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The aim of this study was to investigate the early-life development of the skin microbiome in atopic derma-titis. Nineteen infants with atopic dermatitis and 19 healthy infants were evaluated 3 times, at 3 months intervals, within the first 30 months of life. Tape-strips were collected from volar forearms, cheeks, and ec-zema lesions, and the skin microbiome was assessed by 16S rRNA sequencing. Both the community struc-ture and richness of the skin microbiome of infants with atopic dermatitis differed significantly from that of healthy infants, with greater richness in healthy infants. For infants with atopic dermatitis, the community composition was not dominated by Staphylo-cocci. For healthy infants, community composition and richness correlated significantly with age, while such a pattern was not revealed in infants with atopic der-matitis. This suggests a slower maturation of the skin microbiome in atopic dermatitis, which precedes the staphylococcal predominance observed in older children and adults.

Rothia is a commensal member of the phylum Actinobacteria reported of being a prevalent member in the oral microbiome and among the most observed bacteria in the upper respiratory tract of humans and animals including pigs.

Background: Hand eczema (HE) is frequently associated with Staphylococcus aureus; however, its role in the pathogenesis of HE is poorly understood. Objective: To investigate the temporal variation in S aureus subtypes, ie, clonal complex (CC) types, on the hands and relate it to S aureus colonization in the nose and severity in a cohort of HE patients. Methods: S aureus from the hands and nose of 50 adult HE patients and 50 controls was prospectively identified at 5 visits over 3 weeks. Results: S aureus was identified on the hands of 23 (46%) patients at 2 or more visits and on the hands of 1 control once. Of the HE patients with S aureus colonization, 78% had the same S aureus CC type over time. Twenty-one patients had the same S aureus CC type on the hands and in the nose. Persistent colonization was strongly related to an increased disease severity. Limitations: A relatively small S aureus culture-positive population. Conclusion: The temporal stability of S aureus CC type and high occurrence of the identical subtypes on the hands and in the nose imply that S aureus colonization in patients with HE is of a more permanent nature. Taken together with the finding that persistent colonization and HE severity are clearly related, our results indicate that S aureus may contribute to the perpetuating course of HE.

AIMS: To investigate the 1-year risks of Staphylococcus aureus bacteraemia (SAB), sepsis, and pneumonia in patients who underwent percutaneous coronary intervention and were treated with ticagrelor vs. clopidogrel. METHODS AND RESULTS: In this nationwide observational cohort study, 26 606 patients who underwent urgent or emergent percutaneous coronary intervention (January 2011-December 2017) and initiated treatment with ticagrelor [N = 20 073 (75.5%); median age 64 years (25th-75th percentile 55-72 years); 74.8% men] or clopidogrel [N = 6533 (24.5%); median age 68 years (25th-75th percentile 58-77 years); 70.2% men] were identified using Danish nationwide registries. The 1-year standardized absolute risks of outcomes was calculated based on cause-specific Cox regression models, and average treatment effects between treatment groups were obtained as standardized differences in absolute 1-year risks. The absolute 1-year risk of SAB was 0.10% [95% confidence interval (CI), 0.05-0.15%] in the ticagrelor group and 0.29% (95% CI, 0.17-0.42%) in the clopidogrel group. Compared with clopidogrel, treatment with ticagrelor was associated with a significantly lower absolute 1-year risk of SAB [absolute risk difference -0.19% (95% CI, -0.32% to -0.05%), P value 0.006]. Likewise, treatment with ticagrelor was associated with a significantly lower absolute 1-year risk of sepsis [0.99% (95% CI, 0.83-1.14%) vs. 1.49% (95% CI, 1.17-1.80%); absolute risk difference -0.50% (95% CI, -0.86% to -0.14%), P value 0.007] and pneumonia [3.13% (95% CI, 2.86-3.39%) vs. 4.56% (95% CI, 4.03-5.08%); absolute risk difference -1.43% (95% CI, -2.03% to -0.82%), P value < 0.001] compared with clopidogrel. CONCLUSION: Treatment with ticagrelor was associated with a significantly lower 1-year risk of SAB, sepsis, and pneumonia compared with clopidogrel.

