therapies a promising strategy for preventing RVVC.

Why do some women experience recurrent vulvovaginal candidiasis (RVVC), while others only have one episode?

Recurrent vulvovaginal candidiasis (RVVC) occurs in women who experience multiple episodes of VVC, typically four or more within a year. The key difference between women with RVVC and those with a single episode is often the underlying imbalance in the vaginal microbiome and the immune system. Women with RVVC commonly have a decreased abundance of Lactobacillus species, which leads to a higher pH environment and greater availability of nutrients for Candida growth. Additionally, women with RVVC may have an impaired immune response, with neutrophil dysfunction or genetic predispositions that prevent effective clearance of the yeast. The presence of biofilms, where Candida adheres to vaginal tissues and forms a protective matrix, is another factor contributing to recurrence. Biofilms make Candida more resistant to antifungal treatments and immune responses, leading to chronic infection. Hormonal changes, diabetes, antibiotic use, and stress can also act as triggers for recurrence, making RVVC more common in susceptible individuals.

How can the microbiome be manipulated to help treat and prevent vulvovaginal candidiasis (VVC)?

Restoring a healthy vaginal microbiome is a crucial strategy for treating and preventing vulvovaginal candidiasis (VVC), especially in cases of recurrent infections. Probiotics containing Lactobacillus species are the most common intervention to help restore the balance of the vaginal microbiome. These probiotics work by outcompeting Candida for nutrients and space, as well as producing lactic acid to maintain the acidic pH that inhibits Candida growth. Probiotic treatments, whether oral or topical, have been shown to reduce the recurrence of VVC, particularly when used in conjunction with antifungal therapy. Furthermore, dietary changes that promote the growth of beneficial bacteria, such as consuming fiber-rich foods and limiting refined sugars, can support a healthier microbiome. In some cases, personalized microbiome testing may provide insights into specific imbalances, allowing for more targeted treatments, such as custom probiotic formulations, to restore a protective microbiota. As we learn more about the interactions between the microbiome, immune system, and Candida, future therapies may include even more precise approaches to manipulating the vaginal microbiome to prevent and treat VVC.

Research Feed

March 2, 2024

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What was reviewed?

This paper reviewed the vaginal microbiota (VMB) and its relationship with vulvovaginal candidiasis (VVC), focusing on how disruptions in the vaginal microbial community contribute to the disease. It explored current antifungal treatment challenges, such as drug resistance and recurrence, and assessed emerging microbiome-based therapies including probiotics, postbiotics, synbiotics, and vaginal microbiota transplantation (VMT). The review synthesized findings from clinical trials, microbiome sequencing studies, and in vitro and animal research to evaluate how these interventions might restore vaginal microbial balance and improve VVC outcomes.

Who was reviewed?

The review drew on data from reproductive-age women, especially those affected by VVC or vaginal dysbiosis. It incorporated studies analyzing the vaginal microbial communities dominated by Lactobacillus species in healthy women versus dysbiotic communities associated with VVC. Clinical trials evaluating probiotic and postbiotic therapies and early-stage research on VMT were also included. The review highlighted key microbial signatures linked to vaginal health and infection, emphasizing the role of Candida species and the loss of protective Lactobacillus strains in disease progression.

Most important findings

The review identified that a healthy vaginal microbiota is dominated by Lactobacillus species, which produce lactic acid to maintain an acidic environment that suppresses Candida growth and modulates immune responses. Disruptions to this balance, through factors like antibiotics or hormonal changes, reduce Lactobacillus levels and raise vaginal pH, facilitating Candida overgrowth and VVC development. Conventional antifungal treatments face limitations due to resistance and recurrence. Probiotics, particularly Lactobacillus strains, demonstrated antifungal and immunomodulatory effects by competing with Candida, producing antimicrobial compounds, and supporting mucosal defenses. Postbiotics offer similar benefits without risks related to live microbes, while synbiotics enhance probiotic survival and activity. Vaginal microbiota transplantation is a promising but still experimental approach to restore microbial balance more effectively.

