Acute myeloid leukaemia presenting with ecthyma gangrenosum as the first manifestation: A case report.

RATIONALE: Ecthyma gangrenosum (EG) is an uncommon cutaneous infection usually associated with Pseudomonas aeruginosa bacteremia in immunocompromised patients, particularly those with underlying malignant diseases. Despite its rarity, especially in immunocompetent or nondiagnosed immunodeficiency patients, EG can present as the first manifestation of an underlying immunosuppression. PATIENT CONCERNS: A 42-year-old Japanese man was admitted to our hospital with a 3-day history of a painless red macule on his right forearm and fever. DIAGNOSES: Blood culture on admission revealed the presence of Pseudomonas aeruginosa, whereas pus culture of the skin lesion showed Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus positivity. INTERVENTIONS: Additional bone marrow aspirate examination and immunophenotyping were performed to confirm the diagnosis of acute promyelocytic leukaemia with PML-retinoic acid alpha receptor. OUTCOMES: The patient was successfully treated with a 14-day course of antibiotics, and no evidence of relapse was noted. The patient achieved complete remission after treatment for acute promyelocytic leukaemia. LESSONS: It should be kept in mind that EG is an important cutaneous infection that is typically associated with P aeruginosa bacteremia and the presence of underlying immunodeficiency, such as acute leukaemia.

Staphylococcus epidermidis protease EcpA can be a deleterious component of the skin microbiome in atopic dermatitis.

BACKGROUND: Staphylococcus aureus and Staphylococcus epidermidis are the most abundant bacteria found on the skin of patients with atopic dermatitis (AD). S aureus is known to exacerbate AD, whereas S epidermidis has been considered a beneficial commensal organism. OBJECTIVE: In this study, we hypothesized that S epidermidis could promote skin damage in AD by the production of a protease that damages the epidermal barrier. METHODS: The protease activity of S epidermidis isolates was compared with that of other staphylococcal species. The capacity of S epidermidis to degrade the barrier and induce inflammation was examined by using human keratinocyte tissue culture and mouse models. Skin swabs from atopic and healthy adult subjects were analyzed for the presence of S epidermidis genomic DNA and mRNA. RESULTS: S epidermidis strains were observed to produce strong cysteine protease activity when grown at high density. The enzyme responsible for this activity was identified as EcpA, a cysteine protease under quorum sensing control. EcpA was shown to degrade desmoglein-1 and LL-37 in vitro, disrupt the physical barrier, and induce skin inflammation in mice. The abundance of S epidermidis and expression of ecpA mRNA were increased on the skin of some patients with AD, and this correlated with disease severity. Another commensal skin bacterial species, Staphylococcus hominis, can inhibit EcpA production by S epidermidis. CONCLUSION: S epidermidis has commonly been regarded as a beneficial skin microbe, whereas S aureus has been considered deleterious. This study suggests that the overabundance of S epidermidis found on some atopic patients can act similarly to S aureus and damage the skin by expression of a cysteine protease.

Staphylococcus epidermidis Boosts Innate Immune Response by Activation of Gamma Delta T Cells and Induction of Perforin-2 in Human Skin.

Perforin-2 (P-2) is an antimicrobial protein with unique properties to kill intracellular bacteria. Gamma delta (GD) T cells, as the major T cell population in epithelial tissues, play a central role in protective and pathogenic immune responses in the skin. However, the tissue-specific mechanisms that control the innate immune response and the effector functions of GD T cells, especially the cross-talk with commensal organisms, are not very well understood. We hypothesized that the most prevalent skin commensal microorganism, Staphylococcus epidermidis, may play a role in regulating GD T cell-mediated cutaneous responses. We analyzed antimicrobial protein P-2 expression in human skin at a single cell resolution using an amplified fluorescence in situ hybridization approach to detect P-2 mRNA in combination with immunophenotyping. We show that S. epidermidis activates GD T cells and upregulates P-2 in human skin ex vivo in a cell-specific manner. Furthermore, P-2 upregulation following S. epidermidis stimulation correlates with increased ability of skin cells to kill intracellular Staphylococcus aureus. Our findings are the first to reveal that skin commensal bacteria induce P-2 expression, which may be utilized beneficially to modulate host innate immune responses and protect from skin infections.

Resident macrophages acquire innate immune memory in staphylococcal skin infection.

Staphylococcus aureus (S. aureus) is a common colonizer of healthy skin and mucous membranes. At the same time, S. aureus is the most frequent cause of skin and soft tissue infections. Dermal macrophages (Mφ) are critical for the coordinated defense against invading S. aureus, yet they have a limited life span with replacement by bone marrow derived monocytes. It is currently poorly understood whether localized S. aureus skin infections persistently alter the resident Mφ subset composition and resistance to a subsequent infection. In a strictly dermal infection model we found that mice, which were previously infected with S. aureus, showed faster monocyte recruitment, increased bacterial killing and improved healing upon a secondary infection. However, skin infection decreased Mφ half-life, thereby limiting the duration of memory. In summary, resident dermal Mφ are programmed locally, independently of bone marrow-derived monocytes during staphylococcal skin infection leading to transiently increased resistance against a second infection.

Staphylococcus aureus Fatty Acid Kinase FakA Modulates Pathogenesis during Skin Infection via Proteases.

Staphylococcus aureus fatty acid kinase FakA is necessary for the incorporation of exogenous fatty acids into the lipid membrane. We previously demonstrated that the inactivation of fakA leads to decreased α-hemolysin (Hla) production but increased expression of the proteases SspAB and aureolysin in vitro, and that the ΔfakA mutant causes larger lesions than the wild type (WT) during murine skin infection. As expected, necrosis is Hla dependent in the presence or absence of FakA, as both hla and hla ΔfakA mutants are unable to cause necrosis of the skin. At day 4 postinfection, while the ΔfakA mutant maintains larger and more necrotic abscesses, bacterial numbers are similar to those of the WT, indicating the enhanced tissue damage of mice infected with the ΔfakA mutant is not due to an increase in bacterial burden. At this early stage of infection, skin infected with the ΔfakA mutant has decreased levels of proinflammatory cytokines, such as interleukin-17A (IL-17A) and IL-1α, compared to those of WT-infected skin. At a later stage of infection (day 7), abscess resolution and bacterial clearance are hindered in ΔfakA mutant-infected mice. The paradoxical findings of decreased Hla in vitro but increased necrosis in vivo led us to investigate the role of the proteases regulated by FakA. Utilizing Δaur and ΔsspAB mutants in both the WT and fakA mutant backgrounds, we found that the absence of these proteases in a fakA mutant reduced dermonecrosis to levels similar to those of the WT strain. These studies suggest that the overproduction of proteases is one factor contributing to the enhanced pathogenesis of the ΔfakA mutant during skin infection.

Structural Superiority of Guanidinium-Rich, Four-Armed Copolypeptides: Role of Multiple Peptide-Membrane Interactions in Enhancing Bacterial Membrane Perturbation and Permeability.

The development of novel antimicrobials is a top priority to address the growing epidemic of multidrug-resistant pathogens. Since cationic nonamphiphilic star-shaped antimicrobials are promising molecular scaffolds that provide a high charge density in binding anionic bacterial bilayers, this research aimed to further increase their membrane perturbation capability by introducing guanidinium groups to the antimicrobials via enhancing membrane insertion. In particular, computational simulation and experimental investigations revealed that our designed guanidinium-rich alternating copolypeptide, four-armed poly(arginine-alt-glycine), can interact with both the headgroups and unsaturated tails of phospholipids in bacterial membranes through multiple interactions, including electrostatic, cation-π, and T-shaped π-π interactions, allowing it to penetrate deeper inside the biologically inaccessible high-energy barrier of the hydrophobic lipid bilayer interior to cause membrane permeabilization and precipitation of the bacterial cytoplasm. Furthermore, glycine was observed to have a unique effect in enhancing the performance of arginine-based copolypeptide. Four-armed poly(arginine-alt-glycine) exhibited broad-spectrum antimicrobial activity, high bactericidal efficiency, and negligible hemolysis. The in vivo antibacterial performance of the copolypeptide was superior to that of doxycycline in a mouse model of Pseudomonas aeruginosa skin infection, accompanied by negligible local and systemic toxicity. Our results demonstrate that this guanidinium-rich, nonamphiphilic, star-shaped structure may promote the development of next-generation antimicrobials.

