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Longitudinal 10-year prospective survey of fungaemia in Slovak Republic: trends in etiology in 310 episodes☆
Diagnostic Microbiology and Infectious Disease 36 (2000) 7–11
Mycology
Longitudinal 10-year prospective survey of fungaemia in Slovak Republic: trends in etiology in 310 episodes夞 Vladimı´r Krcˇme´ry, Jr.*, Gabriela Kovacˇicˇova´ on behalf of the Slovak Fungaemia study group Department of Medicine University of Trnava, Hornopotocna 23, 917 00 Trnava, Slovak Republic Received 28 April 1999; revised and accepted 31 August 1999 Partially presented as Abstr. 355 at 36-IDSA Annual Meeting, Denver 9.–12.11. 1998
Abstract A 10-year prospective survey of fungaemia in the Slovak Republic, involving 31 microbiology laboratories and 71 hospitals, was conducted from 1989 –1998 (10 years): 310 fungaemias were analyzed for etiology, clinical characteristics, therapy, and outcome. C. albicans was responsible for 191 (61.6%) fungaemias, non-albicans Candida spp. (NAC) for 97 (31.3%), non-Candida yeasts for 18 (5.8%) and moulds (Fusarium spp.) for four fungaemias. The most frequent NAC isolated from blood cultures were C. parapsilosis—30 (9.7%), C. krusei—18 (5.8%), C. tropicalis—14 (4.5%), and C. glabrata—10 (3.2%). Secular trends in etiology showed a sustaining decrease of C. albicans (from 100% in 1989 to 50.7% in 1998) and increase of NAC (from 0% in 1989 –1990 to 46.3% in 1998). Non-Candida yeasts and moulds showed a stable proportion during the investigated period. There were statistically significant differences in etiology of fungaemia various subgroups of patients: non-albicans Candida spp. was significantly more frequent observed among subgroups of patients with pancreatitis and coma (53.3% vs. 31.3%, p ⱕ 0.02) and less frequently in the subgroup of neonates (15.0% vs. 31.3%, p ⱕ 0.006). Vice versa, C. albicans appeared more frequently in neonates (85%). © 2000 Elsevier Science Inc. All rights reserved.
1. Introduction Several large hospital-based epidemiologic surveillances of fungaemia were conducted in the last 5 years; however, only few were national in scope (Beck Sague et al., 1993; Pfaller et al., 1998, 1999; Voss et al., 1996) or international (Viscoli et al., 1999). The study performed in the Netherlands for a 9-year period, involving five university hospitals, was published by Voss et al. in 1996 and involved 670 cases. At least two large studies were conducted in the United States in 1990 and 1998. In addition to these nationwide studies, several hospital or patient-type (cancer, HIV, neonates) studies (Fraser et al., 1992; Goldman et al., 1993; Harvey et al., 1987; Horn et al., 1985; Knaus et al., 1985; Komshian et al., 1989; Kunova et al., 1995; Rex et al., 1994, 1995; Wey et al., 1988) with 60 –500 cases have been reported in the literature. The largest two reported studies on fungaemias in cancer patients were conducted by the Euro夞 Supported by Grant PL 970002–1/5097–1/6098 of the Ministry of Education and European Committees (1998 –1999). * Corresponding author. Tel.: ⫹412-7-5292-4308.
pean Organization for Research and Treatment of Cancer (EORTC), which reported more than 240 fungaemias (Viscoli et al., 1999), and a second even larger study was published by Abi-Said et al. on 491 fungaemias from a single cancer institution (Abi-Said et al., 1997). Several other smaller studies on cancer patients (Bow et al., 1995; Guiot et al., 1994; Karabinis et al., 1988; Lecciones et al., 1992) summarized risk factors, but not longitudinal trends on epidemiology and etiology of fungaemia in cancer patients. The current study reports longitudinal results of the etiology of fungaemia in a 10-year national surveillance of fungaemia, based on 310 cases from 71 hospitals in the Slovak Republic, from a non-HIV patient population. 2. Materials and methods 2.1. Study design A national prospective longitudinal 10-year surveillance of fungaemia was conducted in Slovakia using 31 departments of clinical microbiology that serve 71 hospitals with approximately 8,900 beds for 5.5 million citizens. All lab-
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Table 1 Occurrence and etiology of fungaemia between 1989 –1998 in the Slovak Republic Total no. of episodes
C. albicans C. parapsilosis C. krusei C. tropicalis C. glabrata C. guillermondii C. lusitaniae Other NSC* Non-albicans Candida Total Trichosporon beigeli Trichosporon pullans Cryptococcus laurentii Blastoschizomyces capitatus Hansenula anomala Rhodotorula rubra Non-Candida yeast Total Moulds (Fusarium spp.) TOTAL
No. of fungaemic episodes in particular years (%)
No. of infected patients (%)
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
