International Journal of Infectious Diseases

Transcription

1 International Journal of Infectious Diseases 14 (2010) e954 e966 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: Review Relative frequency of albicans and the various non-albicans Candida spp among isolates from inpatients in various parts of the world: a systematic review Matthew E. Falagas a,b,c, *, Nikos Roussos a, Konstantinos Z. Vardakas a a Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, Marousi, Athens, Greece b Department of Medicine, Henry Dunant Hospital, Athens, Greece c Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA ARTICLE INFO SUMMARY Article history: Received 19 January 2010 Received in revised form 29 March 2010 Accepted 9 April 2010 Corresponding Editor: Andy Hoepelman, Utrecht, the Netherlands Keywords: Incidence Candidemia Intensive care unit Background: Candidemia is among the leading causes of nosocomial bloodstream infections and is associated with significant mortality. Several centers have published data regarding the incidence and relative frequency of Candida spp. Objective: We performed a systematic review to summarize and evaluate the available evidence regarding the distribution of the relative frequency of Candida spp isolated from blood, according to geographic region and study design, during the period 1996 to Methods: We searched PubMed and Scopus and retrieved 81 relevant articles reporting data on the relative frequency of Candida spp. Results: albicans was the predominant species in almost all studies. The highest proportion of albicans was found in North and Central Europe and the USA. Non-albicans species were more common in South America, Asia, and South Europe. glabrata was commonly isolated in the USA and North and Central Europe; parapsilosis in South America, South Europe, and several parts of Asia; and tropicalis in South America and Asia. The relative frequency of krusei was low in all regions. Significant differences were noted depending on study design (surveillance study, multicenter or single centre, prospective or retrospective) and setting ( or intensive care unit). Conclusions: Significant geographic variation is evident among cases of in different parts of the world. Local epidemiological data continue to be of major significance. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Introduction * Corresponding author. Tel.: ; fax: address: m.falagas@aibs.gr (M.E. Falagas). Candidemia is the fourth most common nosocomial bloodstream infection in the USA. 1,2 The incidence of has risen over the last two decades, in several parts of the globe and in different settings, 3,4 mostly due to an increase in the use of more aggressive therapy practices (mainly intensive chemotherapy of hematological malignancies, transplantation, and intensive care unit (ICU) use, and to a lesser extent the use of immunosuppressive agents for the treatment of autoimmune diseases and other diseases and even life prolongation), which have created a previously non-existent immunocompromised population. 5,6 Also, a shift in the relative frequency of each Candida spp isolated in blood has been reported Candidemia is associated with considerable mortality Therefore, in patients with accumulating risk factors for, in whom the probability for is high, clinicians use empirical treatment long before laboratory results on species identification and antibiograms are available, when the infection is suspected. 19,20 In order to apply an effective treatment, it is essential to have a valid, regularly updated knowledge of the proportion of Candida spp causing. A significant variability in the relative frequency of has been noticed in different regions within a given country. In addition, significant variability has been noticed within studies, especially in multicenter studies enrolling patients in different settings (e.g., ICU, s, outpatients, etc.) and studies lasting for longer periods, which have reported different distributions of Candida spp, not only within regions but also over time. In the current study we sought to assess the proportions in which different Candida spp are isolated worldwide. Methods We performed searches in the PubMed and Scopus databases (until January 2009) using the following keywords: Candida, /$36.00 see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi: /j.ijid

2 M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e955, Candida bloodstream infection, Candida epidemiology, Candida species trends, species distribution, species spectrum, and ICU and performed additional handpicked searches in the bibliographies of the retrieved articles and reviews. Two of the authors (NR, KZV) independently performed the electronic search. Studies were included in the review only if they were written in the English language. We also excluded studies if they were completed prior to year 1997 in order to study the epidemiology of over the last decade. The rationale behind this choice was two-fold: first, to describe the epidemiology of in recent years (and the possible changes during these years) and second, to minimize bias associated with changes in clinical practice through the years. In addition, several reviews have been published describing the distribution of Candida spp among patients with in the years prior to For studies conducted both before and after this time point, we either extracted the data of interest after year 1996 whenever possible or, when data regarding each year of the study period were not available, included the entirety of their findings if more than half the years of the study period were after We extracted data regarding the overall incidence of in these settings, the total number of Candida spp isolates in the observed cases, and the relative proportion of each Candida spp in each study. We grouped the collected articles in three categories: multicenter or surveillance studies, cohort studies performed in