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Increasing mupirocin resistance in pediatric methicillin-resistant Staphylococcus aureus skin and soft-tissue infections in New York: A genomic approach
1747 Immune signatures of psoriasis: Comparison of genetic expression profiles in psoriasis patients after therapy with biologic agents Dario Kivelevitch, MD, Baylor Institute for Immunology Research, Dallas, TX, United States; Mamta Sharma, PhD, Baylor Institute for Immunology Research, Dallas, TX, United States; Bobbak Mansouri, MD, Baylor University Medical Center, Dallas, TX, United States; Mahir Patel, MD, Baylor University Medical Center, Dallas, TX, United States; Caitriona Ryan, MD, Baylor University Medical Center, Dallas, TX, United States; Alan Menter, MD, Baylor University Medical Center, Dallas, TX, United States; Gerlinde Obermoser, MD, Baylor Institute for Immunology Research, Dallas, TX, United States
Conclusions: Prevalence of mupirocin resistance in MRSA appears to have risen over recent years in our pediatric population, which raises the alarming possibility that mupirocin use could drive selection of MRSA. This emergence in resistance may be associated with spread of the mupA plasmid, rather than a strain epidemic. Future comparative and phylogenomic analysis will be needed to test the hypothesis of clonal expansion and contrast this with dissemination of the mupA plasmid into multiple lineages. Commercial support: None identified.
Background: Psoriasis is a chronic inflammatory skin disease associated with dysregulation of the immune system. Over 40 genes have been linked with its pathogenesis. Materials and methods: Adult patients with moderate to severe plaque psoriasis initiating either adalimumab or ustekinumab treatment were enrolled alongside healthy controls in this study. Patients were not allowed to use topicals treatments for 2 weeks, systemic medication for 4 weeks, TNFa inhibitors for 12 weeks, and ustekinumab for at least 24 weeks prior to enrollment. Blood samples were collected at baseline and after 16 weeks of therapy in TempusTM tubes for microarray analysis. Microarray data were analyzed with Genespring12. Results: A total of 35 patients (ustekinumab 24, adalimumab 11) and 32 healthy subjects were enrolled. Mean PASI was 15.4 and 5.6 at baseline and week 16, respectively (63.6% mean improvement). Seven patients treated with ustekinumab and 1 patient treated with adalimumab were non-responders to treatment at week 16. At baseline, 482 genes were differentially expressed (DEG) between untreated patients and healthy subjects (FDR P ¼ .05) (342 up-regulated and 142 downregulated). Using a modular analysis framework, we found up-regulation of modules related to inflammation (M4.2), interferon response (M1.2, M3.4 and M5.12) and neutrophils (M5.15) in psoriasis. Further analysis showed 73 DEG (FDR P ¼.05) (38 up-regulated and 35 down-regulated) between ustekinumab responders at week 16 compared to baseline with significant down-regulation in the IFN, PI3K signaling and carbohydrate metabolism pathways. Adalimumab responders at week 16 compared to baseline presented 200 DEG (P ¼ .01) (88 up-regulated and 112 down-regulated) with significant down-regulation of TLR, PPAR, and NF-Kß signaling pathways. We also found 57 DEG (P ¼ .01) (14 up-regulated and 43 down-regulated) that allowed us to differentiate ustekinumab responders from nonresponders at baseline. The most significant differences in responders compared to non-responders were up-regulation of HLA-DRB4 and carbohydrates metabolism pathways and down-regulation of tetrahydrobiopterin synthesis. Conclusions: We describe a discrete psoriasis signature in the blood relating mainly to inflammation, interferon and myeloid linage transcripts. Furthermore our preliminary results suggest that blood microarray biomarkers may have the potential to be a valuable assessment tool to predict treatment response in individual patients. Commercial support: None.