3 (100) 0 0 0 0 0 0 0 0
6 (100) 0 0 0 0 0 0 0 0
8 (80.0) 1 0 0 0 0 0 0 1 (1.0)
18 (78.3) 1 1 1 1 0 0 0 4 (17.4)
18 (66.7) 2 2 2 1 0 0 0 7 (25.9)
17 (60.7) 2 2 2 1 0 0 0 7 (25.0)
19 (63.3) 2 2 2 1 1 0 0 8 (26.6)
26 (55.3) 3 2 1 2 2 1 4 15 (31.9)
42 (60.9) 11 6 2 2 0 1 2 24 (34.8)
34 (50.7) 8 3 4 2 1 1 12 31 (46.3)
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 1
0 0 1 0
1 1 0 0
1 0 1 0
1 2 1 1
3 0 0 0
1 0 1 0
0 0 0
0 0 0
0 0 0
0 0 1 (4.3)
0 1 2 (7.4)
1 0 3 (10.8)
0 0 2 (6.7)
0 0 5 (10.6)
0 0 3 (4.3)
0 0 2 (3.0)
1 1 18 (5.8)
0
0
1 (10.0)
0
0
1 (3.5)
1 (3.3)
1 (2.1)
0
0
4 (1.3)
3
6
10
23
27
28
30
47
69
67
310
oratories were supplied with a protocol that was identical to a protocol used in 1989 –1995 for a fungaemia survey performed in Cancer Hospitals. Of the 31 microbiology departments serving 71 hospitals, 19 (26.8%) reported at least one blood culture positive for fungi within the last 10 years. Since 1988, an universal methodology for routine blood culturing system has been recommended in Slovakia: three bottles (aerobic, anaerobic, fungal) with blood from each patient (Bactec BBL Sparks MD, USA or Bact-Alert Organon Teknika Heidelberg, Germany) were incubated. After 24, 48, and 72 h the blood was inoculated to Blood agar, MacConkey and Sabouraud agar plates that were assessed after 24, 48, and 72 h: species were determined with Mycotube (Roche Basel) or Vitek Jr. identification systems (Bio Merieux, Hazelwood, Mo. USA). From the 314 reviewed protocols, 310 met the inclusion criteria, that is, a definition of a single fungaemic episode or several positive blood cultures (BC) for fungi and a fever ⬎38°C within 48 h from the first positive blood culture. Of 310 patients, 165 had cancer, 80 neonates, 35 surgery and trauma, and 30 had coma and pancreatitis as underlying disease. If the patient had multiple BC within 1 month, this was still considered to be one fungaemic episode (one case). Etiology, risk factors, therapy, and outcome were recorded for each patient (case). Antifungal susceptibility was tested in only 91 reported episodes (about one third), because methods of antifungal susceptibility testing in Slovakia were only approved by the Ministry of Health in 1997; therefore, results of antifungal susceptibility will be reported sepa-
191 (61.6) 30 (9.7) 18 (5.6) 14 (4.1) 10 (3.2) 4 (1.9) 3 (0.9) 18 (5.8) 97 (31.3) 7 3 4 2
rately. Differences in species among subgroups of 310 patients were assessed with 2 test (EPI INFO-20 ID computerized package).
3. Results 3.1. Secular trends in occurrence of fungaemia Candida albicans showed decreasing tendency during the period (1989 –1998) (Table 1). In 1989 –1990 100% of all strains were Candida albicans, in 1991 80%, in 1992 78.3%, but only 50.7% in 1998. Non-albicans Candida (NAC) represented an increase from 0% in 1991 to 46.3% in 1998 (Table 1), as indicated in Figure 1. Concerning nonCandida yeasts (NCY), there was a stable tendency of occurrence during the 10-year period. The lowest percentage is evident in 1998 —1.5%, and the highest percentage of isolated non-Candida yeasts was in 1994 —10.8% and in 1996 —10.6% (Table 1). Moulds were only isolated exceptionally (four cases). 3.2. Etiology of fungaemia C. albicans represented 61.6% of all 310 fungaemias. In 1989 –1998 the second most frequent organism was C. parapsilosis, 30 episodes (9.9%); C. krusei, 18 episodes (5.8%); C. tropicalis, 14 (4.1%); C. glabrata, 10 (3.2%); C. guillermondii, 4 (1.2%); C. lusitaniae, 0.9%; and other
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Table 2 Etiology in various subgroups of patients
Posit. BC per episode Two and more posit. BC Catheter related C. albicans non-albicans Candida spp. C. tropicalis C. parapsilosis C. krusei C. glabrata Other Candida spp. Non-Candida yeasts Molds Antifungal prophylaxis (breakthrough) -during prophylaxis/therapy with KET FLU ITR AmB a
Total n ⫽ 310
Cancer n ⫽ 165
Neonates n ⫽ 80
Noncancer surgery ⫹ trauma n ⫽ 35
Coma pancreatitis n ⫽ 30
1,85 81 (26,1) 23 (7,4) 191 (61,6) 97 (31,3) 14 (4,5) 30 (9,7) 18 (5,8) 10 (3,2) 25 (8,1) 18 (5,7) 4 (1,3) 69 (22,2)
1,75 30 (18,2) 19 (11,5) 89 (53,9) 55 (33,3) 10 (6,7) 17 (10,9) 13 (7,8) 6 (3,6) 9 (4,2) 16 (9,7) 4 (3,0) 5 (33,3)
1,8 16 (20) 1 (1,25) 68 (85) 12 (15)c 0 5 (6,25) 0 0 7 (9,25) 0 0 11 (13,8)
2,4 21 (60)a 2 (5,8) 20 (54,2) 15 (42,9) 3 (8,7) 3 (8,7) 3 (8,7) 1 (2,9) 6 (17,1) 1 (2,9) 0 8 (22,9)
2,1 14 (47,7)b 1 (3,3) 14 (43,3) 16 (53,3)d 1 (3,3) 5 (16,7) 2 (6,6) 3 (10) 45 (13,2) 1 (3,3) 0 5 (16,7)
26 (8,4)
17 (10,3)
7 (9,25)
1 (2,9)
1 (3,3)
23 (7,4) 11 (3,5) 19 (6,1)
9 (5,4) 11 (6,7) 18 (10,9)
3 (3,75) 0 1 (1,25)
7 (20) 0 0
4 (13,3) 0 0
p ⱕ 0.0001, b p ⱕ 0.03, c p ⱕ 0.006, d p ⱕ 0.02.