BACKGROUND: Treatment with dabigatran, an oral direct thrombin inhibitor, reduces the virulence of Staphylococcus aureus in in vitro and in vivo models. However, it remains to be determined whether dabigatran reduces the risk of S. aureus infections in humans. We investigated the incidence rate of S. aureus bacteremia (SAB) in patients with atrial fibrillation treated with the direct thrombin inhibitor dabigatran compared with patients treated with the factor Xa-inhibitors rivaroxaban, apixaban, and edoxaban. METHODS: In this observational cohort study, 112 537 patients with atrial fibrillation who initiated treatment with direct oral anticoagulants (August 2011-December 2017) were identified from Danish nationwide registries. The incidence rates of SAB in patients treated with dabigatran versus patients treated with the factor Xa-inhibitors were examined by multivariable Cox regression accounting for time-dynamic changes in exposure status during follow-up. RESULTS: A total of 112 537 patients were included. During a median follow-up of 2.0 years, 186 patients in the dabigatran group and 356 patients in the factor Xa-inhibitor group were admitted with SAB. The crude incidence rate of SAB was lower in the dabigatran group compared with the factor Xa-inhibitor group (22.8 [95% confidence interval [CI], 19.7-26.3] and 33.8 [95% CI, 30.5-37.6] events per 10 000 person-years, respectively). In adjusted analyses, dabigatran was associated with a significantly lower incidence rate of SAB compared with factor Xa-inhibitors (incidence rate ratio, .76; 95% CI, .63-.93). CONCLUSIONS: Treatment with dabigatran was associated with a significantly lower incidence rate of SAB compared with treatment with factor Xa-inhibitors.

Background: While Staphylococcus aureus (S. aureus) colonization has been thoroughly studied in atopic dermatitis (AD), where S. aureus is related to flares and considered a trigger factor, S. aureus colonization in hand eczema (HE) has only been sparsely studied. Objectives: To examine the 1-week prevalence of S. aureus colonization in HE patients, and its association with severity, HE subtype, AD, and nasal S. aureus colonization compared with healthy controls. Methods: In a case-control study of 50 adult HE patients and 50 healthy controls, bacterial swabs from lesional skin (patients only), non-lesional skin (dorsal hand), and the nasal cavity were sampled for culturing of S. aureus on days 1, 3, 5 and 8. Participants were characterized by demographics, AD, HE subtype, filaggrin gene mutation status, and HE severity. Results: Twenty-seven HE patients (54%) were colonized with S. aureus on the hand compared to one control (2%) (P <.01). Nasal S. aureus colonization was found in 72% of patients and 22% of controls (P <.01). For patients, S. aureus colonization on the hands was associated with an atopic HE subtype and HE severity (P =.01 and P <.01, respectively). Conclusions: Both hand and nasal S. aureus colonization were highly prevalent among HE-patients and may have an impact on the persistence of HE.

Atopic dermatitis is a common inflammatory skin disease with a complex pathogenesis that includes imbalanced immune system signalling, impaired skin barrier and enhanced Staphylococcus aureus skin colonization. The skin bacterial communities are characterized by increasing abundance of S. aureus, leading to reduced diversity compared with the bacterial communities on healthy skin, and increasing disease severity. In contrast, fungal communities are richer and more diverse on the skin of patients with atopic dermatitis, although distribution of the most common species is similar in patients and controls. Filaggrin deficiency in atopic dermatitis skin might be related to the enhanced skin colonization by S. aureus. In addition, S. aureus expressing variant virulence factors have been shown to elicit atopic dermatitis-like phenotypes in mice, indicating that specific S. aureus strains can induce flare-ups. This review aims to provide an overview of the recent literature on the skin microbiome in atopic dermatitis.

More than 55 million mink skins were produced globally in 2017. As a consequence, a large number of people are employed in mink production worldwide. In Denmark, farmed mink were found to constitute a reservoir of methicillin-resistant Staphylococcus aureus (MRSA) clonal complex (CC) 398 and 6000 mink farm workers in Denmark are potentially exposed to LA-MRSA CC398. The study aim was to elucidate the source of LA-MRSA CC398 in mink farms and to investigate possible transmission to humans. In total, 161 LA-MRSA CC398 isolates from mink (n = 65), mink feed (n = 16) and humans (n = 80) with reported contact to mink, were whole-genome sequenced and compared to 183 LA-MRSA CC398 isolates from Danish pigs and an international collection of 89 S. aureus CC398 isolates. Most of the mink-associated isolates clustered within the predominant LA-MRSA CC398 lineages circulating in the Danish pig production, supporting that pigs are a source of LA-MRSA CC398 in mink feed, mink, and mink farmers.