s, and studies conducted in ICUs. This was done in order to create more homogenous populations. Then, each of these populations was studied according to three subcategories: their geographic distribution, the study design (prospective or retrospective), and age of the studied population. The relative frequency of different Candida spp bloodstream infections was studied within each of these subgroups. In addition, if data were available, the changes in the relative frequency of Candida spp over time were studied. Results We retrieved 22 articles 1,2,21 40 reporting data from multicenter -based or surveillance studies, 41 articles 23,41 80 reporting data from s, and 18 articles 23,56,57,60,62,81 93 regarding studies conducted in ICUs. The extracted data from these articles are presented in Tables 1 3 (five studies 23,56,57,60,62 were eligible for both Tables 2 and 3 since they reported data for at the and ICU level). albicans was the dominant species in almost all studies included in this review. Geographic distribution Surveillance studies When data from surveillance studies only were reviewed, albicans predominated in the countries of North Europe and Switzerland (>60%), was equally isolated in the remaining European countries and the USA (ranging from 45% to 58%), and was lower in Asia and South America (approximately 40 42%). Accordingly, nonalbicans species predominated in Asia. The highest proportions of glabrata were reported in studies from the USA ( %) and the UK (22.7%) and the lowest were reported in studies from Brazil and Kuwait (4.9% and 5.6%, respectively). parapsilosis was more frequently isolated in Kuwait (30.6%), South America ( %), Spain (23%), and Australia (19.9%), and the lowest proportion was found in Switzerland (1 5%) and North Europe (4.4%). tropicalis held higher proportions in South America ( %) and Taiwan (22.4%), intermediate in the USA (11 12%), and lowest in Central and North Europe (4%). krusei was not commonly isolated (ranging from 1% to 4%), except from one study in Finland and one in France Table 1 Relative frequency of Candida spp in in multicenter and laboratory-based surveillance studies Trends in relative species proportions Other Candida norvegensis dubliniensis inconspicua famata lusitaniae guillermondii krusei tropicalis parapsilosis glabrata albicans Incidence Total number of blood isolates a Author, year [Ref.] Study design/ observation time period/ participating NA % 12% 21% 6% 1% - - 2% 1% albicans was responsible for less than 50% of cases in 7 of 20 medical centers 1997, SENTRY program (20 medical centers in 13 European countries) Europe Pfaller et al [34] % 13.6% 13.3% 7.2% 1.9% 1.4% 0.7% 0.3% 0.2% 0.3% 0.2% 2% The study showed an increasing incidence of glabrata along with increasing age Ranges: cases/1000 or cases/ patient-days , ECMM multinational study (106 from 7 countries) Tortorano et al., 2004 [39] 51% 9% 23% 10% 4% % The study suggested that the increased frequency of parapsilosis may be attributed to the presence of intravenous devices and parenteral nutrition cases/ population/ year, or 0.53 cases/1000 or 0.73 cases/ patient-days , area of Barcelona (covered by 14 s) Spain Almirante et al., 2006 [21]

3 Table 1 (Continued ) Author, year [Ref.] Study design/ observation time period/ participating Incidence Total number of blood isolates a albicans glabrata parapsilosis tropicalis Other krusei guillermondii lusitaniae famata inconspicua dubliniensis norvegensis Candida Trends in relative species proportions e956 France Martin et al., 2005 [31] , area of Lyon (covered by a group of s) Ranges from 0.1 to 3.7 cases/ % 12.6% 12.1% 10.1% 10.6% - 0.5% 1% % The study described an increase in the incidence of glabrata and krusei Ireland Boo et al., 2005 (part I) [23] , 10 s (original period ) UK Odds et al., 2007 [33] , 19 tertiary s in Scotland Switzerland Marchetti et al., 2004 [30] , 17 university and tertiary care s (original period ) Belgium Swinne 2002, et al., 2004 [37] national surveillance program (28 s participating) Iceland Asmundsdottir et al., 2002 [22] , nationwide study (original period ) For the period: 0.48 cases/1000 /year or cases/ patients 4.8 cases/ population/year or 5.9 cases/ acute occupied beds/year For year 2000: 0.54 cases/ patientdays or 0.36 cases/ : 79.5%, : 58.3% : 6.4%, : 12.5% : 11.5%, : 19.8% : 2.6%, : 5.2% : The study 0%, : 5.2% demonstrated a rising proportion of glabrata % 22.7% 11.7% 2% 1% 3.3% 2% - - 3% - - The study showed an unusually high frequency of dubliniensis 464 c 65 70% 15% 1 5% 5 9% 1 2% % No shift to azole-resistant Candida spp was observed over the original 10-year study period NA % 23.2% 12.8% 2.9% 2.5% 0.9% 0.5% % - The study concluded that the frequency of non-albicans species in is increasing (compared to older studies) 4.9 cases/ population/year % 12.9% 11.4% 5.7% % - The relative frequency of Candida species in did not change significantly during the 2 halves of the original study period M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 Finland Lyyticainen , et al., 2002 [29] surveillance program (4 s participating) Poikonen , et al., 2003 [35] data from NIDR program (original period ) NA % 6.5% 12.9% 2.3% % Candidemia from non-albicans species was less common compared to other studies cases/ population/year % 8.5% 5.6% 3% 8.5% % The study reported no notable shift from albicans to non-albicans species

