Seminational Surveillance of Fungemia in Denmark: Notably High Rates of Fungemia and Numbers of Isolates with Reduced Azole Susceptibility

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1 JOURNAL OF CLINICAL MICROBIOLOGY, Sept. 2005, p Vol. 43, No /05/$ doi: /jcm Copyright 2005, American Society for Microbiology. All Rights Reserved. Seminational Surveillance of Fungemia in Denmark: Notably High Rates of Fungemia and Numbers of Isolates with Reduced Azole Susceptibility Maiken Cavling Arendrup, 1 * Kurt Fuursted, 2 Bente Gahrn-Hansen, 3 Irene Møller Jensen, 4 Jenny Dahl Knudsen, 5,7 Bettina Lundgren, 5 Henrik C. Schønheyder, 6 and Michael Tvede 7 Unit of Mycology and Parasitology, Statens Serum Institut, Copenhagen, 1 Department of Clinical Microbiology, Skejby Hospital, Aarhus University Hospital, Aarhus, 2 Department of Clinical Microbiology, Odense University Hospital, Odense, 3 Department of Clinical Microbiology, Herlev University Hospital, Herlev, 4 Department of Clinical Microbiology, Hvidovre University Hospital, Hvidovre, 5 Department of Clinical Microbiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, 6 and Department of Clinical Microbiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 7 Denmark Received 2 March 2005/Returned for modification 10 April 2005/Accepted 30 May 2005 The aim of this study was to present the first set of comprehensive data on fungemia in Denmark including the distribution of species and range of susceptibility to major antifungal compounds based on a seminational surveillance study initiated in The catchment area of the participating hospitals had a population of 2.8 million, or 53% of the Danish population. A total of 303 episodes of fungemia were registered (annual rate, 11 of 100,000 people or 0.49 of 1,000 hospital discharges). Candida species accounted for 97.4% of the fungal pathogens. C. albicans was the predominant species (63%), but the proportion varied from 57% to 72% among participating departments of clinical microbiology. C. glabrata was the second most frequent species (20%; range, 8% to 32%). C. krusei was a rare isolate (3%) and occurred only at two of the participating hospitals. Retrospective data retrieved from the Danish laboratory systems documented a continuous increase of candidemia cases since the early 1990s. For the 272 susceptibility-tested isolates, MICs of amphotericin B and caspofungin were within the limits expected for the species or genus. However, decreased azole susceptibility, defined as a fluconazole MIC of >8 g/ml and/or itraconazole MIC of >0.125 g/ml, was detected for 11 Candida isolates that were neither C. glabrata nor C. krusei. Including intrinsically resistant fungi, we detected decreased susceptibility to fluconazole and/or itraconazole in 87 (32%) current Danish bloodstream fungal isolates. We showed a continuous increase of fungemia in Denmark and an annual rate in 2003 to 2004 higher than in most other countries. The proportion of bloodstream fungal isolates with reduced susceptibility to fluconazole and/or itraconazole was also notably high. Epidemiology of candidemia has been subjected to numerous studies. Overall, the incidence has been rising over the past decades, although recent studies from intensive care units in the United States and tertiary hospitals in Switzerland have shown a decrease (11, 24, 26). Variations in the rate and species distribution between countries and hospital settings are prominent. Thus, fungemia in most European studies accounts for far less than 5% of bloodstream infections (BSI), in contrast to the United States (6 to 8% of BSI), and although C. albicans is the predominant species on both sides of the Atlantic, the percentage varies, being 50% in the United States and Spain, over 56% in a recent European study covering France, Germany, Austria, Spain, Sweden, and the United Kingdom, and 70% in a recent study in Finland (1, 5, 18, 20, 21, 25). The distribution of non-c. albicans species has changed over time, and the prevalence of C. glabrata especially has been shown in many studies to be on the rise, which is important due to its intrinsic decreased fluconazole susceptibility (4, 24, 26). In Norway, the rate has remained low and the species distribution rather unchanged during the last decade, whereas in Finland, an increase was observed from 1995 to 1999 (18, 20, 21). There are few data on the epidemiology of fungemia in Denmark. Two such studies covered one university hospital over a 10-year period, and one covered one county. These studies demonstrated rates from 1% to 1.5% of BSI in the time period from 1984 to 1998 (3, 13, 22). In order to update our knowledge of fungemia in Denmark, we initiated a prospective semi-national surveillance study in 2003 in which six university departments of clinical microbiology participated