Introduction: Staphylococcus aureus bacteremia (SAB) is a high-risk infection and feared complication related to hemodialysis. This study aimed to investigate incidence and risk factors for SAB depending on hemodialysis access type. Methods: The Danish National Registry on Regular Dialysis and Transplantation was used to identify patients from January 1, 1996 to December 31, 2011 with end-stage kidney disease. Patients were followed until death, the first episode of SAB, or end of study (December 31, 2011). Independent risk factors were assessed by multivariable Poisson regression with time-updated exposure variables. Findings: Total of 9997 patients were included. The initial modality of renal replacement therapy was hemodialysis in 6826 patients and peritoneal dialysis in 2882 patients; 289 patients had preemptive kidney transplantation. SAB occurred in 1278 patients (12.8%). The incidence rate of SAB declined after 90 days and leveled off after 270 days in hemodialysis, peritoneal dialysis, and kidney transplanted. As compared to peritoneal dialysis, the adjusted rate ratio (RR) for SAB was 7.42 (95% CI 5.63–9.79) in uncuffed central venous catheter (CVC), 5.68 (95% CI 4.39–7.36) in cuffed CVC, 4.43 (95% CI 2.10–9.53) in arteriovenous graft, and 3.40 (95% CI 2.79–4.15) in arteriovenous fistula. SAB risk did not differ between uncuffed and cuffed CVC. The risk of SAB was increased during the first three months of renal replacement therapy especially for CVC (RR 11.37 [95% CI7.09–18.22]) compared with peritoneal dialysis. Diabetes mellitus (RR 1.35 [95% CI 1.20–1.51]) and male sex (RR 1.15 [95% CI 1.03–1.29]) were also associated with SAB. Discussion: Patients on hemodialysis had a high incidence rate of SAB, particularly those undergoing hemodialysis via CVC. SAB risk was comparable for cuffed and uncuffed CVC. Diabetes mellitus, male sex, and the first three months in renal replacement therapy were independently associated with SAB.

We report a fatal aspergillosis case in which STRAf typing and whole-genome sequencing substantiated in vivo emergence of an azole-resistant Aspergillus fumigatus with a 120-bp tandem repeat in the promoter region of cyp51A. This event, previously restricted to the environment, challenges current understanding of azole resistance development in A. fumigatus.

Objectives: A microbiotic profile characterized by decreased abundance and richness has been described in inflammatory bowel disease (IBD). Recently, sequencing the microbiome to the species level has become possible, which can improve our understanding of the gut to host interaction in IBD. We aimed to describe the microbiotic profile in paediatric IBD and compare it to disease phenotype and disease course. Methods: Faecal samples were collected from a cross-sectional cohort. The microbiome analysis was performed using 16S and 18S rRNA sequencing with the miSeq instrument. Inflammatory activity was assessed by faecal calprotectin. Data regarding medical treatment and surgery in the year after faecal sampling were collected from patient charts. Results: One hundred and forty-three (143) paediatric IBD patients and 34 healthy controls (HC) were included. We found a reduced richness in IBD patients compared to HCs (controls vs. ulcerative colitis (UC), p <.001 and controls vs. Crohn’s disease (CD), p =.04)). Moreover, a high degree of intestinal inflammation and extensive disease extent was associated with reduced richness in UC (p =.02 and p =.04, respectively). Nine species were significantly associated with a healthy microbiome and three species were associated with IBD. Lastly, we found that the composition of the microbiome could distinguish between CD, UC and HCs. Conclusions: In this study, we found that the microbiome could discriminate between IBD phenotypes and predict which patients were at risk of surgery. In the future, this could be included as part of the diagnostic work-up in IBD patients.

