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Topical gentian violet compared with nystatin oral suspension for the treatment of oropharyngeal candidiasis in HIV-1-infected participants.

ABSTRACT: Compare the safety and efficacy of topical gentian violet with that of nystatin oral suspension (NYS) for the treatment of oropharyngeal candidiasis in HIV-1-infected adults in resource-limited settings.Multicenter, open-label, evaluator-blinded, randomized clinical trial at eight international sites, within the AIDS Clinical Trials Group.Adult HIV-infected participants with oropharyngeal candidiasis, stratified by CD4 cell counts and antiretroviral therapy status at study entry, were randomized to receive either gentian violet (0.00165%, BID) or NYS (500?000 units, QID) for 14 days.Cure or improvement after 14 days of treatment. Signs and symptoms of oropharyngeal candidiasis were evaluated in an evaluator-blinded manner.The study was closed early per Data Safety Monitoring Board after enrolling 221 participants (target?=?494). Among the 182 participants eligible for efficacy analysis, 63 (68.5%) in the gentian violet arm had cure or improvement of oropharyngeal candidiasis versus 61 (67.8%) in the NYS arm, resulting in a nonsizable difference of 0.007 (95% confidence interval: -0.129, 0.143). There was no sizable difference in cure rates between the two arms (-0.0007; 95% confidence interval: -0.146, 0.131). No gentian violet-related adverse events were noted. No sizable differences were identified in tolerance, adherence, quality of life, or acceptability of study drugs. In gentian violet arm, 61 and 39% of participants reported 'no' and 'mild-to-moderate' staining, respectively. Cost for medication procurement was significantly lower for gentian violet versus NYS (median $2.51 and 19.42, respectively, P?=?0.01).Efficacy of gentian violet was not statistically different than NYS, was well tolerated, and its procurement cost was substantially less than NYS.

SUBMITTER: Mukherjee PK

PROVIDER: S-EPMC5127761 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Topical gentian violet compared with nystatin oral suspension for the treatment of oropharyngeal candidiasis in HIV-1-infected participants.

Mukherjee Pranab K PK Chen Huichao H Patton Lauren L LL Evans Scott S Lee Anthony A Kumwenda Johnstone J Hakim James J Masheto Gaerolwe G Sawe Frederick F Pho Mai T MT Freedberg Kenneth A KA Shiboski Caroline H CH Ghannoum Mahmoud A MA Salata Robert A RA

AIDS (London, England) 20170101 1

<h4>Objective</h4>Compare the safety and efficacy of topical gentian violet with that of nystatin oral suspension (NYS) for the treatment of oropharyngeal candidiasis in HIV-1-infected adults in resource-limited settings.<h4>Design</h4>Multicenter, open-label, evaluator-blinded, randomized clinical trial at eight international sites, within the AIDS Clinical Trials Group.<h4>Study participants and intervention</h4>Adult HIV-infected participants with oropharyngeal candidiasis, stratified by CD4 ...[more]

PMID: 27677161

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Project description:BackgroundIn endemic communities, zoonotic tungiasis, a severe skin disease caused by penetrating female sand fleas, is a public health hazard causing significant human and animal morbidity. No validated drugs are currently available for treatment of animal tungiasis. Due to the reservoir in domestic animals, integrated management of human and animal tungiasis is required to avert its negative effects.Methods and principal findingsA topical aerosol containing chlorfenvinphos 4.8%, dichlorphos 0.75% and gentian violet 0.145% licensed to treat tick infestations, myiasis and wound sepsis in animals in the study area, was tested for its potential tungicidal effects in a randomized controlled field trial against pig tungiasis in rural Uganda. Animals with at least one embedded flea were randomized in a treatment (n = 29) and a control (n = 26) group. One week after treatment, 58.6% of the treated pigs did not show any viable flea lesion whereas all control pigs had at least one viable lesion. After treatment the number of viable lesions (treated median = 0, overall range = 0-18 vs. control median = 11.5, range = 1-180) and the severity score for estimating acute pathology in pig tungiasis (treated median = 1, range = 0-3.5 vs. control median = 7, range = 0-25) were significantly lower in treated than in control pigs (p < 0.001). In the treatment group the median number of viable flea lesions decreased from 8.5 to 0 (p < 0.001). Similarly, the median acute severity score dropped from 6 to 1 (p < 0.001). Every pig in the treatment group showed a decrease in the number of viable fleas and tungiasis-associated acute morbidity while medians for both increased in the control group.ConclusionsThe study demonstrates that a topical treatment based on chlorfenvinphos, dichlorphos and gentian violet is highly effective against pig tungiasis. Due to its simplicity, the new approach can be used for the treatment of individual animals as well as in mass campaigns.