in collecting all fungal BSI isolates for identification to the species level and susceptibility testing. Here, we present the results from the first year of the program (May 2003 to April 2004), showing a notably high rate of candidemia and of isolates with decreased susceptibility to azole antifungal compounds. Retrospective data of candidemia rates since 1992 are included and document a continuous increase over time. Half of the Danish population is covered, and this study thus provides the most comprehensive study of fungemia in Denmark to date. * Corresponding author. Mailing address: Unit of Mycology and Parasitology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark. Phone: (45) Fax: (45) mad@ssi.dk. MATERIALS AND METHODS Surveillance and population. During a 1-year period from May 2003 to April 2004, fungal BSI isolates were prospectively collected at the six major Danish departments of clinical microbiology at Rigshospitalet and Hvidovre Hospital (serving Copenhagen City hospitals), Herlev Hospital (serving hospitals in the 4434

2 VOL. 43, 2005 FUNGEMIA IN DENMARK 4435 Copenhagen), Odense University Hospital (serving hospitals in the Funen), Skejby Hospital (serving hospitals in the Aarhus), and Aalborg Hospital (serving hospitals in the North Jutland). The six departments served one or more university hospitals as well as the district hospitals in the municipality of Copenhagen and the respective counties with a total population of 2,870,000, or 53% of the Danish population. Besides serving the population of their respective catchment areas, the university hospitals are secondary or tertiary care centers for all of Denmark. Of note, all solid organ transplantations and autologous bone marrow transplantations in Denmark are performed at the participating hospitals and all allogeneic bone marrow transplantations and liver transplantations are performed at Rigshospitalet. However, it was not feasible to determine the contribution of referred cases. The characteristics of the six participating departments of clinical microbiology are depicted in Table 1. In the study period, all departments used an automated blood culture system, three laboratories used BacT/ALERT (biomérieux, Marcy l Etoile, France), and three used BacTec (Becton Dickinson, Franklin Lakes, NJ). Most departments used one aerobic and one anaerobic culture bottle per blood culture set; however, at two centers, the number of culture bottles per blood culture was higher in order to increase the likelihood of detecting low-grade bacteremia/ fungemia (Table 1). Information on the total number of bloodstream infections was retrieved from the departments laboratory information systems. Only one isolate was included from an episode of fungemia, which was defined as the isolation of a fungus from any number of blood cultures drawn within a 21-day period. Eighty-eight percent of the isolates were sent to the reference laboratory, the Unit of Mycology and Parasitology at Statens Serum Institut, Copenhagen, Denmark, for verification of species identification and susceptibility testing. The isolates not referred and thus not included in the susceptibility data consisted of 9 of 65 isolates from Rigshospitalet (2 C. albicans, 2 C. glabrata, 1 C. parapsilosis, and 4 Candida species) and 26 of 45 isolates from Hvidovre Hospital (17 C. albicans, 6 C. glabrata, 2 C. tropicalis, and 1 C. parapsilosis). Species identification. Species identification was based on colony morphology on CHROMagar plates at 35 C (CHROMagar Co., Paris, France), microscopic morphology on cornmeal agar and rice and Tween 80 agar (SSI Diagnostica, Hilleroed, Denmark), growth at 35 C and 42 C, and use of a commercial system (ATB ID32C; biomérieux, Marcy l Etoile, France). Susceptibility testing. Susceptibility testing was performed according to the NCCLS document M27-A2 (12). A fluconazole (Pfizer A/S, Ballerup, Denmark) stock dilution of 10,000 g/ml and amphotericin B (A2411; Sigma-Aldrich, Vallensbaek Strand, Denmark), caspofungin (Merck, Sharp and Dohme, Glostrup, Denmark), and itraconazole (Janssen-Cilag, Birkeroed, Denmark) stock dilutions of 5,000 g/ml were prepared in dimethyl sulfoxide (D8779; Sigma-Aldrich). Twofold dilutions were prepared in microtiter plates and stored at 20 C until use. Microtiter plates were read spectrophotometrically at 490 nm after resuspending yeast sediments from the bottom of the wells by pipetting. The MIC was defined as the lowest drug dilution giving 100% growth inhibition for amphotericin B and 80% growth inhibition for the other compounds. With fluconazole, some C. albicans isolates showed the trailing phenotype; i.e., they were classified as resistant if a strict 80% inhibition endpoint was used but as susceptible if a 50% endpoint was applied. These isolates were considered susceptible but