Greatest implications of this review

This review highlights the need to shift VVC management from solely antifungal drugs toward therapies that restore vaginal microbiota balance, aiming to reduce recurrence and drug resistance. Probiotics, postbiotics, synbiotics, and vaginal microbiota transplantation represent promising adjuncts or alternatives but require further high-quality clinical trials to confirm their safety, optimal protocols, and long-term efficacy. Integrating microbiome-focused treatments into clinical practice could improve patient outcomes by targeting the ecosystem dynamics underlying VVC rather than just the pathogen.

December 30, 2024

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What was studied?

This study investigated the dual anti-Candida and anti-inflammatory effects of VAGINNE®, a fermentation broth derived from Lactobacillus crispatus, Lactobacillus gasseri, and Lactobacillus jensenii, in treating vulvovaginal candidiasis (VVC). Using a controlled mouse model of Candida albicans-induced vaginal infection, the researchers examined the microbiome composition, cytokine levels, and tissue integrity following treatment with VAGINNE® compared to a standard antifungal agent (nystatin) and untreated controls.

Who was studied?

The experimental subjects were female BALB/c mice, aged seven weeks. The researchers inoculated the mice with Candida albicans to mimic human VVC and then divided them into four groups: a healthy control group, an infected group, a nystatin-treated group, and a group treated with VAGINNE®. They conducted microbiological, immunological, and histological analyses on vaginal lavage samples, plasma, and vaginal tissues.

Most Important Findings

VAGINNE® demonstrated a dual mechanism of action in combating Candida albicans. It significantly reduced the fungal burden in the vagina (from 1.67 × 10⁷ CFU/mL in infected controls to 6.15 × 10⁶ CFU/mL) and simultaneously restored beneficial Lactobacillus populations, reaching 1.19 × 10⁸ CFU/mL compared to just 1.20 × 10⁷ CFU/mL in infected animals. Histologically, mice treated with VAGINNE® exhibited preserved vaginal epithelial structure and reduced tissue invasion by fungal hyphae. Immunologically, VAGINNE® decreased levels of key proinflammatory cytokines associated with Th17-mediated immunity. Specifically, IL-17A, IL-22, and IL-23 were significantly reduced in vaginal tissues, while systemic inflammation markers IL-6 and IL-1β were also suppressed in plasma. These cytokines are crucial in fungal immunity but also contribute to excessive inflammation and tissue damage in VVC.

Thus, VAGINNE® not only restored microbiome balance and modulated the immune response, reducing local and systemic inflammation. This combination of microbial suppression and immune regulation reflects a targeted and multifaceted therapeutic strategy, contrasting the fungistatic nature of conventional azoles, which often leads to recurrence and resistance.

Greatest Implications of the Study

This study offers compelling evidence that microbiome-modulating therapies, particularly those using Lactobacillus-derived products, can effectively treat vulvovaginal candidiasis through both antifungal and anti-inflammatory mechanisms. VAGINNE® holds promise as a probiotic-based alternative to azole antifungals, especially in light of increasing drug resistance and recurrence rates in VVC. By promoting Lactobacillus regrowth, reducing fungal load, and downregulating cytokine-driven inflammation, VAGINNE® could support a paradigm shift in VVC management toward microbiome-friendly interventions. However, further clinical trials in human populations are necessary to confirm its safety and efficacy before widespread application.

February 25, 2020

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What was reviewed?

This review article provided an extensive overview of vulvovaginal candidiasis (VVC), focusing on epidemiology, host immune response, fungal pathogenicity, microbiome interactions, and innovative therapeutic strategies. Specifically, it examined current knowledge surrounding Candida albicans and other Candida species as major pathogens in VVC, emphasizing the complexity of host-pathogen interactions and the multifactorial nature of this prevalent infection.

Who was reviewed?

The article synthesized information from various studies and clinical trials involving women who experience acute or recurrent VVC. It also included insights gained from animal models and cell-based studies designed to investigate underlying pathogenic mechanisms and host immune responses associated with VVC.

What were the most important findings?

The review highlighted several crucial findings regarding VVC pathogenesis. Candida albicans emerged as the primary causative agent, accounting for over 90% of cases, although non-albicans Candida (NAC) species, notably Candida glabrata, also significantly contributed to disease incidence. Key host-pathogen interactions were identified, including the yeast-to-hypha morphological transition as a critical event driving disease, accompanied by secretion of virulence factors such as candidalysin, a peptide essential for triggering inflammation. The NLRP3 inflammasome pathway was shown to be activated by candidalysin and other virulence factors, leading to neutrophil recruitment and inflammatory cytokine production, thus causing symptomatic inflammation rather than fungal clearance.

The microbiome was recognized as a potential factor influencing VVC development. Although Lactobacillus species generally maintain vaginal health through acid production, studies offered mixed findings regarding their protective role against Candida colonization. Some Lactobacillus strains provided antifungal effects, while others showed limited inhibitory activity, suggesting strain-specific differences in microbiome composition could influence susceptibility to infection.

What are the greatest implications of this review?

The implications of this review are significant for clinical management and research directions. Recognizing VVC as an immunopathology rather than purely an infection emphasizes the need for treatments targeting inflammatory pathways, such as NLRP3 inflammasome inhibitors, alongside traditional antifungal therapies. The variability in microbial interactions points to personalized therapeutic approaches involving probiotics and microbiome modulation. Additionally, insights into fungal pathogenicity mechanisms, especially candidalysin's role, could guide the development of novel antifungal agents or vaccines, potentially reducing the global burden of VVC and recurrent episodes.

January 28, 2020

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What was reviewed?

This review analyzed existing knowledge of vaginal microbiota (VMB) in relation to vaginal health and recurrent vulvovaginal infections (RVVI), focusing specifically on bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis (TV). The authors critically assessed current insights derived from advanced molecular techniques, highlighting how both bacterial and fungal communities influence vaginal health, and discussed the interactions among these communities and their role in the pathogenesis of recurrent infections.

Who was reviewed?

This critical review evaluated literature from diverse sources, including peer-reviewed studies identified through databases such as PubMed and Google Scholar. Included were studies employing both culture-dependent and culture-independent methods to characterize vaginal microbial communities in healthy women and those suffering from recurrent vaginal infections, including bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis.

What were the most important findings?

The review highlights the complexity and variability of vaginal microbiota, challenging the traditional view that Lactobacillus dominance universally signifies vaginal health. While Lactobacilli typically protect vaginal health by producing lactic acid, maintaining acidic conditions that prevent infections, certain species such as L. iners can instead contribute to instability and disease susceptibility. In bacterial vaginosis, reduced Lactobacilli and increased anaerobes, especially Gardnerella vaginalis, play a critical role. G. vaginalis contributes significantly to disease through biofilm formation and secretion of virulence factors, including vaginolysin and sialidases.

For vulvovaginal candidiasis and trichomoniasis, microbial interactions are key determinants of disease progression. Candida albicans, usually harmless in its yeast form, can shift to a pathogenic hyphal state under elevated pH or disrupted microbiota, highlighting crucial interactions between bacteria and fungi in maintaining health. In trichomoniasis, Trichomonas vaginalis actively damages vaginal epithelial cells and suppresses beneficial Lactobacilli through mechanisms including protease secretion and biofilm formation, exacerbated by symbiotic interactions with mycoplasmas and dsRNA viruses that further enhance virulence.

What are the greatest implications of this review?

This review stresses the importance of understanding individual variability and complex interactions within the vaginal microbiota when managing recurrent vulvovaginal infections. It emphasizes that traditional beliefs, such as universal Lactobacillus dominance indicating vaginal health, are oversimplifications. This knowledge demands that clinicians adopt more nuanced diagnostics and personalized approaches to treatment. Furthermore, the authors highlight critical gaps in our understanding of the fungal and parasitic components of the vaginal microbiota, suggesting a need for further research utilizing comparative genomics and longitudinal microbiome profiling to guide improved clinical management strategies for RVVI.

September 9, 2022

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What was reviewed?

This review evaluated the current management strategies for recurrent vulvovaginal candidiasis (RVVC), summarizing clinical guidelines, real-world clinical practices, therapeutic challenges, and expert opinions from a panel of European specialists. It specifically reviewed the effectiveness and limitations of existing antifungal therapies, diagnostic approaches, pathogen characteristics, and future therapeutic options.

Who was reviewed?

The review analyzed the collective expertise of a panel of 10 European gynecology specialists from countries including Belgium, Finland, France, Germany, Hungary, Italy, Poland, Romania, Spain, and the UK. These experts discussed RVVC management through structured online sessions, covering diagnosis, treatment regimens, patient experiences, and novel therapies. Their insights were compared against published scientific evidence and current clinical guidelines.

What were the most important findings?

The review identifies recurrent vulvovaginal candidiasis (RVVC) as primarily caused by Candida albicans, although infections by non-albicans species, particularly Candida glabrata, are increasingly common. Resistance to standard antifungal treatments like fluconazole, though still uncommon, is gradually rising due to repeated and prolonged exposure to antifungal medications. Fluconazole remains the recommended first-line treatment for acute episodes and maintenance therapy, yet a significant proportion of women experience recurrence after discontinuing maintenance treatment, highlighting the necessity for improved long-term therapeutic options.

The complexity of RVVC is underscored by its intricate microbiological environment, where interactions between Candida species, the host immune system, and vaginal microbiota play critical roles. Neutrophil dysfunction, genetic susceptibility, and diminished populations of protective Lactobacillus species in the vaginal microbiome significantly contribute to disease recurrence and severity. Diagnostic approaches relying on microscopy and culture are crucial but inconsistently implemented, often compromised by prior patient self-treatment. The review emphasizes promising future therapies, such as the selective antifungal oteseconazole and the novel glucan synthase inhibitor ibrexafungerp, alongside emerging immunotherapeutic vaccines targeting critical fungal proteins, which offer significant potential to improve patient outcomes.

What are the greatest implications of this review?

The review underscores the urgent need for optimized diagnostic and treatment strategies for RVVC. It suggests that clinicians should carefully consider personalized regimens due to the significant recurrence rates and variability in patient response. New therapeutic agents, especially those targeting resistant strains and immune pathways, hold significant promise and should be a focus of future research. Moreover, enhancing clinician and patient awareness about RVVC's substantial impact on quality of life is vital for better patient care and adherence.

March 29, 2019

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What was studied?

This study explored contemporary patient perspectives regarding vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC), focusing on incidence, clinical symptoms, diagnosis methods, management strategies, and post-treatment outcomes.

Who was studied?

The research involved 284 non-pregnant women recruited from university-affiliated Obstetrics and Gynecology clinics, as well as general community settings. The participants included predominantly Caucasian women (78%), along with African American (14%) and Asian women (8%), covering reproductive, perimenopausal, and postmenopausal age ranges.

What were the most important findings?

The study reaffirmed historical prevalence rates, with 78% of women experiencing at least one episode of VVC, and 34% having RVVC (defined as ≥4 episodes annually). Major clinical symptoms consistently reported were itching (91%), burning (68%), redness (58%), and cottage cheese-like discharge (56%). Antibiotic usage emerged as the leading identifiable risk factor (38%), followed by sexual intercourse (22%) and humid weather (11%). However, 55% reported episodes as idiopathic, with no identifiable trigger. Physicians diagnosed most cases (73%) using pelvic examinations and lab tests, prescribed antifungal treatments, and achieved an 84% symptom relief rate. In contrast, self-diagnosed/self-treated cases reported significantly lower relief rates (57%). Within RVVC patients, 71% relied on continual or intermittent antifungal therapy to control symptoms effectively, whereas nearly 20% failed to obtain adequate relief despite ongoing treatment.

What are the greatest implications of this study?

This study highlights the enduring high prevalence of VVC/RVVC despite advancements in diagnostic and therapeutic methods. It emphasizes the need for continued research into more effective, targeted treatments and indicates the importance of accurate clinical diagnosis over self-management. Furthermore, the similarity in symptom profiles between episodic VVC and RVVC suggests that future innovations in diagnostic and treatment strategies could benefit all affected populations. Clinicians should particularly note the high percentage of idiopathic cases, indicating the complexity of prevention and treatment approaches.

November 7, 2020

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What was reviewed?

This paper provides a comprehensive narrative review of vulvovaginal candidosis (VVC), focusing on the current concepts, challenges, and perspectives related to the epidemiology, pathogenesis, and diagnosis of this common fungal infection. It systematically synthesizes existing literature on the prevalence, microbial factors, host-pathogen interactions, diagnostic approaches, and virulence mechanisms of Candida species, particularly Candida albicans, the primary pathogen implicated. The review excludes treatment strategies but highlights the clinical burden and research gaps that remain in understanding VVC.

Who was reviewed?

The review draws on a broad spectrum of studies encompassing symptomatic and asymptomatic women of reproductive age worldwide. It includes epidemiological data from various countries, microbiological characterizations of Candida species isolated from vaginal samples, and immunological studies investigating host responses to Candida colonization and infection. The reviewed populations primarily consist of immunocompetent women, with an emphasis on those experiencing acute and recurrent vulvovaginal candidosis (RVVC).

What were the most important findings?

The review underscores that VVC affects approximately 70-75% of women at least once in their lifetime, with 5-8% developing recurrent episodes (RVVC). Candida albicans dominates as the causative species in 90-95% of infections, while non-albicans species, such as C. glabrata, C. tropicalis, and others, cause milder infections. The transition from Candida colonization to pathogenic infection involves complex virulence factors, including adhesins from the ALS gene family (notably ALS1-3 and ALS9), hydrolytic enzymes like secreted aspartyl proteinases (Saps), and phospholipases, which enhance fungal adherence, tissue invasion, and immune evasion. The formation of hyphae and the secretion of candidalysin toxin are crucial for tissue damage and immune activation. Host immune responses, including neutrophil recruitment and inflammasome activation, also critically shape disease outcomes.

Diagnostic challenges arise because colonization does not always equate to infection; microscopy detects hyphae in only 50-80% of cases, and culture or molecular methods improve sensitivity. Furthermore, over-the-counter self-treatment without proper diagnosis often leads to ineffective management and potential antifungal resistance. The review also highlights that Candida forms biofilms, which may contribute to antifungal resistance in vaginal infections, though researchers have yet to fully elucidate its exact role in VVC. The vaginal mycobiome in asymptomatic women is more diverse than previously appreciated, indicating a need to differentiate commensalism from pathogenic states more clearly.

What are the greatest implications of this review?

This review emphasizes the critical need for improved diagnostic accuracy to distinguish colonization from infection and prevent unnecessary or inappropriate antifungal use that drives resistance. It signals that future research should focus on the molecular mechanisms of Candida virulence, host-pathogen interactions, and the role of biofilms to identify new therapeutic targets. The growing understanding of the vaginal mycobiome and its complexity calls for integrative microbiome-based diagnostics and personalized treatment strategies. Furthermore, the review advocates for intensified research efforts and clinical awareness of VVC as a significant and neglected women's health issue, encouraging the exploration of alternative therapies, including probiotics and vaccination, which show promise in preclinical studies. Ultimately, better integration of microbiome insights into clinical practice will enhance patient outcomes and management of vulvovaginal candidosis.

April 21, 2020

What was studied?

This experimental study investigated the antifungal efficacy of lactoferrin (LF) against a wide range of clinically relevant yeasts and molds, and its potential to act synergistically with common antifungal drugs. The authors evaluated the minimum inhibitory concentrations (MICs) of lactoferrin from three different sources and analyzed how iron saturation, digestion state, and source purity influenced LF activity and synergy with antifungals, particularly amphotericin B (AMB).

Who was studied?

The study focused on 22 yeast species and 24 mold species, using both clinical isolates and reference strains. Key organisms included Candida albicans, Cryptococcus neoformans, C. glabrata, and Saccharomyces cerevisiae. In vivo efficacy was tested using a Galleria mellonella infection model inoculated with Candida and Cryptococcus species.

What were the most important findings?

Lactoferrin displayed broad antifungal activity against yeasts. The iron-depleted (apo) form was more active than the iron-rich (holo) form, affirming that iron chelation plays a major role in LF’s antifungal function. However, synergy with amphotericin B was independent of iron saturation and instead depended on peptide fragments within LF, highlighting that proteolytic digestion enhances its efficacy.