NAC, 18 episodes (5.8%). Moulds caused only 1.3% of all fungaemias. Non-Candida yeast (NYC) were isolated in 18 episodes (5.8%): Trichosporon beigelii in seven episodes, Trichosporon pullulans in three episodes, Cryptococcus laurentii in four episodes, Sacharomyces cerevisiae in one episode, Blastoschizomyces capitatus in two episodes, Hansenula anomala in one episode, and Rhodotorula rubra in one episode. Moulds were responsible surprisingly for only four episodes (Fusarium solani)—1.3% (Table 1). 3.3. Differences in etiology among various groups of patients There were statistically significant differences in etiology of fungaemia various subgroups of patients (Table 2) non-albicans Candida spp. was significantly more frequent observed among subgroups of patients with pancreatitis and coma (53.3% vs. 31.3%, p ⱕ 0.02) and less frequently in the subgroup of neonates (15.0% vs. 31.3%, p ⱕ 0.006). Vice versa, C. albicans appeared more frequently in neonates (85%).
4. Discussion In 1990 –1992 The National Nosocomial Infection Surveillance System (NNISS) found fungi to be the fourth most common pathogen causing bloodstream infections (Beck Sague et al., 1993). C. albicans is the Candida species predominantly isolated from blood cultures (Pfaller et al., 1998, 1999; Sandven et al., 1998). In some institutions the proportion of non-albicans Candida isolates from blood
cultures actually is about 1:1 (Voss et al., 1996) or exceeded that of C. albicans (Abi-Said et al., 1997; Wenzel, 1995). Candida glabrata was the second most frequent Candida species to cause infections in the US and Norway (Pfaller et al., 1998; Sandven et al., 1998), whereas in Canada and South America this is true for Candida parapsilosis (Pfaller et al., 1998). Second commonest pathogen (after C. albicans) in our survey was C. parapsilosis followed by C. krusei and C. tropicalis. Several studies of fungaemia have been published within last the 10 years, however, most of these studies were hospital based (Abi-Said et al., 1997; Bow et al., 1997; Demitrovicova et al., 1997; Fraser et al., 1992; Harvey et al., 1987; Kim-Stamos et al., 1995; Wey et al., 1988; White et al., 1997) or had a multicentric focus on specific patient populations (Viscoli et al., 1999; Voss et al., 1996). The majority of isolates (55–76%) were C. albicans. Voss et al., in 1996 collected fungaemias over an 8-year period in different patient populations (ICU, cancer, surgery)—75% were C. albicans and only 25% NAC. In a study from surgical department (Abele-Horn et al., 1996)—50 of 72 cases were infected by C. albicans (70%). Rex et al., (1994) assessed 232 pathogenic bloodstream Candida isolates from a mixed patient populations in the United States. 129 (55%) were C. albicans. Nguyen Hong et al., (1995), in another study in the US, collected 446 cases from six centers, within 5 years. C. albicans was responsible for 51% and NAC for 44%. All types of patients were enrolled (Nguyen Hong et al., 1995). Different etiology was observed among cancer patients: Viscoli et al., (1999) collected 244 candidemia cases from 41 cancer centers throughout Europe for 3 years. C. albicans represented only 45%, but NAC 53%. In the study
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from a single cancer institution was published in 1997 by Abi Said et al.,, reported 491 fungemic episodes within 1988 –1992 from blood cultures from a single cancer institution (MD Anderson Cancer Institute Houston), and showed a similar proportion of C. albicans to NAC (Abi Said et al., 1997). However, Huttova et al. in 1998 collected 40 fungaemias in neonates from five pediatric clinics— 92.5% were attributable to C. albicans and only 7.5% attributable to C. parapsilosis. There were some nationally based surveillance studies of fungaemia that showed secular trends in the incidence of fungaemia in a longitudinal design—several from the US (Beck Sague et al., 1993; Pfaller et al., 1998, 1999), one from the Netherlands (Voss et al., 1996), and one from the Norway (Sandven et al., 1998). Studies from the US (Beck Sague et al., 1993; Pfaller et al., 1993) showed an increasing incidence of Candida spp., but the proportion of C. albicans and NAC was relatively stable in the second Dutch multicentric study, C. albicans represented 60% and NAC 40% and the proportion of C. albicans (CA) to NAC in 1992–1995 was relatively stable (Voss et al., 1996). The Norwegian study showed also stable proportion of CA to NAC in 1991 to 1996 (Sandven et al., 1998). Our survey showed different results—the proportion of CA and NAC within 10 years showed a sustaining decrease of CAin favor of NAC, which represented 0 –10% in 1989 –1991, but in 1998 increased to 46.3%. The increase of NAC in Slovakia may be explained by several factors. First, there is an increasing intensity of medical technology, including antineoplastic chemotherapy, organ transplantation etc. (For example, from 1989 until 1998, three new BMT units, three renal, and two heart transplant centers were opened in Bratislava, Slovakia). Second, an increasing number of intravascular devices were inserted. In 1989, six major university inserted 750 intravascular catheters. Correspondingly, in 1999, 13,500 central or peripherial venous catheters were inserted