not included in the statistical calculations. C. parapsilosis strain ATCC was included as a control in each run. Consumption of antifungal compounds. Information on consumption of itraconazole and fluconazole in defined daily doses (DDD) was available from the Danish Medicines Agency and from hospital pharmacies serving the participating university hospitals. RESULTS Epidemiology. During the first year of the surveillance program, a total of 303 episodes of fungemia were registered and for 272 patients, information on gender and age was available. Fifty-six percent were male and 44% female. The median age was 65 years (range, 0 to 92 years); only 5% of the patients were below 20 years of age, 77% were older than 50 years, and 38% were older than 70 years. The median age varied little (62 to 67 years) among patients with different fungal species, with the exception of patients with C. parapsilosis (56 years) and patients with a group of miscellaneous yeast genera (51 years). However, the proportions of isolates from patients above 70 years of age varied somewhat more: C. albicans, 37%; C. glabrata, 47%; C. tropicalis, 44%; C. parapsilosis, 25%; C. krusei, 22%; Candida spp., 38%; and other genera, 25%. The species distribution is shown in Table 1. Candida species accounted for 97.4% of the fungal isolates, and C. albicans was the predominant species (63%). However, the proportion varied considerably among the participating hospitals, i.e., from 57% at Hvidovre Hospital in Copenhagen to 72% at the hospitals in the counties of Copenhagen and Funen. C. glabrata was the second most frequent species (overall 20%), again with considerable variation in frequency (8 to 32%). C. krusei was a rare isolate (3%) and detected only at Rigshospitalet in Copenhagen and in the Aarhus. Mixed infections due to two different Candida species occurred in four cases, three of which were a combination of C. albicans and C. glabrata and one of which was C. parapsilosis and C. kefyr. Overall, fungi accounted for 3.1% of the bloodstream infections, 0.49 of 1,000 discharges (Table 1), or 11 per 100,000 people. The number of fungemia episodes was increasing over the period from 1992 to 2004, as shown in Fig. 1. Antifungal susceptibility testing. Susceptibility testing for amphotericin B, caspofungin, fluconazole, and itraconazole was done for a total of 272 isolates (88%). MIC distributions are shown in Fig. 2. All but one isolate were amphotericin B susceptible as defined by a MIC of 1 g/ml (one C. glabrata isolate had a MIC of 2 g/ml). For caspofungin, a bell-shaped uniform population was seen with MICs from 0.03 to 4 g/ ml; however, a tail of six non-candida isolates (2.2%) with MICs of 8 g/ml was observed and included one isolate of Trichosporon asahii, one of Cryptococcus neoformans, two of Rhodotorula spp., one of Geotrichum capitatum, and one of Fusarium sp. (MICs of 8, 16, 16, 16, 16, and 16 g/ml, respectively). Within the genus Candida, a tendency of higher MICs was observed for non-c. albicans isolates (MIC 50 [MIC at which 50% of the isolates tested were inhibited] of 0.5 g/ml; range, 0.06 to 4 g/ml) than for C. albicans isolates (MIC 50 of 0.25 g/ml; range, 0.03 to 1 g/ml) (Fig. 2). The susceptibility pattern for the azoles was more complex. Thus, the majority of Candida isolates were susceptible, with the exception of those belonging to the intrinsically less susceptible or resistant species C. glabrata and C. krusei. However, decreased azole susceptibility, defined as a fluconazole MIC of 8 and/or an itraconazole MIC of g/ml, was detected among 11 Candida isolates (Fig. 2 and Table 1). Non-Candida fungi with fluconazole MICs of 8 g/ml and/or itraconazole MICs of included two isolates of Saccharomyces cerevisiae (MICs of fluconazole-itraconazole given in parentheses) (4 and 0.5, 16 and 1, respectively), one of G. capitatum (32 and 0.5), two of Rhodotorula spp. ( 64 and 1, 64 and 2, respectively), and one of Fusarium sp. ( 64 and 16 g/ml). Altogether, 87 of the 272 fungal isolates tested thus showed decreased susceptibility to either fluconazole and/or itraconazole (32%). Fluconazole and itraconazole consumption. The total annual usage of fluconazole in Denmark has increased 44% from 255,685 to 368,945 DDD over a 5-year period from 1999 to The fluconazole and itraconazole use at the participating centers and their primary health care sectors is shown in Table 2. The highest usage was observed at Rigshospitalet and in the primary healthcare sector in the Copenhagen City area. How-

