- Email: [email protected]
Evolution of fungemia in an Italian region
Journal Pre-proof Evolution of fungemia in an italian region Anna Prigitano Caterina Cavanna Marco Passera Marina Gelmi Eugenio Sala Cristina Ossi Anna Grancini Maria Calabr`o Simone Bramati Milvana Tejada Fabiola Lallitto Claudio Farina Vanina. Rognoni Maria Antonietta Fasano Beatrice Pini Luisa Roman`o Massimo Cogliati Maria Carmela Esposto Anna Maria Tortorano Prof
PII:
S1156-5233(19)30131-3
DOI:
https://doi.org/doi:10.1016/j.mycmed.2019.100906
Reference:
MYCMED 100906
To appear in:
´ Journal de Mycologie Medicale
Received Date:
16 April 2019
Revised Date:
9 September 2019
Accepted Date:
9 October 2019
Please cite this article as: Prigitano A, Cavanna C, Passera M, Gelmi M, Sala E, Ossi C, Grancini A, Calabr`o M, Bramati S, Tejada M, Lallitto F, Farina C, Rognoni V, Fasano MA, Pini B, Roman`o L, Cogliati M, Esposto MC, Tortorano AM, Evolution of fungemia in an italian ´ region, Journal de Mycologie Medicale (2019), doi: https://doi.org/10.1016/j.mycmed.2019.100906
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
EVOLUTION OF FUNGEMIA IN AN ITALIAN REGION. Anna Prigitano1, Caterina Cavanna2, Marco Passera3, Marina Gelmi4, Eugenio Sala5, Cristina Ossi6, Anna Grancini7, Maria Calabrò8, Simone Bramati9, Milvana Tejada10, Fabiola Lallitto2, Claudio Farina3, Vanina. Rognoni11, Maria Antonietta Fasano12, Beatrice Pini13, Luisa Romanò1, Massimo Cogliati1, Maria Carmela Esposto1, Anna Maria Tortorano1 Department of Biomedical Sciences for Health, Università degli Studi di Milano
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Microbiology and Virology Unit IRCCS Policlinico San Matteo, Pavia
3
Microbiology Institute, ASST ‘Papa Giovanni XXIII’, Bergamo, Italy
4
Microbiology Laboratory, A.O. Spedali Civili, Brescia
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Microbiology - ASST Lariana, Como
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Laboratory of Microbiology and Virology, San Raffaele Scientific Institute, Milano
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Microbiology Laboratory, Fondazione IRCCS Cà Granda O. Maggiore Policlinico, Milano
8
Microbiology Section, Humanitas Research Hospital, Milano
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Microbiology Laboratory, Ospedale San Gerardo, Monza
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Medicina di Laboratorio, IRCCS Policlinico San Donato, Milano
11
Microbiology Unit, ASST Lodi
12
Microbiology and Virology Unit, ASST Bergamo Ovest Treviglio
13
Laboratory of Microbiology and Virology, ASST Lecco
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Corresponding author
Prof. Anna Maria Tortorano
Department of Biomedical Science for Health Università degli Studi di Milano Via Pascal 36 20133 Milano, Italy Tel. +39 02 503 15145 Fax +39 02 503 15146 Email [email protected]
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Abstract Background. Fungemia represents a public health concern. Knowing aetiology and activity of the antifungals is critical for the management of bloodstream infections. Therefore, surveillance on local/international levels is desirable for a prompt administration of appropriate therapy. Methods. Data on fungi responsible for fungemia and antifungal susceptibility profiles were collected from a laboratory-based surveillance over 2016-17 in 12 hospitals located in Lombardia, Italy. The trend of this infection in twenty years was analysed. Results. A total of 1024 episodes were evaluated. Rate of candiaemia progressively increased up to 1.46/1 000 admissions. C.albicans was the most common species (52%), followed by C.parapsilosis (15%) and C
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glabrata (13%). As in the previous surveys the antifungal resistance is rare (echinocandins <2%, fluconazole 6%, amphotericin B 0.6%). Fungi other than Candida were responsible for 18 episodes: Cryptococcus neoformans (5 cases), Fusarium spp. (4), Magnusiomyces clavatus (3), Saccharomyces
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cerevisiae (3), Rhodotorula spp. (2), Exophiala dermatitidis (1). All fungi, except S.cerevisiae, were intrinsically resistant to echinocandins. Some isolates showed also elevated azole MIC.
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Conclusions. No particular changes in terms of species distribution and antifungal susceptibility patterns was noted. However, surveillance programs are needed to monitor trends in antifungal resistance, steer
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stewardship activities, orient empirical treatment.
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Keywords: Fungemia; candidaemia; Candida; antifungal resistance; epidemiology.
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Introduction Fungemia represents a public health concern being associated with high mortality rate (30-40%), increased length of hospital stay and costs [1]. Candida species are the most frequent cause of fungemia. Other yeasts, such as Saccharomyces, Rhodotorula, Cryptococcus, or moulds, such as Fusarium spp., are rarely involved. Candida bloodstream infection (BSI) is extensively investigated in patients undergoing chemotherapy because of hematologic malignancies or autologous or allogeneic hematopoietic stem cell transplantation [2], in medical and surgical patients in intensive care unit (ICU) [3-5], and more recently in patients hospitalised in Internal Medicine wards [6]. Broad spectrum antibiotics use, critical care therapies, major
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gastrointestinal surgery and chemotherapy cause dysbiosis and damage of the mucous membrane barrier favouring translocation of Candida from the gut to the bloodstream. In addition, the use of invasive procedures, such as indwelling vascular catheters and total parenteral nutrition, and the impairment of
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the immune system due to underlying malignancy or its treatment represent further risk factors for candidaemia [2-6].
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As recently emphasized by Castanheira [7], knowing the local epidemiology of Candida aetiology and the activity of the antifungal agents against these fungal isolates is critical for the clinical management of BSI,
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due to the delay of culture methods and the further delay of antifungal susceptibility results. Therefore, surveillance on local and international levels is desirable for a prompt administration of an appropriate antifungal therapy [7].
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The aim of the present study (FUNG-LO 2016-2017) is to report data concerning fungemia from a
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laboratory-based survey carried out in one Italian region (Lombardia, 10 036 258 inhabitants) in the period 2016-17 and to analyse the trend of this infection in the last twenty years. Materials and Methods
The study prospectively included all cases of fungemia, defined by at least one positive blood culture yielding a fungal species, occurred from January 2016 to December 2017 in 12 hospitals located in Lombardia, Italy. Cases with isolation of a different species or of the same species from a blood sample collected at least 10 days apart were included in the study. Data concerning date of positive blood culture, species identification, antifungal susceptibility profile, and admission hospital ward were provided by each clinical microbiology laboratory in anonymous form on a specific database. Bloodcultures were processed using BacT/Alert (BioMérieux, Marcy l’Etoile, France) in eight participant hospitals and BD-Bactec (Becton Dickinson, Franklin Lakes, NJ, USA) in four using classic aerobic bottles.
