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A lung abscess is a necrotising infection leading to loss of healthy lung tissue. It develops over several weeks, and the typical presentation includes cough, fever, and general deterioration. The clinical work-up includes contrast-enhanced CT-scans, and frequently flexible bronchoscopy with broncho-alveolar lavage as described in this review. The infection commonly represents aspiration of oral bacterial flora, including anaerobic microbes. Penicillin resistance is common. A lung abscess generally requires long-term, tailored antibiotic treatment. The patient should consult a dentist to identify possible dental foci.

We report a coronavirus disease 2019 case with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persisting beyond 333 days in an immunocompromised patient with chronic lymphocytic leukemia, asymptomatically carrying infectious SARS-CoV-2 at day 197 postdiagnosis. In addition, viral sequencing indicates major changes in the spike protein over time, temporally associated with convalescent plasma treatment.

Methicillin-resistant Staphylococcus aureus (MRSA) clonal complex (CC) 398 has spread from pigs to humans, but rarely from person to person. This strain of MRSA has been considered less virulent than others. Livestock-associated MRSA CC398 (LA-MRSA CC398) is particularly known to colonize pig farmers. Recent studies have shown an increasing number of people colonized with LA-MRSA CC398 and invasive infections caused by LA-MRSA CC398. The case of a previously healthy, 61-year-old woman admitted to a Danish regional hospital is reported here. She presented with fever, severe back pain, and bilateral hyperreflexia of patellar and Achilles reflexes. Blood tests revealed leukocytosis and elevated C-reactive protein. Empiric antimicrobial therapy with intravenous piperacillin–tazobactam was initiated, but blood cultures grew MRSA and antimicrobial therapy was changed to intravenous vancomycin. Whole-genome sequencing showed that the MRSA strain belonged to LA-MRSA CC398 spa type t011 and was Panton–Valentine leukocidin-negative. Magnetic resonance imaging revealed an epidural abscess at the level of L1–L4. Surgery was performed and pus from the abscess grew MRSA. The duration of antimicrobial therapy was 12 weeks. This case report describes bacteremia with LA-MRSA CC398 in a previously healthy patient without exposure to livestock or previous admission to a hospital. This highlights the risk of person-to-person transmission of LA-MRSA CC398 and brings into question whether LA-MRSA CC398 may have a greater pathogenic potential than previously assumed. Keywords: Antimicrobial resistance, Bacteremia, Livestock, Methicillin-resistant Staphylococcus aureus, Epidural abscess

BACKGROUND: Candidemia is the most frequent pediatric fungal infection, but incompletely elucidated in population-based settings. We performed a nationwide cohort study including all pediatric patients with candidemia in Denmark from 2004 to 2014 to determine age, incidence, species distribution, underlying diseases, patient management and outcomes.METHODS: All candidemia episodes were identified through the active nationwide fungemia surveillance program. Susceptibility testing followed the EUCAST E.Def 7 (European Committee on Antifungal Susceptibility Testing, Edition Definitive) reference method. χ test, Fisher exact test and Venn diagrams were used for statistical analyses.RESULTS: One hundred fifty-three pediatric patients (≤ 15 years) with 158 candidemia episodes were identified. The overall annual incidence rate was 1.3/100,000 population, higher for neonates (5.7/100,000 live births) and low birth weight neonates (103.8/100,000 live births). From 2004 to 2009 to 2010 to 2014, the proportion of Candida albicans decreased from 74.4% to 64.7%, whereas fluconazole resistance increased from 7.8% to 17.7%. Virtually all patients had at least 1 underlying disease (98.6%) and multimorbidity was common (43.5%, ≥2 underlying diseases). Underlying diseases differed by age with heart malformations and gastrointestinal disease prevalent in children younger than 3 years. The overall 30-days mortality was 10.2% and highest for neonates (17.1%). Mortality increased from 2004 to 2010 to 2014, driven by an increase among older children.CONCLUSION: This first nationwide epidemiologic study of pediatric candidemia confirmed a high incidence among neonates and a substantial burden of comorbidities. Moreover, an increasing proportion of fluconazole resistant nonalbicans species was observed. Our findings underline the importance of choosing correct treatment and continuous surveillance of pediatric candidemia.