3 4436 ARENDRUP ET AL. J. CLIN. MICROBIOL. TABLE 1. Characteristics of the six participating centers, rate of fungemia, and characteristics of the fungal bloodstream isolates recovered in the period from May 2003 to April 2004 a Parameter Copenhagen Funen Aarhus North Jutland Hvidovre and Rigshospitalet b Copenhagen City hospitals All centers Characteristics of participating centers No. of hospitals (university/district) 4 (3/1) 9 (1/8) 8 (3/5) 7 (1/6) 1 (1/0) 5 (1/4) 34 (10/24) Population served in the catchment area 600, , , ,000 70, ,000 2,800,000 No. of discharges in ,000 97, ,000 95,402 62, , ,332 Blood culture system BacTec BacTec BacT/ALERT BacT/ALERT BacTec BacT/ALERT No. of bottles per blood culture (days of culture) 4 (5) 2 (6) 2 (6) 3 (7) 2 (7) 2 (6) Rates of fungemia Fungal BSI (%) c No. of fungal infections per 1,000 discharges Species distribution j C. albicans 26 (72) 34 (72) 35 (63) 35 (60) 38 (58) 25 (57) 193 (63) C. glabrata 3 (8) 8 (17) 10 (18) 18 (31) 10 (15) 14 (32) 63 (20) C. tropicalis 4 (11) 1 (2) 3 (5) 3 (7) 11 (4) C. parapsilosis 1 (3) 2 (4) 3 (5) 4 (6) 1 (2) 11 (4) C. krusei 4 (7) 5 (8) 9 (3) Candida spp. d 1 (3) 1 (2) 3 (5) 1 (2) 5 (8) 1 (2) 12 (4) Other genera e 1 (3) 2 (4) 1 (2) 3 (5) 1 (2) 8 (3) Total Reduced azole susceptibility among Candida spp. Genuine SDD or R Candida spp. f 3 (8) 8 (17) 14 (25) 18 (31) 15 (23) 14 (32) 72 (23) Acquired SDD or R Candida spp. g C. albicans C. albicans, C. albicans, C. albicans, C. albicans C. guilliermondii, C. albicans C. parapsilosis, C. tropicalis, 11 (4) C. parapsilosis h C. guillermondii i a Centers were ranked according to the proportion of C. albicans isolates. b Rigshospitalet, the university hospital of Copenhagen. c Only significant positive blood culture findings are included in the BSI calculation in the North Jutland, making the percentage of fungal BSI seem higher. d Three C. famata isolates, two of each of the species C. guilliermondii, C. kefyr, C. holmii, and C. pelliculosa, and one Candida species. e Two isolates of Saccharomyces cerevisiae and one of the following species: Cryptococcus neoformans, Rhodotorula glutinis and Rhodotorula sp., Trichosporon asahii, Geotrichum capitatum, and Fusarium sp. f C. glabrata and C. krusei. SDD, susceptible dose dependent; R, resistant. Values are numbers of isolates. Values in parentheses are percentages. g For the participating centers, each isolate with reduced susceptibility to fluconazole (MIC 8) and/or to itraconazole (MIC 0.125) is indicated by organism name. Highly resistant isolates with MICs of itraconazole of 16 and of fluconazole of 64 g/ml are in boldface. For all centers, the value given is the total number of isolates, and the value in parentheses is a percentage. h Out of 50 isolates, 44 were tested. i Out of 30 isolates, 10 were tested. j Values are numbers of isolates. Values in parentheses are percentages.

4 VOL. 43, 2005 FUNGEMIA IN DENMARK 4437 FIG. 1. Epidemiology of candidemia in Denmark in the period from 1992 to Rigshospitalet data from 1992 to 1995 and for Hvidovre Hospital data from 1992 to 1999 were not available due to changes in the catchment areas served by these institutions.

5 4438 ARENDRUP ET AL. J. CLIN. MICROBIOL. Downloaded from FIG. 2. MIC distributions for the 272 fungal isolates. Values for amphotericin B, caspofungin, fluconazole, and itraconazole are presented as the number of isolates per MIC for each fungal species. ever, a direct correlation was not observed between azole usage and detection of isolates with decreased susceptibility to azoles. DISCUSSION This first comprehensive Danish study on fungemia included approximately half the Danish population and demonstrated a notably high annual rate of fungemia, which was consistent with a steady increase in numbers of cases of candidemia since the early 1990s. Sandven et al. reported a low and rather constant annual rate of candidemia in Norway from 1991 to 1999 (2.2% of BSI or 2.17 per 100,000 people), whereas Poikonen et al. reported annual rates to increase in Finland from 1.7 to 2.2 per 100,000 people from 1995 to 1999 (18, 20, 21). In this context, our estimated annual rate of 11 per 100,000 people seems very high. Part of the explanation could be that the Norwegian and Finnish studies were nationwide and included more district hospitals, but even if in theory, no cases of fungemia were detected in the part (47%) of the Danish population not included in the current study, the annual rate would still be as high as 5.8 per 100,000 people. A recent Swedish study recorded 191 cases of candidemia from January 1998 to December 1999 in four university and two district hospitals which served a population of 2.5 to 3 million (9); the annual rate was 3.5 per 100,000 people, and although the study population was similar to ours, still the Danish figure was much higher. It remained in the high range compared to candidemia rates in Iowa, Atlanta, and San Francisco, which were on the order of 6 to 8 per 100,000 people, and was comparable to the rate of 10 per 100,000 people reported in a recent survey in Connecticut and Baltimore (4, 7, 8). It is somewhat surprising that the Danish figures seem to differ distinctively from those of the other Nordic countries and to approach the American ones, as Denmark and the other Nordic countries are known for a restrictive use of antimicrobial agents. Also, the epidemiology does not seem to follow a current trend in some American and European studies where rates of candidemia are leveling off or even decreasing after a continuous rise in the 1980s and early 1990s (11, 17, 24, 26). Moreover, in Denmark, the number of C. albicans as well as non-c. albicans cases has also been rising in contrast to recent findings elsewhere (11, 24, 26). It remains to be determined if this could be a consequence on January 5, 2019 by guest

6 VOL. 43, 2005 FUNGEMIA IN DENMARK 4439 TABLE 2. Azole use in the hospital setting (DDD/1,000 discharges) and in the primary health care sector (DDD/1,000 inhabitants) served by the six centers a Parameter Copenhagen Funen of the restrictive use of antifungal prophylaxis and preemptive therapy, as a number of studies have shown an impact on the numbers of candidemia cases in general and on those due to C. albicans in particular (2, 6, 15, 23, 24). Thirty-eight percent of our patients were older than 70 years of age, and only 5% and 2% were under the age of 20 and 1 year, respectively. Thus, patients were older than those in a recent European study of fungemia including 2,089 cases from France, Germany, Austria, Italy, Spain, Sweden, and the United Kingdom. This cannot be explained by differences in demographics, as in both study populations, approximately 10% were above the age of 70, but it reflected a higher candidemia rate among youngsters and children in the European study, where 15% and 8% were under the age of 20 and 1 year, respectively (25). The proportion of candidemic patients over the age of 70 years was highest for C. glabrata (47%), which is in accordance with findings that fungemia with C. glabrata becomes more frequent with increasing age (9, 14, 16, 25). Conversely, C. parapsilosis was more frequent in the younger population (median age, 56 years), but actually C. parapsilosis caused only one of seven cases of candidemia in patients below the age of 1 year. Hence, we did not find an overrepresentation among neonates as reported by others (8 10, 14, 16, 19). We demonstrated a low prevalence of resistance against amphotericin B and caspofungin, and only strains other than Candida had MICs higher than 2 to caspofungin. This is not surprising, as this study covered the first year after the introduction of caspofungin into the Danish market. Reduced susceptibility to azoles was demonstrated mainly for isolates with intrinsic resistance mechanisms to azoles such as C. glabrata, C. krusei, and some non-candida strains. Interestingly, though, a number of isolates with elevated MICs of fluconazole and/or itraconazole were detected, especially at centers with a high frequency of C. glabrata and C. krusei isolates, which suggests a common selection mechanism for such isolates. Altogether, 32% (95% confidence interval of 26.5 to 37.9%) of the fungal Aarhus North Jutland Rigshospitalet Hvidovre, Copenhagen City hospitals No. of fungal BSI with reduced 5 (14%) 10 (21%) 18 (32%) 22 (38%) 17 b (26% b ) 17 b (38% b ) susceptibility to azoles Hospital setting (DDD/1,000 discharges) Fluconazole Itraconazole Primary health care setting (DDD/1,000 inhabitants) Fluconazole c c Itraconazole c c a Centers were ranked according to the proportion of C. albicans isolates, and the total number of fungal BSI with reduced azole susceptibility is indicated. b Not all isolates from Rigshospitalet and Hvidovre were susceptibility tested, making the number and percentage minimum figures. c Data of azole usage for the population in the Copenhagen area were available only for the joined regions served by Rigshospitalet and Hvidovre. BSI showed either intrinsically or acquired reduced susceptibility to either fluconazole and/or itraconazole, and this is considerably higher than the prevalence of 18.6% (95% confidence interval of 11.6 to 27.6%) detected among fungal BSI in Norway with reduced susceptibility to fluconazole (21). A remarkable increase of 44% in the Danish fluconazole consumption was seen in the period from 1999 to Although the highest use of azoles was observed at Rigshospitalet and in the primary health care setting in the Copenhagen City area, we did not observe a direct correlation between the use of fluconazole and itraconazole and the incidence of intrinsically and acquired decreased fluconazole susceptibility in the different regions. In conclusion, this study has shown a remarkably high rate of fungemia in Denmark, not only compared to the other Nordic countries but probably also in a global perspective. 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