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"Infectious skin diseases"
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Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis
Background
Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma.
Objective
The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD.
Methods
This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates.
Results
Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43;
p
< 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44;
p
< 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31;
p
< 0.01). Systemic anti-infective medication use was lower with dupilumab.
Conclusions
Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD.
ClinicalTrials.gov Identifiers
NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.
Journal Article
Starting the SToP trial: Lessons from a collaborative recruitment approach
Recruitment in research can be challenging in Australian Aboriginal contexts. We aimed to evaluate the SToP (See, Treat, Prevent skin infections) trial recruitment approach for Aboriginal families to identify barriers and facilitators and understand the utility of the visual resource used.
This qualitative participatory action research used purposive sampling to conduct six semi-structured interviews with staff and five yarning sessions with Aboriginal community members from the nine communities involved in the SToP trial that were audio recorded and transcribed verbatim before thematic analysis.
Community members valued the employment of local Aboriginal facilitators who used the flipchart to clearly explain the importance of healthy skin and the rationale for the SToP trial while conducting recruitment. A prolonged process, under-developed administrative systems and stigma of the research topic emerged as barriers.
Partnering with a local Aboriginal organisation, employing Aboriginal researchers, and utilising flip charts for recruitment was seen by some as successful. Strengthening governance with more planning and support for recordkeeping emerged as future success factors.
Our findings validate the importance of partnership for this critical phase of a research project. Recruitment strategies should be co-designed with Aboriginal research partners. Further, recruitment rates for the SToP trial provide a firm foundation for building partnerships between organisations and ensuring Aboriginal perspectives determine recruitment methods.
Journal Article
Potential Synergistic Action of Bioactive Compounds from Plant Extracts against Skin Infecting Microorganisms
The skin is an important organ that acts as a physical barrier to the outer environment. It is rich in immune cells such as keratinocytes, Langerhans cells, mast cells, and T cells, which provide the first line of defense mechanisms against numerous pathogens by activating both the innate and adaptive response. Cutaneous immunological processes may be stimulated or suppressed by numerous plant extracts via their immunomodulatory properties. Several plants are rich in bioactive molecules; many of these exert antimicrobial, antiviral, and antifungal effects. The present study describes the impact of plant extracts on the modulation of skin immunity, and their antimicrobial effects against selected skin invaders. Plant products remain valuable counterparts to modern pharmaceuticals and may be used to alleviate numerous skin disorders, including infected wounds, herpes, and tineas.
Journal Article
Telavancin Versus Vancomycin for the Treatment of Complicated Skin and Skin-Structure Infections Caused by Gram-Positive Organisms
Background. Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. Methods. We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged ⩾18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). Results. A total of 1867 patients were randomized and received ⩾1 dose of study medication. In the clinically evaluable population, at 7–14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, −2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, −1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, −0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. Conclusions. Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.
Journal Article
Research progress on the application of nanobodies in immunity and infectious skin diseases
In response to the limitations of traditional therapies for immune and infectious skin diseases in terms of tissue penetration, cost, and drug resistance, nanobodies derived from camelids and containing only a single heavy chain variable domain have shown significant advantages: their small molecular weight ensures excellent skin penetration ability, the extended CDR3 domain enables precise targeting of hidden epitopes, and they have excellent stability (tolerance to extreme pH, temperature, protease) and low-cost production potential. In the treatment of immune skin diseases, nanobodies effectively synergistically block key inflammatory pathways through multivalent/multispecific design, demonstrating deep therapeutic effects beyond some traditional therapies in areas such as psoriasis, atopic dermatitis, and hidradenitis suppurativa. In the field of infectious skin diseases, it effectively blocks the process of pathogen infection by efficiently neutralizing key virulence factors (such as invasion proteins, adhesion factors, toxins) of viruses, bacteria, fungi, and parasites, and has the potential to serve as a highly specific diagnostic tool. Future research and development will focus on multi-target optimization, artificial intelligence assisted design, new transdermal/long-acting delivery systems, and precision medicine strategies, promoting nanobodies as an efficient and precise solution to revolutionize the treatment of skin diseases.
Journal Article
Age-based health and economic burden of skin and soft tissue infections in the United States, 2000 and 2012
The aim of this study was to compare the incidence of skin and soft tissue infections (SSTIs) across healthcare settings and analyze direct healthcare expenditures related to SSTIs in 2000 and 2012 in the United States.
We performed a retrospective, cross-sectional analysis of nationally representative data from the Medical Expenditure Panel Surveys. Population-based incidence rates were examined for all healthcare settings that include inpatient visits, emergency department visits and ambulatory visits for SSTIs. The direct costs of healthcare services utilization were reported. Population-based prescribing rates for each antimicrobial class during ambulatory visits were compared.
A total of 2.4 million patients experienced an SSTI in 2000 compared to 3.3 million in 2012 (40% increase). From 2000 to 2012, the incidence of patients with at least one hospital visit for SSTIs increased 22%, ambulatory care visits increased 30%, and emergency department visits increased 40%. The incidence of SSTIs in children and adolescents declined 50% (from 150 to 76 per 10,000 person; RR = 0.51, 95% CI: 0.38-0.67; p<0.001) whereas SSTIs in older adults (> 65 years of age) increased almost 2-fold (from 67 to 130 per 10,000 person; RR = 1.94, 95% CI: 1.44-2.61; p<0.001). The annual incidence of SSTI in adults did not change significantly from 2000 to 2012 (from 84 to 81 per 10,000 person; RR = 0.96, 95% CI: 0.71-1.31; p = 0.41). The total estimated direct healthcare costs of SSTIs increased 3-fold from $4.8 billion in 2000 to $15.0 billion in 2012, largely driven by an 8-fold increase in ambulatory expenditures for SSTIs. Total population-based antimicrobial prescription rates for SSTIs increased 4-fold from 2000 to 2012 (from 59.5 to 250.4 per 10,000 person).
The highest healthcare utilization for SSTI treatment occurred in the ambulatory care setting and also accounted for the largest increase in overall direct expenditures from 2000 to 2012.
Journal Article
Emergence of Fungal-Like Organisms: Prototheca
The genus
Prototheca
consists of achlorophyllic algae that are ubiquitous in the environment and animal intestines. However, this organism has forfeited its photosynthetic ability and switched to parasitism. In 1894, Krüger described two microorganisms isolated in Germany from mucous flux of
Tilia
and
Ulmus
spp., namely
Prototheca moriformis
and
P. zopfii
. Based on their yeast-like colony morphology, Krüger classified these organisms as fungi. The genus is now included within the class Trebouxiophyceae, order Chlorellales, and family Chlorellaceae. Historically, protothecosis and infections caused by green algae have been studied in the field of medical mycology.
Prototheca
spp. have been found to colonize human skin, fingernails, the respiratory tract, and digestive system. Although human infection by
Prototheca
is considered rare, an increase in infections has been noted among immunosuppressed patients, those on corticosteroid treatment, or both. Moreover, the first human outbreak of protothecal algaemia and sepsis was recently reported in a tertiary care chemotherapy oncology unit in 2018.
Prototheca
is also a causative pathogen of bovine disease.
Prototheca zopfii
and
P. blaschkeae
are associated with bovine mastitis, which causes a reduction in milk production and secretion of thin, watery milk containing white flakes. Economic losses are incurred either directly via reduced milk production and premature culling of affected animals or indirectly as a result of treatment and veterinary care expenses. Thus, knowledge of this fungal-like pathogen is essential in human and veterinary medicine. In this mini-review, I briefly introduce human and animal protothecoses.
Journal Article
A Regional Initiative to Reduce Skin Infections amongst Aboriginal Children Living in Remote Communities of the Northern Territory, Australia
Linked to extreme rates of chronic heart and kidney disease, pyoderma is endemic amongst Aboriginal children in Australia's Northern Territory (NT). Many of those with pyoderma will also have scabies. We report the results of a community-based collaboration within the East Arnhem Region, which aimed to reduce the prevalence of both skin infections in Aboriginal children.
Commencing September 2004, we conducted an ecological study that included active surveillance for skin infections amongst children aged <15 years in five remote East Arnhem communities over a three year period. Screening was undertaken by trained local community workers, usually accompanied by another project team member, using a standard data collection form. Skin infections were diagnosed clinically with the aid of a pictorial flip chart developed for the purpose. Topical 5% permethrin was provided for age-eligible children and all household contacts whenever scabies was diagnosed, whilst those with pyoderma were referred to the clinic for treatment in accordance with current guidelines. In addition, annual mass scabies treatment (5% permethrin cream) was offered to all community residents in accordance with current guidelines but was not directly observed. Pyoderma and scabies prevalence per month was determined from 6038 skin assessments conducted on 2329 children. Pyoderma prevalence dropped from 46.7% at baseline to a median of 32.4% (IQR 28.9%-41.0%) during the follow-up period - an absolute reduction of 14.7% (IQR 4.7%-16.8%). Compared to the first 18 months of observation, there was an absolute reduction in pyoderma prevalence of 18 cases per 100 children (95%CI -21.0, -16.1, p
Journal Article
Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections
Soft-tissue infections are common, generally of mild to modest severity, and are easily treated with a variety of agents. An etiologic diagnosis of simple cellulitis is frequently difficult and generally unnecessary for patients with mild signs and symptoms of illness. Here, Stevens et al present details of a study on practice guidelines for the diagnosis and management of Skin and Soft-Tissue Infections.
Journal Article
Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?
Summary
Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.
Introduction
Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk.
Methods
FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (
n
= 3,906) or denosumab 60 mg every 6 months (
n
= 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, “Infections and Infestations,” was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored.
Results
Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab.
Conclusions
Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.
Journal Article