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group ( P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log 10 copies/mL ( p Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

International audience; Although substantial efforts have been made to investigate about the composition of the microbiota, fungi that constitute the mycobiota play a pivotal role in maintaining microbial communities and physiological processes in the body. Here, we conducted an international survey focusing on laboratory's current procedures regarding their goals and practices of mycobiota characterisation using NGS. A questionnaire was proposed to laboratories affiliated to working groups from ECMM (NGS study group) and ESCMID (ESGHAMI and EFISG study groups). Twenty-six questionnaires from 18 countries were received. The use of NGS to characterise the mycobiota was not in routine for most of the laboratories (N = 23, 82%), and the main reason of using NGS was primary to understand the pathophysiology of a dysbiosis (N = 20), to contribute to a diagnosis (N = 16) or to implement a therapeutic strategy (N = 12). Other reported reasons were to evaluate the exposome (environmental studies) (N = 10) or to investigate epidemics (N = 8). Sputum is the main sample studied, and cystic fibrosis represents a major disease studied via the analysis of pulmonary microbiota. No consensus has emerged for the choice of the targets with 18S, ITS1 and ITS2 used alternatively among the laboratories. Other answers are detailed in the manuscript. We report a photography of mycobiota analysis that may become a major tool in the near future. We can draw some conclusions on the diversity of approaches within the answers of the 27 laboratories and underline the need for standardisation.

Background: Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality. Methods: Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression). Results: Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92). Conclusion: A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue. Keywords: Candidaemia, Candida, Epidemiology, Outcome, Mortality

Karen Rokkedal Lausch,1 Mette Søgaard,2,3 Flemming Schønning Rosenvinge,4,5 Helle Krogh Johansen,6 Trine Boysen,7 Bent Løwe Røder,8 Klaus Leth Mortensen,1,9Lene Nielsen,10 Lars Lemming,9 Bente Olesen,10 Christine Leitz,11 Lise Kristensen,9,12 Esad Dzajic,13 Lars Jørgen Østergaard,1 Henrik Carl Schønheyder,14,15 Maiken Cavling Arendrup6,16,17 1Department of Infectious Disease, Aarhus University Hospital, 8200 Aarhus, Denmark; 2Department of Cardiology, Aalborg University Hospital, 9000 Aalborg, Denmark; 3Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, 9000 Aalborg, Denmark; 4Department of Clinical Microbiology, Odense University Hospital, 5000 Odence C, Denmark; 5Department of Clinical Microbiology, Lillebaelt Hospital, 5500 Middelfart, Denmark; 6Department of Clinical Microbiology, Rigshospitalet, 2100 Copenhagen, Denmark; 7Department of Clinical Microbiology, Hvidovre Hospital, 2650 Hvidovre, Denmark; 8Department of Clinical Microbiology, Hospital of Slagelse, Slagelse Sygehus, 4200 Slagelse, Denmark; 9Department of Clinical Microbiology, Aarhus University Hospital, 8200 Aarhus, Denmark; 10Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, 2730 Herlev, Denmark; 11Department of Clinical Microbiology, Viborg Regionshospital, 8800 Viborg, Denmark; 12Department of Clinical Microbiology, Herning Regionshospital, 7400 Herning, Denmark; 13Department of Clinical Microbiology, Sydvestjysk Sygehus, 6700 Esbjerg, Denmark; 14Department of Clinical Microbiology, Aalborg University Hospital, 9000 Aalborg, Denmark; 15Department of Clinical Medicine, University of Aalborg, 9000 Aalborg, Denmark; 16Unit of Mycology, Statens Serum Institute, 2300 København, Denmark; 17Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark Background: In accordance with international guidelines, primary antifungal treatment (AFT) of candidemia with echinocandins has been nationally recommended in Denmark since 2009. Our nationwide cohort study describes the management of candidemia treatment focusing on the impact of prophylactic AFT on species distribution, the rate of adherence to the recommended national guidelines for AFT, and the effect of AFT on patient outcomes.Materials and methods: Incident candidemia cases from a 2-year period, 2010–2011, were included. Information on AFT was retrospectively collected from patient charts. Vital status was obtained from the Danish Civil Registration System. HRs of mortality were reported with 95% CIs using Cox regression.Results: A total of 841 candidemia patients was identified. Prior to candidemia diagnosis, 19.3% of patients received AFT (162/841). The risk of non-albicans candidemia increased after prior AFT (59.3% vs 45.5% among nontreated). Echinocandins as primary AFT were given for 44.2% (302/683) of patients. Primary treatment with echinocandins resulted in adequate treatment in a higher proportion of patients (97.7% vs 72.1%) and was associated with lower 0- to 14-day mortality compared with azole treatment (adj. HR 0.76, 95% CI: 0.55–1.06). Significantly lower 0- to 14-day mortality was observed for patients with Candida glabrata and Candida krusei with echinocandin treatment compared with azole treatment (adj. HR 0.50, 95% CI: 0.28–0.89), but not for patients with Candida albicans or Candida tropicalis.Conclusion: The association shown between prior AFT and non-albicans species underlines the importance of treatment history when selecting treatment for candidemia. Compliance with national recommendations was low, but similar to previously reported international rates. Primary treatment of candidemia with echinocandins compared with azoles yielded both a higher proportion of adequately treated patients and improved mortality rates. This real-life setting supports guidelines recommendation, and further focus on compliance with these seems warranted. Keywords: candidemia, candida, antifungal treatment, echinocandin, azole, Candida albicans, Candida glabrata