4 Norway Sandven , et al., 2006 [36] nationwide surveillance (original study period ) Range cases/ population % 13.4% 4.4% 6.8% 1.3% 0.2% % 0.7% 0.5% The study reported no notable shift from albicans to non-albicans species USA Edmond et al., 1999 [1] , 49 s Hajjeh et al., 2004 [27] , 47 s in 2 states (14 in Baltimore and 33 in Connecticut) Wisplinghoff et al., 2004 [2] , SCOPE nationwide surveillance study Dieckema , et al., 2002 [25] 16 s in the state of Iowa South America Godoy , et al., 2003 [26] 5 tertiary s from 4 countries Brazil Colombo , et al., 2006 [24] 11 tertiary s Japan Takakura , et al., 2004 [38] nationwide surveillance (105 participating) Taiwan Kung , et al., 2007 [28] community-onset NA % 19.8% 9.9% 12.2% % glabrata was the dominant nonalbicans species with the exception of pediatric patients where the main non-albicans was parapsilosis Baltimore: 24 cases/ population/year Connecticut: 7 cases/ population/year % 24% 13% 12% 2% - 1% % - 0.2% The study showed an increasing frequency of glabrata (consistent with the results of previous studies) NA % 18.8% 11.4% 11.2% 2.4% % The relative frequencies of albicans and parapsilosis have increased and those of tropicalis and glabrata have decreased 6 cases/ population/year NA cases/1000 or 0.37 cases/1000 patient-days % 20% 7% 11% 2% - 0.8% 0.4% % The study showed an increase in the relative frequency of glabrata along with increasing age 42% 7.7% 21.3% 24.2% - 2.9% 1.9% The study depicts the high prevalence of tropicalis % 4.9% 20.5% 20.9% 1.1% 2.4% % The study showed that tropicalis and parapsilosis are the dominant pathogens NA % 17.9% 23% 11.6% 2.4% 1.3% 0.6% 0.7% - 0.2% - 1.5% The study showed that the relative frequency of albicans tends to decrease with age NA % 17.2% 15.5% 22.4% 1.7% 1.7% - 1.7% The study showed a high frequency of parapsilosis possibly due to its abundance in the community M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e957

5 Table 1 (Continued ) Author, year [Ref.] Study design/ observation time period/ participating Incidence Total number of blood isolates a albicans glabrata parapsilosis tropicalis Other krusei guillermondii lusitaniae famata inconspicua dubliniensis norvegensis Candida Trends in relative species proportions e958 Kuwait Mokkadas , et al., 2007 [32] tertiary s in Kuwait NA % 5.6% 30.6% 12.4% 1.6% % The study showed a high frequency of parapsilosis consistent with previous studies Australia Chen Prospective surveillance, et al., 2006 [90] cases/ population % 15.4% 19.9% 5.1% 4.3% % - 4.0% Ref., reference; NA, relevant data were not available; ECMM, European Confederation on Medical Mycology; NIDR, National Infectious Disease Register; SCOPE, Surveillance and Control of Pathogens of Epidemiological Importance. a Refers to the total number of Candida isolates from blood (or to the total number of episodes where the former was not available from the original study). b Includes Candida spp not depicted in the Table and Candida spp not identified to species level. c Approximate numbers calculated from figure. Table 2 Relative frequency of Candida spp in in -based studies Author, year [Ref.] Europe Portugal Costa-de-Oliveira et al., 2008 [56] Greece Samonis et al., 2008 [68] Italy Luzzati et al., 2005 [63] Bedini et al., 2006 [47] Caggiano et al., 2008 [50] Ireland McMullan et al., 2002 [64] Study design/ observation time period/ participating 2004, university , tertiary , tertiary (original period ) , tertiary , university , university (original period ) Total number of blood isolates a albicans glabrata parapsilosis tropicalis krusei guillermondii lusitaniae famata inconspicua dubliniensis norvegensis Other Candida Incidence 95 43% 9% 32% 16% cases of fungemia/ % 13.6% 14.3% 21.4% 2.1% 1.4% 1.4% NA % 6.6% 17.9% 4.7% 0.8% 4.7% 1.9% 1.9% % 11.3% NA % 12.8% 22.3% 15.9% 3.2% 2.1% 2.1% % 0.9 cases/ patient-days % 4.5% 35.5% 4.5% 3.2% 3.2% - 0.6% % cases/ % 27% 11% 6.4% % NA M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966

6 Boo et al., 2005 (part II) [23] Metwally et al., 2007 [66] UK Schelenz et al., 2003 [71] Aliyu et al., 2006 [43] Switzerland Garbino et al., 2002 [58] Belgium Lagrou et al., 2007 [61] Netherlands Verduyn Lunel et al., 2006 [73] Sweden Klingspor et al., 2004 [60] Hungary Doczi et al., 2002 [56] North America USA Baran et al., 2001 [45] Abelson et al., 2005 [42] Morrell et al., 2005 [91] South America Brazil Antunes et al., 2004 [43] Aquino et al., 2005 [44] Barberino et al., 2006 [46] , tertiary , university , teaching , tertiary , university (original period ) , university , 5 university s , 6 s , university (original period ) , tertiary care (original period also: ) , tertiary care pediatric (original period ) , teaching , tertiary care , tertiary , 3 tertiary s 66 50% 18.2% 21.2% 6.1% % - 1.5% - 1.5% 0.48 cases/1000 /year % 17.2% 12% 3.3% - 2.6% - 0.7% - 0.7% - - NA % 20% 5.4% 8.5% 0.8% - 0.8% cases/ % 24.2% 10.5% 5.3% 4.2% 2.1% 2.1% % NA % 21.3% 4% 4% 5.3% 2.6% % cases/ patient-days % 22.6% 9.8% 4.5% 1.2% 0.2% 1.2% % - 0.2% During the study period: 1.68!1.3 cases of fungemia/ patient-days (a similar rate for is reported) % 19.6% 9% 7.3% 3.4% 0.3% 1.7% % - 1.4% 0.82 cases/ patient-days % 15.8% 7.1% 2% 1% 0.5% 2.5% % 1.5% 0.32 cases/1000 patients ized >1 day % 2.5% 4.2% 3.3% 5.8% % NA 98 50% 7% 24% 16% 2% % During the study period: 0.09!0.06 cases/ % 2.2% 27.5% 11.8% 3.4% - 2.2% On average: 6 cases of fungemia/1000 inpatients % 12.7% 15.9% 12.7% 1.3% NA % 3.3% 25.8% 13.3% 1.7% 1.7% 0.8% 1.7% - 0.8% - 2.5% NA % 6.9% 24.4% 15.3% 4.6% 0.8% 0.8% % NA 25 56% 4% 4% 16% 0% 4% - 4% % NA M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e959

7 Table 2 (Continued ) Author, year [Ref.] Study design/ observation time period/ participating Total number of blood isolates a albicans glabrata parapsilosis tropicalis krusei guillermondii lusitaniae famata inconspicua dubliniensis norvegensis Other Candida Incidence e960 Medrano et al., 2006 [65] Colombo et al., 2007 [54] Chang et al., 2008 [52] Franka et al., 2008 [40] Argentina Giusiano et al., 2004 [60] Asia Turkey Yapar et al., 2006 [78] Celebi et al., 2008 [52] Saudi Arabia Bukharie, 2002 [49] Osoba et al., 2003 (abstract only available) [67] United Arab Emirates Ellis et al., 2003 (abstract only available) [57] Israel Samra et al., 2005 [69] Weinberger et al., 2005 [76] India Verma et al., 2003 [75] Capoor et al., 2005 [50] Xess et al., 2007 [78] Taiwan Cheng et al., 2006 [54] , tertiary , 4 tertiary s , tertiary care , tertiary , pediatric , tertiary , tertiary , teaching , , , tertiary , 3 tertiary s , tertiary , tertiary 2005, tertiary care , tertiary 50 28% 4% 36% 16% - 12% % NA % 3% 23% 17% 1% 6% 1% % 1.66 cases/ % 5.2% 34.4% 14.6% NA % 7% 9% 15% 2% 2% 1% % 1.27 cases/ % 10.9% 28.3% 15% - 2.2% 2.2% 4.3% % NA % 3.8% 12.5% 20.2% 1% 3.8% % 0.56 cases/ % 6.9% 21.6% 15.7% 4.9% - 3.9% % 5.1 cases/ % 3% 44% 8% 6% 3% NA 82 46% 4.8% 10.8% 10.8% 6% % NA 60 45% 5% 5% 15% - - 1% 2% % 0.77 cases/ % 9.8% 20.4% 24.6% 0.7% NA 272 c 55% 10% 16% 16% 2% 0.4% 0.4% % 1% NA 21 33% 9.5% 9.5% 33% 4.8% 4.8% 4.8% cases/ % - 23% 60% NA % 17.5% 20% 35.3% 3.3% 1% % NA % 5.2% 17.5% 16.5% - 2.3% - 0.8% % NA M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966