Uncommon Association Between Diabetic Ketoacidosis, Thyrotoxicosis, Cutaneous Abscess and Acute Pericarditis in an Immunocompetent Patient: A Single Case Report and Literature Review.

INTRODUCTION: The typical factors precipitating diabetic ketoacidosis (DKA) include infections (30%), cessation of antidiabetic medication (20%), and a new diagnosis of diabetes (25%). The etiology remains unknown in 25% of cases. Less frequent causes cited in the literature include severe thyrotoxicosis and, infrequently, pericarditis. Few publications have described the role of human T lymphotropic virus type 1 (HTLV-1) in endocrine and metabolic disorders. Based on a clinical case associated with several endocrine and metabolic disorders, we suggest a potential role for HTLV-1, an endemic virus in the Amazonian area, and review the literature concerning the role of this virus in thyroiditis, pericarditis and diabetes mellitus. CASE REPORT: A fifty-year-old Surinamese woman without any medical history was admitted for diabetic ketoacidosis. No specific anti-pancreatic autoimmunity was observed, and the C-peptide level was low, indicating atypical type-1 diabetes mellitus. DKA was associated with thyrotoxicosis in the context of thyroiditis and complicated by nonbacterial pericarditis and a Staphylococcus aureus subcutaneous abscess. The patient was infected with HTLV-1. CONCLUSION: To our knowledge, this uncommon association is described for the first time. Few studies have analyzed the implications of HTLV-1 infection in thyroiditis and diabetes mellitus. We did not find any reports describing the association of pericarditis with HTLV-1 infection. Additional studies are necessary to understand the role of HTLV-1 in endocrine and cardiac disorders.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in erythrodermic cutaneous T-cell lymphoma (CTCL) patients.

Erythroderma can occur in cutaneous T-cell lymphoma (CTCL). Staphylococcus aureus (S. aureus) prevalence is increased in CTCL patients and contributes to CTCL disease flares. Our primary aim was to describe S. aureus infections, including resistance patterns and the antibiotic treatment regimens used, in erythrodermic CTCL patients. This was a retrospective chart review of erythrodermic CTCL patients who had S. aureus infection or colonization and were treated at the UT MD Anderson Cancer Center's Melanoma Skin Center between 2012 and 2016. Twenty-six erythrodermic CTCL patients had 50 documented S. aureus colonization or infection events. Patients had an improvement in body surface area (BSA) or modified Severity Weighted Assessment Tool (mSWAT) in 53% events treated for S. aureus. Seventeen of the 50 (34%) events were due to methicillin-resistant S. aureus (MRSA). One-third (33%) of MRSA events were initially treated with dicloxacillin. The MRSA isolates were sensitive to trimethoprim-sulfamethoxazole (92%) and doxycycline (88%). Patients treated in the outpatient setting (OR 0.073; 95% CI 0.008-0.627; p = 0.017) and patients with a previous history of topical anti-S. aureus decolonization treatments before S. aureus event as stand-alone (OR 0.125; 95% CI 0.018-0.887; p = 0.038) or in combination treatment with systemic antibiotics (OR 0.094; 95% CI 0.009-0.944; p = 0.045) were less likely to see improvement in BSA or mSWAT from S. aureus treatment. Treatment of S. aureus improved CTCL skin score in a high number of erythrodermic patients. The MRSA prevalence was high in erythrodermic CTCL patients. Clinicians should consider using empiric MRSA antibiotic coverage for these patients.

Microbiologic characteristics and antibiotic resistance rates of diabetic foot infections / Perfil microbiológico e de resistência bacteriana no pé diabético infectado

ABSTRACT Purpose: the purpose of this research was to identify the sociodemographic and microbiological characteristics and antibiotic resistance rates of patients with diabetic foot infections, hospitalized in an emergency reference center. Methods: it was an observational and transversal study. The sociodemographic data were collected by direct interview with the patients. During the surgical procedures, specimens of tissue of the infected foot lesions were biopsied to be cultured, and for bacterial resistance analysis. Results: the sample consisted of 105 patients. The majority of patierns were men, over 50 years of age, married and with low educational level. There was bacterial growth in 95 of the 105 tissue cultures. In each positive culture only one germ was isolated. There was a high prevalence of germs of the Enterobacteriaceae family (51,5%). Gram-negative germs were isolated in 60% of cultures and the most individually isolated germs were the Gram-positive cocci, Staphylococcus aureus (20%) and Enterococcus faecalis (17,9%). Regarding antibiotic resistance rates, a high frequency of Staphylococcus aureus resistant to methicillin (63,0%) and to ciprofloxacin (55,5%) was found; additionally, 43,5% of the Gram-negative isolated germs were resistant to ciprofloxacin. Conclusions: the majority of patients were men, over 50 years of age, married and with low educational level. The most prevalent isolated germs from the infected foot lesions were Gram-negative bacteria, resistant to ciprofloxacin, and the individually most isolated germ was the methicillin resistant Staphylococcus aureus.

