Denture stomatitis-An interdisciplinary clinical review.

PURPOSE: An interdisciplinary clinical review on denture stomatitis formulated by experts from prosthodontics, oral medicine, and oral microbiology is presented. The review outlines the etiopathogenesis, clinical features, and management strategies of denture stomatitis from an interdisciplinary perspective. MATERIALS AND METHODS: English-language articles relating to the definition, incidence, gender distribution, geographical distribution, etiology, pathogenesis, symptoms, signs, treatment, and prognosis of denture stomatitis were retrieved via electronic literature search. Relevant articles were summarized for this manuscript with a view toward providing pragmatic information. RESULTS: Denture stomatitis represents a very common, multifactorial infectious, inflammatory, and hyperplastic condition which is primarily caused by poor oral hygiene, poor denture hygiene, and full-time; mainly night-time denture wear, bringing about the emergence of advanced Candida-containing polymicrobial biofilms in close proximity to the host's mucosal tissues. Denture stomatitis shares clinically relevant associations with dental caries, periodontitis, median rhomboid glossitis, angular cheilitis, aspirational pneumonia, and associated mortality. CONCLUSIONS: Effective, long-term treatment of denture stomatitis relies upon sustained patient-driven behavioral change which should focus on daily prosthesis-level cleaning and disinfection, removal of dentures at night, every night, engagement with professional denture maintenance, and when required, denture replacement. Antifungal medications offer limited benefits outside of short-term use due to the emergence of antifungal resistance. For frail, older, medically compromised, and nursing home populations, treatment of denture stomatitis lowers the risk of aspirational pneumonia and associated mortality.

The oral mycobiome: Oral epithelial dysplasia and oral squamous cell carcinoma.

Fungi, a diverse group of eukaryotic organisms, play distinct roles in health and disease. Recent advances in the field of mycobiology have enabled the characterization of the "human mycobiome." The human mycobiome has extensively been studied in various disease models. However, to date, the role of the oral mycobiome in oral carcinogenesis has yet to be elucidated. Candida albicans, the most common oral colonizer, has been speculated to display tumorigenic effects; however, the literature lacks consistent documentation from mechanistic studies on whether oral mycobiota act as drivers, facilitators, or passive colonizers of oral premalignancy and cancer. This review article provides an overview of existing hypothesis-driven mechanistic models that outline the complex interplay between the oral mycobiome and oral epithelial dysplasia as well as their potential clinical implications.

Digital Design of a Universal Rat Intraoral Device for Therapeutic Evaluation of a Topical Formulation against Candida-Associated Denture Stomatitis.

Candida-associated denture stomatitis (DS) is a persistent and chronic oral infection of the denture-bearing palatal mucosa. DS stems from the ability of the fungal opportunistic pathogen Candida albicans to adhere to denture material and invade palatal tissue. Although DS is the most prevalent form of oral candidiasis, there are currently no feasible therapeutic strategies for the prevention of this recurrent condition. We developed a peptide-based antimicrobial bioadhesive formulation specifically designed for oral topical formulation. In this study, we aimed to evaluate the applicability of the novel formulation for the prevention of C. albicans colonization on denture material and development of clinical disease. To that end, using the latest technological advances in dental digital design and three-dimensional (3D) printing, we fabricated an intraoral device for rats with universal fit. The device was successfully installed and used to develop clinical DS. Importantly, by taking a preventative therapeutic approach, we demonstrated the potential clinical utility of the novel formulation as a safe and feasible prophylactic agent against DS.

Evaluation of the Antifungal and Wound-Healing Properties of a Novel Peptide-Based Bioadhesive Hydrogel Formulation.