in those hospitals (Foltan, 1999). Third, according to the data from the State Institute of Drug Control, in Slovakia, consumption of antifungals increased remarkably within the last 10 years. In 1989, only 125 g of AmB was used, but in 1998 this increased to 1790g (all i.v., because oral AmB is not registered in Slovakia). Consumption of itraconazole increased from 0 g in 1989 –1993 to 455 g in 1996. Consumption of fluconazole in 1998 increased 20-fold in comparison with 1990. Selection pressure of antifungals (mainly azoles), may be the third reason for etiological changes within the investigated period (Foltan, 1999). This phenomenon has been observed by several researchers (Komshian et al., 1989; McCabe et al., 1996; McQuillen et al., 1992; Rex et al., 1995; Wingard et al., 1995), but not by other investigators (Ellis et al., 1994; Goodman et al., 1992; Kunova et al., 1995). Finally, NAC (mainly C. krusei and C. glabrata) were significantly less common in those groups of patients that were less frequently exposed to prophylaxis with azoles (such as neo-
nates), in comparison with cancer or ICU patients, who received fluconazole for prophylaxis or initial therapy more frequently (NAC proportion was 42.9% and 53.3% in comparison to 15% in neonates ( p ⬍ 0.006 and 0.02). Only a small proportion of moulds (Fusarim spp.) was detected over the study period, probably because the cultures were incubated only for 72 h. However, the proportion of moulds also in other published European studies (Viscoli et al., 1999; Voss et al., 1997) was lower than in the United States. However, there were several limitations of this prospective study, e.g., risk of underreporting of fungi attributable to short incubation time (C. glabrata), or absence of taking enough blood cultures in some small hospitals. Therefore, large prospective epidemiological studies on fungaemia are required to apply preventive and early therapeutic strategies. The fact that every fourth patient with fungaemia died, underscores the importance of both hospital—and country—wide-based surveillances of fungal bloodstream infections. In addition, early detection of changes in etiology and epidemiology helps to establish the optimal antifungal agents for initial therapy, because different species exert different in vitro and in vivo susceptibility against different antifungals. Acknowledgments Members of the Slovak Fungaemia study group: Kiskova´ Marcela (Trnava), Babel’a Ro´bert (Trnava), Kru´pova´ Iveta (Bratislava), Kunova´ Alena (Bratislava), Trupl Jan (Bratislava), Lisˇkova´ Anna (Nitra), Hanzen Juraj (Bratislava), Milosˇovicˇ Peter (Bratislava), Lamosˇova´ Marta (Pod. Biskupice), Huttova´ Ma´ria (Trnava), Purgelova´ Anna (B. Bystrica), Sˇtefikova´ Elena (Prievidza), Szo¨venyiova´ Zuzana (Kosˇice), Sejnova´ Da´sˇa (Bratislava), Filka Jozef (Kosˇice), Pisarcˇikova´ Ma´ria (Nitra), Belesˇova´ Viera (Ruzˇomberok), Pola´kova´ Viera (Vranov n/Topl’ov), Hajdukova´ Ma´ria (Cˇadca), Orsa´gh Maria´n (Ruzˇomberok), Macˇekova´ L’ubica (Trnava), Cso¨lleyova´ Eva (Dunajska´ Streda), Kralinsky´ Karol (B. Bystrica), Mocikova´ Katarı´na (B. Bystrica), Mardiak Jozef (Bratislava), Sˇufliarsky Jozef (Bratislava), Milovsky´ Vladimı´r (Trnava), Koller Ja´n (Bratislava), Glosova´ Libusˇe (Trencˇ´ın), Bagova´ Ma´ria (Bratislava), To´thova´ Elena (Kosˇice), Obertik Tanya (Bratislava), and West Dan (Scranton, USA). References Abele-Horn, M., Kopp, U., Sternberg, A., Ohly, A., Dauber, W., Russwurm, W., Bu¨chinger, O., & Nagengast, P. (1996). A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 6, 426 – 432. Abi-Said, D., Annaisie, E., Uzun, D., Raad, I., Pinczowski, H., & Vartivarian, S. (1997). The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 24, 1122–1128. Anaissie, E. J. & Bodey, G. P. (1991). Trichosporonosis—meeting the challenge Eur J Clin Microbiol Infect Dis 9, 711–720.
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tions due to Candida albicans: Frequency of occurrence and antifungal susceptibility in the SCOPE program. Diagn Microbiol Infect Dis 31, 327–332. Pfaller, M. A., Jones, R. N., Messer, S. A., Edmond, M. B., Wenzel, R. P., & the SCOPE Participant Group. (1998). National surveillance of nosocomial blood stream infections due to species of Candida other than Candida albicans: Frequency of occurrence and antifungal susceptibility in the SCOPE program. Diagn Microbiol Infect Dis 30, 121–129. Pfaller, M. A., Messer, S. A., Houston, A., Rangel-Frausto, M. S., Wiblin, T., Blumberg, H. M., Edwards, J. E., Jarvis, W., Martin, M. A., Neu, H. C., Saiman, L., Patterson, J. E., Dibb, J. C., Roldam, C. M., Rinaldi, M. G., & Wenzel, R. P. (1998). National epidemiology of mycoses survey: A multicenter study of strain variation and antifungal susceptibility among isolates of Candida species. Diagn Microbiol Infect Dis 31, 289 –296. Pfaller, M. A., Messer, S. A., Hollis, R. J., Jones, R. N., Doern, G. V., Brandt, M. E., & Hajjeh, R. A. (1999). Trends in species distribution and susceptibility to fluconazole among bloodstream isolates of Candida species in the United States. Diagn Microbiol Infect Dis 33, 217–222. Rex, J. H., Bennett, J. E., Sugar, A. M., Pappas, P. G., van der Horst, C. M., Edwards, J. E., Washburn, R. G., Scheld, W. M., Karchmer, A. W., Dine, A. P., Levenstein, M. J., & Webb, C. D., for the Candidemia Study Group. (1994). A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia. N Engl J Med 331, 1325–1330. Rex, J. H., Rinaldi, M. G., & Pfaller, M. A. (1995). Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 39, 1– 8. Sandven, P., Bevanger, L., Digranes, A., Gaustand, P., Haukland, H. H., Steinbaak, M., & the Norwegian Yeast Study Group. (1998). Constant low rate of fungaemia in Norway, 1991 to 1996. J Clin Microbiol 36, 3455–3459. Van’t Wout, J. W. (1996). Fluconazole in treatment of Candida infections caused by non-albicans species. Eur J Clin Microbiol Infect Dis 15, 362–363. Verweij, P. E., Donelly, J. P., Kullberg, B. J., Meis, J. F. G. M., & De Pauw, B. E. (1994). Amphotericin B versus amphotericin B plus 5-flucytosine: Poor results in the treatment of proven systemic mycoses in neutropenic patients. Infection 22, 81– 85. Viscoli, C., Girmenia, C., Marinus, A., Collette, L., Martino, F., vandercam, B., Doyen, C., Lebeau, B., Spence, D., Krcmery, V., De Pauw, B., Meunier, F., & the Invasive Fungal Infection Group of the EORTC. (1999). Candidemia in cancer patients: A prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 28, 1071–1079. Voss, A., Kluytmans, J. A. J. W., Koeleman, J. G. M., Spanjaard, L., Vandenbroucke-Grauls, C. M. J. E., Verbrugh, H. A., Vos, M. C., Weersink, A. Y. L., Hoogkamp-Korstajne, J. A. A., & Meis, J, F, G. M. (1996). Occurrence of yeasts bloodstream infections between 1987 and 1995 in five Dutch university hospitals. Eur J Clin Microbiol Infect Dis 15, 909 –912. Voss, A., Le Noble, J. L. M. L., Verduyn Lunel, F. M., Foudraine, N., & Meis, J. F. G. M. (1997). Candidemia in intensive care unit patients: Risk factors for mortality. Infection 25, 8 –11. Walsh, T. & Pizzo, P. (1996). Fungaemia in HIV-positive children. Clin Infect Dis 20, 732–740. Wenzel, R. P. (1995). Nosocomial candidemia: Risk factors and attributable mortality. Clin Infect Dis 20, 1531–1534. Wey, S. B., Mori, M., Pfaller, M. A., Woolson, R. F., & Wenzel, R. P. (1988). Hospital-acquired candidemia. The attributable mortality and excess length of stay. Arch Intern Med 148, 2642–2645. White, M. (1997). Epidemiology of invasive candidiasis. Int J Infect Dis 51, 7–10. Wingard, J. R. (1995). Importance of Candida species other than C. albicans. Antimicrob Agents Chemother 12, 133–139.
Mycology
Longitudinal 10-year prospective survey of fungaemia in Slovak Republic: trends in etiology in 310 episodes夞 Vladimı´r Krcˇme´ry, Jr.*, Gabriela Kovacˇicˇova´ on behalf of the Slovak Fungaemia study group Department of Medicine University of Trnava, Hornopotocna 23, 917 00 Trnava, Slovak Republic Received 28 April 1999; revised and accepted 31 August 1999 Partially presented as Abstr. 355 at 36-IDSA Annual Meeting, Denver 9.–12.11. 1998
Abstract A 10-year prospective survey of fungaemia in the Slovak Republic, involving 31 microbiology laboratories and 71 hospitals, was conducted from 1989 –1998 (10 years): 310 fungaemias were analyzed for etiology, clinical characteristics, therapy, and outcome. C. albicans was responsible for 191 (61.6%) fungaemias, non-albicans Candida spp. (NAC) for 97 (31.3%), non-Candida yeasts for 18 (5.8%) and moulds (Fusarium spp.) for four fungaemias. The most frequent NAC isolated from blood cultures were C. parapsilosis—30 (9.7%), C. krusei—18 (5.8%), C. tropicalis—14 (4.5%), and C. glabrata—10 (3.2%). Secular trends in etiology showed a sustaining decrease of C. albicans (from 100% in 1989 to 50.7% in 1998) and increase of NAC (from 0% in 1989 –1990 to 46.3% in 1998). Non-Candida yeasts and moulds showed a stable proportion during the investigated period. There were statistically significant differences in etiology of fungaemia various subgroups of patients: non-albicans Candida spp. was significantly more frequent observed among subgroups of patients with pancreatitis and coma (53.3% vs. 31.3%, p ⱕ 0.02) and less frequently in the subgroup of neonates (15.0% vs. 31.3%, p ⱕ 0.006). Vice versa, C. albicans appeared more frequently in neonates (85%). © 2000 Elsevier Science Inc. All rights reserved.
1. Introduction Several large hospital-based epidemiologic surveillances of fungaemia were conducted in the last 5 years; however, only few were national in scope (Beck Sague et al., 1993; Pfaller et al., 1998, 1999; Voss et al., 1996) or international (Viscoli et al., 1999). The study performed in the Netherlands for a 9-year period, involving five university hospitals, was published by Voss et al. in 1996 and involved 670 cases. At least two large studies were conducted in the United States in 1990 and 1998. In addition to these nationwide studies, several hospital or patient-type (cancer, HIV, neonates) studies (Fraser et al., 1992; Goldman et al., 1993; Harvey et al., 1987; Horn et al., 1985; Knaus et al., 1985; Komshian et al., 1989; Kunova et al., 1995; Rex et al., 1994, 1995; Wey et al., 1988) with 60 –500 cases have been reported in the literature. The largest two reported studies on fungaemias in cancer patients were conducted by the Euro夞 Supported by Grant PL 970002–1/5097–1/6098 of the Ministry of Education and European Committees (1998 –1999). * Corresponding author. Tel.: ⫹412-7-5292-4308.