639 Increasing mupirocin resistance in pediatric methicillin-resistant Staphylococcus aureus skin and soft-tissue infections in New York: A genomic approach Margo Lederhandler, Columbia University Medical Center, New York, NY, United States; Hannah Smith, Columbia University Medical Center, New York, NY, United States; Chanelle Ryan, Columbia University Medical Center, New York, NY, United States; Lorena Diaz, PhD, Universidad El Bosque, Bogota, Colombia; Malcolm Rothmann, Columbia University Medical Center, New York, NY, United States; Susan Whittier, PhD, Columbia University Medical Center, New York, NY, United States; Christine Lauren, MD, Columbia University Medical Center, New York, NY, United States; Paul Planet, MD, PhD, Columbia University Medical Center and American Museum of Natural History, New York, NY, United States Background: Topical mupirocin is widely used for outpatient management of Staphylococcus aureus cutaneous infection and decolonization in both the inpatient and outpatient settings. Recent studies have suggested a strong association between exposure to mupirocin and development of resistance. The prevalence of high-level mupirocin resistance, conferred by the plasmid-borne mupA gene, could be increased by either selection of mupirocin-resistant clones or through spread of the plasmid. Objectives: To determine the prevalence of mupirocin resistance over time in pediatric methicillin-resistant S aureus (MRSA) skin and soft-tissue infection (SSTI), and to test the hypothesis that the increase in resistance is due to clonal expansion of a particular strain of MRSA. Methods: We performed a retrospective cohort study. A consecutive convenience sampling of MRSA, previously collected and routinely stored, from children under 18 with SSTI at CUMC Children’s Hospital and affiliated outpatient centers from similar dates over the year was conducted for 2010-2012. In total, 239 samples were obtained and E-tested for mupirocin resistance. Whole genomes were sequenced using the MiSeq and Illumina platforms for 4 MRSA isolates, 2 of which were mupirocin-resistant, from patients with atopic dermatitis (AD). Results: The overall rate of resistance was 13.4% (32/239 samples). We saw a rise in MRSA mupirocin resistance across the 3 years: 11.8% in 2010 (9/76 samples), 12.7% in 2011 (10/79 samples), and 15.5% in 2012 (13/84 samples). Of the 4 MRSA samples chosen for whole genome sequencing from patients with known AD, all were found to be multilocus sequence type 8 and clonal complex 8; the 2 mupirocin-resistant samples were spa type t008 and t068, while the 2 sensitive samples were t008 and t064. Both mupirocin-resistant samples carried the mupA gene. Only one of the resistant samples carried the ACME and speG genes, while both carried sek, seq, lukS-PV and lukF-PV genes.
MAY 2015
1940 Maintaining the folliculogenicity of adult cultured epidermal cells Chih-Chieh (Tom) Chan, MD, Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan; Mai-Yi Fan, MS, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Wei-Hung Wang, MS, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Sung-Jan Lin, MD, PhD, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan Current options in treating androgenetic alopecia include surgical redistribution of hairs and medical treatments with oral finasteride and topical minoxidil. These clinically available surgical or nonsurgical treatment modalities do not increase a patient’s follicular units and are only effectual on mild or moderate hair loss individuals. To ultimately solve the problem of hair loss, the best way is to generate new hair follicles. In previous works of bioengineering new hair miniorgans, newborn epidermal cells are required to develop de novo hair formation, with the consideration that cell source would be a problem in clinical application. Therefore, to establish bioengineering follicular unit from in vitro expanded adult cells would be the major task in hair regeneration field, and the most critical problem is the elasticity and availability of adult cells. Successful hair follicle neogenesis in adult life depends on existence of both capable dermal cells and epidermal keratinocytes that recapitulate embryonic organogenesis. In tissue engineering, the maintenance and restoration of the trichogenic potential of epidermal cells while expanding them remains a challenge since adult epidermal cells lose trichogenicity upon cultivation. To solve the problem, we used adult dermal papilla cells as an instructive feeder to guide the cultivated adult keratinocyte differentiation. These educated keratinocytes were able to produce new hair fibers in hair regeneration patch assay after coculture with dermal papillar cells, which implies the in vitro mesenchymalepithelial interaction help to regain the trichogenicity of cultivated adult epidermal cells. Cultivated keratinocytes showed significant follicular genes expression with dermal papilla cell feeder support, indicating the cells were poised toward a hair follicle fate. And this process is associated with activated Wnt/beta-catenin signaling. This study demonstrates a platform on which new hair regeneration can be achieved by cultured adult cells. Commercial support: None identified.
