scholarly journals 149. Efficacy of Cochleated Amphotericin B (CAMB) in Mouse and Human Mucocutaneous Candidiasis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S204-S205
Author(s):  
Jigar V Desai ◽  
Amanda Urban ◽  
Doris Z Swaim ◽  
Elise Ferre ◽  
Benjamin Colton ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Clinical Improvement ◽  
Clinical Efficacy ◽  
Chronic Mucocutaneous Candidiasis ◽  
Vaginal Tissue ◽  
Dose Escalation Study ◽  
Fungal Burden ◽  
Mucocutaneous Candidiasis ◽  
Inherited Susceptibility

Abstract Background Candida albicans causes debilitating mucosal infections in patients with inherited susceptibility to chronic mucocutaneous candidiasis (CMC), often requiring long-term azole-based treatment. Due to increasing azole resistance, alternative treatments are desirable. Acquired resistance to amphotericin B (AMB) is rare but AMB use is limited by parenteral administration and nephrotoxicity. Cochleated AMB (CAMB) is a new oral formulation of AMB and thus an attractive option for oropharyngeal candidiasis (OPC), esophageal candidiasis (EC) and vulvovaginal candidiasis (VVC). We assessed the efficacy of CAMB in mouse models of OPC and VVC and in 4 patients with azole resistant CMC manifesting as OPC, EC or VVC. Methods Act1 -/- mice were infected with C. albicans in models of OPC and VVC and were treated once daily via oral gavage with CAMB or vehicle or intraperitoneal AMB-deoxycholate (AMBd) from day 1 through 4 post-infection (pi). At day 5 pi, the tongue or vaginal tissue was harvested to quantify fungal burden. Patients with azole resistant CMC enrolled in a phase 2A CAMB dose escalation study. The primary endpoint was clinical improvement at 2 weeks based on an efficacy scale, followed by optional extension for long-term suppression of CMC to assess safety and efficacy. Results CAMB-treated mice had significantly reduced tongue and vaginal tissue fungal burden compared to vehicle-treated mice, while they exhibited comparable fungal control relative to AMBd-treated mice. Among 4 CAMB-treated patients, 3 reached clinical efficacy by 2 weeks at a dose of 400 mg twice daily and one reached clinical efficacy at 200 mg twice daily. Three of 4 patients continued on the extension phase past 48 months with sustained clinical improvement of OPC and EC; patient #3 had relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical response was not seen for onychomycosis or VVC. CAMB was safe and well-tolerated without renal toxicity. Conclusion Oral administration of CAMB in IL-17-signaling deficient mice resulted in reduced tongue and vaginal tissue fungal burden during mucosal C. albicans infections. A proof-of-concept clinical trial in humans with inherited CMC showed efficacy in OPC and EC with good tolerability and safety. Disclosures Benjamin Colton, PharmD, Merck (Shareholder)Pfizer (Shareholder) Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Theresa Matkovits, PhD, Matinas BioPharma (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder) Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)

Candida Esophagitis and Laryngitis in Chronic Mucocutaneous Candidiasis

PEDIATRICS ◽  
1980 ◽  
Vol 66 (3) ◽  
pp. 380-384
Author(s):  
Roger H. Kobayashi ◽  
Howard M. Rosenblatt ◽  
Jean M. Carney ◽  
William J. Byrne ◽  
Marvin E. Ament ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Topical Therapy ◽  
Signs And Symptoms ◽  
Poor Correlation ◽  
Chronic Mucocutaneous Candidiasis ◽  
Oral Lesions ◽  
Mucocutaneous Candidiasis ◽  
Left Mainstem ◽  
Repeat Endoscopy ◽  
Intravenous Amphotericin

Five children (aged 11 to 19 years) with lifelong chronic mucocutaneous candidiasis had 12 episodes of esophageal and/or laryngeal candidiasis documented by endoscopy. Symptoms included hoarseness (8/12), dysphagia (6/12), and hemoptysis (1/12). There was poor correlation between oral lesions and esophageal or laryngeal involvement. On fiberoptic endoscopy, the esophagus was involved alone in four episodes (33%), the larynx in two episodes (17%), and both structures in six episodes (50%). In six of eight instances, the esophagram was nondiagnostic or markedly underestimated the extent of inflammation. Intravenous amphotericin B or miconazole resulted in the resolution of these infections for variable periods of time. Repeat endoscopy was used to follow the course of the disease. Aerosolized amphotericin B was effective on one occasion in clearing candidal lesions of the larynx and one small area of the left mainstem bronchus. Oral topical therapy was not beneficial. Since the signs and symptoms of laryngitis or esophagitis are often minimal or absent and complications, including strictures, may arise from chronic inflammation, periodic endoscopy and systemic therapy may be necessary.