RESUMO Objetivo: identificar o perfil sociodemográfico, microbiológico e de resistência bacteriana em pacientes com pé diabético infectado. Métodos: tratou-se de estudo observacional, transversal que avaliou os perfis sóciodemográfico e microbiológico de pacientes portadores de pé diabético infectado internados em Pronto Socorro de referência. Os dados sociodemográficos foram coletados por meio de entrevista. Foram colhidos, durante os procedimentos cirúrgicos, fragmentos de tecidos das lesões podais infectadas para realização de cultura/antibiograma. Resultados: a amostra foi composta por 105 pacientes. O perfil sociodemográfico mais prevalente foi o de pacientes do sexo masculino, acima dos 50 anos, casados e com baixa escolaridade. Das 105 amostras de fragmentos de tecidos colhidos para realização de cultura e antibiograma, 95 foram positivas, com crescimento de um único germe em cada um dos exames. Houve predomínio de germes da família Enterobacteriaceae (51,5%). Germes Gram-negativos foram isolados em 60,0% das culturas e os espécimes mais isolados individualmente foram os cocos Gram-positivos, Staphylococcus aureus (20,0%) e Enterococcus faecalis (17,9%). Considerando-se os perfis de resistência bacteriana, verificou-se alta taxa de Staphylococcus aureus resistente à meticilina (63,0%) e à ciprofloxacino (55,5%); verificou-se, também, que 43,5% dos germes Gram-negativos eram resistentes à ciprofloxacino. Conclusões: o perfil sociodemográfico majoritário, foi o de homens, com mais de 50 anos e com baixa escolaridade. Concluímos que os germes mais prevalentes nas lesões podais dos pacientes diabéticos foram os Gram-negativos, resistentes ao ciprofloxacino e que o germe mais isolado individualmente foi o Staphylococcus aureus resistente à meticilina.

The bactericidal effect of lysostaphin coupled with liposomal vancomycin as a dual combating system applied directly on methicillin-resistant Staphylococcus aureus infected skin wounds in mice.

BACKGROUND AND AIM: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of surgical infection, and its resistance to numerous conventional antibiotics makes treatment difficult. Although vancomycin is often an effective agent for the initial therapy of MRSA, clinical failure sometimes occurs. Therefore, there is an urgent need to develop better therapies. Here, we prepared some vancomycin-loaded nanoliposomes coupled with anti-staphylococcal protein (lysostaphin) and evaluated their in vitro and in vivo efficacy as a topical MRSA therapy. METHODS: Vancomycin was encapsulated in liposomes, and the coupling of lysostaphin with the surface of liposomes was carried out through cyanuric functional groups. The bactericidal efficacies and a full characterization were evaluated. To define different nanoliposomal-bacterium interactions and their bactericidal effect, flow cytometry was employed. Finally, in vivo, the topical antibacterial activity of each formulation was measured against surgical wound MRSA infection in a mouse model. RESULTS: High encapsulation and conjugation efficiency were achieved for all formulations. All the formulations showed a significant reduction in bacterial counts (p<0.05). The targeted liposomes more effectively suppress bacterial infection in vitro and in vivo relative to equivalent doses of untargeted vancomycin liposome. The flow cytometry results confirmed liposome-bacterium interactions, which increased during the incubation time. The maximum binding rate and the bactericidal effect were significantly higher in targeted liposomes (p<0.05) compared with control liposomes. CONCLUSION: Our data suggest a novel nano-vehicle (lysostaphin-conjugated coupled liposomal vancomycin) which could be used as a great topical antimicrobial construct for treatment of MRSA skin infections.

Staphylococcus aureus Epicutaneous Infection Is Suppressed by Lactococcus lactis Strain Plasma via Interleukin 17A Elicitation.

BACKGROUND: Lactococcus lactis strain Plasma (LC-Plasma) was revealed to stimulate plasmacytoid dendritic cells and induce antiviral immunity in vitro and in vivo. In this study, we assessed the effects of LC-Plasma on skin immunity. METHODS: To evaluate the effect of LC-Plasma on skin immunity and Staphylococcus aureus epicutaneous infection, lymphocyte activities in skin-draining lymph nodes (SLNs) and gene expression in skin were analyzed after 2 weeks of oral administration of LC-Plasma. To evaluate the mechanisms of interleukin 17A production, SLN lymphocytes were cultured with or without LC-Plasma, and the interleukin 17A concentrations in supernatants were measured. RESULTS: Oral administration of LC-Plasma activated plasma dendritic cells in SLNs, augmented skin homeostasis, and elicited suppression of Staphylococcus aureus, Staphylococcus epidermidis, and Propionibacterium acnes proliferation. In addition, significant suppression of the S. aureus burden and reduced skin inflammation were observed following oral administration of LC-Plasma. Furthermore, a subsequent in vitro study revealed that LC-Plasma could elicit interleukin 17A production from CD8+ T cells and that its induction mechanism depended on the Toll-like receptor 9 signaling pathway, with type I interferon partially involved. CONCLUSIONS: Our results suggest that LC-Plasma oral administration enhances skin homeostasis via plasma dendritic cell activation in SLNs, resulting in suppression of S. aureus epicutaneous infection and skin inflammation.

Caracterización de los pacientes con bacteriemia por Staphylococcus aureus resistente a la meticilina en un hospital militar de alta complejidad / Characterization of patients with bacteremia by methicillin-resistant Staphylococcus aureus in a high-complexity military hospital

Resumen Introducción. En las Fuerzas Militares de Colombia, cerca de 500.000 de sus miembros asisten a consulta en los establecimientos sanitarios militares. En esta población, Staphylococcus aureus resistente a la meticilina (SAMR) se ha convertido en un agente patógeno de gran incidencia. Objetivo. Caracterizar los pacientes con diagnóstico de bacteriemia por SAMR en el Hospital Militar Central entre el 2012 y el 2015. Materiales y métodos. Se llevó a cabo un estudio observacional descriptivo de revisión retrospectiva de historias clínicas de pacientes mayores de 18 años, hospitalizados y con hemocultivos positivos para S. aureus resistente a la meticilina. Para la identificación de los pacientes se empleó el sistema Whonet, version 5.6. Resultados. De los 177 cultivos positivos para S. aureus, el 24,8 % (n=44) correspondió a SAMR, con mayor prevalencia en pacientes militares activos(n=20m 45,4 %). Se observó una frecuencia similar para la bacteriemia por SAMR adquirida en la comunidad y la adquirida en el hospital, siendo más frecuente (n=37, 84 %) el fenotipo de la comunidad en ambos grupos. El principal foco infeccioso fueron los tejidos blandos, seguidos por el tejido pulmonar. Se presentaron mayores tasas de complicaciones (61%, n=13) en la bacteriemia adquirida en el hospital; 34,9 % (n=15),de los pacientes tuvieron una estancia hospitalaria prolongada atribuible a las complicaciones desencadenadas por la bacteriemia. Conclusiones. La población más afectada por SAMR fueron los pacientes militares activos (n=20, 45,4 %), con una frecuencia similar de la bacteriemia adquirida en la comunidad (n=18, 43,2 %) y la adquirida en el hospital (n=25, 56,8 %), y el principal foco infeccioso fueron los tejidos blandos. Dados estos resultados, es necesario adelantar estudios para establecer la prevalencia de infecciones por SAMR en la piel.

Abstract Introduction: In Colombia, there are about 500,000 members in the national armed forces who consult military health institutions. In this population, methicillin-resistant Staphylococcus aureus (MRSA) has become a high-incidence pathogen. Objective: The aim of this study was to characterize patients with MRSA bacteremia in the Hospital Militar Central between 2012 and 2015. Materials and methods: This was an observational descriptive study with a retrospective review of clinical histories of hospitalized patients older than 18 years of age with positive blood cultures for methicillin-resistant S. aureus. The identification of the patients was made using the Whonet system, version 5.6. Results: From cultures positive for S. aureus, 24.8% were methicillin-resistant strains, with a higher prevalence in active military personnel. A similar frequency was observed for community-acquired MRSA bacteremias and those acquired at the hospital, with the community phenotype being the most frequent in both groups. The main infectious focus related to the development of bacteremia was soft tissue, followed by pulmonary tissue. There were higher complication rates in nosocomial bacteremias; 34.9% of the patients had prolonged stays attributable to complications triggered by the bacteremia. Conclusions: Active military personnel was the most affected population by MRSA, with a similar frequency in community-acquired and nosocomial bacteremias. The main infectious focus was soft tissue. Taking into account these data, studies that establish the prevalence of skin infections by MRSA should be carried out.

Resistance to leukocytes ties benefits of quorum sensing dysfunctionality to biofilm infection.

Social interactions play an increasingly recognized key role in bacterial physiology1. One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density2. While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in vitro culture. This has been explained by the fitness cost an individual mutant, a 'quorum cheater', saves at the expense of the community3. QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection4, as well as medical device infection and associated bacteraemia5-7. However, despite the frequently proposed use of QS blockers to control virulence8, the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here, we show that in the major human pathogen Staphylococcus aureus, quorum cheaters arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in vivo setting. Our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.

A new T helper 17 cytokine in hidradenitis suppurativa: antimicrobial and proinflammatory role of interleukin-26.

BACKGROUND: Interleukin (IL)-26 is a signature T helper 17 cytokine described as a proinflammatory and antimicrobial mediator. So far, IL-26 has been reported in several immune-mediated inflammatory diseases, but its involvement in inflammatory skin disorders is poorly known. OBJECTIVES: To investigate the role of IL-26 in hidradenitis suppurativa (HS), through its involvement in antimicrobial activity. METHODS: IL-26 was assessed in patients with HS through gene expression and protein analysis at skin and circulating levels. Ex vivo HS organ skin cultures, together with IL-26 antibody treatment, were performed to determine the IL-26 activity. Peripheral blood mononuclear cells (PBMCs) from patients with HS and healthy controls were either silenced or not with IL-26 small interfering (si)RNA in order to measure its antimicrobial, cytotoxic and phagocytic activities against Staphylococcus aureus. RESULTS: Firstly, we observed that IL-26 is able to modulate the proinflammatory response at the immune cell level. IL-26 was increased in the plasma of patients with HS compared with healthy controls. Subsequently, we explored the bactericidal, cytotoxic and phagocytic activities of PBMCs against S. aureus in patients with HS and healthy controls. These activities were lower in patients with HS than in controls. Remarkably, the killing activities were reduced when healthy control PBMCs were transfected with IL-26 siRNA. However, the transfection did not affect the killing activity of HS PBMCs, supporting the idea that IL-26 lacks efficacy in HS. CONCLUSIONS: Our findings suggest that infection susceptibility in HS might be related to IL-26. Although the role of bacteria remains controversial in HS, this paper supports that there is a defect of antimicrobial response in these patients. What's already known about this topic? Interleukin (IL)-26 is a T helper 17 cytokine described as an antimicrobial and proinflammatory mediator. IL-26 has been reported in immune-mediated inflammatory diseases, but its involvement in inflammatory skin disorders remains unclear. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder characterized by deficiency of IL-20 and IL-22 (a close homologue of IL-26), which causes antimicrobial peptide pauperization leading to severe and recurrent skin infections. What does this study add? IL-26 plasma levels are higher in patients with HS than in healthy control individuals. The antimicrobial activity of IL-26 might be ineffective in patients with HS. What is the translational message? Cutaneous antimicrobial incompetence in HS could be related to IL-26.

Characterization, mechanism of action and optimization of activity of a novel peptide-peptoid hybrid against bacterial pathogens involved in canine skin infections.

Integumentary infections like pyoderma represent the main reason for antimicrobial prescription in dogs. Staphylococcus pseudintermedius and Pseudomonas aeruginosa are frequently identified in these infections, and both bacteria are challenging to combat due to resistance. To avoid use of important human antibiotics for treatment of animal infections there is a pressing need for novel narrow-spectrum antimicrobial agents in veterinary medicine. Herein, we characterize the in vitro activity of the novel peptide-peptoid hybrid B1 against canine isolates of S. pseudintermedius and P. aeruginosa. B1 showed potent minimum inhibitory concentrations (MICs) against canine S. pseudintermedius and P. aeruginosa isolates as well rapid killing kinetics. B1 was found to disrupt the membrane integrity and affect cell-wall synthesis in methicillin-resistant S. pseudintermedius (MRSP). We generated 28 analogues of B1, showing comparable haemolysis and MICs against MRSP and P. aeruginosa. The most active analogues (23, 26) and B1 were tested against a collection of clinical isolates from canine, of which only B1 showed potent activity. Our best compound 26, displayed activity against P. aeruginosa and S. pseudintermedius, but not the closely related S. aureus. This work shows that design of target-specific veterinary antimicrobial agents is possible, even species within a genus, and deserves further exploration.

Staphylococcus epidermidis-induced Interleukin-1 Beta and Human Beta-defensin-2 Expression in Human Keratinocytes is Regulated by the Host Molecule A20 (TNFAIP3).

Staphylococcus epidermidis is an abundant skin commensal capable of activating cutaneous defense responses, such as induction of cytokines and antimicrobial peptides. To permanently colonize human skin and prevent inflammation S. epidermidis needs to control the induction of host defense mediators. We report here that S. epidermidis induces expression of the host regulator protein A20 in human keratinocytes, thereby controlling expression and release of interleukin-1 beta. siRNA-mediated knockdown of A20 expression strongly enhanced the induction of interleukin-1 beta gene expression and protein release in keratinocytes stimulated with S. epidermidis. Furthermore, siRNA-mediated knockdown of A20 resulted in enhanced gene expression and secretion of the antimicrobial peptide human beta-defensin-2 in keratinocytes facing S. epidermidis. Mechanistically, A20 negatively controlled S. epidermidis-induced activation of the transcription factor NF-kappaB. Together, these data indicate that S. epidermidis exploits A20 to attenuate cutaneous defense responses, which may help S. epidermidis to persist on human skin.

An unusual deep fungal infection with Nigrospora sphaerica in HIV positive patient.

A 34-year-old HIV positive male with a CD4+ cell count of 133 cell/mm3 presented with multiple crusted and hemorrhagic ulcers on the face, scalp, trunk, and limbs for 3 months. Skin biopsies showed granulomatous inflammation with microabscesses and lots of hyphae and spores. PCR identified the fungus as Nigrospora sphaerica. This is mainly a plant pathogen which rarely causes opportunistic infections in humans. After a thorough literature search we found very few reported cases of human infection by this fungus worldwide but none in Africa. We therefore report the first case of human infection by Nigrospora sphaerica in the African continent.

Aurein-Derived Antimicrobial Peptides Formulated with Pegylated Phospholipid Micelles to Target Methicillin-Resistant Staphylococcus aureus Skin Infections.

Antimicrobial peptides have been the focus of considerable research; however, issues associated with toxicity and aggregation have the potential to limit clinical applications. Here, a derivative of a truncated version of aurein 2.2 (aurein 2.2Δ3), namely peptide 73, was investigated, along with its d-amino acid counterpart (D-73) and a retro-inverso version (RI-73). A version that incorporated a cysteine residue to the C-terminus (73c) was also generated, as this form is required to covalently attach antimicrobial peptides to polymers (e.g., polyethylene glycol (PEG) or hyperbranched polyglycerol (HPG)). The antimicrobial activity of the 73-derived peptides was enhanced 2- to 8-fold, and all the derivatives eradicated preformed Staphylococcus aureus biofilms. Formulation of the peptides with compatible polyethylene glycol (PEG)-modified phospholipid micelles alleviated toxicity toward human cells and reduced aggregation. When evaluated in vivo, the unformulated d-enantiomers aggregated when injected under the skin of mice, but micelle encapsulated peptides were well absorbed. Pegylated micelle formulated peptides were investigated for their potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. Formulated peptide 73 reduced abscess size by 36% and bacterial loads by 2.2-fold compared to the parent peptide aurein 2.2Δ3. Micelle encapsulated peptides 73c and D-73 exhibited superior activity, further reducing abscess sizes by 85% and 63% and lowering bacterial loads by 510- and 9-fold compared to peptide 73.