8 Wang et al., 2004 [75] Tsai et al., 2008 [72] Singapore Tan et al., 2008 [71] Korea Lee et al., 2007 [62] 2002, university , tertiary , 3 s , 8 university s % 13% 13.9% 21.7% 1.3% 1.3% NA % 11.7% 10.6% 12.2% % NA % 16.1% 14.3% 26.9% 0.7% 0.4% % - 1.5% NA % 11% 22% 14% 1% 2% NA Ref., reference; NA, relevant data were not available. a Refers to the total number of Candida isolates from blood (or to the total number of episodes where the former was not available). b c Includes Candida spp not depicted in the Table and Candida spp not identified to species level. Number of patients with. Table 3 Relative frequency of Candida spp in in ICU patients Author, year, country [Ref.] Study design/ observation time period/ participating Trubenova et al., 2001, Slovakia [90] Doczi et al., 2002, Hungary [56] Rani et al., 2002, India [84] Roilides et al., 2004, Greece [86] Boo, et al., 2005 Ireland (part II) [23] Shetty et al., USA, 2005 [87] Giusiano et al., 2005, Argentina [59] Total number of blood isolates a albicans glabrata parapsilosis tropicalis krusei guillermondii l usitaniae famata inconspicua dubliniensis norvegensis Other Incidence Candida NA, PICU 42 41% 0% 48% 7% 2% % NA , adult ICUs and PICUs % 3.3% 3.3% 3.3% % NA NA, 2000, NICU 50 4% % % NA 2004, NICU , ICU 59 65% 2% 16% 7% - 3% 5% % NA % 24.2% 18.2% 6.1% % - 3% - - Range: cases/1000 or cases / patientdays % 14.3% 25.7% % NA , 7 PICUs NA, , PICU % 10.9% 28.3% 15.2% - 2.2% 2.2% 4.3% % NA M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e961

9 e962 Table 3 (Continued ) Author, year, country [Ref.] Study design/ observation time period/ participating Total number of blood isolates a albicans l glabrata parapsilosis tropicalis krusei guillermondii usitaniae famata inconspicua dubliniensis norvegensis Other Incidence Candida Rodriguez et al., 2006, Spain [85] Comert et al., 2007, Turkey [83] Bassetti et al., 2006, Italy [79] Lagrou et al., 2007, Belgium [61] Costa-de-Oliveira et al., 2007, Portugal [55] Dimopoulos et al., 2007, Greece [84] Bougnoux et al., 2008, France [80] Fridkin et al., 2006, USA [85] Playford et al., 2008, Australia [92] Chow et al., 2008, USA [93] Vardakas et al., 2009, Greece [94] , 5 NICUs 24 29% 4% 67% cases/ live-births or 1.1 cases/100 ICU discharges % 13% 21.7% - 8.7% 17.4% NA , ICU % 15% 23% 9% 13% cases/ patients/year , medical and surgical ICU % 22.6% 9.8% 4.5% 1.2% 0.2% 1.2% % - 0.2% NA , NICUs, hematology, ICUs and emergency units 2004, ICU % 9.3% 30.9% 15.5% - 1% 1% NA , mixed medical surgical ICU , medical, surgical, hematological and burn ICUs , 128 NICUs (participants of NNISS) , Australian ICUs , 2 ICUs , 1 medical, surgical ICU % 14.3% 5.4% 10.7% 1.8% - 1.8% % - - NA % 17% 13.5% 8.5% 3.5% % 6.7 cases/1000 or 0.69 cases/1000 patientdays % 2% 33.7% 3.8% 0.2% - 2.3% cases/1000 patient-days % 17.9% 7.8% 5.6% 3.9% - 0.5% 0.5% % 2.06 cases/ % 22.6% 8.2% 8.9% 2.1% - 2.8% % - - NA % 4.3% 4.3% 10.9% 2.2% 4.3% - 6.5% cases/1000 patient-days Ref., reference; ICU, intensive care unit; PICU, pediatric intensive care unit; NICU, neonatal intensive care unit; NNISS, National Nosocomial Infection Surveillance System; NA, relevant data were not available. a Refers to the total number of Candida isolates from blood (or to the total number of episodes where the former was not available from the original study). b Includes Candida spp not depicted in the Table and Candida spp not identified to species level. M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966

10 M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e963 (8.5% and 10.6%, respectively). Other Candida spp were isolated in 2 9% of cases. Hospital-based studies albicans was the dominant species in North and Central Europe and the USA. Non-albicans species predominated in South America, South Europe, and Asia. The highest proportion of albicans was reported in one study conducted in Hungary (81.7%), followed by studies from Northern Europe ( %), Taiwan (63.7%), and Switzerland (61.3%). The lowest figures were observed in Asian countries (17% and 19%). glabrata was more prevalent in studies from Europe, reaching proportions of 19.6% to 27%. Zero proportions were reported in a study from India and low proportions were also reported in studies from the USA (2.2%), Hungary (2.5%), and Saudi Arabia (3%). The frequency of parapsilosis was highest in Saudi Arabia (44%), Italy (35.5%), and Portugal (32%), followed by most studies of American origin (eight out of 10 report proportions of 23 36%). The lower rates were reported in Switzerland and Brazil (4% for both studies). tropicalis was higher in Asia (33 60%) and South America ( %, average 15.5%) and lower in North (2 8.5%) and Central Europe (3.3 7%). As in the surveillance studies, the proportion of krusei was low (1 6%) in all regions. Rates for other Candida spp ranged from 0.2% to 13.2%. ICUs In general very few studies were available and the majority of them were performed in neonatal and pediatric ICUs. In these studies albicans predominated in Hungary (88.3%), Greece ( %), Australia (62%), Belgium (59.8%), and the USA ( % in pediatric ICUs). On the other hand, non-albicans was higher in India (96%) and South Europe (77%). The