J AM ACAD DERMATOL
AB31
Conclusions: Prevalence of mupirocin resistance in MRSA appears to have risen over recent years in our pediatric population, which raises the alarming possibility that mupirocin use could drive selection of MRSA. This emergence in resistance may be associated with spread of the mupA plasmid, rather than a strain epidemic. Future comparative and phylogenomic analysis will be needed to test the hypothesis of clonal expansion and contrast this with dissemination of the mupA plasmid into multiple lineages. Commercial support: None identified.
Background: Psoriasis is a chronic inflammatory skin disease associated with dysregulation of the immune system. Over 40 genes have been linked with its pathogenesis. Materials and methods: Adult patients with moderate to severe plaque psoriasis initiating either adalimumab or ustekinumab treatment were enrolled alongside healthy controls in this study. Patients were not allowed to use topicals treatments for 2 weeks, systemic medication for 4 weeks, TNFa inhibitors for 12 weeks, and ustekinumab for at least 24 weeks prior to enrollment. Blood samples were collected at baseline and after 16 weeks of therapy in TempusTM tubes for microarray analysis. Microarray data were analyzed with Genespring12. Results: A total of 35 patients (ustekinumab 24, adalimumab 11) and 32 healthy subjects were enrolled. Mean PASI was 15.4 and 5.6 at baseline and week 16, respectively (63.6% mean improvement). Seven patients treated with ustekinumab and 1 patient treated with adalimumab were non-responders to treatment at week 16. At baseline, 482 genes were differentially expressed (DEG) between untreated patients and healthy subjects (FDR P ¼ .05) (342 up-regulated and 142 downregulated). Using a modular analysis framework, we found up-regulation of modules related to inflammation (M4.2), interferon response (M1.2, M3.4 and M5.12) and neutrophils (M5.15) in psoriasis. Further analysis showed 73 DEG (FDR P ¼.05) (38 up-regulated and 35 down-regulated) between ustekinumab responders at week 16 compared to baseline with significant down-regulation in the IFN, PI3K signaling and carbohydrate metabolism pathways. Adalimumab responders at week 16 compared to baseline presented 200 DEG (P ¼ .01) (88 up-regulated and 112 down-regulated) with significant down-regulation of TLR, PPAR, and NF-Kß signaling pathways. We also found 57 DEG (P ¼ .01) (14 up-regulated and 43 down-regulated) that allowed us to differentiate ustekinumab responders from nonresponders at baseline. The most significant differences in responders compared to non-responders were up-regulation of HLA-DRB4 and carbohydrates metabolism pathways and down-regulation of tetrahydrobiopterin synthesis. Conclusions: We describe a discrete psoriasis signature in the blood relating mainly to inflammation, interferon and myeloid linage transcripts. Furthermore our preliminary results suggest that blood microarray biomarkers may have the potential to be a valuable assessment tool to predict treatment response in individual patients. Commercial support: None.