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The identification of the isolates was performed locally using Vitek 2 Yeast cards BioMérieux (one laboratory), Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS, Bruker Daltonics, Bremen, Germany) (two), Vitek MS BioMérieux (nine). Also antifungal susceptibility was performed locally using Sensititre YeastOne (SYO, Thermo Scientific Trek Diagnostic Systems, East Grinstead, UK) in all centres except two that used Vitek 2 (BioMérieux). Only data from centres using SYO were included in the analysis. Antifungals tested were those included in the SYO panel, namely amphotericin B, anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, voriconazole and flucytosine. Minimal inhibitory concentration (MIC) values obtained with SYO were interpreted according to Clinical
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Laboratory and Standards Institute (CLSI) species-specific breakpoints or, in case of lack of these breakpoints, according to the SYO epidemiological cutoff values (ECV) to identify wild type or non-wild type isolates [8, 9].
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MIC at which 90% of the isolates was inhibited (MIC90) was calculated only for species with more than 10 isolates tested.
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Number of admissions and patient days were collected for each hospital. Hospital specific rates were calculated using the total number of patients admitted in each institution during the surveillance period
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as the denominator. Day-hospital patients and healthy newborns were excluded. The wards of hospitalization were grouped as follows: medical wards (internal medicine, infectious
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diseases, gastroenterology, pneumology), surgical wards (general surgery, cardio surgery, solid organ transplant centre, neurosurgery, urology), intensive care units (ICU) and haematology including
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hematopoietic stem cell transplant centres.
The results of the present survey were compared with the previous ones carried out in the same region [10-12].
The Chi-square test was used to compare proportions. A value of p <0.05 (two-tailed) was considered to be statistically significant. Results A total of 1024 episodes of fungemia, including 1006 Candida BSIs, occurred in the 2-year period, 20162017. Episode rate of candidaemia, available for 11 hospitals that reported all episodes, was 1.46/1 000 admissions (range, 0.41 to 2.33) and 1.8/10 000 patient days (range, 0.05 to 3.0). Compared to our previous data, a progressive increase in the last 20 years was shown starting from 0.38/1 000 admissions (p<0.001) and 0.44/10 000 patient days (p<0.001) in 1997-99 [10-12].
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In the present study, males accounted for 58.8% of the cases. The mean age was 67 years, ranging from 8 days to 99 years, and median 71 years. 30% of the episodes occurred in the cohort 70-79 years. A progressive increase of the episodes in subjects of ≥80 years of age from 8% in ‘90s to 24.5% in 2016-17 was observed (p <0.001). In the recent survey C. albicans was the most common aetiology (547/1006, 54.4%), followed by C. glabrata (205/1006, 20.4%), C. parapsilosis species complex (161/1006, 16%), and C.tropicalis (56/1006, 5.6%). Over the 20 years the proportion of C. parapsilosis remains stable (from 15% to 16%), while the proportion of C. albicans and C. glabrata was fluctuating from 52% to 59% (p=0.02) and from 13% to 20% (p<0.001), respectively (Figure 1).
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C. glabrata ranked two in the oldest patients accounting for 22.9% of the episodes occurred in the age group of ≥ 70 years, and up to 27% of the episodes in the ≥80 year old people. No difference of C. glabrata aetiology was noted according to the used bloodculture method (20.1% and 20.5% using BactAlert and
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Bactec, respectively) and the patient gender (19.8% in female vs 20.1% in male patients). In neonates only two species were responsible of BSIs, namely C. albicans accounted for 75% (9/12) and
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C. parapsilosis (25%). C. albicans accounted for 63.8% (23/36) of BSIs occurred in children (≤15 year old), followed by C. parapsilosis (21.4%, 8/36). No C. glabrata infection occurred in this age group.
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C. albicans predominated in BSIs diagnosed in ICU, in surgical and in medical wards, causing 60%, 58.7% and 50% of the episodes, respectively. C. glabrata occurred particularly in medical wards (22.9%) (Figure
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2). In haematology wards C. albicans represented 45% of aetiologies. A large variation of species among the different centres reporting ≥60 episodes was observed: C.
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parapsilosis aetiology ranged from 10% to 22% (p<0.05), and C. glabrata from 12% to 26% (p<0.001). C. albicans was responsible of 46% up to 62% (p = 0.05) of BSI in the hospital with the lowest and the highest number of ICU beds, respectively.
No C. auris BSIs have been identified.
More rare Candida species were identified as aetiology of 38 episodes (3.8%) in the 2016-17 survey, namely C. krusei (10 episodes), C. lusitaniae (n=9), C. guilliermondii (n=7) C. dubliniensis (n=4), C. kefyr (n=3), C. norvegensis (n=2) C. utilis (n=2), and C. intermedia (n=1). Table 1 shows the antifungal susceptibility pattern of the most representative Candida species isolates. Echinocandin resistance ranged from 0-0.4% for C. albicans up to 1.9% for C. tropicalis. The percentage of fluconazole and voriconazole resistance, according to CLSI species specific breakpoints, among C. albicans isolates was low (1.2 and 1.4%, respectively). 10% of C. tropicalis isolates was resistant to fluconazole and only 1.9% to voriconazole. The number of posaconazole non-wild type isolates was limited for all these
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species. 6% of C. parapsilosis isolates were resistant to fluconazole and voriconazole, and posaconazole non-wild type, while among the nine fluconazole resistant C. parapsilosis isolates all had posaconazole MICs <0.12 mg/L and all voriconazole MICs 0.25-0.5 mg/L except one with MIC 4 mg/L. One out of the eight fluconazole resistant C. tropicalis was also resistant to the other azoles. Amphotericin B exhibited good activity against all Candida isolates as only six (three C. albicans, one C. glabrata, one C. krusei and one C. norvegensis) had a MIC value of 2 mg/L. The antifungal susceptibility pattern of the rare Candida species is reported in Table 2. On the basis of the SYO ECVs of azoles, available for C. dubliniensis, C. guilliermondii, and C. lusitaniae, only one C. lusitaniae isolate was non-wild type for fluconazole.
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Fungi other than Candida were the aetiology of 18 episodes. Cryptococcus neoformans was isolated from five patients. Fusarium spp. and Magnusiomyces clavatus caused fungemia in four and three patients with haematological malignancies, respectively. Other fungi were Saccharomyces cerevisiae isolated from
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three patients, Rhodotorula mucillaginosa, R. rubra and Exophiala dermatitidis isolated from one patient each.
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All yeast or yeast–like filamentous fungi, except S. cerevisiae, were intrinsically resistant to echinocandins. Some isolates showed also elevated MIC values of azoles (Table 3). SYO was not used to test the antifungal
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susceptibility of C. neoformans, Fusarium spp. and Exophiala dermatitidis isolates. Discussion
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A laboratory-based survey of fungemia was carried out in the period 2016-17 in Lombardia, an Italian
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region subject to similar studies over the past two decades [10-12]. The progressive increase of the incidence rate of Candida BSIs over the 20 years may be due to the increase number of high-risk patients, to the 30% increase of >65 year old population, and changes in healthcare policies with home care for less serious patients and hospitalization of the more severe ones, and to the decline of days of hospitalization (www.istat.it). The rate of the current epidemiological data was higher compared to that reported in the nationwide surveillance performed in other countries such as Denmark where the rate ranged from 0.34 to 0.37 per 1000 discharges [13]. In most of the published surveys [14-16] the number of episodes was referred to inhabitants. However we did not refer to the inhabitants as often the hospitalized patients were outside the town where the hospital is located or even outside of the region. As it concerns the aetiology of the BSIs occurred in 2016-2017, C. albicans predominated (54.4%), followed by C. glabrata (20.4%). The increase of C. glabrata aetiology, that reached up to 27% of the episodes in the ≥80 year old people, may be linked to the increase of old population in the last 20 years (www.istat.it).
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No C. glabrata BSI occurred in neonates and children. C. albicans represented less than 50%, namely 45%, only in BSIs occurred in haematology wards where C.parapsilosis and more rare species emerged as a consequence of the large use of antifungal prophylaxis in this patient population. Regarding C. auris, a species of particular public health concern due to the intrinsic resistance to fluconazole and rapid development of resistance to other antifungals, no cases have been identified. Some differences in aetiology were noted compared to the Danish experience [13]. In our experience the blood culture system does not seem to have influenced the detection of C. glabrata and gender did not have impact on this species. Antifungal susceptibility testing is recommended for Candida bloodstream isolates and the CLSI and the
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European Committee on Antibiotic Susceptibility Testing (EUCAST) developed standard methodologies [8,17] that however are not used in clinical laboratories as cumbersome and time consuming. Although the SYO is the method widely used to routinely test the antifungal susceptibility of Candida
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isolates interpretative criteria of results obtained with this commercial method are not available. As a consequence, the MIC values are interpreted on the basis of CLSI interpretative categories due to the
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favourable comparison between MICs obtained by the commercial SYO and the reference CLSI method. Species specific clinical breakpoints are not available for all Candida species and antifungals and, in these
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cases, the SYO ECVs were used to identify wild type or non-wild type isolates [9]. As in the previous surveys conducted in the same region [11, 12, 18, 19] the antifungal resistance among
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Candida causing BSIs remains rare. Echinocandin resistance was limited (<2%) and a reduced number of Candida isolates (six out of 1006) had an amphotericin B MIC value of 2 mg/L. Taking into account all the
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species for which the fluconazole breakpoints or SYO ECVs are available, the rate of resistance or nonwild type is very low (6%) compared to the experiences in England where up to 18% of candidaemia resulted with reduced or non susceptibility to fluconazole in the period 2012-2016 [20]. This discrepancy could be attributed to the different incidence of C. glabrata in the surveys: 20.4% in our survey vs 25% in the English survey (p = 0.001).
Only one isolate among the rare Candida species resulted non-wild type for fluconazole on the basis of the SYO ECVs for azoles and, unlike the results of the Austrian screening of yeast bloodstream isolates [21], our C. guilliermondii isolates did not show the high resistance to both azoles and echinocandins. Among fungi other than Candida, only occasionally isolated from BSIs, Cryptococcus, Magnusiomyces and Rhodotorula were intrinsically resistant to echinocandins, and some isolates had also elevated azole MIC values.
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Conclusions Despite the introduction of new antifungals and new classes of antifungals, the present survey did not show particular changes in terms of species distribution and antifungal susceptibility patterns. However, surveillance programs are needed to monitor trends in antifungal resistance, steer antifungal stewardship activities, orient empirical treatment and improve outcomes of these severe fungal infections.
Competing interest
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None declared. Funding
This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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SEIFEM 2015-B report. Haematologica 2017;102(10):e407-e410. doi: 10.3324/haematol.2017.172536. [3] Tortorano AM, Dho G, Prigitano A, Breda G, Grancini A, Emmi V, et al. Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008). Mycoses 2012;55(1):73-9. doi: 10.1111/j.1439-0507.2011.02044.x.
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[6] Falcone M, Tiseo G, Tascini C, Russo A, Sozio E, Raponi G, et al. Assessment of risk factors for candidaemia in non-neutropenic patients hospitalized in internal medicine wards: a multicenter study. Eur J Intern Med 2017;41:33-8. doi: 10.1016/j.ejim.2017.03.005. [7] Castanheira M. Fungemia surveillance in Denmark demonstrates emergence of non-albicans candida species and higher antifungal usage and resistance rates than in other nations. J Clin Microbiol 2018;56(4). pii: e01907-17. doi: 10.1128/JCM.01907-17. [8] Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard, 3rd edn. 2008. CLSI document M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA.
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[9] Espinel-Ingroff A, Turnidge J, Alastruey-Izquierdo A, Botterel F, Canton E, Castro C, et al. Method-dependent epidemiological cutoff values for detection of triazole resistance in Candida and Aspergillus species for the Sensititre Yeastone colorimetric broth and Etest agar diffusion
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methods. Antimicrob Agents Chemother 2018;63(1). pii: e01651-18. doi: 10.1128/AAC.0165118.
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[10] Tortorano AM, Biraghi E, Astolfi A, Ossi C, Tejada M, Farina C, et al.
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one Italian region. J Hosp Infect 2002;51(4):297-304.
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[14] Chapman B, Slavin M, Marriott D, Halliday C, Kidd S, Arthur I, et al.
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[16] Hesstvedt L, Gaustad P, Andersen CT, Haarr E, Hannula R, Haukland HH, eta al. Twenty-two years of candidaemia surveillance: results from a Norwegian national study. Clin Microbiol Infect 2015;21(10):93845. doi: 10.1016/j.cmi.2015.06.008. [17] Arendrup MC, Meletiadis J, Mouton JW, Lagrou K, Hamal P, Guinea J and the Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). Method for the determination of broth dilution minimum Inhibitory concentrations of antifungal agents for yeasts. EUCAST definitive document E.DEF 7.3.1; 2017.
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10.1111/myc.12892.
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bloodstream isolates collected during a 10-year period in Austria. Mycoses 2019;62(4):357-67. doi:
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Figure 1. Candida species distribution shown as percentage of isolates in the different surveys conducted in Lombardia, Italy.
Figure 2. Species distribution shown as percentage of isolates according to wards in the 2016-2017 survey (number
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of episodes)
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Table 1. MIC90, MIC range, number of resistant isolates according to CLSI species-specific breakpoints, and number of non wild-type isolates according to Espinel
glabrata
No. isolates
490
178
MIC90
0.5
64
150
52
10
1
2
0.125-256
0.125128
9 (6%)
5 (10%)
10*
148
51
10
0.125
0.5
0.5
0.06-≥8
0.03-0.5
1 (0.7%) 2 (3.9%)
0
Range
0.125-256
0.5-256
R CLSI
6 (1.2%)
21 (12%)
486
181
MIC90
0.125
1
Range
0.015-≥16
R CLSI
10 (2.0%)
47 (25.9%)
484
177
145
49
10
2
0.06
0.25
0.5
0.008-≥8
0.03-≥8 0.008-0.125
0.06-≥8
0.12-0.5
20 (4.1%)
2 (1.1%)
0
1 (2%)
0
No. isolates
495
155
149
52
10
MIC90
0.03
2
0.03
0.25
0.5
Range
0.008-≥8
0.03-≥8
0.008-4 0.008-≥8
0.12-1
No. isolates
MIC90 Range Non-WT
0.06-≥16
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Posaconazole No. isolates
Voriconazole
albicans
C. C. C. parapsilosis tropicalis krusei
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Itraconazole
C.
rn
Fluconazole
C.
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Ingroff et al. [9].
0.06
0.015-4.0
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R CLSI
7 (1.4%)
No. isolates
183
0.125
0.06
f
Range
0.015-0.5
0.015-0.5
R CLSI
0
1 (0.5%)
494
184
MIC90
0.125
0.125
Range
0.008-≥8
0.008-0.5
R CLSI
2 (0.4%)
No. isolates
150
52
2
0.125
0.12
0.0150.12
0.015-4
0 1 (1.9%)
0
150
52
10
1
0.125
0.50
0.03-1
0.015-2 00.06-0.5
1 (0.5%)
0
0
0
183
150
52
10
0.015
4
0.06
0.06
0.008-4 0.008-0.125
0.015-≥8
0.008-1 0.03-0.06
1 (0.2%)
0
1 (0.7%)
1 (1.9%)
0
No. isolates
482
183
150
50
10
MIC90
0.25
0.06
0.25
64
16
Range
0.06-64
0.O6-64
0.06-2
0.06-64
4-16
R CLSI
3 (0.7%)
2 (1.1%)
0 13 (26%)
0
No. isolates
Range R CLSI
491
0.015
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MIC90
Flucytosine
489
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Micafungin
0
10
MIC90
Caspofungin
1 (1.9%)
10 (6.4%)
rn
Anidulafungi n
1 (0.7%)
Pr epr oo
Non-WT
n.a.
15
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Amphotericin B No. isolates
184
152
52
10
MIC90
1
1
1
1
Range
0.12-2
0.12-2
0.12-1
0.12-1
0.25-2
R CLSI
n.a.
n.a.
n.a.
n.a.
n.a.
f
490
Pr epr oo
1
n.a.: not available; R CLSI: resistant isolates according to species-specific breakpoints established by CLSI; Non-WT: non wild-type isolates according to Espinel Ingroff et al. [9].
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* intrinsically resistant
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Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le
1
3
4 -
-
-
-
1
4 1
1
-
1
1
1
-
-
-
-
-
-
-
16
32
-
-
-
2
1 1
-
-
-
-
-
-
-
1
2
1
4
3
1
2
1
3
2
-
2
2 3
4 6
1
-
-
-
-
6 5
-
8
3
al
2
Pr epr oo
4
Jo u
guilliermon dii (7)
-
rn
Species Drug dubliniensis Anidulafu (4) ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
No. of isolates with MIC (mg/L) ≤0.0 0.01 08 5 0.03 0.06 0.12 0.25 0.5 1 2 4
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Table 2. Antifungal susceptibility profile of rare Candida species (number of isolates).
-
-
-
-
-
-
1
-
17
Page 17 of 22
kefyr (3)
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
1
6
-
-
-
Pr epr oo
f
-
1
-
1 1 -
-
-
-
1 1 -
1
-
-
-
-
1
1
-
-
1
1
1
1
2
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
3 -
-
-
-
-
3
-
-
-
1
3
-
-
1
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
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intermedia (1)
-
rn
Amphoter icinB
3
-
-
18
Page 18 of 22
4 6
1 -
-
-
-
3
3
1
1
3
-
1
1
-
-
-
1
1
-
3
1
1 4
-
2
1
3 4 -
2
3
-
1
1
1
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
-
-
1
1
-
-
2 -
1
-
-
-
-
-
1
2
-
-
-
1 2
-
f
4
Pr epr oo
2
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norvegensis Anidulafu (2) ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
rn
lusitaniae (8)
1
1
-
-
19
Page 19 of 22
-
-
1
f
1
2
1
1
-
-
-
1
1
-
1 -
-
-
-
-
-
-
-
-
2
1 -
Pr epr oo
-
-
1 1
2
-
-
rn
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
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utilis (2)
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Table 3. Pattern of antifungal susceptibility of fungi other than Candida.
AND
CAS
MIC
FLZ
ITZ
PSZ
VRZ
AMB
5FC
Magnusiomyces clavatus
2
8
2
32
0.25
0.5
0.5
1
0.25
Magnusiomyces clavatus
1
8
1
4
0.12
0.25
0.06
1
0.06
Magnusiomyces clavatus
2
8
2
32
0.5
1
0.5
1
0.25
Rhodotorula mucillaginosa
8
8
8
128
4
4
4
0.5
0.06
Rhodotorula rubra
4
4
4
0.5
1
2
0.25
0.12
Saccharomyces cerevisiae
al
Pr epr oo
f
MIC (mg/L)
0.015
0.015
Saccharomyces cerevisiae
0.06
0.06
Saccharomyces cerevisiae
0.06
0.03
rn
128 2
0.125
0.25
0.12
0.25
0.06
0.125
32
1
2
0.5
0.5
0.06
0.03
8
1
2
0.25
0.5
0.06
Jo u
0.06
AND: anidulafungin; CAS: caspofungin; MIC: micafungin; FLZ: fluconazole; ITZ: itraconazole; PSZ: posaconazole; VRZ: voriconazole; AMB: amphotericin B; 5FC: flucytosine
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Page 22 of 22
22
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f
PII:
S1156-5233(19)30131-3
DOI:
https://doi.org/doi:10.1016/j.mycmed.2019.100906
Reference:
MYCMED 100906
To appear in:
´ Journal de Mycologie Medicale
Received Date:
16 April 2019
Revised Date:
9 September 2019
Accepted Date:
9 October 2019
Please cite this article as: Prigitano A, Cavanna C, Passera M, Gelmi M, Sala E, Ossi C, Grancini A, Calabr`o M, Bramati S, Tejada M, Lallitto F, Farina C, Rognoni V, Fasano MA, Pini B, Roman`o L, Cogliati M, Esposto MC, Tortorano AM, Evolution of fungemia in an italian ´ region, Journal de Mycologie Medicale (2019), doi: https://doi.org/10.1016/j.mycmed.2019.100906
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
EVOLUTION OF FUNGEMIA IN AN ITALIAN REGION. Anna Prigitano1, Caterina Cavanna2, Marco Passera3, Marina Gelmi4, Eugenio Sala5, Cristina Ossi6, Anna Grancini7, Maria Calabrò8, Simone Bramati9, Milvana Tejada10, Fabiola Lallitto2, Claudio Farina3, Vanina. Rognoni11, Maria Antonietta Fasano12, Beatrice Pini13, Luisa Romanò1, Massimo Cogliati1, Maria Carmela Esposto1, Anna Maria Tortorano1 Department of Biomedical Sciences for Health, Università degli Studi di Milano
2
Microbiology and Virology Unit IRCCS Policlinico San Matteo, Pavia
3
Microbiology Institute, ASST ‘Papa Giovanni XXIII’, Bergamo, Italy
4
Microbiology Laboratory, A.O. Spedali Civili, Brescia
5
Microbiology - ASST Lariana, Como
6
Laboratory of Microbiology and Virology, San Raffaele Scientific Institute, Milano
7
Microbiology Laboratory, Fondazione IRCCS Cà Granda O. Maggiore Policlinico, Milano
8
Microbiology Section, Humanitas Research Hospital, Milano
9
Microbiology Laboratory, Ospedale San Gerardo, Monza
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Medicina di Laboratorio, IRCCS Policlinico San Donato, Milano
11
Microbiology Unit, ASST Lodi
12
Microbiology and Virology Unit, ASST Bergamo Ovest Treviglio
13
Laboratory of Microbiology and Virology, ASST Lecco
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Corresponding author
Prof. Anna Maria Tortorano
Department of Biomedical Science for Health Università degli Studi di Milano Via Pascal 36 20133 Milano, Italy Tel. +39 02 503 15145 Fax +39 02 503 15146 Email [email protected]
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Abstract Background. Fungemia represents a public health concern. Knowing aetiology and activity of the antifungals is critical for the management of bloodstream infections. Therefore, surveillance on local/international levels is desirable for a prompt administration of appropriate therapy. Methods. Data on fungi responsible for fungemia and antifungal susceptibility profiles were collected from a laboratory-based surveillance over 2016-17 in 12 hospitals located in Lombardia, Italy. The trend of this infection in twenty years was analysed. Results. A total of 1024 episodes were evaluated. Rate of candiaemia progressively increased up to 1.46/1 000 admissions. C.albicans was the most common species (52%), followed by C.parapsilosis (15%) and C
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glabrata (13%). As in the previous surveys the antifungal resistance is rare (echinocandins <2%, fluconazole 6%, amphotericin B 0.6%). Fungi other than Candida were responsible for 18 episodes: Cryptococcus neoformans (5 cases), Fusarium spp. (4), Magnusiomyces clavatus (3), Saccharomyces
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cerevisiae (3), Rhodotorula spp. (2), Exophiala dermatitidis (1). All fungi, except S.cerevisiae, were intrinsically resistant to echinocandins. Some isolates showed also elevated azole MIC.
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Conclusions. No particular changes in terms of species distribution and antifungal susceptibility patterns was noted. However, surveillance programs are needed to monitor trends in antifungal resistance, steer
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stewardship activities, orient empirical treatment.
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Keywords: Fungemia; candidaemia; Candida; antifungal resistance; epidemiology.
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Introduction Fungemia represents a public health concern being associated with high mortality rate (30-40%), increased length of hospital stay and costs [1]. Candida species are the most frequent cause of fungemia. Other yeasts, such as Saccharomyces, Rhodotorula, Cryptococcus, or moulds, such as Fusarium spp., are rarely involved. Candida bloodstream infection (BSI) is extensively investigated in patients undergoing chemotherapy because of hematologic malignancies or autologous or allogeneic hematopoietic stem cell transplantation [2], in medical and surgical patients in intensive care unit (ICU) [3-5], and more recently in patients hospitalised in Internal Medicine wards [6]. Broad spectrum antibiotics use, critical care therapies, major
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gastrointestinal surgery and chemotherapy cause dysbiosis and damage of the mucous membrane barrier favouring translocation of Candida from the gut to the bloodstream. In addition, the use of invasive procedures, such as indwelling vascular catheters and total parenteral nutrition, and the impairment of
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the immune system due to underlying malignancy or its treatment represent further risk factors for candidaemia [2-6].
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As recently emphasized by Castanheira [7], knowing the local epidemiology of Candida aetiology and the activity of the antifungal agents against these fungal isolates is critical for the clinical management of BSI,
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due to the delay of culture methods and the further delay of antifungal susceptibility results. Therefore, surveillance on local and international levels is desirable for a prompt administration of an appropriate antifungal therapy [7].
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The aim of the present study (FUNG-LO 2016-2017) is to report data concerning fungemia from a
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laboratory-based survey carried out in one Italian region (Lombardia, 10 036 258 inhabitants) in the period 2016-17 and to analyse the trend of this infection in the last twenty years. Materials and Methods
The study prospectively included all cases of fungemia, defined by at least one positive blood culture yielding a fungal species, occurred from January 2016 to December 2017 in 12 hospitals located in Lombardia, Italy. Cases with isolation of a different species or of the same species from a blood sample collected at least 10 days apart were included in the study. Data concerning date of positive blood culture, species identification, antifungal susceptibility profile, and admission hospital ward were provided by each clinical microbiology laboratory in anonymous form on a specific database. Bloodcultures were processed using BacT/Alert (BioMérieux, Marcy l’Etoile, France) in eight participant hospitals and BD-Bactec (Becton Dickinson, Franklin Lakes, NJ, USA) in four using classic aerobic bottles.
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The identification of the isolates was performed locally using Vitek 2 Yeast cards BioMérieux (one laboratory), Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS, Bruker Daltonics, Bremen, Germany) (two), Vitek MS BioMérieux (nine). Also antifungal susceptibility was performed locally using Sensititre YeastOne (SYO, Thermo Scientific Trek Diagnostic Systems, East Grinstead, UK) in all centres except two that used Vitek 2 (BioMérieux). Only data from centres using SYO were included in the analysis. Antifungals tested were those included in the SYO panel, namely amphotericin B, anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, voriconazole and flucytosine. Minimal inhibitory concentration (MIC) values obtained with SYO were interpreted according to Clinical
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Laboratory and Standards Institute (CLSI) species-specific breakpoints or, in case of lack of these breakpoints, according to the SYO epidemiological cutoff values (ECV) to identify wild type or non-wild type isolates [8, 9].
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MIC at which 90% of the isolates was inhibited (MIC90) was calculated only for species with more than 10 isolates tested.
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Number of admissions and patient days were collected for each hospital. Hospital specific rates were calculated using the total number of patients admitted in each institution during the surveillance period
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as the denominator. Day-hospital patients and healthy newborns were excluded. The wards of hospitalization were grouped as follows: medical wards (internal medicine, infectious
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diseases, gastroenterology, pneumology), surgical wards (general surgery, cardio surgery, solid organ transplant centre, neurosurgery, urology), intensive care units (ICU) and haematology including
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hematopoietic stem cell transplant centres.
The results of the present survey were compared with the previous ones carried out in the same region [10-12].
The Chi-square test was used to compare proportions. A value of p <0.05 (two-tailed) was considered to be statistically significant. Results A total of 1024 episodes of fungemia, including 1006 Candida BSIs, occurred in the 2-year period, 20162017. Episode rate of candidaemia, available for 11 hospitals that reported all episodes, was 1.46/1 000 admissions (range, 0.41 to 2.33) and 1.8/10 000 patient days (range, 0.05 to 3.0). Compared to our previous data, a progressive increase in the last 20 years was shown starting from 0.38/1 000 admissions (p<0.001) and 0.44/10 000 patient days (p<0.001) in 1997-99 [10-12].
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In the present study, males accounted for 58.8% of the cases. The mean age was 67 years, ranging from 8 days to 99 years, and median 71 years. 30% of the episodes occurred in the cohort 70-79 years. A progressive increase of the episodes in subjects of ≥80 years of age from 8% in ‘90s to 24.5% in 2016-17 was observed (p <0.001). In the recent survey C. albicans was the most common aetiology (547/1006, 54.4%), followed by C. glabrata (205/1006, 20.4%), C. parapsilosis species complex (161/1006, 16%), and C.tropicalis (56/1006, 5.6%). Over the 20 years the proportion of C. parapsilosis remains stable (from 15% to 16%), while the proportion of C. albicans and C. glabrata was fluctuating from 52% to 59% (p=0.02) and from 13% to 20% (p<0.001), respectively (Figure 1).
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C. glabrata ranked two in the oldest patients accounting for 22.9% of the episodes occurred in the age group of ≥ 70 years, and up to 27% of the episodes in the ≥80 year old people. No difference of C. glabrata aetiology was noted according to the used bloodculture method (20.1% and 20.5% using BactAlert and
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Bactec, respectively) and the patient gender (19.8% in female vs 20.1% in male patients). In neonates only two species were responsible of BSIs, namely C. albicans accounted for 75% (9/12) and
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C. parapsilosis (25%). C. albicans accounted for 63.8% (23/36) of BSIs occurred in children (≤15 year old), followed by C. parapsilosis (21.4%, 8/36). No C. glabrata infection occurred in this age group.
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C. albicans predominated in BSIs diagnosed in ICU, in surgical and in medical wards, causing 60%, 58.7% and 50% of the episodes, respectively. C. glabrata occurred particularly in medical wards (22.9%) (Figure
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2). In haematology wards C. albicans represented 45% of aetiologies. A large variation of species among the different centres reporting ≥60 episodes was observed: C.
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parapsilosis aetiology ranged from 10% to 22% (p<0.05), and C. glabrata from 12% to 26% (p<0.001). C. albicans was responsible of 46% up to 62% (p = 0.05) of BSI in the hospital with the lowest and the highest number of ICU beds, respectively.
No C. auris BSIs have been identified.
More rare Candida species were identified as aetiology of 38 episodes (3.8%) in the 2016-17 survey, namely C. krusei (10 episodes), C. lusitaniae (n=9), C. guilliermondii (n=7) C. dubliniensis (n=4), C. kefyr (n=3), C. norvegensis (n=2) C. utilis (n=2), and C. intermedia (n=1). Table 1 shows the antifungal susceptibility pattern of the most representative Candida species isolates. Echinocandin resistance ranged from 0-0.4% for C. albicans up to 1.9% for C. tropicalis. The percentage of fluconazole and voriconazole resistance, according to CLSI species specific breakpoints, among C. albicans isolates was low (1.2 and 1.4%, respectively). 10% of C. tropicalis isolates was resistant to fluconazole and only 1.9% to voriconazole. The number of posaconazole non-wild type isolates was limited for all these
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species. 6% of C. parapsilosis isolates were resistant to fluconazole and voriconazole, and posaconazole non-wild type, while among the nine fluconazole resistant C. parapsilosis isolates all had posaconazole MICs <0.12 mg/L and all voriconazole MICs 0.25-0.5 mg/L except one with MIC 4 mg/L. One out of the eight fluconazole resistant C. tropicalis was also resistant to the other azoles. Amphotericin B exhibited good activity against all Candida isolates as only six (three C. albicans, one C. glabrata, one C. krusei and one C. norvegensis) had a MIC value of 2 mg/L. The antifungal susceptibility pattern of the rare Candida species is reported in Table 2. On the basis of the SYO ECVs of azoles, available for C. dubliniensis, C. guilliermondii, and C. lusitaniae, only one C. lusitaniae isolate was non-wild type for fluconazole.
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Fungi other than Candida were the aetiology of 18 episodes. Cryptococcus neoformans was isolated from five patients. Fusarium spp. and Magnusiomyces clavatus caused fungemia in four and three patients with haematological malignancies, respectively. Other fungi were Saccharomyces cerevisiae isolated from
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three patients, Rhodotorula mucillaginosa, R. rubra and Exophiala dermatitidis isolated from one patient each.
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All yeast or yeast–like filamentous fungi, except S. cerevisiae, were intrinsically resistant to echinocandins. Some isolates showed also elevated MIC values of azoles (Table 3). SYO was not used to test the antifungal
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susceptibility of C. neoformans, Fusarium spp. and Exophiala dermatitidis isolates. Discussion
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A laboratory-based survey of fungemia was carried out in the period 2016-17 in Lombardia, an Italian
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region subject to similar studies over the past two decades [10-12]. The progressive increase of the incidence rate of Candida BSIs over the 20 years may be due to the increase number of high-risk patients, to the 30% increase of >65 year old population, and changes in healthcare policies with home care for less serious patients and hospitalization of the more severe ones, and to the decline of days of hospitalization (www.istat.it). The rate of the current epidemiological data was higher compared to that reported in the nationwide surveillance performed in other countries such as Denmark where the rate ranged from 0.34 to 0.37 per 1000 discharges [13]. In most of the published surveys [14-16] the number of episodes was referred to inhabitants. However we did not refer to the inhabitants as often the hospitalized patients were outside the town where the hospital is located or even outside of the region. As it concerns the aetiology of the BSIs occurred in 2016-2017, C. albicans predominated (54.4%), followed by C. glabrata (20.4%). The increase of C. glabrata aetiology, that reached up to 27% of the episodes in the ≥80 year old people, may be linked to the increase of old population in the last 20 years (www.istat.it).
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No C. glabrata BSI occurred in neonates and children. C. albicans represented less than 50%, namely 45%, only in BSIs occurred in haematology wards where C.parapsilosis and more rare species emerged as a consequence of the large use of antifungal prophylaxis in this patient population. Regarding C. auris, a species of particular public health concern due to the intrinsic resistance to fluconazole and rapid development of resistance to other antifungals, no cases have been identified. Some differences in aetiology were noted compared to the Danish experience [13]. In our experience the blood culture system does not seem to have influenced the detection of C. glabrata and gender did not have impact on this species. Antifungal susceptibility testing is recommended for Candida bloodstream isolates and the CLSI and the
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European Committee on Antibiotic Susceptibility Testing (EUCAST) developed standard methodologies [8,17] that however are not used in clinical laboratories as cumbersome and time consuming. Although the SYO is the method widely used to routinely test the antifungal susceptibility of Candida
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isolates interpretative criteria of results obtained with this commercial method are not available. As a consequence, the MIC values are interpreted on the basis of CLSI interpretative categories due to the
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favourable comparison between MICs obtained by the commercial SYO and the reference CLSI method. Species specific clinical breakpoints are not available for all Candida species and antifungals and, in these
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cases, the SYO ECVs were used to identify wild type or non-wild type isolates [9]. As in the previous surveys conducted in the same region [11, 12, 18, 19] the antifungal resistance among
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Candida causing BSIs remains rare. Echinocandin resistance was limited (<2%) and a reduced number of Candida isolates (six out of 1006) had an amphotericin B MIC value of 2 mg/L. Taking into account all the
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species for which the fluconazole breakpoints or SYO ECVs are available, the rate of resistance or nonwild type is very low (6%) compared to the experiences in England where up to 18% of candidaemia resulted with reduced or non susceptibility to fluconazole in the period 2012-2016 [20]. This discrepancy could be attributed to the different incidence of C. glabrata in the surveys: 20.4% in our survey vs 25% in the English survey (p = 0.001).
Only one isolate among the rare Candida species resulted non-wild type for fluconazole on the basis of the SYO ECVs for azoles and, unlike the results of the Austrian screening of yeast bloodstream isolates [21], our C. guilliermondii isolates did not show the high resistance to both azoles and echinocandins. Among fungi other than Candida, only occasionally isolated from BSIs, Cryptococcus, Magnusiomyces and Rhodotorula were intrinsically resistant to echinocandins, and some isolates had also elevated azole MIC values.
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Conclusions Despite the introduction of new antifungals and new classes of antifungals, the present survey did not show particular changes in terms of species distribution and antifungal susceptibility patterns. However, surveillance programs are needed to monitor trends in antifungal resistance, steer antifungal stewardship activities, orient empirical treatment and improve outcomes of these severe fungal infections.
Competing interest
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None declared. Funding
This research did not receive any specific grant from funding agencies in the public, commercial,
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or not-for-profit sectors.
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References
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SEIFEM 2015-B report. Haematologica 2017;102(10):e407-e410. doi: 10.3324/haematol.2017.172536. [3] Tortorano AM, Dho G, Prigitano A, Breda G, Grancini A, Emmi V, et al. Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008). Mycoses 2012;55(1):73-9. doi: 10.1111/j.1439-0507.2011.02044.x.
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[6] Falcone M, Tiseo G, Tascini C, Russo A, Sozio E, Raponi G, et al. Assessment of risk factors for candidaemia in non-neutropenic patients hospitalized in internal medicine wards: a multicenter study. Eur J Intern Med 2017;41:33-8. doi: 10.1016/j.ejim.2017.03.005. [7] Castanheira M. Fungemia surveillance in Denmark demonstrates emergence of non-albicans candida species and higher antifungal usage and resistance rates than in other nations. J Clin Microbiol 2018;56(4). pii: e01907-17. doi: 10.1128/JCM.01907-17. [8] Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard, 3rd edn. 2008. CLSI document M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA.
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[9] Espinel-Ingroff A, Turnidge J, Alastruey-Izquierdo A, Botterel F, Canton E, Castro C, et al. Method-dependent epidemiological cutoff values for detection of triazole resistance in Candida and Aspergillus species for the Sensititre Yeastone colorimetric broth and Etest agar diffusion
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methods. Antimicrob Agents Chemother 2018;63(1). pii: e01651-18. doi: 10.1128/AAC.0165118.
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[10] Tortorano AM, Biraghi E, Astolfi A, Ossi C, Tejada M, Farina C, et al.
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study: changing epidemiology of candidaemia in Lombardy (Italy). Infection 2016;44(6):765-80. [13] Astvad KMT, Johansen HK, Røder BL, Rosenvinge FS, Knudsen JD, Lemming L, et al. Update from a 12-year nationwide fungemia surveillance: increasing intrinsic and acquired resistance causes concern. J Clin Microbiol 2018;56(4). pii: e01564-17. doi: 10.1128/JCM.0156417.
[14] Chapman B, Slavin M, Marriott D, Halliday C, Kidd S, Arthur I, et al.
Changing
epidemiology of candidaemia in Australia. J Antimicrob Chemother 2017;72(4):1103-8. doi: 10.1093/jac/dkw422. [15] Ericsson J1, Chryssanthou E, Klingspor L, Johansson AG, Ljungman P, Svensson E, et al. Candidaemia in Sweden: a nationwide prospective observational survey. Clin Microbiol Infect 2013;19(4):E218-21. doi: 10.1111/1469-0691.12111.
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[16] Hesstvedt L, Gaustad P, Andersen CT, Haarr E, Hannula R, Haukland HH, eta al. Twenty-two years of candidaemia surveillance: results from a Norwegian national study. Clin Microbiol Infect 2015;21(10):93845. doi: 10.1016/j.cmi.2015.06.008. [17] Arendrup MC, Meletiadis J, Mouton JW, Lagrou K, Hamal P, Guinea J and the Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). Method for the determination of broth dilution minimum Inhibitory concentrations of antifungal agents for yeasts. EUCAST definitive document E.DEF 7.3.1; 2017.
[18] Tortorano AM, Rigoni AL, Biraghi E, Prigitano A, Viviani MA; FIMUA-ECMM Candidaemia Study Group. The European Confederation of Medical Mycology (ECMM) survey
from blood. J Antimicrob Chemother 2003;52(4):679-82.
oo f
of candidaemia in Italy: antifungal susceptibility patterns of 261 non-albicans Candida isolates
[19] Tortorano AM, Prigitano A, Biraghi E, Viviani MA; FIMUA-ECMM Candidaemia Study
pr
Group. The European Confederation of Medical Mycology (ECMM) survey of candidaemia in Italy: in vitro susceptibility of 375 Candida albicans isolates and biofilm production. J Antimicrob
e-
Chemother 2005;56(4):777-9.
[20] PHE, Laboratory surveillance of Candidaemia in England, Wales and Northern Ireland: 2016. Health
Pr
Protection Report 2017;11(32).
[21] Beyer R, Spettel K, Zeller I, Lass-Flörl C, Achleitner D, Krause R, et al. Antifungal susceptibility of yeast
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10.1111/myc.12892.
al
bloodstream isolates collected during a 10-year period in Austria. Mycoses 2019;62(4):357-67. doi:
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Figure 1. Candida species distribution shown as percentage of isolates in the different surveys conducted in Lombardia, Italy.
Figure 2. Species distribution shown as percentage of isolates according to wards in the 2016-2017 survey (number
Jo ur n
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Pr
e-
pr
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of episodes)
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Page 12 of 22
Page 13 of 22
13
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rn
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Pr epr oo
f
Table 1. MIC90, MIC range, number of resistant isolates according to CLSI species-specific breakpoints, and number of non wild-type isolates according to Espinel
glabrata
No. isolates
490
178
MIC90
0.5
64
150
52
10
1
2
0.125-256
0.125128
9 (6%)
5 (10%)
10*
148
51
10
0.125
0.5
0.5
0.06-≥8
0.03-0.5
1 (0.7%) 2 (3.9%)
0
Range
0.125-256
0.5-256
R CLSI
6 (1.2%)
21 (12%)
486
181
MIC90
0.125
1
Range
0.015-≥16
R CLSI
10 (2.0%)
47 (25.9%)
484
177
145
49
10
2
0.06
0.25
0.5
0.008-≥8
0.03-≥8 0.008-0.125
0.06-≥8
0.12-0.5
20 (4.1%)
2 (1.1%)
0
1 (2%)
0
No. isolates
495
155
149
52
10
MIC90
0.03
2
0.03
0.25
0.5
Range
0.008-≥8
0.03-≥8
0.008-4 0.008-≥8
0.12-1
No. isolates
MIC90 Range Non-WT
0.06-≥16
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Posaconazole No. isolates
Voriconazole
albicans
C. C. C. parapsilosis tropicalis krusei
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Itraconazole
C.
rn
Fluconazole
C.
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Ingroff et al. [9].
0.06
0.015-4.0
14
Page 14 of 22
R CLSI
7 (1.4%)
No. isolates
183
0.125
0.06
f
Range
0.015-0.5
0.015-0.5
R CLSI
0
1 (0.5%)
494
184
MIC90
0.125
0.125
Range
0.008-≥8
0.008-0.5
R CLSI
2 (0.4%)
No. isolates
150
52
2
0.125
0.12
0.0150.12
0.015-4
0 1 (1.9%)
0
150
52
10
1
0.125
0.50
0.03-1
0.015-2 00.06-0.5
1 (0.5%)
0
0
0
183
150
52
10
0.015
4
0.06
0.06
0.008-4 0.008-0.125
0.015-≥8
0.008-1 0.03-0.06
1 (0.2%)
0
1 (0.7%)
1 (1.9%)
0
No. isolates
482
183
150
50
10
MIC90
0.25
0.06
0.25
64
16
Range
0.06-64
0.O6-64
0.06-2
0.06-64
4-16
R CLSI
3 (0.7%)
2 (1.1%)
0 13 (26%)
0
No. isolates
Range R CLSI
491
0.015
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MIC90
Flucytosine
489
al
Micafungin
0
10
MIC90
Caspofungin
1 (1.9%)
10 (6.4%)
rn
Anidulafungi n
1 (0.7%)
Pr epr oo
Non-WT
n.a.
15
Page 15 of 22
Amphotericin B No. isolates
184
152
52
10
MIC90
1
1
1
1
Range
0.12-2
0.12-2
0.12-1
0.12-1
0.25-2
R CLSI
n.a.
n.a.
n.a.
n.a.
n.a.
f
490
Pr epr oo
1
n.a.: not available; R CLSI: resistant isolates according to species-specific breakpoints established by CLSI; Non-WT: non wild-type isolates according to Espinel Ingroff et al. [9].
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* intrinsically resistant
16
Page 16 of 22
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le
1
3
4 -
-
-
-
1
4 1
1
-
1
1
1
-
-
-
-
-
-
-
16
32
-
-
-
2
1 1
-
-
-
-
-
-
-
1
2
1
4
3
1
2
1
3
2
-
2
2 3
4 6
1
-
-
-
-
6 5
-
8
3
al
2
Pr epr oo
4
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guilliermon dii (7)
-
rn
Species Drug dubliniensis Anidulafu (4) ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
No. of isolates with MIC (mg/L) ≤0.0 0.01 08 5 0.03 0.06 0.12 0.25 0.5 1 2 4
f
Table 2. Antifungal susceptibility profile of rare Candida species (number of isolates).
-
-
-
-
-
-
1
-
17
Page 17 of 22
kefyr (3)
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
1
6
-
-
-
Pr epr oo
f
-
1
-
1 1 -
-
-
-
1 1 -
1
-
-
-
-
1
1
-
-
1
1
1
1
2
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
3 -
-
-
-
-
3
-
-
-
1
3
-
-
1
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
Jo u
intermedia (1)
-
rn
Amphoter icinB
3
-
-
18
Page 18 of 22
4 6
1 -
-
-
-
3
3
1
1
3
-
1
1
-
-
-
1
1
-
3
1
1 4
-
2
1
3 4 -
2
3
-
1
1
1
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
-
-
1
1
-
-
2 -
1
-
-
-
-
-
1
2
-
-
-
1 2
-
f
4
Pr epr oo
2
Jo u
norvegensis Anidulafu (2) ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
-
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
rn
lusitaniae (8)
1
1
-
-
19
Page 19 of 22
-
-
1
f
1
2
1
1
-
-
-
1
1
-
1 -
-
-
-
-
-
-
-
-
2
1 -
Pr epr oo
-
-
1 1
2
-
-
rn
al
Anidulafu ngin Caspofun gin Micafungi n Fluconazo le Voriconaz ole Posaconaz ole Itraconazo le Amphoter icinB
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utilis (2)
20
Page 20 of 22
Table 3. Pattern of antifungal susceptibility of fungi other than Candida.
AND
CAS
MIC
FLZ
ITZ
PSZ
VRZ
AMB
5FC
Magnusiomyces clavatus
2
8
2
32
0.25
0.5
0.5
1
0.25
Magnusiomyces clavatus
1
8
1
4
0.12
0.25
0.06
1
0.06
Magnusiomyces clavatus
2
8
2
32
0.5
1
0.5
1
0.25
Rhodotorula mucillaginosa
8
8
8
128
4
4
4
0.5
0.06
Rhodotorula rubra
4
4
4
0.5
1
2
0.25
0.12
Saccharomyces cerevisiae
al
Pr epr oo
f
MIC (mg/L)
0.015
0.015
Saccharomyces cerevisiae
0.06
0.06
Saccharomyces cerevisiae
0.06
0.03
rn
128 2
0.125
0.25
0.12
0.25
0.06
0.125
32
1
2
0.5
0.5
0.06
0.03
8
1
2
0.25
0.5
0.06
Jo u
0.06
AND: anidulafungin; CAS: caspofungin; MIC: micafungin; FLZ: fluconazole; ITZ: itraconazole; PSZ: posaconazole; VRZ: voriconazole; AMB: amphotericin B; 5FC: flucytosine
21
Page 21 of 22
Page 22 of 22
22
al
rn
Jo u
Pr epr oo
f