relative frequency of glabrata was highest in Ireland (24.2%) and lowest in neonatal ICUs in the USA (2%). parapsilosis was higher in Spain (67%), followed by Slovakia (48%) and the USA (33.7%), and was lower in Greece (4.3%) and Hungary (3.3%). tropicalis was most commonly isolated in India (92%), but its proportion was low in Ireland (6.1%) and the USA (3.8%). Finally krusei was similarly low (up to 3.5%) in all regions with the exception of one study from Turkey (8.7%). Prospective and retrospective studies Twelve out of 21 surveillance and multicenter studies identified albicans as the dominant pathogen in patients with ; all were performed in Europe and the USA. Three studies showed that albicans and non-albicans spp are equally isolated from blood samples (meaning that the proportion of albicans was in the range of 45 55%) and six more that non-albicans spp are the most frequently isolated pathogens, all in South America and Asia. On the other hand, prospective -based studies showed that non-albicans spp predominated (10 out of 15); all these studies were performed in South America, Asia, and Europe. Only two studies, one performed in Sweden and another in Israel, showed that albicans was the dominant species. Retrospective studies summarizing data from s showed that albicans dominated over non-albicans spp (13 out of 25). Four studies reported that albicans and non-albicans spp were equally isolated from blood ( albicans in the range of 48 52%) and eight more reported that non-albicans spp predominated. Very few retrospective ICU studies (n = 4) have been published and the reported outcomes are contradictory, with two showing predominance of albicans and two of non-albicans. Distribution according to age Data regarding the relative frequency of Candida spp according to age are limited (17 studies provided data). Again, differences were noted according to study design. Surveillance studies showed that albicans is the major pathogen in all populations (neonates, pediatrics, and adults). However, ICU- and -based studies reported variable distributions. Studies performed in neonates showed that non-albicans species, mainly parapsilosis, predominate (in three out of four). Conclusions could not be drawn from results in children and adults, since studies favoring both albicans and non-albicans species have been published. Changes over time Data regarding changes in the relative frequency of the Candida spp over time in the individual studies were available only for 12 surveillance studies. An increasing relative frequency of glabrata was reported in five studies, 23,25,27,31,39 all conducted in Central and North Europe and the USA. In two of them, an increase in the relative frequency of glabrata was noticed with increasing age. 25,39 A decrease in glabrata was reported in one study conducted in the USA. 2 The same study reported an increase in the relative frequency of albicans and parapsilosis, and a decrease in tropicalis. An increase in krusei was reported in one study, 31 while an overall increase in non-albicans species was reported in two studies conducted in Belgium and Japan. 37,38 In the Japanese study, the relative frequency of non-albicans species increased with increasing age. No shift towards non-albicans species was reported in four studies, all conducted in Europe. 22,30,35,36 Discussion The main finding of this review is that the epidemiology of is considerably different in the various parts of the world, but it appears that it follows specific patterns. In general, albicans is the predominately isolated pathogen in North and Central Europe and the USA. On the other hand, non-albicans species predominate in Asia, South Europe, and South America. No data have been published for Africa. The highest proportion of albicans was reported in North and Central Europe, followed by the USA, South Europe, and South America, while the lowest frequency was reported in Asia. The highest proportions of glabrata were reported in North and Central Europe. In the USA its proportion varied depending on the setting and/or study design and in Asia depending on the setting and the specific geographical region. The lowest proportion was reported in South Europe. For parapsilosis the highest proportion was reported in a very small study in Slovakia, followed by South Europe and South America and Asia. Again, the reported data from the USA varied depending on setting and/or study design. The highest proportions of tropicalis were found in Eastern Asia and Argentina, but in general its proportion varied depending on setting, study design, and geographical region. The proportion of krusei was generally low in all settings and geographic regions. Data on other Candida spp were not reported regularly. Data regarding changes in the relative frequency of Candida spp isolated from blood were available from 12 surveillance and multicenter studies. An increase in the frequency of glabrata was reported in five studies, all conducted in Europe and the USA. Four additional studies conducted in Europe reported no shift towards non-albicans species. Data regarding changes over time were not available from other parts of the world. Geographic variation may mirror clinical practice in different parts of the globe. For example, the higher incidence of glabrata in studies in the USA and parts of Europe may be a result of the extensive use of fluconazole both for prophylaxis and treatment during the past years, especially in patients with hematological malignancies. However, this should not be considered as the single