Most critically, LF synergized strongly with AMB against 19 of 22 yeast species, producing 4-fold reductions in AMB concentrations needed to inhibit growth. This combination therapy significantly reduced fungal burden and improved survival in the Galleria mellonella model, confirming in vivo relevance. Scanning electron microscopy (SEM) imaging showed that LF disrupted fungal morphology and, when combined with AMB, induced pore formation, hyphal thinning, and capsule collapse in Candida and Cryptococcus. The LF-AMB combination also impaired key virulence traits like biofilm formation and hyphal elongation in Candida, and capsule and cell size modulation in Cryptococcus, all of which are critical to pathogenesis and immune evasion.

While LF alone exerted antifungal activity via iron sequestration and membrane damage, its synergy with AMB appears to rely on facilitating AMB’s cell entry and amplifying intracellular stress. These results underscore its multifaceted role as both an iron chelator and membrane-disrupting peptide complex.

What are the implications of this study?

This study provides compelling evidence that lactoferrin, particularly when derived from digested, iron-depleted sources, could serve as a low-toxicity, broad-spectrum antifungal adjunct. Its synergy with amphotericin B could enable lower dosing, reduce side effects, and enhance treatment efficacy against drug-resistant or biofilm-associated fungal infections. For microbiome-centered therapies, LF offers dual promise: direct suppression of fungal overgrowth and support for microbial balance via targeted pathogen reduction without broad-spectrum collateral damage. Moreover, its ability to impair fungal virulence traits suggests a novel pathway to disarm pathogenic fungi without solely relying on fungicidal pressure, potentially slowing the emergence of resistance.

January 18, 2017

What was reviewed?

This review examined the antifungal properties of lactoferrin (Lf) and its derived peptides, especially lactoferricin, lactoferrampin, and Lf(1–11), highlighting their mechanisms of action and potential for synergistic use with antifungal drugs. The paper consolidated findings from multiple in vitro and some in vivo studies to explain how these molecules exert direct antifungal activity, modulate immune responses, and interact with current antifungal agents like azoles.

Who was reviewed?

The review synthesized studies involving a broad spectrum of fungal pathogens, particularly various Candida species, Cryptococcus, Aspergillus, and several plant-pathogenic molds. It also discussed work done on mammalian Lf peptides derived from human and bovine sources, tested on both wild-type and resistant fungal strains. Mechanistic and structural insights were drawn from both laboratory experiments and structural analyses of peptide variants.

What were the most important findings?

Lactoferrin and its derived peptides exhibit significant antifungal activity through membrane destabilization, iron chelation, and, in some cases, induction of fungal apoptosis-like processes. While initial assumptions attributed Lf’s antifungal effect to iron sequestration, more recent evidence points to direct membrane interaction and intracellular disruption as the primary mechanisms. These peptides quickly penetrate fungal cells, alter membrane potential, cause ROS accumulation, and trigger apoptosis pathways in C. albicans and S. cerevisiae.

Lf-derived peptides, especially bLfcin and Lfampin, show broad-spectrum activity at lower MICs than the full protein, and structural modifications enhance this potency. Synergy was most notable with azole-class drugs, where co-treatment reduced MICs for fluconazole and itraconazole-resistant Candida strains. For microbiome study, these findings are crucial: Lf and its peptides act selectively, impairing fungal overgrowth without broad-spectrum microbial destruction, preserving beneficial taxa, and possibly reinforcing mucosal barrier integrity through indirect immune modulation.

What are the implications of this review?

This review highlights lactoferrin’s therapeutic versatility, not only as a standalone antifungal agent but also as a synergistic enhancer of existing antifungal drugs. Its derived peptides, due to higher potency and customizable structures, represent promising leads for targeted antifungal drug design. For microbiome-informed clinical strategies, Lf peptides offer a selective approach to managing fungal overgrowth, reducing the risk of resistance development, and preserving microbial homeostasis. Their ability to weaken virulence traits (e.g., biofilm formation, hyphal growth) while enhancing host immune responses aligns well with personalized, microbiome-centered care pathways.

December 1, 2019

•

What was Studied?