Project description:Candida dubliniensis is a newly identified species of Candida that is phenotypically similar to but genetically distinct from C. albicans. This organism has been recovered with increasing frequency from the oral cavities of human immunodeficiency virus (HIV)-infected and AIDS patients and has been implicated as a causative agent of oral candidiasis and systemic disease. In the present study we characterized the molecular mechanisms of resistance to fluconazole (FLC) in C. dubliniensis clinical isolates from two different HIV-infected patients with oropharyngeal candidiasis. Isolates were identified to the species level by phenotypic and genotypic tests. DNA-typing techniques were used to assess strain identity. Antifungal susceptibility testing was performed by NCCLS techniques. Northern blotting analysis was used to monitor the expression of genes encoding lanosterol demethylase (ERG11) and efflux transporters (CDR and MDR1) in matched sets of C. dubliniensis-susceptible and -resistant isolates by using probes generated from their homologous C. albicans sequences. In addition, ERG11 genes were amplified by PCR, and their nucleotide sequences were determined in order to detect point mutations with a possible effect in the affinity for azoles. Decreasing susceptibilities to FLC were detected in C. dubliniensis isolates recovered from both patients during the course of treatment. FLC-resistant C. dubliniensis isolates from one patient demonstrated combined upregulation of the MDR1, CDR1, and ERG11 genes. Among the isolates from the second patient, all isolates showing decreased susceptibility to FLC demonstrated upregulation of MDR1, whereas the levels of mRNA for the ERG11 genes remained constant and the expression of CDR genes was negligible. Fourteen point mutations were found in the ERG11 genes of the isolates with decreased susceptibility to FLC. These data demonstrate that the development of azole resistance in C. dublinensis clinical isolates from HIV-infected patients treated with FLC is mediated by multiple molecular mechanisms of resistance, similar to the observations found in the case of C. albicans.

Project description:Oropharyngeal candidiasis (OPC) is the most prevalent oral infection in immunocompromised patients, primarily associated with Candida albicans. Increasing evidence points to a significant role of mucosal bacteria on the transition of C. albicans from commensal to pathogenic. In this work, we hypothesized that changes in the abundance or composition of the mucosal bacterial microbiota induced by dietary sucrose during the development of OPC can modulate C. albicans virulence. C. albicans burdens and mucosal lesions were evaluated in a mouse cortisone immunosuppression model amended with sucrose. We also analyzed the mucosal bacterial composition using 16S rRNA gene sequencing and culture methods. In immunocompetent mice, sucrose significantly increased total bacterial burdens and reduced alpha diversity, by increasing the relative abundance of mitis group streptococci. In immunocompromised mice, C. albicans infection was associated with a significantly reduced bacterial alpha diversity due to an increase in the relative abundance of enterococci. When exposed to dietary sucrose, these mice had reduced C. albicans burdens and reduced bacterial alpha diversity, associated with an increase in the relative abundance of Lactobacillus. SparCC correlation networks showed a significant negative correlation between Lactobacillus and Enterococcus in all Candida-infected mice. Depletion of lactobacilli with antibiotic treatment partially restored C. albicans burdens in mice receiving sucrose. In coculture in vitro experiments, mouse oral Lactobacillus johnsonii isolates inhibited growth of Enterococcus faecalis isolates and C. albicans. These results support the hypothesis that the sucrose-induced attenuation of C. albicans virulence was a result of changes in the mucosal bacterial microbiome characterized by a reduction in enterococci and an increase in lactobacilli. IMPORTANCE By comparing Candida albicans virulence and the mucosal bacterial composition in a mouse oral infection model, we were able to dissect the effects of the host environment (immunosuppression), infection with C. albicans, and local modulating factors (availability of sucrose as a carbon source) on the mucosal bacterial microbiome and its role on fungal virulence. We showed that changes in endogenous microbial communities in response to sucrose can lead to attenuation of fungal disease. We also showed that Lactobacillus johnsonii may curtail Candida virulence both by inhibiting its growth and by inhibiting the growth of potentially synergistic bacteria such as enterococci. Our results support the concept that Candida pathogenesis should be viewed in the contexts of both a susceptible host and a mucosal bacterial microbiota conducive to virulence.

Project description:Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC.

Project description:Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B's high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.

Project description:ImportanceTriggering the extrinsic apoptotic pathway is an effective way to kill cutaneous T-cell lymphoma (CTCL) cells in vitro and ex vivo.ObjectiveTo compare small molecules that induce extrinsic apoptosis in CTCL to identify and analyze compounds that induce high levels of tumor cell death and block tumor cell growth.Design, setting, and participantsFrom November 5, 2014, to January 30, 2018, this study performed high-throughput small molecule screening of 1710 compounds followed by detailed analysis of the ability of gentian violet (GV) to promote apoptosis and inhibit proliferation of CTCL cells.ExposuresIn vitro and ex vivo analyses using enzyme-linked immunosorbent assays, flow cytometry, and immunoblotting.Main outcomes and measuresApoptosis, cleaved caspases, extrinsic apoptotic death receptors and ligands, cell proliferation, nuclear factor-?B expression, and other factors.ResultsThis study used high-throughput screening to detect cleaved caspase 8 induced in CTCL cells by 1710 unique compounds. The nonprescription, topical antimicrobial remedy GV induced more total apoptosis than did nitrogen mustard (mechlorethamine). Furthermore, GV induced 4 to 6 times greater apoptosis in CTCL lines than in normal keratinocytes, suggesting a favorable topical toxicity profile. In addition to increasing caspase 8, GV also upregulated death receptors 4 and 5, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and Fas ligand but not the Fas receptor, TNF receptor, or TNF-? ligand. These results are consistent with induction of extrinsic apoptosis via the Fas and TNF-related apoptosis-inducing ligand pathways. Increased phosphorylation of phospholipase C-?1, Ca2+ influx, and reactive oxygen species were also detected, indicating that the mechanism of Fas ligand upregulation involves key elements of the activation-induced cell death pathway. In ex vivo studies, 1-?mol/L GV induced up to 90% CTCL apoptosis in Sézary blood cells. In addition, GV reduced expression of antiapoptotic myeloid cell leukemia 1 and proproliferative nuclear factor-?B components and increased inhibitory ?B levels. This finding was associated with cell cycle arrest and reduced CTCL tumor cell proliferation. Furthermore, the CTCL killing associated with GV was augmented when used in combination with methotrexate.Conclusions and relevanceThis study found that GV attacked tumor viability and growth in CTCL. Although purple at neutral pH, GV can be rendered colorless by altering its pH. These preclinical findings may help to broaden knowledge of the antineoplastic features of GV and provide a rationale for clinical studies of its use as a novel, inexpensive, topical therapy for CTCL that is available worldwide.

Dataset Information

Topical gentian violet compared with nystatin oral suspension for the treatment of oropharyngeal candidiasis in HIV-1-infected participants.

Publications

Topical gentian violet compared with nystatin oral suspension for the treatment of oropharyngeal candidiasis in HIV-1-infected participants.

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