639 Increasing mupirocin resistance in pediatric methicillin-resistant Staphylococcus aureus skin and soft-tissue infections in New York: A genomic approach Margo Lederhandler, Columbia University Medical Center, New York, NY, United States; Hannah Smith, Columbia University Medical Center, New York, NY, United States; Chanelle Ryan, Columbia University Medical Center, New York, NY, United States; Lorena Diaz, PhD, Universidad El Bosque, Bogota, Colombia; Malcolm Rothmann, Columbia University Medical Center, New York, NY, United States; Susan Whittier, PhD, Columbia University Medical Center, New York, NY, United States; Christine Lauren, MD, Columbia University Medical Center, New York, NY, United States; Paul Planet, MD, PhD, Columbia University Medical Center and American Museum of Natural History, New York, NY, United States Background: Topical mupirocin is widely used for outpatient management of Staphylococcus aureus cutaneous infection and decolonization in both the inpatient and outpatient settings. Recent studies have suggested a strong association between exposure to mupirocin and development of resistance. The prevalence of high-level mupirocin resistance, conferred by the plasmid-borne mupA gene, could be increased by either selection of mupirocin-resistant clones or through spread of the plasmid. Objectives: To determine the prevalence of mupirocin resistance over time in pediatric methicillin-resistant S aureus (MRSA) skin and soft-tissue infection (SSTI), and to test the hypothesis that the increase in resistance is due to clonal expansion of a particular strain of MRSA. Methods: We performed a retrospective cohort study. A consecutive convenience sampling of MRSA, previously collected and routinely stored, from children under 18 with SSTI at CUMC Children’s Hospital and affiliated outpatient centers from similar dates over the year was conducted for 2010-2012. In total, 239 samples were obtained and E-tested for mupirocin resistance. Whole genomes were sequenced using the MiSeq and Illumina platforms for 4 MRSA isolates, 2 of which were mupirocin-resistant, from patients with atopic dermatitis (AD). Results: The overall rate of resistance was 13.4% (32/239 samples). We saw a rise in MRSA mupirocin resistance across the 3 years: 11.8% in 2010 (9/76 samples), 12.7% in 2011 (10/79 samples), and 15.5% in 2012 (13/84 samples). Of the 4 MRSA samples chosen for whole genome sequencing from patients with known AD, all were found to be multilocus sequence type 8 and clonal complex 8; the 2 mupirocin-resistant samples were spa type t008 and t068, while the 2 sensitive samples were t008 and t064. Both mupirocin-resistant samples carried the mupA gene. Only one of the resistant samples carried the ACME and speG genes, while both carried sek, seq, lukS-PV and lukF-PV genes.
MAY 2015
1940 Maintaining the folliculogenicity of adult cultured epidermal cells Chih-Chieh (Tom) Chan, MD, Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan; Mai-Yi Fan, MS, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Wei-Hung Wang, MS, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Sung-Jan Lin, MD, PhD, Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan Current options in treating androgenetic alopecia include surgical redistribution of hairs and medical treatments with oral finasteride and topical minoxidil. These clinically available surgical or nonsurgical treatment modalities do not increase a patient’s follicular units and are only effectual on mild or moderate hair loss individuals. To ultimately solve the problem of hair loss, the best way is to generate new hair follicles. In previous works of bioengineering new hair miniorgans, newborn epidermal cells are required to develop de novo hair formation, with the consideration that cell source would be a problem in clinical application. Therefore, to establish bioengineering follicular unit from in vitro expanded adult cells would be the major task in hair regeneration field, and the most critical problem is the elasticity and availability of adult cells. Successful hair follicle neogenesis in adult life depends on existence of both capable dermal cells and epidermal keratinocytes that recapitulate embryonic organogenesis. In tissue engineering, the maintenance and restoration of the trichogenic potential of epidermal cells while expanding them remains a challenge since adult epidermal cells lose trichogenicity upon cultivation. To solve the problem, we used adult dermal papilla cells as an instructive feeder to guide the cultivated adult keratinocyte differentiation. These educated keratinocytes were able to produce new hair fibers in hair regeneration patch assay after coculture with dermal papillar cells, which implies the in vitro mesenchymalepithelial interaction help to regain the trichogenicity of cultivated adult epidermal cells. Cultivated keratinocytes showed significant follicular genes expression with dermal papilla cell feeder support, indicating the cells were poised toward a hair follicle fate. And this process is associated with activated Wnt/beta-catenin signaling. This study demonstrates a platform on which new hair regeneration can be achieved by cultured adult cells. Commercial support: None identified.
J AM ACAD DERMATOL
AB31