pean Organization for Research and Treatment of Cancer (EORTC), which reported more than 240 fungaemias (Viscoli et al., 1999), and a second even larger study was published by Abi-Said et al. on 491 fungaemias from a single cancer institution (Abi-Said et al., 1997). Several other smaller studies on cancer patients (Bow et al., 1995; Guiot et al., 1994; Karabinis et al., 1988; Lecciones et al., 1992) summarized risk factors, but not longitudinal trends on epidemiology and etiology of fungaemia in cancer patients. The current study reports longitudinal results of the etiology of fungaemia in a 10-year national surveillance of fungaemia, based on 310 cases from 71 hospitals in the Slovak Republic, from a non-HIV patient population. 2. Materials and methods 2.1. Study design A national prospective longitudinal 10-year surveillance of fungaemia was conducted in Slovakia using 31 departments of clinical microbiology that serve 71 hospitals with approximately 8,900 beds for 5.5 million citizens. All lab-
0732-8893/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 5 - 8 8 9 3 ( 9 9 ) 0 0 0 9 6 - 6
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Table 1 Occurrence and etiology of fungaemia between 1989 –1998 in the Slovak Republic Total no. of episodes
C. albicans C. parapsilosis C. krusei C. tropicalis C. glabrata C. guillermondii C. lusitaniae Other NSC* Non-albicans Candida Total Trichosporon beigeli Trichosporon pullans Cryptococcus laurentii Blastoschizomyces capitatus Hansenula anomala Rhodotorula rubra Non-Candida yeast Total Moulds (Fusarium spp.) TOTAL
No. of fungaemic episodes in particular years (%)
No. of infected patients (%)
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
3 (100) 0 0 0 0 0 0 0 0
6 (100) 0 0 0 0 0 0 0 0
8 (80.0) 1 0 0 0 0 0 0 1 (1.0)
18 (78.3) 1 1 1 1 0 0 0 4 (17.4)
18 (66.7) 2 2 2 1 0 0 0 7 (25.9)
17 (60.7) 2 2 2 1 0 0 0 7 (25.0)
19 (63.3) 2 2 2 1 1 0 0 8 (26.6)
26 (55.3) 3 2 1 2 2 1 4 15 (31.9)
42 (60.9) 11 6 2 2 0 1 2 24 (34.8)
34 (50.7) 8 3 4 2 1 1 12 31 (46.3)
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 1
0 0 1 0
1 1 0 0
1 0 1 0
1 2 1 1
3 0 0 0
1 0 1 0
0 0 0
0 0 0
0 0 0
0 0 1 (4.3)
0 1 2 (7.4)
1 0 3 (10.8)
0 0 2 (6.7)
0 0 5 (10.6)
0 0 3 (4.3)
0 0 2 (3.0)
1 1 18 (5.8)
0
0
1 (10.0)
0
0
1 (3.5)
1 (3.3)
1 (2.1)
0
0
4 (1.3)
3
6
10
23
27
28
30
47
69
67
310
oratories were supplied with a protocol that was identical to a protocol used in 1989 –1995 for a fungaemia survey performed in Cancer Hospitals. Of the 31 microbiology departments serving 71 hospitals, 19 (26.8%) reported at least one blood culture positive for fungi within the last 10 years. Since 1988, an universal methodology for routine blood culturing system has been recommended in Slovakia: three bottles (aerobic, anaerobic, fungal) with blood from each patient (Bactec BBL Sparks MD, USA or Bact-Alert Organon Teknika Heidelberg, Germany) were incubated. After 24, 48, and 72 h the blood was inoculated to Blood agar, MacConkey and Sabouraud agar plates that were assessed after 24, 48, and 72 h: species were determined with Mycotube (Roche Basel) or Vitek Jr. identification systems (Bio Merieux, Hazelwood, Mo. USA). From the 314 reviewed protocols, 310 met the inclusion criteria, that is, a definition of a single fungaemic episode or several positive blood cultures (BC) for fungi and a fever ⬎38°C within 48 h from the first positive blood culture. Of 310 patients, 165 had cancer, 80 neonates, 35 surgery and trauma, and 30 had coma and pancreatitis as underlying disease. If the patient had multiple BC within 1 month, this was still considered to be one fungaemic episode (one case). Etiology, risk factors, therapy, and outcome were recorded for each patient (case). Antifungal susceptibility was tested in only 91 reported episodes (about one third), because methods of antifungal susceptibility testing in Slovakia were only approved by the Ministry of Health in 1997; therefore, results of antifungal susceptibility will be reported sepa-
191 (61.6) 30 (9.7) 18 (5.6) 14 (4.1) 10 (3.2) 4 (1.9) 3 (0.9) 18 (5.8) 97 (31.3) 7 3 4 2
rately. Differences in species among subgroups of 310 patients were assessed with 2 test (EPI INFO-20 ID computerized package).