This study examined the use of intravaginal boric acid (BA) maintenance therapy in women with recurrent vulvovaginal candidiasis (rVVC) and recurrent bacterial vaginosis (rBV). The researchers performed a retrospective chart review to evaluate clinicians' approaches to prescribing BA for these conditions, focusing on dosage, duration of use, patient satisfaction, and side effects. The study aimed to assess the effectiveness, tolerability, and satisfaction of long-term BA therapy in real-world clinical settings.

Who was Studied?

The study reviewed the medical records of 78 patients from a Johns Hopkins University-affiliated outpatient gynecology clinic. These patients were prescribed intravaginal BA for either rVVC, rBV, or both conditions. The patients were selected based on specific criteria, including multiple visits where BA usage was documented, and those who were prescribed a long-term BA regimen (more than a month). Patients were excluded if there was insufficient documentation regarding the initiation or duration of BA use.

What were the Most Important Findings?

The study revealed that maintenance therapy with intravaginal boric acid was commonly prescribed for rVVC and rBV, with an average duration of use estimated at 13.3 months. A significant portion of patients (37.2%) used BA for a year or more, with some patients continuing therapy for more than three years. The treatment regimen typically included a 7-14 day induction phase with BA, followed by a maintenance phase where patients used 300mg or 600mg of BA 2-3 times per week.

Despite the lack of long-term safety data, the study found high patient satisfaction with BA therapy (76.9%), though a small number of patients (16.7%) were dissatisfied, typically due to continued or worsening symptoms. The study also indicated that patients with rVVC were more likely to receive BA as part of an antifungal induction regimen, while patients with rBV were often prescribed antibiotics in addition to BA. Side effects were rare, with a few patients reporting vaginal irritation or leaking, but these effects were generally manageable.

What are the Implications of this Study?

This study provides real-world evidence supporting the use of intravaginal boric acid as a long-term treatment for recurrent vulvovaginal candidiasis and bacterial vaginosis. Despite the absence of large-scale prospective studies, the findings suggest that BA is well-tolerated over extended periods and that it may be an effective option for women with azole-resistant infections. This study's insights into patient satisfaction, side effects, and clinical practice could inform future treatment guidelines and clinical trials for rVVC and rBV. However, more robust, prospective studies are needed to confirm the efficacy and long-term safety of BA maintenance therapy and to compare it with other available treatments.

References

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Microbiota in vaginal health and pathogenesis of recurrent vulvovaginal infections: a critical review. Kalia, N., Singh, J. & Kaur, M.. (Ann Clin Microbiol Antimicrob 19, 5 (2020))
Management of recurrent vulvovaginal candidosis: Narrative review of the literature and European expert panel opinion. Donders, G., Sziller, I. O., Paavonen, J., Hay, P., De Seta, F., Bohbot, J. M., Kotarski, J., Vives, J. A., Szabo, B., Cepuliené, R., & Mendling, W. (2022). (Frontiers in Cellular and Infection Microbiology, 12, 934353)
Vulvovaginal Candidosis: Current Concepts, Challenges and Perspectives. Sustr, V., Foessleitner, P., Kiss, H., & Farr, A. (2020). (Journal of Fungi, 6(4), 267)
Management of recurrent vulvovaginal candidosis: Narrative review of the literature and European expert panel opinion. Donders, G., Sziller, I. O., Paavonen, J., Hay, P., De Seta, F., Bohbot, J. M., Kotarski, J., Vives, J. A., Szabo, B., Cepuliené, R., & Mendling, W. (2022). (Frontiers in Cellular and Infection Microbiology, 12, 934353)
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Dual Mechanisms of Action: Anti-Candida and Anti-Inflammatory Potential of Lactobacillus Fermentation Broth in Treating Vulvovaginal Candidiasis. Horng H-C, Xu J-W, Kuo Y-S, Chen Y-S, Chiu Y-H, Tsui K-H, Tung Y-T.. (Journal of Fungi. 2025; 11(1):18)
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Clinical Evaluation of Polymerase Chain Reaction Coupled with Quantum Dot Fluorescence Analysis for Diagnosis of Candida Infection in Vulvovaginal Candidiasis Practice. Fan W, Li J, Chen L, Wu W, Li X, Zhong W, Pan H.. (Infect Drug Resist. 2023 Jul 25;16:4857-4865)
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Vulvovaginal Candidiasis (VVC)

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