11 e964 M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 reason since this should have led to a higher incidence of krusei infections as well. Moreover, glabrata bloodstream infections have also been associated with increasing patient age, underlying disease (mainly cancer), geographic variation, use of specific antibiotics (piperacillin tazobactam and vancomycin), use of central venous catheters, administration of total parenteral nutrition, and the isolation system used for species identification. parapsilosis has been associated with nosocomial outbreaks underlying a break in infection control programs, formation of biofilms in central catheters and other implanted devices, and the use of parenteral nutrition. tropicalis and krusei have mainly been associated with hematological malignancies and neutropenia. krusei has also been associated with the use of piperacillin tazobactam and vancomycin. 94 On the other hand, this may just represent a different species distribution around the globe, as seen for several and not only microorganisms. Commercially available methods for species identification have become increasingly available over time. In addition, we should underline the possibility of an increasing number of species previously considered non-pathogenic that have emerged as true opportunistic pathogens in immunocompromised individuals. 94 The study design may play an additional important role. It is suggested that surveillance studies provide the most representative and comprehensive data. These studies showed that albicans is still the predominant pathogen of in general, but local epidemiology may be strikingly different. Countries in South Europe may be the best example in this case. We found that although European surveillance studies reported that albicans is isolated in over 50% of cases, non-albicans species were more frequently isolated in single centre studies performed in South European countries. This finding emphasizes the significance of local epidemiological data. Finally, although parapsilosis was found to be an important pathogen in neonatal ICUs, no other possible relationship was found between age and Candida spp. These findings may have potential implications for the treatment of choice in patients with suspected. Therefore, in regions with a high incidence of glabrata, fluconazole should probably not be considered as a first-line treatment. Further, in neonatal ICUs, where a significant proportion of is due to parapsilosis, empirical treatment with echinocandins may be withheld following data showing decreased susceptibility of this pathogen to echinocandins, especially caspofungin. 95 However, it should be noted that the clinical significance of this finding has not yet been determined. Again, physicians should be aware of the local epidemiological patterns. The considerable number of retrospective studies included in this review is among its most important limitations. Therefore, it is not possible to guarantee that they have included all from the period analyzed. In addition, 33 studies had a population of episodes smaller than 100. This figure is mainly found in the studies performed in ICUs (13/18 studies), followed by -based studies (17/41 of cohorts); hence the distribution in percentage of the different Candida spp could have limited validity. In the reported ICU series, there was a predominance of children and neonates. Therefore, extrapolation of the results to adult patients admitted to the ICU should be done with caution. In conclusion, significant variation is evident among cases of in different geographic regions, even within the same continent and probably the same country. albicans remains the main species isolated from blood, but increasing incidence of other Candida spp has also been reported. Local epidemiological data continue to be of major significance. Conflict of interest: No conflict of interest to declare. References 1. Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP. Nosocomial bloodstream infections in United States s: a three-year analysis. Clin Infect Dis 1999;29: Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US s: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004;39: Pfaller MA, Diekema DJ. Role of sentinel surveillance of : trends in species distribution and antifungal susceptibility. J Clin Microbiol 2002;40: Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in combined medical surgical intensive care units in the United States. Infect Control Hosp Epidemiol 2000;21: Ostrosky-Zeichner L, Pappas PG. Invasive candidiasis in the intensive care unit. Crit Care Med 2006;34: Kollia K, Velegraki A. Candidemia. Arch Hellen Med 2008;25: Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 2003;3: Morgan J. Global trends in : review of reports from Curr Infect Dis Rep 2005;7: Nguyen MH, Peacock Jr JE, Morris AJ, Tanner DC, Nguyen ML, Snydman DR, et al. The changing face of : emergence of non-candida albicans species and antifungal resistance. Am J Med 1996;100: Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother 2005;56(Suppl 1):i San Miguel LG, Cobo J, Otheo E, Sanchez-Sousa A, Abraira V, Moreno S. Secular trends of in a large tertiary- from 1988 to 2000: emergence of Candida parapsilosis. Infect Control Hosp Epidemiol 2005;26: Sandven P. Epidemiology of. Rev Iberoam Micol 2000;17: Singh N. Changing spectrum of invasive candidiasis and its therapeutic implications. Clin Microbiol Infect 2001;7(Suppl 2): Snydman DR. Shifting patterns in the epidemiology of nosocomial Candida infections. Chest 2003;123:500S 3S. 15. Sobel JD. The emergence of non-albicans Candida species as causes of invasive candidiasis and. Curr Infect Dis Rep 2006;8: Falagas ME, Apostolou KE, Pappas VD. Attributable mortality of : a systematic review of matched cohort and case control studies. Eur J Clin Microbiol Infect Dis 2006;25: Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, et al. Attributable mortality of nosocomial, revisited. Clin Infect Dis 2003;37: Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner The epidemiology and attributable outcomes of in adults and children ized in the United States: a propensity analysis. Clin Infect Dis 2005;41: Guery BP, Arendrup MC, Auzinger G, Azoulay E, Borges Sá M, Johnson EM, et al. Management of invasive