3. Results 3.1. Secular trends in occurrence of fungaemia Candida albicans showed decreasing tendency during the period (1989 –1998) (Table 1). In 1989 –1990 100% of all strains were Candida albicans, in 1991 80%, in 1992 78.3%, but only 50.7% in 1998. Non-albicans Candida (NAC) represented an increase from 0% in 1991 to 46.3% in 1998 (Table 1), as indicated in Figure 1. Concerning nonCandida yeasts (NCY), there was a stable tendency of occurrence during the 10-year period. The lowest percentage is evident in 1998 —1.5%, and the highest percentage of isolated non-Candida yeasts was in 1994 —10.8% and in 1996 —10.6% (Table 1). Moulds were only isolated exceptionally (four cases). 3.2. Etiology of fungaemia C. albicans represented 61.6% of all 310 fungaemias. In 1989 –1998 the second most frequent organism was C. parapsilosis, 30 episodes (9.9%); C. krusei, 18 episodes (5.8%); C. tropicalis, 14 (4.1%); C. glabrata, 10 (3.2%); C. guillermondii, 4 (1.2%); C. lusitaniae, 0.9%; and other
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Table 2 Etiology in various subgroups of patients
Posit. BC per episode Two and more posit. BC Catheter related C. albicans non-albicans Candida spp. C. tropicalis C. parapsilosis C. krusei C. glabrata Other Candida spp. Non-Candida yeasts Molds Antifungal prophylaxis (breakthrough) -during prophylaxis/therapy with KET FLU ITR AmB a
Total n ⫽ 310
Cancer n ⫽ 165
Neonates n ⫽ 80
Noncancer surgery ⫹ trauma n ⫽ 35
Coma pancreatitis n ⫽ 30
1,85 81 (26,1) 23 (7,4) 191 (61,6) 97 (31,3) 14 (4,5) 30 (9,7) 18 (5,8) 10 (3,2) 25 (8,1) 18 (5,7) 4 (1,3) 69 (22,2)
1,75 30 (18,2) 19 (11,5) 89 (53,9) 55 (33,3) 10 (6,7) 17 (10,9) 13 (7,8) 6 (3,6) 9 (4,2) 16 (9,7) 4 (3,0) 5 (33,3)
1,8 16 (20) 1 (1,25) 68 (85) 12 (15)c 0 5 (6,25) 0 0 7 (9,25) 0 0 11 (13,8)
2,4 21 (60)a 2 (5,8) 20 (54,2) 15 (42,9) 3 (8,7) 3 (8,7) 3 (8,7) 1 (2,9) 6 (17,1) 1 (2,9) 0 8 (22,9)
2,1 14 (47,7)b 1 (3,3) 14 (43,3) 16 (53,3)d 1 (3,3) 5 (16,7) 2 (6,6) 3 (10) 45 (13,2) 1 (3,3) 0 5 (16,7)
26 (8,4)
17 (10,3)
7 (9,25)
1 (2,9)
1 (3,3)
23 (7,4) 11 (3,5) 19 (6,1)
9 (5,4) 11 (6,7) 18 (10,9)
3 (3,75) 0 1 (1,25)
7 (20) 0 0
4 (13,3) 0 0
p ⱕ 0.0001, b p ⱕ 0.03, c p ⱕ 0.006, d p ⱕ 0.02.
NAC, 18 episodes (5.8%). Moulds caused only 1.3% of all fungaemias. Non-Candida yeast (NYC) were isolated in 18 episodes (5.8%): Trichosporon beigelii in seven episodes, Trichosporon pullulans in three episodes, Cryptococcus laurentii in four episodes, Sacharomyces cerevisiae in one episode, Blastoschizomyces capitatus in two episodes, Hansenula anomala in one episode, and Rhodotorula rubra in one episode. Moulds were responsible surprisingly for only four episodes (Fusarium solani)—1.3% (Table 1). 3.3. Differences in etiology among various groups of patients There were statistically significant differences in etiology of fungaemia various subgroups of patients (Table 2) non-albicans Candida spp. was significantly more frequent observed among subgroups of patients with pancreatitis and coma (53.3% vs. 31.3%, p ⱕ 0.02) and less frequently in the subgroup of neonates (15.0% vs. 31.3%, p ⱕ 0.006). Vice versa, C. albicans appeared more frequently in neonates (85%).
4. Discussion In 1990 –1992 The National Nosocomial Infection Surveillance System (NNISS) found fungi to be the fourth most common pathogen causing bloodstream infections (Beck Sague et al., 1993). C. albicans is the Candida species predominantly isolated from blood cultures (Pfaller et al., 1998, 1999; Sandven et al., 1998). In some institutions the proportion of non-albicans Candida isolates from blood
cultures actually is about 1:1 (Voss et al., 1996) or exceeded that of C. albicans (Abi-Said et al., 1997; Wenzel, 1995). Candida glabrata was the second most frequent Candida species to cause infections in the US and Norway (Pfaller et al., 1998; Sandven et al., 1998), whereas in Canada and South America this is true for Candida parapsilosis (Pfaller et al., 1998). Second commonest pathogen (after C. albicans) in our survey was C. parapsilosis followed by C. krusei and C. tropicalis. Several studies of fungaemia have been published within last the 10 years, however, most of these studies were hospital based (Abi-Said et al., 1997; Bow et al., 1997; Demitrovicova et al., 1997; Fraser et al., 1992; Harvey et al., 1987; Kim-Stamos et al., 1995; Wey et al., 1988; White et al., 1997) or had a multicentric focus on specific patient populations (Viscoli et al., 1999; Voss et al., 1996). The majority of isolates (55–76%) were C. albicans. Voss et al., in 1996 collected fungaemias over an 8-year period in different patient populations (ICU, cancer, surgery)—75% were C. albicans and only 25% NAC. In a study from surgical department (Abele-Horn et al., 1996)—50 of 72 cases were infected by C. albicans (70%). Rex et al., (1994) assessed 232 pathogenic bloodstream Candida isolates from a mixed patient populations in the United States. 129 (55%) were C. albicans. Nguyen Hong et al., (1995), in another study in the US, collected 446 cases from six centers, within 5 years. C. albicans was responsible for 51% and NAC for 44%. All types of patients were enrolled (Nguyen Hong et al., 1995). Different etiology was observed among cancer patients: Viscoli et al., (1999) collected 244 candidemia cases from 41 cancer centers throughout Europe for 3 years. C. albicans represented only 45%, but NAC 53%. In the study
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from a single cancer institution was published in 1997 by Abi Said et al.,, reported 491 fungemic episodes within 1988 –1992 from blood cultures from a single cancer institution (MD Anderson Cancer Institute Houston), and showed a similar proportion of C. albicans to NAC (Abi Said et al., 1997). However, Huttova et al. in 1998 collected 40 fungaemias in neonates from five pediatric clinics— 92.5% were attributable to C. albicans and only 7.5% attributable to C. parapsilosis. There were some nationally based surveillance studies of fungaemia that showed secular trends in the incidence of fungaemia in a longitudinal design—several from the US (Beck Sague et al., 1993; Pfaller et al., 1998, 1999), one from the Netherlands (Voss et al., 1996), and one from the Norway (Sandven et al., 1998). Studies from the US (Beck Sague et al., 1993; Pfaller et al., 1993) showed an increasing incidence of Candida spp., but the proportion of C. albicans and NAC was relatively stable in the second Dutch multicentric study, C. albicans represented 60% and NAC 40% and the proportion of C. albicans (CA) to NAC in 1992–1995 was relatively stable (Voss et al., 1996). The Norwegian study showed also stable proportion of CA to NAC in 1991 to 1996 (Sandven et al., 1998). Our survey showed different results—the proportion of CA and NAC within 10 years showed a sustaining decrease of CAin favor of NAC, which represented 0 –10% in 1989 –1991, but in 1998 increased to 46.3%. The increase of NAC in Slovakia may be explained by several factors. First, there is an increasing intensity of medical technology, including antineoplastic chemotherapy, organ transplantation etc. (For example, from 1989 until 1998, three new BMT units, three renal, and two heart transplant centers were opened in Bratislava, Slovakia). Second, an increasing number of intravascular devices were inserted. In 1989, six major university inserted 750 intravascular catheters. Correspondingly, in 1999, 13,500 central or peripherial venous catheters were inserted in those hospitals (Foltan, 1999). Third, according to the data from the State Institute of Drug Control, in Slovakia, consumption of antifungals increased remarkably within the last 10 years. In 1989, only 125 g of AmB was used, but in 1998 this increased to 1790g (all i.v., because oral AmB is not registered in Slovakia). Consumption of itraconazole increased from 0 g in 1989 –1993 to 455 g in 1996. Consumption of fluconazole in 1998 increased 20-fold in comparison with 1990. Selection pressure of antifungals (mainly azoles), may be the third reason for etiological changes within the investigated period (Foltan, 1999). This phenomenon has been observed by several researchers (Komshian et al., 1989; McCabe et al., 1996; McQuillen et al., 1992; Rex et al., 1995; Wingard et al., 1995), but not by other investigators (Ellis et al., 1994; Goodman et al., 1992; Kunova et al., 1995). Finally, NAC (mainly C. krusei and C. glabrata) were significantly less common in those groups of patients that were less frequently exposed to prophylaxis with azoles (such as neo-
nates), in comparison with cancer or ICU patients, who received fluconazole for prophylaxis or initial therapy more frequently (NAC proportion was 42.9% and 53.3% in comparison to 15% in neonates ( p ⬍ 0.006 and 0.02). Only a small proportion of moulds (Fusarim spp.) was detected over the study period, probably because the cultures were incubated only for 72 h. However, the proportion of moulds also in other published European studies (Viscoli et al., 1999; Voss et al., 1997) was lower than in the United States. However, there were several limitations of this prospective study, e.g., risk of underreporting of fungi attributable to short incubation time (C. glabrata), or absence of taking enough blood cultures in some small hospitals. Therefore, large prospective epidemiological studies on fungaemia are required to apply preventive and early therapeutic strategies. The fact that every fourth patient with fungaemia died, underscores the importance of both hospital—and country—wide-based surveillances of fungal bloodstream infections. In addition, early detection of changes in etiology and epidemiology helps to establish the optimal antifungal agents for initial therapy, because different species exert different in vitro and in vivo susceptibility against different antifungals. Acknowledgments Members of the Slovak Fungaemia study group: Kiskova´ Marcela (Trnava), Babel’a Ro´bert (Trnava), Kru´pova´ Iveta (Bratislava), Kunova´ Alena (Bratislava), Trupl Jan (Bratislava), Lisˇkova´ Anna (Nitra), Hanzen Juraj (Bratislava), Milosˇovicˇ Peter (Bratislava), Lamosˇova´ Marta (Pod. Biskupice), Huttova´ Ma´ria (Trnava), Purgelova´ Anna (B. Bystrica), Sˇtefikova´ Elena (Prievidza), Szo¨venyiova´ Zuzana (Kosˇice), Sejnova´ Da´sˇa (Bratislava), Filka Jozef (Kosˇice), Pisarcˇikova´ Ma´ria (Nitra), Belesˇova´ Viera (Ruzˇomberok), Pola´kova´ Viera (Vranov n/Topl’ov), Hajdukova´ Ma´ria (Cˇadca), Orsa´gh Maria´n (Ruzˇomberok), Macˇekova´ L’ubica (Trnava), Cso¨lleyova´ Eva (Dunajska´ Streda), Kralinsky´ Karol (B. Bystrica), Mocikova´ Katarı´na (B. Bystrica), Mardiak Jozef (Bratislava), Sˇufliarsky Jozef (Bratislava), Milovsky´ Vladimı´r (Trnava), Koller Ja´n (Bratislava), Glosova´ Libusˇe (Trencˇ´ın), Bagova´ Ma´ria (Bratislava), To´thova´ Elena (Kosˇice), Obertik Tanya (Bratislava), and West Dan (Scranton, USA). References Abele-Horn, M., Kopp, U., Sternberg, A., Ohly, A., Dauber, W., Russwurm, W., Bu¨chinger, O., & Nagengast, P. (1996). A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 6, 426 – 432. Abi-Said, D., Annaisie, E., Uzun, D., Raad, I., Pinczowski, H., & Vartivarian, S. (1997). The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 24, 1122–1128. Anaissie, E. J. & Bodey, G. P. (1991). Trichosporonosis—meeting the challenge Eur J Clin Microbiol Infect Dis 9, 711–720.
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