Oral candidiasis (OC) caused by the fungal pathogen Candida albicans is the most common opportunistic infection in immunocompromised populations. The dramatic increase in resistance to common antifungal agents has emphasized the importance of identifying alternative therapeutic options. Antimicrobial peptides have emerged as promising drug candidates due to their antimicrobial properties; specifically, histatin-5 (Hst-5), a peptide naturally produced and secreted by human salivary glands, has demonstrated potent activity against C. albicans However, as we previously demonstrated vulnerability for Hst-5 to proteolysis by C. albicans proteolytic enzymes at specific amino acid residues, a new variant (K11R-K17R) was designed with amino acid substitutions at the identified cleavage sites. The new resistant peptide demonstrated no cytotoxicity to erythrocytes or human oral keratinocytes. To evaluate the potential of the new peptide for clinical application, we utilized our FDA-approved polymer-based bioadhesive hydrogel as a delivery system and developed a therapeutic formulation specifically designed for oral topical application. The new formulation was demonstrated to be effective against C. albicans strains resistant to the traditional antifungals, and the in vitro therapeutic efficacy was found to be comparable to that of the common topical antifungal agents in clinical use. Importantly, in addition to its antifungal properties, our findings also demonstrated that the new peptide variant induces cell proliferation and rapid cell migration of human oral keratinocytes, indicative of wound healing properties. The findings from this study support the progression of the novel formulation as a therapeutic agent against oral candidiasis, as well as a therapeutic modality for promoting wound healing.

Modulation of Staphylococcus aureus Response to Antimicrobials by the Candida albicans Quorum Sensing Molecule Farnesol.

In microbial biofilms, microorganisms utilize secreted signaling chemical molecules to coordinate their collective behavior. Farnesol is a quorum sensing molecule secreted by the fungal species Candida albicans and shown to play a central physiological role during fungal biofilm growth. Our pervious in vitro and in vivo studies characterized an intricate interaction between C. albicans and the bacterial pathogen Staphylococcus aureus, as these species coexist in biofilm. In this study, we aimed to investigate the impact of farnesol on S. aureus survival, biofilm formation, and response to antimicrobials. The results demonstrated that in the presence of exogenously supplemented farnesol or farnesol secreted by C. albicans in biofilm, S. aureus exhibited significantly enhanced tolerance to antimicrobials. By using gene expression studies, S. aureus mutant strains, and chemical inhibitors, the mechanism for the enhanced tolerance was attributed to upregulation of drug efflux pumps. Importantly, we showed that sequential exposure of S. aureus to farnesol generated a phenotype of high resistance to antimicrobials. Based on the presence of intracellular reactive oxygen species upon farnesol exposure, we hypothesize that antimicrobial tolerance in S. aureus may be mediated by farnesol-induced oxidative stress triggering the upregulation of efflux pumps, as part of a general stress response system. Hence, in mixed biofilms, C. albicans may influence the pathogenicity of S. aureus through acquisition of a drug-tolerant phenotype, with important therapeutic implications. Understanding interspecies signaling in polymicrobial biofilms and the specific drug resistance responses to secreted molecules may lead to the identification of novel targets for drug development.

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework.

Historically, the nature and extent of host damage by a microbe were considered highly dependent on virulence attributes of the microbe. However, it has become clear that disease is a complex outcome which can arise because of pathogen-mediated damage, host-mediated damage, or both, with active participation from the host microbiota. This awareness led to the formulation of the damage response framework (DRF), a revolutionary concept that defined microbial virulence as a function of host immunity. The DRF outlines six classifications of host damage outcomes based on the microbe and the strength of the immune response. In this review, we revisit this concept from the perspective of Candida albicans, a microbial pathogen uniquely adapted to its human host. This fungus commonly colonizes various anatomical sites without causing notable damage. However, depending on environmental conditions, a diverse array of diseases may occur, ranging from mucosal to invasive systemic infections resulting in microbe-mediated and/or host-mediated damage. Remarkably, C. albicans infections can fit into all six DRF classifications, depending on the anatomical site and associated host immune response. Here, we highlight some of these diverse and site-specific diseases and how they fit the DRF classifications, and we describe the animal models available to uncover pathogenic mechanisms and related host immune responses.

Development and In Vivo Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis.

Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV(+) individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent.

Clinical implications of oral candidiasis: host tissue damage and disseminated bacterial disease.

The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species Candida albicans and the bacterium Staphylococcus aureus are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV(+) and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to S. aureus resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive C. albicans hyphal invasion coupled with S. aureus deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of C. albicans. Further, in contrast to previous findings, S. aureus dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal C. albicans infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals.

Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue.

Candida albicans and Staphylococcus aureus are often co-isolated in cases of biofilm-associated infections. C. albicans can cause systemic disease through morphological switch from the rounded yeast to the invasive hyphal form. Alternatively, systemic S. aureus infections arise from seeding through breaks in host epithelial layers although many patients have no documented portal of entry. We describe a novel strategy by which S. aureus is able to invade host tissue and disseminate via adherence to the invasive hyphal elements of Candida albicans. In vitro and ex vivo findings demonstrate a specific binding of the staphylococci to the candida hyphal elements. The C. albicans cell wall adhesin Als3p binds to multiple staphylococcal adhesins. Furthermore, Als3p is required for C. albicans to transport S. aureus into the tissue and cause a disseminated infection in an oral co-colonization model. These findings suggest that C. albicans can facilitate the invasion of S. aureus across mucosal barriers, leading to systemic infection in co-colonized patients.

In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms.

OBJECTIVES: Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents. METHODS: The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model [fractional inhibitory concentration (FIC) index] and the Bliss independence (BI) model. RESULTS: Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B. CONCLUSIONS: Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.

Adherence of Streptococcus mutans on lithium disilicate porcelain specimens.

STATEMENT OF PROBLEM: Streptococcus mutans can adhere at restored tooth margins to cause recurrent caries. Limited information about surface quality and bacterial adherence is available for lithium disilicate ceramic materials. PURPOSE: The purpose of this in vitro study was to investigate how bacterial adherence is influenced by commercially available preparations of lithium disilicate ceramic materials. MATERIAL AND METHODS: Seventeen rectangular specimens (10×10×4 mm) were fabricated for each type of lithium disilicate material: pressed (Press), milled (CAD), fluorapatite layered (ZirPress/Ceram), and glazed (Ceram Glaze). The surface roughness of each specimen was assessed before incubation with wild-type S mutans for 48 hours at 37°C with Brain Heart Infusion broth media under anaerobic conditions. Adherent bacteria were sonicated, diluted, and plated in triplicate for quantification using the plate count method to assay for colony forming units (CFUs) as an indication of bacterial viability. Statistical analysis was performed with SPSS using an analysis of variance (ANOVA) followed by the Tukey Honestly Significant Difference (HSD) test (α=.05). The Pearson r was used to evaluate the correlation between surface roughness and adherence. RESULTS: The surface roughness of Ceram Glaze (1.32 ±0.19 µm) was significantly the highest, followed by ZirPress/Ceram (0.71 ±0.09 µm), which was significantly rougher than the Press (0.11 ±0.02 µm) and CAD (0.10 ±0.02 µm) groups, which were not significantly different from each other. (F=513.898, P<.001). CFUs (cells/mL) of S mutans were also significantly the highest for Ceram Glaze (61.82 ±13.76), followed by ZirPress/Ceram (28.53 ±2.40), which had significantly higher adherence than CAD (12.86 ±1.70) and Press (6.62 ±2.74), which were not significantly different from each other. (F= 201.721, P<.001). A strong positive association was found between bacterial count and surface roughness (r=.95, P<.001). CONCLUSIONS: The surface roughness of differently prepared lithium disilicate ceramic restorations is closely related to the adherence of S mutans.

Polymicrobial interactions: impact on pathogenesis and human disease.

Microorganisms coexist in a complex milieu of bacteria, fungi, archaea, and viruses on or within the human body, often as multifaceted polymicrobial biofilm communities at mucosal sites and on abiotic surfaces. Only recently have we begun to appreciate the complicated biofilm phenotype during infection; moreover, even less is known about the interactions that occur between microorganisms during polymicrobial growth and their implications in human disease. Therefore, this review focuses on polymicrobial biofilm-mediated infections and examines the contribution of bacterial-bacterial, bacterial-fungal, and bacterial-viral interactions during human infection and potential strategies for protection against such diseases.