Siegbert Rieg

Deficiency of Dermcidin-Derived Antimicrobial Peptides in Sweat of Patients with Atopic Dermatitis Correlates with an Impaired Innate Defense of Human Skin In Vivo

Antimicrobial peptides are an integral part of the epithelial innate defense system. Dermcidin (DCD) is a recently discovered antimicrobial peptide with a broad spectrum of activity. It is constitutively expressed in human eccrine sweat glands and secreted into sweat. Patients with atopic dermatitis (AD) have recurrent bacterial or viral skin infections and pronounced colonization with Staphylococcus aureus. We hypothesized that patients with AD have a reduced amount of DCD peptides in sweat contributing to the compromised constitutive innate skin defense. Therefore, we performed semiquantitative and quantitative analyses of DCD peptides in sweat of AD patients and healthy subjects using surface-enhanced laser desorption ionization time-of-flight mass spectrometry and ELISA. The data indicate that the amount of several DCD-derived peptides in sweat of patients with AD is significantly reduced. Furthermore, compared with atopic patients without previous infectious complications, AD patients with a history of bacterial and viral skin infections were found to have significantly less DCD-1 and DCD-1L in their sweat. To analyze whether the reduced amount of DCD in sweat of AD patients correlates with a decreased innate defense, we determined the antimicrobial activity of sweat in vivo. We showed that in healthy subjects, sweating leads to a reduction of viable bacteria on the skin surface, but this does not occur in patients with AD. These data indicate that reduced expression of DCD in sweat of patients with AD may contribute to the high susceptibility of these patients to skin infections and altered skin colonization.

Mortality of S. aureus bacteremia and infectious diseases specialist consultation – A study of 521 patients in Germany

OBJECTIVES To evaluate the relationship between mortality of bloodstream infection due to Staphylococcus aureus and infectious diseases specialist consultation and other factors potentially associated with outcomes. METHODS A 6-year cohort study was conducted at a 1600-bed university hospital. Consecutive adult patients with S. aureus bacteremia were assessed using a standardised data collection and review form. A new infectious diseases service increased its consultations for S. aureus bacteremia from 33% of cases in 2002 to >80% in 2007. Infectious disease consultation and other factors potentially associated with in-hospital mortality were analysed by multivariate logistic regression. RESULTS A total of 521 patients were studied. All-cause in-hospital mortality was 22%, 90-day mortality was 32%. Factors significantly associated with in-hospital mortality in multivariate analysis were ICU admission (OR 5.8, CI 3.5-9.7), MRSA (OR 2.6, CI 1.4-4.9), age >/=60 years (OR 2.4, CI 1.4-4.2), a diagnosis of endocarditis (OR 2.8, CI 1.4-5.7), a non-fatal underlying disease/comorbidity according to the McCabe classification (OR 0.2, CI 0.1-0.4), and infectious disease specialist consultation (OR 0.6, CI 0.4-1.0). CONCLUSIONS These data suggest that outcome of S. aureus bacteremia may be improved by an expert consultation service.

Expression of innate defense antimicrobial peptides in hidradenitis suppurativa.

BACKGROUND Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of apocrine gland-bearing skin. It is associated with alterations in innate immunity and frequent bacterial infections. OBJECTIVE We investigated the expression of innate defense antimicrobial peptides in patients with HS and different grades of severity. METHODS Skin biopsy specimens and sweat were collected from 36 patients with HS and 57 healthy control subjects for analysis of epithelial antimicrobial peptides by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, enzyme-linked immunosorbent assay, and surface-enhanced laser desorption ionization time-of-flight mass spectrometry. RESULTS We provide evidence that human β-defensin-3 expression is induced in lesional HS skin on transcriptional and protein levels, yet, this up-regulation was not detectable in patients with severe HS (Hurley grade III). In contrast, messenger RNA expression of ribonuclease 7 was significantly diminished in lesional HS skin specimens irrespective of HS severity. Overall levels of dermcidin/dermcidin-derived peptides in sweat and messenger RNA expression of psoriasin in skin biopsy specimens did not differ between patients with HS and healthy control subjects. LIMITATION The relatively small number of samples, in particular in the group of patients with HS and Hurley grade III, is a limitation. CONCLUSION Deficient constitutive production of ribonuclease 7 and, in severe HS, reduced human β-defensin-3 induction may contribute to impaired immunity within the hair follicle and thereby boost HS inflammation and severity.

Tick-borne lymphadenopathy (TIBOLA) acquired in Southwestern Germany

BackgroundTick-borne lymphadenopathy (TIBOLA) was first described in 1997 in a patient in France. The causative agent, Rickettsia slovaca, is transmitted by Dermacentor ticks.Case presentationIn southwestern Germany we encountered a patient with a tick bite at the dorsal scalp that resulted in an eschar and nuchal lymphadenopathy. Additionally, fever, malaise as well as elevated inflammatory markers and transaminases occurred. The characteristic clinical picture along with positive antibody testing for rickettsiae of the tick-borne spotted fever group strongly suggest the diagnosis TIBOLA.ConclusionHuman rickettsioses are emerging infections. Clinicians should be aware of TIBOLA as a newly described rickettsial disease. As in our case, TIBOLA may be encountered in regions/countries where R. slovaca and Dermacentor ticks are prevalent but autochthonous acquisition was not described before.

Resistance against antimicrobial peptides is independent of Escherichia coli AcrAB, Pseudomonas aeruginosa MexAB and Staphylococcus aureus NorA efflux pumps

The role of clinically important multidrug resistance (MDR) efflux pumps in bacterial resistance to various human antimicrobial peptides (AMPs), including cathelicidin LL-37, the alpha-defensins human neutrophil peptides (HNPs)-1-3 and HD-5 and the beta-defensins hBD-2 and -3, was investigated. AMP susceptibility testing was performed by killing assays and standard minimal inhibitory concentration assays. AMP susceptibility was determined in Escherichia coli and Pseudomonas aeruginosa strains overexpressing resistance-nodulation-cell division (RND)-type pumps AcrAB and MexAB, respectively, and in their pump-deficient parental strains. Furthermore, the impact of a member of the major facilitator (MF) efflux pump family was investigated in Staphylococcus aureus overexpressing NorA and in wild-type strains. The E. coli AcrAB and P. aeruginosa MexAB RND-type efflux pumps as well as the S. aureus NorA MF efflux pump were unable to confer resistance to AMPs. These findings do not support a critical role of MDR efflux pumps in the tested pathogens as a strategy to increase virulence by circumventing the antimicrobial action of innate defence AMPs.

Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation

BackgroundImmunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality.Case presentationWe describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1.ConclusionTo our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.

Microarray-Based Genotyping and Clinical Outcomes of Staphylococcus aureus Bloodstream Infection: An Exploratory Study

The clinical course of Staphylococcus aureus bacteremia varies extensively. We sought to determine the relationship between genetic characteristics of the infecting pathogen and clinical outcomes in an exploratory study. In two study centers, 317 blood culture isolates were analyzed by DNA microarray and spa genotyping. By uni- and multivariate regression analyses associations of genotype data with 30-day all-cause mortality, severe sepsis/septic shock, disseminated disease, endocarditis, and osteoarticular infection were investigated. Univariate analysis showed significant association between S. aureus genes/gene-clusters or clonal complexes and clinical endpoints. For example CC15 was associated with 30-day mortality and CC22 with osteoarticular infection. In multivariate analysis methicillin resistance (mecA, OR 4.8 [1.43–16.06]) and the beta-lactamase-gene (bla, OR 3.12 [1.17–8.30]) remained independently associated with 30-day mortality. The presence of genes for enterotoxins (sed/sej/ser) was associated with endocarditis (OR 5.11 [1.14–18.62]). Host factors such as McCabe classification (OR 4.52 [2.09–9.79] for mortality), age (OR 1.06 [1.03–1.10] per year), and community-acquisition (OR 3.40 [1.31–8.81]) had a major influence on disease severity, dissemination and mortality. Individual genotypes and clonal complexes of S. aureus can only partially explain clinical features and outcomes of S. aureus bacteremia. Genotype-phenotype association studies need to include adjustments for host factors like age, comorbidity and community-acquisition.

Differential time to positivity is not predictive for central line-related Staphylococcus aureus bloodstream infection in routine clinical care

OBJECTIVES Many physicians rely on differential time to positivity (DTP) when diagnosing catheter-related bloodstream infection (CRBSI). We evaluated whether DTP from routine blood cultures can predict catheter-related Staphylococcus aureus bloodstream infection. METHODS AND PATIENTS From 2006 to 2011 adult patients with monomicrobial S. aureus bloodstream infection and matched pairs of central and peripheral blood cultures were prospectively followed. CRBSI was defined by the absence of other infective foci and recovery of S. aureus from the catheter tip or catheter exit-site, or local signs of infection at the catheter exit site. A DTP of more than two hours (cut-off) was used to define test positivity. RESULTS CRBSI was present in 30 (34%, prevalence) of 87 patients. In 24 (28%) patients a DTP of more than two hours was measured: eleven patients had CRBSI, ten deep-seated infections, and in three patients an infective focus was not identified. DTP showed a positive predictive value of 0.46 [95% confidence interval (CI) 0.28 to 0.65], and a negative predictive value of 0.70 [95% CI 0.58 to 0.80]. CONCLUSION The low test performance suggests that DTP is not useful in diagnosing CRBSI in routinely obtained blood cultures. Therefore, physicians should not solely rely on DTP and rather promote catheter removal and culture.

Differential activity of innate defense antimicrobial peptides against Nocardia species

BackgroundMembers of the genus Nocardia are ubiquitous environmental saprophytes capable to cause human pulmonary, disseminated and cutaneous nocardiosis or bovine mastitis. Innate immunity appears to play an important role in early defense against Nocardia species. To elucidate the contribution of antimicrobial peptides (AMPs) in innate defense against Nocardia, the activity of human α-defensins human neutrophil peptides (HNPs) 1-3, human β-defensin (hBD)-3 and cathelicidin LL-37 as well as bovine β-defensins lingual and tracheal antimicrobial peptides (LAP, TAP) and bovine neutrophil-derived indolicidin against four important Nocardia species was investigated.ResultsWhereas N. farcinica ATCC 3318 and N. nova ATCC 33726 were found to be susceptible to all investigated human and bovine AMPs, N. asteroides ATCC 19247 was killed exclusively by neutrophil-derived human α-defensins HNP 1-3 and bovine indolicidin. N. brasiliensis ATCC 19296 was found to exhibit complete resistance to investigated human AMPs and to be susceptible only to bovine indolicidin.ConclusionSelected AMPs are capable to contribute to the first line of defense against Nocardia, yet, susceptibility appears to vary across different Nocardia species. Obtained results of neutrophil-derived AMPs to possess the broadest antinocardial spectrum are remarkable, since nocardiosis is characterized by a neutrophil-rich infiltrate in vivo.

Polymorphisms in Fibronectin Binding Proteins A and B among Staphylococcus aureus Bloodstream Isolates Are Not Associated with Arthroplasty Infection.

Background Nonsynonymous single nucleotide polymorphisms (SNPs) in fibronectin binding protein A (fnbA) of Staphylococcus aureus are associated with cardiac device infections. However, the role of fnbA SNPs in S. aureus arthroplasty infection is unknown. Methods Bloodstream S. aureus isolates from a derivation cohort of patients at a single U.S. medical center with S. aureus bacteremia (SAB) and prosthetic hip or knee arthroplasties that were infected (PJI, n = 27) or uninfected (PJU, n = 43) underwent sequencing of fnbA and fnbB. A validation cohort of S. aureus bloodstream PJI (n = 12) and PJU (n = 58) isolates from Germany also underwent fnbA and fnbB sequencing. Results Overall, none of the individual fnbA or fnbB SNPs were significantly associated with the PJI or PJU clinical groups within the derivation cohort. Similarly, none of the individual fnbA or fnbB SNPs were associated with PJI or PJU when the analysis was restricted to patients with either early SAB (i.e., bacteremia occurring <1 year after placement or manipulation of prostheses) or late SAB (i.e., bacteremia >1 year after placement or manipulation of prostheses). Conclusions In contrast to cardiac device infections, there is no association between nonsynonymous SNPs in fnbA or fnbB of bloodstream S. aureus isolates and arthroplasty infection. These results suggest that initial steps leading to S. aureus infection of cardiovascular and orthopedic prostheses may arise by distinct processes.