TREATMENT OF MUCOCUTANEOUS CANDIDIASIS WITH TRANSFER FACTOR

PEDIATRICS ◽  
1974 ◽  
Vol 53 (1) ◽  
pp. 63-70
Author(s):  
Ralph D. Feigin ◽  
Penelope G. Shackelford ◽  
Seth Eisen ◽  
Lynn E. Spitler ◽  
Larry K. Pickering ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Skin Test ◽  
Migration Inhibitory Factor ◽  
Transfer Factor ◽  
Chronic Mucocutaneous Candidiasis ◽  
Myeloperoxidase Activity ◽  
Mucocutaneous Candidiasis ◽  
Receptor Sites ◽  
Stimulation Of

Evaluation of a patient with chronic mucocutaneous candidiasis revealed that the patient lacked delayed hypersensitivity to candida and other skin test antigens and the patient's lymphocytes could not be stimulated in vitro with candida antigen. Phytohemagglutinin stimulation of lymphocytes in vitro was normal. Candidacidal function and myeloperoxidase activity of the patient's leukocytes were normal. The patient's lymphocytes produced migration inhibitory factor in response to candida antigen and the monocyte receptor sites for IgG were intact. Repeated treatments with amphotericin B, alone or with 5-fluorocytosine, were followed by immediate relapse. Four doses of transfer factor were administered and when coupled with amphotericin B on two occasions prompted remissions of 6 and 4 months, respectively.

scholarly journals Successful Therapy of a Patient with a Novel STAT1 Gain of Function Mutation and Life-Threatening Cytopenias with Janus Kinase Inhibitor Ruxolitinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3434-3434 ◽  
Author(s):  
Katja G. Weinacht ◽  
Louis m Charbonnier ◽  
Ashley Plant ◽  
Troy Torgerson ◽  
Sergei Rosenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Opportunistic Infections ◽  
Janus Kinase ◽  
Chronic Mucocutaneous Candidiasis ◽  
Gain Of Function ◽  
Mucocutaneous Candidiasis ◽  
Life Threatening ◽  
Ifn Γ ◽  
Tgf Β1

Abstract Monoallelic gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity. The immunodeficiency is caused by impaired IL-17 immunity and typically presents with chronic mucocutaneous candidiasis, variably associated with other opportunistic infections. The autoimmune manifestations due to exaggerated responsiveness to interferon are more diverse and include SLE, thyroiditis, hepatitis, and alopecia areata. The phenotypic spectrum of STAT1 GOF mutations is extremely wide, ranging from intermittent localized disease to chronic systemic illness and fatality. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor, leaving a void for alternate long-term strategies to control the disease and maintain remission. Recently, we diagnosed a patient suffering from chronic mucocutaneous candidiasis and life-threatening autoimmune cytopenias with a novel monoallelic mutation in the linker domain of STAT1 (c.1633G>A; p.E545K). The mutation caused a profound increase in STAT1 phosphorylation in response to type 1 and 2 interferon without affecting dephosphorylation kinetics, which is mechanistically distinct from all reported STAT1 GOF mutations to date. The potential of naïve patient CD4+ T cells to become IFN- γ or IL-17 producing cells was investigated under TH0 (anti-CD3/28), TH1 (anti-CD3/28, IL-12) and TH17 (anti-CD3/28, IL6, IL-23, TGF-β1) conditions and revealed that patient CD4+ T cells are biased to produce IFN-γ irrespective of polarizing conditions, and resistant to TH17 induction upon stimulation with IL6, IL-23 and TGF-β1. In addition, the patient's proportion of T follicular helper cells (TFH) relative to regulatory T cells (Treg) was increased. Treatment with the Janus Kinase (JAK) 1/2 inhibitor Ruxolitinib reduced the hyperresponsiveness to interferon, normalized the TH1 response, enabled naïve T cells to differentiate into TH17 cells and decreased the TFH to Treg ratio. Under therapeutic dose Ruxolitinib the patient maintained clinical remission with respect to both autoimmunity and mucocutaneous candidiasis. Conclusion: Clinical vigilance for an underlying immune dysregulation syndrome due to abnormal JAK-STAT signaling is critical when evaluating patients with autoimmunity combined with opportunistic infections as JAK-inhibitors represents an effective targeted therapy for long-term disease control even in severely affected patients for whom hematopoietic stem cell transplantation is not available. Disclosures Off Label Use: Ruxolitinib use for STAT1 GOF mutation.

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