Tilman Lingscheid

Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation

Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca++-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation, and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca++-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin’s inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

Low nasal carriage of drug-resistant bacteria among medical students in Vienna.

Background: Multi-drug resistant bacteria are increasing and remain a major public health challenge worldwide. In order to understand the potential role of medical students as a reservoir for circulating pathogenic bacteria and their transmission, we analysed the nasal colonisation among 86 clinically exposed medical students of the Medical University of Vienna, which is integrated into General Hospital of Vienna. Methods: Nasal swabs obtained from 79 students were eligible for further analysis. Nasal swabs were analysed for Gram-positive and Gram-negative bacteria with special emphasis on methicillin-resistant Staphylococcus aureus. Results: 25.3% of participants were positive for Staphylococcus aureus colonization; none of the isolates showed methicillin-resistance or expression of Pantoin-Valentine-leukocidin. However, 2.5% were positive for methicillin-resistant Staphylococcus epidermidis. No participant showed Streptococcus pneumoniae colonisation. Furthermore, 10.1% of the samples displayed growth of Gram-negative bacteria, yet none showed any relevant drug-resistance. Conclusion: In conclusion, our investigation did not reveal any clinically relevant multi-drug resistant bacterial colonisation among clinically exposed medical students in Vienna. This might be explained by well-established hygienic precautions or comparably low circulation of resistant bacteria.

Schistosomiasis in european travelers and migrants: Analysis of 14 years tropnet surveillance data

Schistosomiasis remains one of the most prevalent parasitic diseases worldwide and the infection is frequently found in travelers and migrants. The European Network for Tropical Medicine and Travel Health conducted a sentinel surveillance study on imported schistosomiasis between 1997 and 2010. This report summarizes epidemiological and clinical data from 1,465 cases of imported schistosomiasis. Direct pathogen detection and serology were the main diagnostic tools applied. Of these, 486 (33%) cases were identified among European travelers, 231 (16%) among long-term expatriates, and 748 (51%) among non-European immigrants. Overall, only 18.6% of travelers had received pretravel advice; 95% of infections were acquired in the African region. On species level, Schistosoma mansoni was identified in 570 (39%) and Schistosoma haematobium in 318 (22%) cases; 57.5% of patients were symptomatic. Acute symptoms were reported in 27% of patients leading to earlier presentation within 3 months. Praziquantel was used in all patients to treat schistosomiasis. Many infections were detected in asymptomatic patients. In 47.4% of asymptomatic patients infection was detected by microscopy and in 39% by serology or antigen testing. Schistosomiasis remains a frequent infection in travelers and migrants to Europe. Travelers should be made aware of the risk of schistosomiasis infection when traveling to sub-Saharan Africa. Posttravel consultations particularly for returning expatriates are useful given the high potential for detecting asymptomatic infections.

Assessing Pharmacokinetics of Different Doses of Fosfomycin in Laboratory Rats Enables Adequate Exposure for Pharmacodynamic Models

Fosfomycin has been the subject of numerous pharmacodynamic in vivo models in recent years. The present study set out to determine fosfomycin pharmacokinetics in laboratory rats to enable adequate dosing regimens in future rodent models. Fosfomycin was given intraperitoneally as single doses of 75, 200 and 500 mg/kg bodyweight to 4 Sprague-Dawley rats per dose group. Blood samples were collected over 8 h and fosfomycin concentrations were determined by HPLC-mass spectrometry. Fosfomycin showed a dose-proportional pharmacokinetic profile indicated by a correlation of 0.99 for maximum concentration and area under the concentration-time curve (AUC). The mean AUC0-8 after intraperitoneal administration of 75, 200 or 500 mg/kg bodyweight fosfomycin were 109.4, 387.0 and 829.1 µg·h/ml, respectively. In conclusion, a dosing regimen of 200-500 mg/kg 3 times daily is appropriate to obtain serum concentrations in laboratory rats, closely mimicking human serum concentrations over time.

In vitro activity of doripenem plus fosfomycin against drug-resistant clinical blood isolates.

The in vitro activity of doripenem in combination with fosfomycin was evaluated against a wide range of clinical blood isolates. Bacterial isolates of methicillin-resistant Staphylococcus aureus (MRSA; n = 39), Pseudomonas aeruginosa (n = 18), multidrug-resistant Escherichia coli (n = 10), Enterobacter cloacae (n = 3) and Klebsiella pneumoniae (n = 5) were investigated. For synergism testing the checkerboard test was applied and determined by calculation of the fractional inhibitory concentration index. Checkerboard results were verified by time-kill curve tests on selected isolates. Among MRSA, E. coli and K. pneumoniae, 94.9, 80 and 100% of isolates demonstrated synergism, respectively. Selected isolates demonstrated synergism in time-kill curve tests. P. aeruginosa isolates demonstrated no interaction in all isolates. Doripenem plus fosfomycin shows high efficacy with promising results in vitro.

Hemolysis after Oral Artemisinin Combination Therapy for Uncomplicated Plasmodium falciparum Malaria

Clinicians should be aware of hemolysis in malaria patients with anemia who were given these drugs.

A diagnostic predicament: activated sarcoidosis or pulmonary histoplasmosis. A case report

We report a case of a 41‐year‐old man presenting with persisting fevers over 2 weeks. The patient had spent 4 weeks in Central America. He was in control of a stable stage II sarcoidosis. Laboratory and various microbiological tests as well as chest radiography led to no diagnosis. Activated sarcoidosis was hypothesized as the most likely diagnosis. However, we considered an infectious process as a differential diagnosis, in detail, the travel history imposed histoplasmosis. Chest‐CT documented localized interstitial consolidations. Bronchoscopy with bronchoalveolar lavage (BAL) and biopsy was performed. Results of BAL fluid, biopsy, distinct sarcoidosis serum markers and a borderline positive histoplasmosis‐serology yielded in a diagnostic dilemma as no distinct diagnosis was drawable. After the patient was already started on a prednisolone trial, the final diagnosis – pulmonary histoplasmosis – could be achieved via positive culture and PCR out of the BAL fluid. This case shows the difficult differentiation between an acute exacerbation of a chronic pulmonary disease and a concomitant infection, which was especially aggravated in this case as the histoplasmosis masqueraded an acute picture of sarcoidosis.

Nachweis von Klebsiella pneumoniae und pulmonalen Infiltraten – (K)eine Pneumonie?

In den letzten zwei Jahrzehnten war K. pneumoniae der haufigste isolierte Erreger bei ambulant erworbenen Leberabszessen in asiatischen Landern, sodass das „K. pneumoniae associated community-acquired primary invasive liver abscess syndrome“ als neue Krankheit beschrieben wurde. Siu et al. stellten 2012 eine Definition fur das invasive Syndrom auf. Demzufolge liegt ein invasives Syndrom bei primarem Leberabszess mit extrahepatischen Komplikationen in Form von septischen Embolien bei Nachweis eines K. pneumoniae K1- oder K2-Seroptyp vor [2].