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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.

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,1,9 Lene 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 interna

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

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.

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.