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News Article | February 24, 2017

The deadly fungus, Candida auris, which has been found in hospitals, is resistant to entire classes of antimicrobial drugs, limiting treatment options for those infected. First reported in 2009, the fungus has been linked to invasive infections in nine countries, including the United States, and has caused at least two hospital outbreaks involving more than 30 patients each. Now, in a first-of-its-kind study published in Antimicrobial Agents and Chemotherapy, microbiologists at Case Western Reserve University School of Medicine have provided previously uninvestigated details pertaining to C. auris drug resistance and growth patterns. Based on specimens collected from around the globe, the comprehensive study also provides evidence that a new investigational drug (SCY-078) may help to cure these infections. "This emerging fungal species has started to infect patients globally, causing invasive infections that are associated with a high death rate," said Mahmoud Ghannoum, PhD, MBA, FIDSA, Professor and Director of the Center for Medical Mycology in the Department of Dermatology at Case Western Reserve School of Medicine, and University Hospitals Cleveland Medical Center. "It is multidrug-resistant, and some strains isolated from patients are resistant to all commercially available antifungal drugs. Multidrug-resistance used to be reported for bacteria only, and now we must add fungi to the list." Ghannoum led the investigation of 16 strains of C. auris collected from infected patients in Germany, Japan, Korea, and India. The researchers tested the isolates against a battery of 11 drugs, belonging to different classes of antifungals, to identify drug concentrations that could combat infection. While most samples proved at least partially resistant to drugs tested, low concentrations of an investigational drug (SCY-078) "severely distorted" the fungus and impaired its growth, providing an important step towards the development of this drug to treat C. auris infections. Fungi exposed to the drug could not divide, suggesting it could halt infections or limit their spread. Ghannoum's study is the first to provide details related to the effects of the investigational drug on C. auris. The fungus lurks on catheters in intensive care units, where it forms highly drug-resistant communities, or biofilms. Ghannoum's team exposed fungi in the laboratory to silicone surfaces mimicking catheters. Under high-powered microscopes, they found C. auris formed relatively thin biofilms that weakened when exposed to the investigational drug. The findings were strain-dependent, but suggest applicability for the new drug to combat catheter-associated infections in particular. Previous studies have shown the drug is effective against other Candida species that cause catheter-associated infections, including C. albicans and C. tropicalis. Said Ghannoum, "This drug is especially promising because of its broad anti-Candida activity, including activity against drug-susceptible and resistant strains." The study is also the first to report C. auris does not germinate and produce spores like other fungi, a surprise given its ability to rapidly spread in hospitals. The researchers also discovered only certain strains produce destructive enzymes that commonly help fungi establish infections in body tissue. Despite these apparent weaknesses, the fungus is able to maintain extreme drug-resistance and infect patients. According to the paper, the "multidrug-resistant phenotype of C. auris comes with a major fitness cost." Ghannoum's research provides a foundation for clinical trials to further study the investigational drug and informs doctors desperate for new ways to treat infections caused by C. auris. Said Ghannoum, "Understanding the virulence of C. auris and showing that the investigational drug is effective may lead to the development of new medications to combat this emerging health threat." The Centers for Disease Control and Prevention is actively tracking C. auris infections. Said Ghannoum, "Eradication of Candida auris from hospitals is very difficult and in some cases has led to closing hospital wards." People staying in hospitals for extended periods of time are most at risk. Laboratory workers who identify the species in a patient sample are encouraged to contact state or local public health authorities, or This research was supported in part by Scynexis Inc.; the National Institutes of Health (R01DE024228 to M.A.G. and P.K.M.); and the Swagelok Center for Surface Analysis of Materials, Skin Diseases Research Center (NIAMS P30 AR03970), and Confocal Scanning Laser Microscopy Core of the Genetics Department at Case Western Reserve University. For more information about Case Western Reserve University School of Medicine, please visit: http://case. .

Ahmad I.,Skin Diseases Research Center | Jimenez H.,Skin Diseases Research Center | Yaacob N.S.,Universiti Sains Malaysia | Yusuf N.,Skin Diseases Research Center | And 2 more authors.
Photochemistry and Photobiology | Year: 2012

Malaysian tualang honey possesses strong antioxidant and anti-inflammatory properties. Here, we evaluated the effect of tualang honey on early biomarkers of photocarcinogenesis employing PAM212 mouse keratinocyte cell line. Keratinocytes were treated with tualang honey (1.0%, v/v) before a single UVB (150 mJ cm-2) irradiation. We found that the treatment of tualang honey inhibited UVB-induced DNA damage, and enhanced repair of UVB-mediated formation of cyclobutane pyrimidine dimers and 8-oxo-7,8-dihydro-2'- deoxyguanosine. Treatment of tualang honey inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in murine keratinocyte cell line. The treatment of tualang honey also inhibited UVB-induced inflammatory cytokines and inducible nitric oxide synthase protein expression. Furthermore, the treatment of tualang honey inhibited UVB-induced COX-2 expression and PGE2 production. Taken together, we provide evidence that the treatment of tualang honey to keratinocytes affords substantial protection from the adverse effects of UVB radiation via modulation in early biomarkers of photocarcinogenesis and provide suggestion for its photochemopreventive potential. © 2012 Wiley Periodicals, Inc.

Nasti T.H.,Skin Diseases Research Center | Iqbal O.,Skin Diseases Research Center | Tamimi I.A.,Skin Diseases Research Center | Geise J.T.,Skin Diseases Research Center | And 6 more authors.
Photochemistry and Photobiology | Year: 2011

Ultraviolet (UV) radiation, in particular the midwavelength range (UVB; 290-320 nm), is one of the most significant risk factors for the development of nonmelanoma skin cancer. UVB radiation-induced immunosuppression, which occurs in both humans and laboratory animals, contributes to their pathogenesis. However, there are conflicting reports on the relative role of CD4+ and CD8+ T cells in UVB induced skin cancer. The purpose of this study was to delineate the contribution of these two cell subpopulations to UVB induced immunosuppression and tumor development using C3H/HeN (WT), CD4 knockout (CD4-/-) and CD8 knockout (CD8-/-) mice. We observed that UVB induced skin carcinogenesis was retarded in terms of number of tumors per group, tumor volume and percentage of mice with tumors, in mice deficient in CD4+ T cells compared with wild-type mice, whereas significantly greater (P < 0.05) numbers of tumors occurred in CD8-/- mice. These results indicate that, CD4+ T cells promote tumor development while CD8+ T cells have the opposite effect. Further, we found that CD4+ T cells from tumor-bearing mice produced interleukin (IL)-4, IL-10, and IL-17 whereas CD8+ T cells produced interferon-γ. Manipulation of T-cell subpopulations that are induced by UVB radiation could be a means of preventing skin cancers caused by this agent. © 2010 The American Society of Photobiology.

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