A 62 year-old woman with rheumatoid arthritis (RA) presented with general malaise, shortness of breath, and productive cough. She had had RA for 4 years and had been treated with methotrexate (MTX)...

A patient with Candida spondylitis failed two weeks of fluconazole combined with caspofungin, and the infection relapsed despite six weeks of liposomal amphotericin B followed by two months of fluconazole. Six months therapy with high dose liposomal amphotericin B combined with flucytosine effectively cured the patient., Highlights • A Candida osteomyelitis case failing caspofungin+fluconazole treatment is described. • A relapse was diagnosed after ambisome followed by fluconazole therapy. • Prolonged therapy with increasing dose L-AMB and 5-FC eradicated the infection. • Further clinical studies are warranted to define optimal treatment strategies.

Invasive aspergillosis (IA) is a major cause of death among patients with chronic granulomatous disease (CGD). Few cases of cardiac aspergillosis have been published on CGD patients. Diagnosis of IA in CGD patients can be hampered by lack of characteristic symptoms and clinical signs and the serum galactomannan assay is often negative. We report the first CGD patient with IA presenting as pericarditis where combined antifungal therapy resulted in a successful outcome.

The aim of this study is to calculate the burden of fungal disease in Denmark. We identified all published epidemiology papers reporting fungal infection rates in Denmark. Where no data existed, we used numbers of specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence. Approximately, one in six Danes will suffer from a fungal infection each year, most of which are skin or mucosal diseases causing disability but no deaths. Good data exist on candidaemia where a national voluntary reporting system is in place and have shown a high rate (9.6 per 100,000 inhabitants) compared other European countries. We present estimates of invasive aspergillosis and chronic pulmonary aspergillosis with rates of 4.4 per 100,000 and 3.1 per 100,000 inhabitants, respectively. Further studies are needed in order to better ascertain high-burden fungal infections such as recurrent vulvovaginal candidiasis (~1350 cases in 100,000 women) as well as allergic bronchopulmonary aspergillosis (~131 cases in 100,000 inhabitants) and severe asthma with fungal sensitisation (cases in 100,000 inhabitants). In conclusion, more than 93,000 Danes or about 2% of Denmark's population will have a non-trivial fungal infection during 1 year, which underscores the magnitude of the fungal burden.

A three-month laboratory-based prospective survey was conducted at four major university hospitals covering one-third of the Danish population in order to determine the prevalence, significance, and susceptibility pattern of aspergilli in airway samples. Samples received in January-March 2007 for routine microbiologic investigation were examined for Aspergillus following routine procedures and with extended incubation (5 days). Identification was done by morphologic criteria and susceptibility testing using EUCAST method for azoles and amphotericin B E-test. Invasive aspergillosis (IA) was evaluated using modified EORTC/MSG criteria. A total of 11,368 airway samples were received. Growth of Aspergillus spp. was found in 129 and 151 patients using routine and extended incubation, respectively. Three patients had proven IA (2%), 11 probable (7%), four had allergic bronchopulmonary aspergillosis (ABPA) (3%), but the majority was colonised (88%). Underlying conditions were cystic fibrosis in 82 patients (55%), chronic obstructive pulmonary disease in 19 (13%) and haematological disorder in 11 (7%). Twenty-six patients (18%) were at intensive care unit and 69 (47%) received steroid treatment. Azole MICs were elevated for five isolates as follows (itraconazole, posaconazole, voriconazole MICs [mg/L]): two A. fumigatus isolates (>4; >4; 2 and >4; 0.125; 1), one A. lentulus isolate (2; 2; 0.5) and two A. terreus isolates (2; 2; 2 and 2; 0.125; 1). For four isolates the amphotericin B MIC was >1 μg/ml (3/112 A. fumigatus, 1/2 A. terreus). In conclusion, Aspergillus appears to be an important pathogen in Denmark. Elevated itraconazole MICs were detected in 4% of the isolates including a multi-azole resistant isolate.

Respiratory tract colonization by molds in patients with cystic fibrosis (CF) were analyzed, with particular focus on the frequency, genotype, and underlying mechanism of azole resistance among Aspergillus fumigatus isolates. Clinical and demographic data were also analyzed. A total of 3,336 respiratory samples from 287 CF patients were collected during two 6-month periods in 2007 and 2009. Azole resistance was detected using an itraconazole screening agar (4 mg/liter) and the EUCAST method. cyp51A gene sequencing and microsatellite genotyping were performed for isolates from patients harboring azole-resistant A. fumigatus. Aspergillus spp. were present in 145 patients (51%), of whom 63 (22%) were persistently colonized. Twelve patients (4%) harbored other molds. Persistently colonized patients were older, provided more samples, and more often had a chronic bacterial infection. Six of 133 patients (4.5%) harbored azole-nonsusceptible or -resistant A. fumigatus isolates, and five of those six patients had isolates with Cyp51A alterations (M220K, tandem repeat [TR]/L98H, TR/L98H-S297T-F495I, M220I-V101F, and Y431C). All six patients were previously exposed to azoles. Genotyping revealed (i) microevolution for A. fumigatus isolates received consecutively over the 2-year period, (ii) susceptible and resistant isolates (not involving TR/L98H isolates) with identical or very closely related genotypes (two patients), and (iii) two related susceptible isolates and a third unrelated resistant isolate with a unique genotype and the TR/L98H resistance combination (one patient). Aspergilli were frequently found in Danish CF patients, with 4.5% of the A. fumigatus isolates being azole nonsusceptible or resistant. Genotyping suggested selection of resistance in the patient as well as resistance being achieved in the environment. K.L.M. is member of the ISHAM Working Group on Fungal Respiratory Infections in Cystic Fibrosis and has received travel grants from Pfizer, Schering-Plough (now MSD), and MSD. R.H.J. has received a travel grant from MSD. E.M. was supported by the Ministerio de Ciencia e Innovacion (MICINN; grant number SAF2008-04143) and has been paid for a talk on behalf of Gilead. S.J.H. has received support grants from Gilead, Pfizer, and the Fungal Research Trust and travel grants from Astellas and Schering-Plough and has been paid for talks on behalf of Pfizer and Astellas. M.C.A. has been paid for talks on behalf of Astellas, Merck, Pfizer, Schering-Plough, Spepharm, Gilead, and Swedish Orphan, acted as a consultant for Merck, Astellas, Spepharm, and Pfizer, received research grants from Astellas, Pfizer, Roche, Schering-Plough, and Merck and received travel grants from Astellas, Merck, Pfizer, Schering-Plough, and Swedish Orphan. H.K.J., M.S., T.P., and H.L. have no conflicts to report. Sí

A single mechanism of azole resistance was shown to predominate in clinical and environmental Aspergillus fumigatus isolates from the Netherlands, and a link to the use of azoles in the environment was suggested. To explore the prevalence of azole-resistant A. fumigatus and other aspergilli in the environment in other European countries, we collected samples from the surroundings of hospitals in Copenhagen, Innsbruck, and Madrid, flowerbeds in an amusement park in Copenhagen, and compost bags purchased in Austria, Denmark, and Spain and screened for azole resistance using multidish agars with itraconazole, voriconazole, and posaconazole. EUCAST method E.DEF 9.1 was used to confirm azole resistance. The promoter and entire coding sequence of the cyp51A gene were sequenced to identify azole-resistant A. fumigatus isolates. A. fumigatus was recovered in 144 out of 185 samples (77.8%). Four A. fumigatus isolates from four Danish soil samples displayed elevated azole MICs (8%), and all harbored the same TR/L98H mutation of cyp51A . One A. lentulus isolate with voriconazole MIC of 4 mg/liter was detected in Spain. No azole-resistant aspergilli were detected in compost. Finally, A. terreus was present in seven samples from Austria. Multi-azole-resistant A. fumigatus is present in the environment in Denmark. The resistance mechanism is identical to that of environmental isolates in the Netherlands. No link to commercial compost could be detected. In Spain and Austria, only Aspergillus species with intrinsic resistance to either azoles or amphotericin B were found.

Contains fulltext : 88544.pdf (Publisher’s version ) (Open Access) Four sequential Aspergillus fumigatus isolates from a patient with chronic granulomatous disease (CGD) eventually failing azole-echinocandin combination therapy were investigated. The first two isolates (1 and 2) were susceptible to antifungal azoles, but increased itraconazole, voriconazole and posaconazole MICs were found for the last two isolates (3 and 4). Microsatellite typing showed that the 4 isolates were isogenic, suggesting that resistance had been acquired during azole treatment of the patient. An immunocompromised mouse model confirmed that the in vitro resistance corresponded with treatment failure. Mice challenged with the resistant isolate 4 failed to respond to posaconazole therapy, while those infected by susceptible isolate 2 responded. Posaconazole-anidulafungin combination therapy was effective in mice challenged with isolate 4. No mutations were found in the Cyp51A gene of the four isolates. However, expression experiments of the Cyp51A showed that the expression was increased in the resistant isolates, compared to the azole-susceptible isolates. The microscopic morphology of the four isolates was similar, but a clear alteration in radial growth and a significantly reduced growth rate of the resistant isolates on solid and in broth medium was observed compared to isolates 1 and 2 and to unrelated wild-type controls. In the mouse model the virulence of isolates 3 and 4 was reduced compared to the susceptible ones and to wild-type controls. For the first time, the acquisition of azole resistance despite azole-echinocandin combination therapy is described in a CGD patient and the resistance demonstrated to be directly associated with significant change of virulence.

Caspofungin is used for the treatment of acute invasive candidiasis and as salvage treatment for invasive aspergillosis. We report characteristics of isolates of Candida albicans and Aspergillus fumigatus detected in a patient with breakthrough infection complicating severe gastrointestinal surgery and evaluate the capability of susceptibility methods to identify candin resistance. The susceptibility of C. albicans to caspofungin and anidulafungin was investigated by Etest, microdilution (European Committee on Antibiotic Susceptibility Testing [EUCAST] and CLSI), disk diffusion, agar dilution, and FKS1 sequencing and in a mouse model. Tissue was examined by immunohistochemistry, PCR, and sequencing for the presence of A. fumigatus and resistance mutations. The MICs for the C. albicans isolate were as follows: >32 μg/ml caspofungin and 0.5 μg/ml anidulafungin by Etest, 2 μg/ml caspofungin and 0.125 μg/ml anidulafungin by EUCAST methods, and 1 μg/ml caspofungin and 0.5 μg/ml anidulafungin by CLSI methods. Sequencing of the FKS1 gene revealed a mutation leading to an S645P substitution. Caspofungin and anidulafungin failed to reduce kidney CFU counts in animals inoculated with this isolate ( P > 0.05 compared to untreated control animals), while both candins completely sterilized the kidneys in animals infected with a control isolate. Disk diffusion and agar dilution methods clearly separated the two isolates. Immunohistochemistry and sequencing confirmed the presence of A. fumigatus without FSK1 resistance mutations in liver and lung tissues. Breakthrough disseminated aspergillosis and candidiasis developed despite an absence of characteristic FKS1 resistance mutations in the Aspergillus isolates. EUCAST and CLSI methodology did not separate the candin-resistant clinical isolate from the sensitive control isolate as well as did the Etest and agar methods.

Four cases are presented, immunosuppressed by at least three different mechanisms: one HIV-positive patient with a CD4 count of 0.29 x 10(6)/ml, one malnourished patient, and two kidney-transplanted patients. All patients had a negative interferon (IFN)-gamma test for suspected tuberculosis (TB), but a positive culture. We conclude that a negative IFN-gamma test does not exclude TB disease in immunosuppressed patients.