Staphylococcus aureus is a commensal colonizer of both humans and animals, but also an opportunistic pathogen responsible for a multitude of diseases. In recent years, colonization of pigs by methicillin resistant S. aureus has become a problem with increasing numbers of humans being infected by livestock strains. In S. aureus colonization and virulence factor expression is controlled by the agr quorum sensing system, which responds to and is activated by self-generated, autoinducing peptides (AIPs). AIPs are also produced by coagulase negative staphylococci (CoNS) commonly found as commensals in both humans and animals, and interestingly, some of these inhibit S. aureus agr activity. Here, we have addressed if cross-communication occurs between S. aureus and CoNS strains isolated from pig nares, and if so, how properties such as host factor binding and biofilm formation are affected. From 25 pig nasal swabs we obtained 54 staphylococcal CoNS isolates belonging to 8 different species. Of these, none were able to induce S. aureus agr as monitored by reporter gene fusions to agr regulated genes but a number of agr-inhibiting species were identified including Staphylococcus hyicus, Staphylococcus simulans, Staphylococcus arlettae, Staphylococcus lentus, and Staphylococcus chromogenes. After establishing that the inhibitory activity was mediated via AgrC, the receptor of AIPs, we synthesized selective AIPs to explore their effect on adhesion of S. aureus to fibronectin, a host factor involved in S. aureus colonization. Here, we found that the CoNS AIPs did not affect adhesion of S. aureus except for strain 8325-4. When individual CoNS strains were co-cultured together with S. aureus we observed variable degrees of biofilm formation which did not correlate with agr interactions. Our results show that multiple CoNS species can be isolated from pig nares and that the majority of these produce AIPs that inhibit S. aureus agr. Further they show that the consequences of th

Avian-pathogenic Escherichia coli (APEC) is a subgroup of extraintestinal pathogenic E. coli (ExPEC) presumed to be zoonotic and to represent an external reservoir for extraintestinal infections in humans, including uropathogenic E. coli (UPEC) causing urinary tract infections. Comparative genomics has previously been applied to investigate whether APEC and human ExPEC are distinct entities. Even so, whole-genome-based studies are limited, and large-scale comparisons focused on single sequence types (STs) are not available yet. In this study, comparative genomic analysis was performed on 323 APEC and human ExPEC genomes belonging to sequence type 95 (ST95) to investigate whether APEC and human ExPEC are distinct entities. Our study showed that APEC of ST95 did not constitute a unique ExPEC branch and was genetically diverse. A large genetic overlap between APEC and certain human ExPEC was observed, with APEC located on multiple branches together with closely related human ExPEC, including nearly identical APEC and human ExPEC. These results illustrate that certain ExPEC clones may indeed have the potential to cause infection in both poultry and humans. Previously described ExPEC-associated genes were found to be encoded on ColV plasmids. These virulence-associated plasmids seem to be crucial for ExPEC strains to cause avian colibacillosis and are strongly associated with strains of the mixed APEC/ human ExPEC clusters. The phylogenetic analysis revealed two distinct branches consisting of exclusively closely related human ExPEC which did not carry the virulence-associated plasmids, emphasizing a lower avian virulence potential of human ExPEC in relation to an avian host.

The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10-3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10-4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10-3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-β transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due t

The diversity of OXA-48-like carbapenemases is continually expanding. In this study, we describe the dissemination and characteristics of a novel carbapenem-hydrolyzing class D β-lactamase (CHDL) named OXA-436. In total, six OXA-436-producing Enterobacteriaceae isolates, including Enterobacter asburiae (n = 3), Citrobacter freundii (n = 2), and Klebsiella pneumoniae (n = 1), were identified in four patients in the period between September 2013 and April 2015. All three species of OXA-436-producing Enterobacteriaceae were found in one patient. The amino acid sequence of OXA-436 showed 90.4 to 92.8% identity to the amino acid sequences of other acquired OXA-48-like variants. Expression of OXA-436 in Escherichia coli and kinetic analysis of purified OXA-436 revealed an activity profile similar to that of OXA-48 and OXA-181, with activity against penicillins, including temocillin; limited or no activity against extended-spectrum cephalosporins; and activity against carbapenems. The blaOXA-436 gene was located on a conjugative ∼314-kb IncHI2/IncHI2A plasmid belonging to plasmid multilocus sequence typing sequence type 1 in a region surrounded by chromosomal genes previously identified to be adjacent to blaOXA genes in Shewanella spp. In conclusion, OXA-436 is a novel CHDL with functional properties similar to those of OXA-48-like CHDLs. The described geographical spread among different Enterobacteriaceae and the plasmid location of blaOXA-436 illustrate its potential for further dissemination.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations