MIXINYEST: A MULTICENTER SURVEY ON MIXED YEAST INFECTIONS IN EUROPA - SEIMC
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MixInYest EFISG-Study
MixInYest: a multicenter survey on mixed yeast
infections in Europa
COORDINATORS:
- Ana Alastruey-Izquierdo, Mycology Reference Laboratory, National Centre for
Microbiology, Spain
- Cornelia Lass-Flörl, Division of Hygiene und Medical Microbiology, Medical University
of Innsbruck, Austria
- Sevtap Arikan-Akdagli, Hacettepe University Medical School, Dept. of Medical
Microbiology, Ankara,Turkey
PARTICIPANTS
The project will be opened to all European Microbiology Laboratories and others.
1MixInYest EFISG-Study
Content
Abstract ......................................................................................................................................... 3
Background ................................................................................................................................... 4
Objectives ...................................................................................................................................... 5
Research plan: ............................................................................................................................... 6
Data collection .............................................................................................................................. 7
Collaborators .................................................................................. ¡Error! Marcador no definido.
Expected outcomes ....................................................................................................................... 7
Ethical Considerations and Data Privacy Protection ..................................................................... 8
Authorship Policy .......................................................................................................................... 8
Contact Information ...................................................................................................................... 8
References..................................................................................................................................... 9
Annex I:........................................................................................................................................ 11
2MixInYest EFISG-Study
Abstract
Background: Candida species are a main source of morbidity and mortality in human infections.
Mixed infections due to more than one species of yeasts can be associated with higher mortality
rate and are probably underestimated in current reports. Within the context of a mixed yeast
infection, the co-existence of a yeast species which is putatively resistant to antifungal drug(s)
in clinical use is of uppermost significance in terms of guidance of antifungal therapy and
successful clinical outcome. Therefore, all causative agents of a mixed fungal infection need to
be isolated and identified at species level.
Aim: To study the epidemiology, clinical and microbiological characteristics of mixed fungal
infections in different centers in Europe and beyond.
Methods: Standard laboratory procedures including chromogenic agar will be used to detect
mixed infections caused by two or more yeast species. Strains will be prospectively collected,
identified to species level and sent to a central laboratory. Main clinical data will also be
recorded. In the referral laboratory, strains will be identified by means of sequencing
informative targets and their antifungal susceptibility profiles will be determined by EUCAST
methodology.
Expected results: With this study we will gather information of mixed infections in different
centers. Clinical, epidemiological and microbiological data will be analyzed in order to gain more
knowledge of mixed infections of yeast.
3MixInYest EFISG-Study
Background
Candida species are the most common cause of healthcare-associated bloodstream
infections (BSI) (1) and are associated with significant mortality. Although Candida albicans
remains the most frequent yeast isolated from human samples, the number of non-albicans
species has progressively increased in the last years (2-4). Importantly some of these species are
more difficult-to-treat because of the higher level of antifungal resistance (5).
In addition, polymicrobial BSIs have been associated with higher mortality than monomicrobial
episodes (6). Previous studies indicate that up to 25% of Candida BSI can be associated with
more than one pathogen (7). A population based survey conducted in 30 Spanish hospitals
(CANDIPOP study) detected 159 polymicrobial infections, a bacterial strain was identified in 145
(19.3%) and two different Candida species were simultaneously isolated in 14 (1.9%) out of 752
episodes of candidemia (8). TRANSNET (Transplant-Associated Infection Surveillance Network)
study analyzed invasive Candida infections among organ transplant recipients in the United
States and found that >10% of cases included infection with two or more Candida species (2).
Other surveillance studies have found rates of mixed infections in candidemia between 1.2 to
6% (9-15). However, although tools for detecting mixed infections have been available for years,
current standard procedures may miss to detect them and therefore these numbers are
probably underestimated. Sample processing in clinical laboratories usually involves plating the
sample onto agar media and after incubation, a single colony is picked and analyzed. While
examination of inter-species differences in colony morphology are very helpful in differentiating
and thus processing all species grown in the sample, this evaluation needs expertise and growth
of sufficient number of colonies of each species on the inoculated agar medium. Thus, mixed
infections may remain undetected.
Chromogenic agars are cheap and simple tools that allow the distinction of the most frequent
species of Candida. Differences in enzymatic activities are used to identify a number of species
by producing a characteristic colony color in these media (Figure 1). The most common species
of Candida implicated in human infections are thus differentiated by this method enabling the
detection of mixed infections. However, other methods are also possible (i.e. PNA-FISH).
4MixInYest EFISG-Study
Figure 1. Different colonies of Candida species on Chromogenic agar.
Picture obtained from: http://jcm.asm.org/content/43/11/5768/F1.large.jpg(16)
Objectives
The aim of this work is to study mixed yeast infections in different centers and to broaden the
knowledge on epidemiology, on clinical courses of mixed yeast infections.
Main objectives are to:
- determine the rate of mixed infections
- determine the epidemiology of mixed infections
- analyze possible risk factors for mixed infections
- evaluate the associated mortality
- evaluate the antifungal susceptibility profile of the isolates
5MixInYest EFISG-Study
Research plan:
The prevalence of mixed yeast infections will be investigated by screening prospectively the
presence of two or more species of yeast in sterile clinical samples. The screening will be
performed by plating the sample on chromogenic agars or by other routine standard procedures
(equivalent replacement to chromogenic agar).
For samples which were cultivated for bacterial isolation initially and then turn out to grow
yeasts, it will not be possible to use the chromogenic media at the very initial primary isolation
step (but may be used only after isolation of yeasts and as a medium to subculture).
The following sampling is possible:
1) Processed for bacterial cultures initially but yielded yeast colonies on bacteriological media.
At least five colonies need to be sub-cultured for further processing. Different colony
morphologies if present will be considered as mixed infections and will be further investigated.
2) Processed for fungal cultures at the very initial step for which using chromogenic agar media
as the primary isolation medium will be possible.
3) Processed by a method equivalent to chromogenic agar (needs to be specified in detail).
Samples to be included: all sterile clinical samples, processed at the microbiology department
for 6 months.
Timeline
- April-September 2018 sampling period
- October- December 2018 complete data of CRF and send strains
- January-June 2019 (depending on the number of samples) AFST and id.
- July-December 2019 analysis report and draft paper
6MixInYest EFISG-Study
Data collection
Data to be collected:
- Centre
- Date of isolation
- Strain identification numbers (one per species isolated in the same sample)
- Underlying disease(s)
- Origin of the sample
- Ward
- Type of infection
- Tentative identification
- Identification method*
If possible, these variables will also be recorded:
- Antifungal drug use at the time of isolation
- Outcome of the patient
- AFST (If performed)
- Method for AFST
* The identification of the strains must rely on a more specific identification method, such as
morphology + assimilation profiles, other automated systems (i.e. Sensititre, Vitek), MALDI-TOF,
molecular identification, etc.
Patient characteristics’, epidemiological data, and antifungal treatment (if possible) will be
collected through an online questionnaire using www.clinicalsurveys.net online platform.
At the end of the study the center will need to provide the total number of samples that yielded
yeast growth (mixed + single species) during the study period.
The strains will be referred to Ana Alastruey-Izquierdo, Mycology Reference Laboratory,
National Centre for Microbiology, Spain to:
- Confirm identification to species level by sequencing informative targets
- Antifungal susceptibility profile by EUCAST method
The isolates will be available to any group member.
Expected outcomes
- Abstract for ECCMID
7MixInYest EFISG-Study
- Manuscript
Ethical Considerations and Data Privacy Protection
In the current study 2 aspects have to be considered separately:
1 Documentation of clinical data
2 Work with isolates of Candida species
There is no interventional aspect to this study. Therefore, there are neither associated risks nor
benefits for the patient when participating in the study. The documentation of the clinical data
will take place in an anonymized fashion. There will also be no pseudonyms which would make
a retrospective re-identification of the patient possible. Clinical data collected refers only to
underlying condition and treatment modalities in medical care, such that no re-identification of
the individual case on the basis of these data will be possible. Under these circumstances, we
consider an informed consent of the patient not necessary. Regular data backup, hierarchized
management of rights and authentication protocols ensure the protection of data from
unauthorized access and loss. All clinical data fall under medical confidentiality, and results will
be stored for at least 10 years after publication of results.
To ensure anonymity, the results of microbiological examinations will only be communicated to
the treating physician and entered into the database along with the clinical data in one session
by the treating physician.
Authorship Policy
Authorship will be restricted to those centers contributing clinical/microbiological data. For each
contributing center, there will be authorship positions available. This will extend to a maximum
of two: one clinician, and one microbiologist/medical mycologist, if applicable.
Contact Information
Ana Alastruey-Izquierdo, Mycology Reference Laboratory, National Centre for
Microbiology, Spain.
Email: anaalastruey@isciii.es
Phone: +34918223784
8MixInYest EFISG-Study
References
1. Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate
point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370(13):1198-
208.
2. Andes DR, Safdar N, Baddley JW, Alexander B, Brumble L, Freifeld A, et al. The
epidemiology and outcomes of invasive Candida infections among organ transplant recipients
in the United States: results of the Transplant-Associated Infection Surveillance Network
(TRANSNET). Transpl Infect Dis. 2016.
3. Guinea J, Zaragoza O, Escribano P, Martin-Mazuelos E, Peman J, Sanchez-Reus F, et al.
Molecular identification and antifungal susceptibility of yeast isolates causing fungemia
collected in a population-based study in Spain in 2010 and 2011. Antimicrob Agents Chemother.
2014;58(3):1529-37.
4. Falagas ME, Roussos N, Vardakas KZ. Relative frequency of albicans and the various non-
albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a
systematic review. Int J Infect Dis. 2010;14(11):e954-66.
5. Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M. Candida bloodstream
infections: comparison of species distribution and resistance to echinocandin and azole
antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial
Surveillance Program (2008-2009). Int J Antimicrob Agents. 2011;38(1):65-9.
6. Weinstein MP, Reller LB, Murphy JR. Clinical importance of polymicrobial bacteremia.
Diagn Microbiol Infect Dis. 1986;5(3):185-96.
7. Klotz SA, Chasin BS, Powell B, Gaur NK, Lipke PN. Polymicrobial bloodstream infections
involving Candida species: analysis of patients and review of the literature. Diagn Microbiol
Infect Dis. 2007;59(4):401-6.
8. Puig-Asensio M, Padilla B, Garnacho-Montero J, Zaragoza O, Aguado JM, Zaragoza R, et
al. Epidemiology and predictive factors for early and late mortality in Candida bloodstream
infections: a population-based surveillance in Spain. Clin Microbiol Infect. 2014;20(4):O245-54.
9. Arendrup MC, Bruun B, Christensen JJ, Fuursted K, Johansen HK, Kjaeldgaard P, et al.
National surveillance of fungemia in Denmark (2004 to 2009). J Clin Microbiol. 2011;49(1):325-
34.
10. Chen S, Slavin M, Nguyen Q, Marriott D, Playford EG, Ellis D, et al. Active surveillance for
candidemia, Australia. Emerg Infect Dis. 2006;12(10):1508-16.
11. Cuenca-Estrella M, Rodriguez D, Almirante B, Morgan J, Planes AM, Almela M, et al. In
vitro susceptibilities of bloodstream isolates of Candida species to six antifungal agents: results
from a population-based active surveillance programme, Barcelona, Spain, 2002-2003. J
Antimicrob Chemother. 2005;55(2):194-9.
12. Lockhart SR, Iqbal N, Cleveland AA, Farley MM, Harrison LH, Bolden CB, et al. Species
identification and antifungal susceptibility testing of Candida bloodstream isolates from
population-based surveillance studies in two U.S. cities from 2008 to 2011. J Clin Microbiol.
2012;50(11):3435-42.
13. Lortholary O, Desnos-Ollivier M, Sitbon K, Fontanet A, Bretagne S, Dromer F, et al.
Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a
prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother.
2011;55(2):532-8.
14. Sandven P, Bevanger L, Digranes A, Haukland HH, Mannsaker T, Gaustad P, et al.
Candidemia in Norway (1991 to 2003): results from a nationwide study. J Clin Microbiol.
2006;44(6):1977-81.
15. Tortorano AM, Biraghi E, Astolfi A, Ossi C, Tejada M, Farina C, et al. European
Confederation of Medical Mycology (ECMM) prospective survey of candidaemia: report from
one Italian region. J Hosp Infect. 2002;51(4):297-304.
9MixInYest EFISG-Study
16. Sahand IH, Moragues MD, Eraso E, Villar-Vidal M, Quindos G, Ponton J. Supplementation
of CHROMagar Candida medium with Pal's medium for rapid identification of Candida
dubliniensis. J Clin Microbiol. 2005;43(11):5768-70.
10MixInYest EFISG-Study
Annex I:
MixInYeast: A multicenter survey on mixed yeast
infections in Europe
Case Report Form
Data to be collected:
- Centre
- Date of isolation
- Strain identification numbers (one per species isolated in the same sample)
- Underlying disease(s)
- Origin of the sample
- Ward
- Type of infection
- Tentative identification
- Identification method*
If possible, these variables will also be recorded:
- Antifungal drug use at the time of isolation
- Outcome of the patient
- AFST (If performed)
- Method for AFST
In addition, at the end of the study period the centers will need to provide the total number
of samples processed to calculate incidence of mix infections.
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