candidiasis and in adult non-neutropenic intensive care unit patients: part II. Treatment. Intensive Care Med 2009;35: Guery BP, Arendrup MC, Auzinger G, Azoulay E, Borges Sá M, Johnson EM, et al. Management of invasive candidiasis and in adult non-neutropenic intensive care unit patients: part I. Epidemiology and diagnosis. Intensive Care Med 2009;35: Almirante B, Rodríguez D, Cuenca-Estrella M, Almela M, Sanchez F, Ayats J, et al. Epidemiology, risk factors, and prognosis of Candida parapsilosis bloodstream infections: case control population-based surveillance study of patients in Barcelona, Spain, from 2002 to J Clin Microbiol 2006;44: Asmundsdottir LR, Erlendsdottir H, Gottfredsson M. Increasing incidence of : results from a 20-year nationwide study in Iceland. J Clin Microbiol 2002;40: Boo TW, O Reilly B, O Leary J, Cryan B. Candidaemia in an Irish tertiary referral : epidemiology and prognostic factors. Mycoses 2005;48: Colombo AL, Nucci M, Park BJ, Nouér SA, Arthington-Skaggs B, da Matta DA, et al. Epidemiology of in Brazil: a nationwide sentinel surveillance of in eleven medical centers. J Clin Microbiol 2006;44: Diekema DJ, Messer SA, Brueggemann AB, Coffman SL, Doern GV, Herwaldt LA, et al. Epidemiology of : 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 2002;40: Godoy P, Tiraboschi IN, Severo LC, Bustamante B, Calvo B, Almeida LP, et al. Species distribution and antifungal susceptibility profile of Candida spp. bloodstream isolates from Latin American s. Mem Inst Oswaldo Cruz 2003;98: Hajjeh RA, Sofair AN, Harrison LH, Lyon GM, Arthington-Skaggs BA, Mirza SA, et al. Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program. J Clin Microbiol 2004;42: Kung HC, Wang JL, Chang SC, Wang JT, Sun HY, Hsueh PR, et al. Communityonset at a university, J Microbiol Immunol Infect 2007;40:

12 M.E. Falagas et al. / International Journal of Infectious Diseases 14 (2010) e954 e966 e Lyytikainen O, Lumio J, Sarkkinen H, Kolho E, Kostiala A, Ruutu P. Nosocomial bloodstream infections in Finnish s during Clin Infect Dis 2002;35:e Marchetti O, Bille J, Fluckiger U, Eggimann P, Ruef C, Garbino J, et al. Epidemiology of in Swiss tertiary s: secular trends, Clin Infect Dis 2004;38: Martin D, Persat F, Piens MA, Picot S. Candida species distribution in bloodstream cultures in Lyon, France, Eur J Clin Microbiol Infect Dis 2005;24: Mokaddas EM, Al-Sweih NA, Khan ZU. Species distribution and antifungal susceptibility of Candida bloodstream isolates in Kuwait: a 10-year study. J Med Microbiol 2007;56: Odds FC, Hanson MF, Davidson AD, Jacobsen MD, Wright P, Whyte JA, et al. One year prospective survey of Candida bloodstream infections in Scotland. J Med Microbiol 2007;56: Pfaller MA, Jones RN, Doern GV, Fluit AC, Verhoef J, Sader HS, et al. International surveillance of bloodstream infections due to Candida species in the European SENTRY Program: species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents. SENTRY Participant Group (Europe). Diagn Microbiol Infect Dis 1999;35: Poikonen E, Lyytikainen O, Anttila VJ, Ruutu P. Candidemia in Finland, Emerg Infect Dis 2003;9: Sandven P, Bevanger L, Digranes A, Haukland HH, Mannsaker T, Gaustad P. Candidemia in Norway (1991 to 2003): results from a nationwide study. J Clin Microbiol 2006;44: Swinne D, Watelle M, Suetens C, Mertens K, Fonteyne PA, Nolard N. A one-year survey of in Belgium in Epidemiol Infect 2004;132: Takakura S, Fujihara N, Saito T, Kudo T, Iinuma Y, Ichiyama S. National surveillance of species distribution in blood isolates of Candida species in Japan and their susceptibility to six antifungal agents including voriconazole and micafungin. J Antimicrob Chemother 2004;53: Tortorano AM, Peman J, Bernhardt H, Klingspor L, Kibbler CC, Faure O, et al. Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) -based surveillance study. Eur J Clin Microbiol Infect Dis 2004;23: Chen S, Slavin M, Nguyen Q, Marriott D, Playford EG, Ellis D, Sorrell T, Australian Candidemia Study. Active surveillance for, Australia. Emerg Infect Dis 2006;12: Franca JC, Ribeiro CE, Queiroz-Telles F. [Candidemia in a Brazilian tertiary care : incidence, frequency of different species, risk factors and antifungal susceptibility]. Rev Soc Bras Med Trop 2008;41: Abelson JA, Moore T, Bruckner D, Deville J, Nielsen K. Frequency of fungemia in ized pediatric inpatients over 11 years at a tertiary care institution. Pediatrics 2005;116: Aliyu SH, Enoch DA, Abubakar II, Ali R, Carmichael AJ, Farrington M, et al. Candidaemia in a large teaching : a clinical audit. QJM 2006;99: Antunes AG, Pasqualotto AC, Diaz MC, d Azevedo PA, Severo L Candidemia in a Brazilian tertiary : species distribution and antifungal susceptibility patterns. Rev Inst Med Trop Sao Paulo 2004;46: Aquino VR, Lunardi LW, Goldani LZ, Barth AL. Prevalence, susceptibility profile for fluconazole and risk factors for in a tertiary in southern Brazil. Braz J Infect Dis 2005;9: Baran Jr J, Muckatira B, Khatib R. Candidemia before and during the fluconazole era: prevalence, type of species and approach to treatment in a tertiary care community. Scand J Infect Dis 2001;33: Barberino MG, Silva N, Rebouças C, Barreiro K, Alcântara AP, Netto EM, et al. Evaluation of bloodstream infections by Candida in three tertiary s in Salvador, Brazil: a case control study. Braz J Infect Dis 2006;10: Bedini A, Venturelli C, Mussini C, Guaraldi G, Codeluppi M, Borghi V, et al. Epidemiology of candidaemia and antifungal susceptibility patterns in an Italian tertiary-. Clin Microbiol Infect 2006;12: Bukharie HA. Nosocomial in a tertiary in Saudi Arabia. Mycopathologia 2002;153: Caggiano G, Iatta R, Laneve A, Manca F, Montagna MT. Observational study on candidaemia at a university in southern Italy from 1998 to Mycoses 2008;51: Capoor MR, Nair D, Deb M, Verma PK, Srivastava L, Aggarwal P. Emergence of non-albicans Candida species and antifungal resistance in a tertiary care. Jpn J Infect Dis 2005;58: Celebi S, Hacimustafaoglu M, Ozdemir O, Ozkaya G. Nosocomial candidaemia in children: results of a 9-year study. Mycoses 2008;51: Chang MR, Correia FP, Costa LC, Xavier PC, Palhares DB, Taira DL, et al. Candida bloodstream infection: data from a teaching in Mato Grosso do Sul, Brazil. Rev Inst Med Trop Sao Paulo 2008;50: Cheng YR, Lin LC, Young TG, Liu CE, Chen CH, Tsay RW. Risk factors for -related mortality at a medical center in central Taiwan. J Microbiol Immunol Infect 2006;39: Colombo AL, Guimarães T, Silva LR, de Almeida Monfardini LP, Cunha AK, Rady P, et al. Prospective observational study of in Sao Paulo, Brazil: incidence rate, epidemiology, and predictors of mortality. Infect Control Hosp Epidemiol 2007;28: Costa-de-Oliveira S, Pina-Vaz C, Mendonca D, Goncalves Rodrigues A. A first Portuguese epidemiological survey of fungaemia in a university. Eur J Clin Microbiol Infect Dis 2008;27: Doczi I, Dosa E, Hajdu E, Nagy E. Aetiology and antifungal susceptibility of yeast bloodstream infections in a Hungarian university between 1996 and J Med Microbiol 2002;51: Ellis M, Hedstrom U, Jumaa P, Bener A. Epidemiology, presentation, management and outcome of in a tertiary care teaching in the United Arab Emirates, Med Mycol 2003;41: Garbino J, Kolarova L, Rohner P, Lew D, Pichna P, Pittet D. Secular trends of over 12 years in adult patients at a tertiary. Medicine (Baltimore) 2002;81: Giusiano GE, Mangiaterra M, Rojas F, Gomez V. Yeasts species distribution in neonatal intensive care units in northeast Argentina. Mycoses 2004;47: Klingspor L, Tornqvist E, Johansson A, Petrini B, Forsum U, Hedin G. A prospective epidemiological survey of candidaemia in Sweden. Scand J Infect Dis 2004;36: Lagrou K, Verhaegen J, Peetermans WE, De Rijdt T, Maertens J, Van Wijngaerden E. Fungemia at a tertiary : incidence, therapy, and distribution and antifungal susceptibility of causative species. Eur J Clin Microbiol Infect Dis 2007;26: Lee JS, Shin JH, Lee K, Kim MN, Shin BM, Uh Y, et al. Species distribution and susceptibility to azole antifungals of Candida bloodstream isolates from eight university s in Korea. Yonsei Med J 2007;48: Luzzati R, Allegranzi B, Antozzi L, Masala L, Pegoraro E, Azzini A, et al. Secular trends in nosocomial candidaemia in non-neutropenic patients in an Italian tertiary. Clin Microbiol Infect 2005;11: McMullan R, McClurg R, Xu J, Moore JE, Millar BC, Crowe M, et al. Trends in the epidemiology of Candida bloodstream infections in Northern Ireland between January 1984 and December J Infect 2002;45: Medrano DJ, Brilhante RS, Cordeiro Rde A, Rocha MF, Rabenhorst SH, Sidrim JJ. Candidemia in a Brazilian : the importance of Candida parapsilosis. Rev Inst Med Trop Sao Paulo 2006;48: Metwally L, Walker MJ, Coyle PV, Hay RJ, Hedderwick S, McCloskey BV, et al. Trends in and antifungal susceptibility in a university in Northern Ireland J Infect 2007;55: Osoba AO, Al-Mowallad AW, McAlear DE, Hussein BA. Candidemia and the susceptibility pattern of Candida isolates in blood. Saudi Med J 2003;24: Samonis G, Kofteridis DP, Saloustros E, Giannopoulou KP, Ntziora F, Christidou A, et al. Candida albicans versus non-albicans bloodstream infection in patients in a tertiary : an analysis of microbiological data. Scand J Infect Dis 2008;40: Samra Z, Yardeni M, Peled N, Bishara J. Species distribution and antifungal susceptibility of Candida bloodstream isolates in a tertiary medical center in Israel. Eur J Clin Microbiol Infect Dis 2005;24: Schelenz S, Gransden WR. Candidaemia in a London teaching : analysis of 128 cases over a 7-year period. Mycoses 2003;46: Tan TY, Tan AL, Tee NW, Ng LS. A retrospective analysis of antifungal susceptibilities of Candida bloodstream isolates from Singapore s. Ann Acad Med Singapore 2008;37: Tsai CC, Wang CC, Kuo HY, Chiang DH, Lin ML, Liu CY, et al. Adult at a medical center in northern Taiwan: a retrospective study. J Microbiol Immunol Infect 2008;41: Verduyn Lunel F, Koeleman JG, Spanjaard L, Vandenbroucke-Grauls C, Schultz C, Verbrugh HA, et al. Trends in fungaemia and antifungal susceptibility in the Netherlands. Neth J Med 2006;64: Verma AK, Prasad KN, Singh M, Dixit AK, Ayyagari A. Candidaemia in patients of a tertiary health from north India. Indian J Med Res 2003;117: Wang JL, Chang SC, Hsueh PR, Chen Y Species distribution and fluconazole susceptibility of Candida clinical isolates in a medical center in J Microbiol Immunol Infect 2004;37: Weinberger M, Leibovici L, Perez S, Samra Z, Ostfeld I, Levi I, et al. Characteristics of candidaemia with Candida albicans compared with non-albicans Candida species and predictors of mortality. J Hosp Infect 2005;61: Xess I, Jain N, Hasan F, Mandal P, Banerjee U. Epidemiology of in a tertiary care centre of north India: 5-year study. Infection 2007;35: Yapar N, Uysal U, Yucesoy M, Cakir N, Yuce A. Nosocomial bloodstream infections associated with Candida species in a Turkish University Hospital. Mycoses 2006;49: Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for mortality. Antimicrob Agents Chemother 2005;49: Bassetti M, Righi E, Costa A, Fasce R, Molinari MP, Rosso R, et al. Epidemiological trends in nosocomial in intensive care. BMC Infect Dis 2006;6: Bougnoux ME, Kac G, Aegerter P, d Enfert C, Fagon JY. Candidemia and candiduria in critically ill patients admitted to intensive care units in France: incidence, molecular diversity, management and outcome. Intensive Care Med 2008;34: Comert F, Kulah C, Aktas E, Eroglu O, Ozlu N. Identification of Candida species isolated from patients in intensive care unit and in vitro susceptibility to fluconazole for a 3-year period. Mycoses 2007;50: Dimopoulos G, Karabinis A, Samonis G, Falagas ME. Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis 2007;26: Fridkin SK, Kaufman D, Edwards JR, Shetty S, Horan T. Changing incidence of Candida bloodstream infections among NICU patients in the United States: Pediatrics 2006;117: