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Journal of Clinical Microbiology logoLink to Journal of Clinical Microbiology
. 2001 Sep;39(9):3254–3259. doi: 10.1128/JCM.39.9.3254-3259.2001

International Surveillance of Bloodstream Infections Due to Candida Species: Frequency of Occurrence and In Vitro Susceptibilities to Fluconazole, Ravuconazole, and Voriconazole of Isolates Collected from 1997 through 1999 in the SENTRY Antimicrobial Surveillance Program

M A Pfaller 1,*, D J Diekema 1,2, R N Jones 1,, H S Sader 3, A C Fluit 4, R J Hollis 1, S A Messer 1; The SENTRY Participant Group
PMCID: PMC88327  PMID: 11526159

Abstract

A surveillance program (SENTRY) of bloodstream infections (BSI) in the United States, Canada, Latin America, and Europe from 1997 through 1999 detected 1,184 episodes of candidemia in 71 medical centers (32 in the United States, 23 in Europe, 9 in Latin America, and 7 in Canada). Overall, 55% of the yeast BSIs were due to Candida albicans, followed by Candida glabrata and Candida parapsilosis (15%), Candida tropicalis (9%), and miscellaneous Candida spp. (6%). In the United States, 45% of candidemias were due to non-C. albicans species. C. glabrata (21%) was the most common non-C. albicans species in the United States, and the proportion of non-C. albicans BSIs was highest in Latin America (55%). C. albicans accounted for 60% of BSI in Canada and 58% in Europe. C. parapsilosis was the most common non-C. albicans species in Latin America (25%), Canada (16%), and Europe (17%). Isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to fluconazole (97 to 100% at ≤8 μg/ml). Likewise, 97 to 100% of these species were inhibited by ≤1 μg/ml of ravuconazole (concentration at which 50% were inhibited [MIC50], 0.007 to 0.03 μg/ml) or voriconazole (MIC50, 0.007 to 0.06 μg/ml). Both ravuconazole and voriconazole were significantly more active than fluconazole against C. glabrata (MIC90s of 0.5 to 1.0 μg/ml versus 16 to 32 μg/ml, respectively). A trend of increased susceptibility of C. glabrata to fluconazole was noted over the three-year period. The percentage of C. glabrata isolates susceptible to fluconazole increased from 48% in 1997 to 84% in 1999, and MIC50s decreased from 16 to 4 μg/ml. A similar trend was documented in both the Americas (57 to 84% susceptible) and Europe (22 to 80% susceptible). Some geographic differences in susceptibility to triazole were observed with Canadian isolates generally more susceptible than isolates from the United States and Europe. These observations suggest susceptibility patterns and trends among yeast isolates from BSI and raise additional questions that can be answered only by continued surveillance and clinical investigations of the type reported here (SENTRY Program).


It is now well accepted that antimicrobial resistance is an important concern with respect to virtually all major groups of pathogenic microorganisms, including viruses, bacteria, parasites, and fungi. Numerous approaches to control this ever-increasing problem have been suggested (2, 10, 27, 30). One critical component in every suggested mode of intervention is the need for continued monitoring or surveillance of resistance on a global scale. Surveillance of antibacterial resistance is now being conducted by several different groups with the common goal of providing accurate data for use in the development of empiric treatment recommendations, for the development of guidelines and policies for appropriate antimicrobial utilization, for assessing the progress and effectiveness of various intervention efforts, and for tailoring or improving antimicrobial susceptibility testing (AST) methods and resistance screening (2, 10, 13).

Although innate or acquired resistance to available antifungal agents is now recognized among pathogenic fungi, particularly the Candida species, the true extent of the resistance problem among fungi causing hematogenously disseminated or bloodstream infections (BSI) is largely unknown. Among the several active antimicrobial resistance surveillance programs now in existence, the SENTRY Antimicrobial Surveillance Program is the only system that monitors BSI due to Candida spp. as well as bacterial species (5, 6, 13, 22). The SENTRY Program is comprehensive, longitudinal, and global in scope and utilizes a central laboratory concept to monitor trends in microbial spectra and resistance in 74 sentinel sites in 22 nations.

Since 1997, one of the important objectives of the SENTRY Program has been the study of the frequency of occurrence and antifungal resistance among species of Candida causing BSI in the United States, Canada, Latin America, and Europe (5, 16, 21, 22). The rank order of occurrence and resistance profiles of the various species of Candida causing BSI is important in establishing empiric treatment protocols and in judging the potential impact of newer antifungal agents. Using this approach, a number of important and unusual resistance phenotypes have been detected over the three-year period from 1997 to 1999 (5, 16, 21, 22). Examples that will be discussed herein include Candida glabrata isolates resistant to amphotericin B, Candida krusei isolates resistant to amphotericin B, fluconazole, and 5-fluorocytosine (5FC), cross-resistance to established and investigational triazoles, and decreased resistance to fluconazole among C. glabrata isolates and to itraconazole among Candida tropicalis isolates. Species differences occurring among different geographic regions have also been noted.

MATERIALS AND METHODS

Study design.

The SENTRY Program was established in 1997 to monitor the predominant pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections via a broad network of sentinel hospitals categorized by geographic location and size (5, 16, 21, 22). The present report focuses on BSI due to Candida spp. from U.S., Canadian, Latin American, and European sites. BSI due to Candida spp. were reported from 32 monitored medical centers in the United States, 23 in Europe, 9 in Latin America, and 7 in Canada over the three-year period from January 1997 through December 1999.

Each participant hospital contributed results (organism identification, date of isolation, and hospital location) for consecutive blood culture isolates (one isolate per patient) of Candida spp. judged to be clinically significant by local criteria, detected in each calendar month during the study period. All isolates were stored on agar slants and sent on a regular basis to the University of Iowa College of Medicine (Iowa City) for storage and further characterization by reference identification and susceptibility testing (14, 29).

Organism identification.

All fungal blood culture isolates were identified at the participating institutions by the routine method in use at each laboratory. Upon receipt at the University of Iowa, the isolates were subcultured onto potato dextrose agar (Remel, Lenexa, Kans.) and CHROMagar Candida medium (Hardy Laboratories, Santa Maria, Calif.) to ensure viability and purity. Confirmation of species identification was performed with Vitek and API products (bioMerieux, St. Louis, Mo.) as recommended by the manufacturer or by conventional methods as required (29). Isolates were stored as suspensions in water or on agar slants at an ambient temperature until needed.

Susceptibility testing.

Antifungal susceptibility testing of isolates of Candida spp. was performed by the reference broth microdilution method described by the NCCLS (14). Susceptibility of isolates to amphotericin B was determined using Etest (AB BIODISK, Sonia, Sweden) and RPMI 1640 agar with 2% glucose (Remel, Lenexa, Kans.) as described previously (17). Standard powders of fluconazole (Pfizer, Inc., New York, N.Y.), voriconazole (Pfizer), ravuconazole (Bristol-Myers Squibb, Wallingford, Conn.), itraconazole (Janssen, Beerse, Belgium), and 5-fluorocytosine (5FC; Sigma, St. Louis, Mo.) were obtained from their respective manufacturers. Following incubation at 35°C for 48 h, the MICs of fluconazole, voriconazole, ravuconazole, itraconazole, and 5FC were read as the lowest concentration at which a prominent decrease in turbidity relative to the growth control well was observed (14). Amphotericin B MICs determined by Etest were read after 48 h of incubation at 35°C and were determined to be at 100% inhibition of growth where the border of the elliptical inhibition zone intercepted the scale on the strip edge (17). Quality control (QC) was ensured by testing the NCCLS (14)-recommended strains, Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019.

Interpretive criteria for susceptibility to fluconazole (susceptibility breakpoint, MIC of ≤8 μg/ml), itraconazole (susceptible, MIC of ≤0.12 μg/ml), and 5FC (susceptible, MIC of ≤4 μg/ml) were those published by Rex et al. (23) and the NCCLS (14). These breakpoints apply to all Candida spp. (including C. glabrata) with the exception of C. krusei, which is considered inherently resistant to fluconazole regardless of the MIC obtained (14). Interpretive criteria have not yet been defined for amphotericin B; however, because the study of Nguyen et al. (15) suggested that amphotericin B MICs of >1 μg/ml may indicate clinically resistant isolates of Candida spp., we determined the percentage of isolates inhibited by ≤1 μg/ml to be susceptible in this surveillance study. Likewise, the investigational triazoles, voriconazole and ravuconazole, have not been assigned interpretive breakpoints. For purposes of comparison and because preliminary pharmacokinetic data indicate that achievable serum levels for these agents may range from 2 to 6 μg/ml depending on the dosing regimen (26), we have employed a susceptibility breakpoint of ≤1 μg/ml for both voriconazole and ravuconazole.

Statistical analysis.

Comparison of species distribution and/or MIC distribution by other factors (e.g., year, geographic region) were made using the chi-square test with Yates' correction for categorical variables and the Wilcoxon rank sum test for ordinal variables (MICs). All reported P values are two-tailed.

RESULTS AND DISCUSSION

During the 36-month study period, a total of 1,184 BSI isolates (episodes) of Candida spp. were submitted by 71 study centers in the United States (32 centers, 589 isolates), Canada (7 centers, 161 isolates), Latin America (9 centers, 132 isolates), and Europe (23 centers, 302 isolates). These isolates accounted for 3% of all BSI isolates (bacterial and fungal) from nosocomial and community-acquired infections and 9% of nosocomial BSI (bacterial and fungal) isolates submitted by SENTRY participants from 1997 to 1999. Candida spp. was the fourth-most-common nosocomial BSI isolate category, preceded only by Staphylococcus aureus, coagulase-negative staphylococci, and enterococci (data not shown). The original identification assigned by the participating center was confirmed for 97% of the isolates submitted. Among the 1,184 BSI, 75% were nosocomial (detected more than 48 h after admission to a hospital), and 50% occurred in patients hospitalized in an intensive care unit (ICU).

The frequencies of BSI due to the various species of Candida in each country over the three-year period are presented in Table 1. Of the 1,184 yeast BSI whose organisms were identified, 55% were due to C. albicans, 15% were due to C. glabrata, 15% were due to C. parapsilosis, 9% were due to C. tropicalis, and 6% were due to miscellaneous Candida spp. The rank order of the various species differed according to geographic location. C. albicans was the predominant species in all four geographic areas, accounting for 45 to 60% of all BSI. C. glabrata was the second-most-common species in the United States (21% of BSI; P ≤ 0.01 compared to prevalence in other geographic areas) but ranked either third or fourth in the other areas. In contrast to the case in the United States, C. glabrata was very uncommon in Latin America (6% of all isolates; P ≤ 0.001 compared to U.S. results). C. parapsilosis was the second-most-common Candida species, causing BSI in Latin America (25%; P ≤ 0.001 compared to U.S. results), Canada (16%), and Europe (19%; P ≤ 0.001 compared to U.S. results). C. krusei was encountered infrequently (1 to 2%) in all geographic areas.

TABLE 1.

Species distribution of Candida bloodstream isolates: SENTRY Program, 1997 to 1999

Species % Isolates by geographic areaa
U.S. (n = 589) Canada (n = 161) Latin America (n = 132) Europe (n = 302)
C. albicans 55 60 45 58
C. glabrata 21b 12 6 10
C. parapsilosis 11 16 25c 19c
C. tropicalis 9 6 16d 7
C. krusei 2 2 1 1
Candida spp. 2 4 7 5
a

n, no. tested. U.S., United States. 

b

P ≤ 0.01 compared to prevalence in other geographic areas. 

c

P ≤ 0.001 compared to prevalence in the United States. 

d

P ≤ 0.03 compared to prevalence in other geographic areas. 

The rank order of species in all four geographic areas was relatively stable over the three-year period. However, the overall rank order may not represent the situation in individual medical centers. The percentages of candidemias due to C. albicans varied considerably among the individual participating study sites (Table 2). C. albicans was clearly the predominating species in certain medical centers, accounting for ≥70% of candidemias in Turkey-3 (73%), France-3 (73%), Italy-2 (88%), Switzerland (80%), Turkey-2 (74%), New Mexico (82%), New York-3 (70%), Texas-2 (83%), Nova Scotia (71%), and Ontario (85%) (a numerical suffix indicates a particular site within a state or country). In contrast, C. albicans accounted for ≤40% of BSI in Germany-1 (21%), Spain-2 (29%), Massachusetts (38%), New York-2 (37%), North Carolina (35%), and Brazil-1 (24%).

TABLE 2.

Geographic location and percent of Candida bloodstream infections attributable to C. albicans (SENTRY Program, 1997 to 1999)

Locationa No. of isolates % C. albicans
Europe
 Turkey-1 11 73
 Turkey-2 23 74
 France-1 11 55
 France-3 11 73
 Germany-1 19 21
 Italy-1 35 66
 Italy-2 17 88
 Portugal 39 46
 Spain-1 21 67
 Spain-2 14 29
 Switzerland 15 80
United States
 Indiana 31 48
 Arizona 13 62
 New Mexico 22 82
 Chicago 58 52
 Iowa 24 58
 Massachusetts 29 38
 New York-1 29 41
 New York-2 38 37
 New York-3 44 70
 California-1 17 53
 California-2 25 56
 Washington 17 47
 Missouri 64 52
 Texas-1 16 50
 Texas-2 12 83
 Texas-3 12 58
 Kentucky 17 59
 North Carolina 17 35
 Virginia 44 68
 Utah 12 58
Canada
 Alberta 26 54
 Manitoba 37 62
 Nova Scotia 34 71
 Ontario 13 85
 Quebec 35 51
Latin America
 Argentina 14 43
 Brazil-1 29 24
 Brazil-2 24 50
 Brazil-3 35 54
 Chile 14 64
a

Only those sites with ≥10 BSI isolates are shown. Where results were available for more than one site within a state or country, the numerical suffix indicates the individual site. 

These data demonstrate that although C. albicans may continue to play a dominant role as a cause of fungemia in many centers, it has been supplanted by C. glabrata in certain U.S. centers and by C. parapsilosis or C. tropicalis in some European and Latin American centers. The reasons for such dramatic differences in Candida species causing BSI remains speculative, although the emergence of C. glabrata in certain centers has been linked to utilization of fluconazole prophylaxis (1, 3), and infections attributable to C. parapsilosis are often associated with hyperalimentation and breaches of catheter care and of infection control practice (12, 18, 19, 22).

In vitro susceptibility results for the 1,184 isolates tested with fluconazole, ravuconazole, and voriconazole are shown in Table 3. Fluconazole was active in all regions, with 90 to 98% of isolates susceptible (S) to a drug concentration of ≤8 μg/ml. Isolates from Canada (concentration at which 90% of the isolates are inhibited [MIC90], 4 μg/ml; 96% S) and Latin America (MIC90, 4 μg/ml; 98% S) were more susceptible than those from the United States (MIC90, 16; 90% S) and Europe (MIC90, 8 μg/m; 90% S) due to the presence of resistance (MIC, ≥64 μg/ml) among C. glabrata isolates in the latter two regions. Both ravuconazole (MIC90, 0.12 to 0.5 μg/m; 98 to 99% S) and voriconazole (MIC90, 0.12 to 0.25 μg/ml; 98 to 99% S) were considerably more potent than fluconazole against isolates from all four geographic areas.

TABLE 3.

Activities of fluconazole and investigational antifungal agents against 1,184 BSI isolates of Candida spp. from four geographic regions (SENTRY Program, 1997 to 1999)

Antifungal agent MIC (μg/ml) and % susceptible by countrya
U.S. (n = 589)
Canada (n = 161)
Latin America (n = 132)
Europe (n = 302)
50/90% % S 50/90% % S 50/90% % S 50/90% % S
Fluconazole 0.25/16 90 0.25/4 96 0.25/4 98 0.25/8 90
Ravuconazole 0.015/0.25 98 0.015/0.12 99 0.015/0.25 99 0.007/0.5 98
Voriconazole 0.015/0.25 98 0.015/0.12 99 0.015/0.12 99 0.007/0.25 99
a

n, no. tested. U.S., United States. % S, percent susceptible at a MIC of ≤8 μg/ml (fluconazole) or ≤1 μg/ml (all other agents). 

Table 4 summarizes the in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole for the individual species of Candida from all areas stratified by year. Isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible (97 to 100%) to fluconazole and the investigational triazoles. Interestingly, C. glabrata demonstrated a trend towards increased susceptibility to fluconazole from 1997 (MIC50, 16 μg/ml; 48% S) to 1999 (MIC50, 4 μg/ml; 83% S; P = 0.004 for the trend). This trend was apparent in both the Americas and Europe (data not shown). Reasons for this trend are unclear but may be related to more appropriate uses and improved dosing of fluconazole (3). Both ravuconazole and voriconazole were quite active (MIC50, 0.12 to 0.5 μg/ml; 97 to 100% S) against both C. glabrata and C. krusei. Notably, no trend towards increased resistance to any of the agents tested was observed over the three-year period.

TABLE 4.

In vitro susceptibilities of blood stream infection isolates of Candida spp. to fluconazole and investigational antifungal agents (SENTRY Program, 1997 to 1999)

Species (no. tested) Antifungal agent MIC (μg/ml) and % susceptible by year
1997
1998
1999
50/90% % Sa 50/90% % Sa 50/90% % Sa
C. albicans (658) Fluconazole 0.25/0.5 99 0.25/0.5 98 0.25/0.25 100
Ravuconazole 0.007/0.03 99 0.007/0.03 99 0.007/0.015 100
Voriconazole 0.015/0.06 98 0.007/0.03 99 0.007/0.015 100
C. glabrata (180) Fluconazoleb 16/32 48 8/16 63 4/16 83
Ravuconazole 0.25/1 92 0.25/1 95 0.12/1 94
Voriconazole 0.25/1 91 0.25/1 95 0.12/0.5 96
C. parapsilosis (179) Fluconazole 0.5/2 100 0.5/1 98 0.5/1 100
Ravuconazole 0.015/0.06 100 0.015/0.06 100 0.015/0.06 100
Voriconazole 0.03/0.12 100 0.015/0.06 100 0.015/0.03 100
C. tropicalis (104) Fluconazole 1/2 100 0.5/1 100 0.5/2 97
Ravuconazole 0.03/0.12 100 0.03/0.12 100 0.015/0.12 97
Voriconazole 0.06/0.12 100 0.03/0.12 100 0.03/0.12 97
C. krusei (20) Fluconazole 32/—c 0 32/— 0 16/— 0
Ravuconazole 0.25/— 100 0.25/— 100 0.25/— 100
Voriconazole 0.5/— 100 0.25/— 100 0.25/— 100
a

% S, percent susceptible at a MIC of ≤8 μg/ml (fluconazole) or ≤1 μg/ml (all other agents). 

b

P = 0.0004 for trend in susceptibility by year. 

c

—, MIC90 not calculated because <10 isolates were identified during the year. 

Although it is not shown in Table 4, C. tropicalis demonstrated a trend towards increased susceptibility to itraconazole (susceptible MIC, ≤0.12 μg/ml) from 1997 (MIC50, 0.25 μg/ml; 48% S) to 1999 (MIC50, 0.06 μg/ml; 82% S; P = 0.005). A similar shift was not observed with itraconazole and any other species. More than 97% of C. tropicalis isolates were inhibited by ≤1 μg/ml of itraconazole. This trend is similar to the shift observed with C. glabrata and fluconazole and bears watching.

Despite excellent activity against the vast majority of Candida BSI isolates, cross-resistance was observed with both ravuconazole and voriconazole when they were tested against 12 isolates of C. albicans that were resistant to both fluconazole (MIC, ≥64 μg/ml) and itraconazole (MIC, ≥1 μg/ml) (data not shown) (20). Such isolates are quite rare among those organisms causing BSI but are indicative of the potential for development of complete class resistance against the azoles if fluconazole or itraconazole are misused.

Fluconazole was equally active against Candida BSI isolates from patients hospitalized in the ICU (93% S) and the non-ICU (92% S) setting (Table 5). This finding was in contrast to that observed with bacterial BSI isolates, where ICU-related infection isolates were generally less susceptible to antimicrobial agents than non-ICU strains (5, 7, 9). Similarly, no difference in susceptibility to six different antifungal agents was noted between nosocomial and community-acquired BSI isolates of Candida spp. Again, this observation was distinctly different from the experience with bacterial BSI isolates, where nosocomial strains were almost always more resistant to antimicrobial agents than community-acquired strains (5). Notably, only 70 to 72% of Candida spp. were found to be susceptible to amphotericin B at concentrations of ≤1 μg/ml when tested on RPMI agar using Etest (17). The Etest method has been shown to be the most sensitive and reliable method for identifying strains of Candida with clinically significant resistance to amphotericin B (4, 17, 28).

TABLE 5.

Activity of fluconazole against Candida blood stream isolates from ICU and non-ICU settings (SENTRY Program, 1997 to 1999)

Setting (no. tested) Cumulative % occurrence at MIC (μg/ml) of:
0.12 0.25 0.5 1 2 4 8 16 32 ≥64
ICU (393) 18.8 59.0 70.7 77.1 83.7 88.8 92.9 97.7 99.0 100.0
Non-ICU (402) 12.7 49.3 68.4 76.4 82.1 87.6 91.5 95.5 97.0 100.0

Further examination of selected species susceptibility to amphotericin B revealed striking differences when the isolates were tested on RPMI agar using Etest (Table 6). As has been noted previously, approximately 95% of C. albicans isolates were inhibited by ≤1 μg/ml of amphotericin B compared to only 41% of C. glabrata isolates and 0% of C. krusei isolates (P ≤ 0.01 for comparison of susceptibility by species) (8, 11, 15, 17, 24, 25). This in vitro data is consistent with the clinical experience of breakthrough fungemias with C. glabrata and C. krusei despite treatment with amphotericin B at standard doses of 0.5 to 0.6 mg/kg of body weight/day (25). Current Infectious Diseases Society of America (IDSA) treatment guidelines recommend higher doses of amphotericin B (1 mg/kg/day) when treating C. glabrata and C. krusei fungemia (25). Thus, both C. glabrata and C. krusei may be relatively resistant to both azoles and polyenes and could pose significant therapeutic problems in the future if such strains proliferate. C. krusei is also often resistant (70%) to 5FC as well (20).

TABLE 6.

Activity of amphotericin B (Etest) versus selected Candida species (SENTRY Program, 1997 to 1999)

Species (no. tested) Cumulative % occurrence at MIC (μg/ml) of:
0.06 0.12 0.25 0.5 1 2 4 8
C. albicans (501) 0.4 0.8 5.0 53.1 94.6a 99.6 100.0 100.0
C. glabrata (131) 0.8 0.8 2.3 8.4 41.2a 90.1 98.5 100.0
C. krusei (15) 0.0 0.0 0.0 0.0 0.0a 20.0 80.0 100.0
a

Susceptible breakpoint, P ≤ 0.01 for comparison of susceptibility by species. 

Summary and conclusions.

This most recent analysis of data from the SENTRY Antimicrobial Surveillance Program confirms the fact that Candida spp. remain the fourth-most-common cause of nosocomial BSI (7, 18). Although C. albicans continues to account for approximately one-half of candidemias world-wide, its frequency may vary widely from institution to institution, emphasizing the need for yeast species identification of BSI isolates in individual institutions. Different, and as yet unknown, factors may influence the species distribution of Candida spp. causing BSI. The prominence of C. glabrata in the United States as opposed to the other regions in the SENTRY Program may be influenced by extensive utilization of fluconazole at relatively low doses (<400 mg/day), enhancing selection of this species (3). In contrast, the frequent isolation of C. parapsilosis in other regions may reflect issues of suboptimal catheter care and infection control (1, 12).

Importantly, no increase in resistance to azoles was observed in any of the geographic regions over the three-year study period. The trend towards decreased resistance to fluconazole among C. glabrata isolates and to itraconazole among C. tropicalis isolates is interesting and will require further investigation to determine the factors behind these observations. Although there is some evidence in the literature that both C. glabrata and C. krusei may be relatively resistant to amphotericin B (15, 17, 24, 25), the application of the Etest to a large international collection of Candida spp., such as the SENTRY Program collection, provides information suggesting that elevated MICs of drugs for these species may be more common than anticipated.

Additional data, not previously available, indicate that in contrast to the experience with antibacterial agents, no difference in susceptibility to the existing antifungal agents was observed among ICU versus non-ICU isolates and nosocomial versus community-acquired strains of Candida spp. This may reflect the fact that to the best of our knowledge Candida spp. lack mobile resistance genes and thus require considerably different circumstances and exposures in order to develop high levels of resistance compared to bacterial pathogens.

Finally, although the new triazoles (ravuconazole and voriconazole) display improved potency compared to fluconazole, it is apparent that cross-resistance to these agents may be observed among the rare BSI isolates of Candida that are resistant to both fluconazole and itraconazole. These observations suggest certain susceptibility patterns and trends among yeast isolates from BSI and raise additional questions that can be answered only by continued surveillance and clinical investigations of the type reported here (SENTRY Program).

ACKNOWLEDGMENTS

Kay Meyer and Linda Elliott provided excellent support in the preparation of the manuscript.

The SENTRY Antimicrobial Surveillance Program was supported in part by a research grant from Bristol-Myers Squibb.

We express our appreciation to all SENTRY site participants. Participants contributing data isolates to the study included: The Medical Center of Delaware, Wilmington, Del. (L. Steele-Moore); Clarion Health Methodist Hospital, Indianapolis, Ind. (G. Denys); Henry Ford Hospital (C. Staley); Summa Health System, Akron, Ohio (J. R. Dipersio); Good Samaritan Regional Medical Center (M. Saubolle); Denver General Hospital, Denver, Colo. (M. L. Wilson); University of New Mexico Hospital, Albuquerque, N.M. (G. D. Overturf); University of Illinois at Chicago, Chicago, Ill. (P. C. Schreckenberger); University of Iowa Hospitals and Clinics, Iowa City, Iowa (R. N. Jones); Creighton University, Omaha, Nebr. (S. Cavalieri); Froedtert Memorial Lutheran Hospital-East, Milwaukee, Wisc. (S. Kehl); Boston VAMC, Boston, Mass. (S. Brecher); Columbia Presbyterian Medical Center, New York, N.Y. (P. Della-Latta); Long Island Jewish Medical Center, New Hyde Park, N.Y. (H. Isenberg); Strong Memorial Hospital, Rochester, N.Y. (D. Hardy); Kaiser Regional Laboratory, Berkeley, Calif. (J. Fusco); Sacred Heart Medical Center, Spokane, Wash. (M. Hoffmann); University of Washington Medical Center, Seattle, Wash. (S. Swanzy); Barnes-Jewish Hospital, St. Louis, Mo. (P. R. Murray); Parkland Health & Hospital System, Dallas, Tex. (P. Southern); The University of Texas Medical School, Houston, Tex. (A. Wanger); University of Texas Medical Branch at Galveston, Galveston, Tex. (B. Reisner); University of Louisville Hospital, Louisville, Ky. (J. Snyder); University of Mississippi Medical Center, Jackson, Miss. (J. Humphries); Carolinas Medical Center, Charlotte, N.C. (S. Jenkins); University of Virginia Medical Center, Charlottesville, Va. (K. Hazen); University of Alberta Hospital, Edmonton, Alberta, Canada (R. Rennie); Health Sciences Centre, Winnipeg, Manitoba, Canada (D. Hoban); Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada (K. Forward); Ottawa General Hospital, Ottawa, Ontario, Canada (B. Toye); Royal Victoria Hospital, Montreal, Quebec, Canada (H. Robson); Microbiology Laboratory C.E.M.I.C., Buenos Aires, Argentina (J. Smayvsky); Hospital San Lucas and Olivos Community Hospital, Buenos Aires, Argentina (J. M. Casellas and G. Tome); Lamina LTDA, Rio De Janeiro, Brazil (J. L. M. Sampaio); Unidad De Microbiologia Oriente, Santiago, Chile (V. Prado); Hospital Clinico Universidad Catolica, Santiago, Chile (E. Palavecino); Corp. Para Investig. Biologicas, Medellin, Columbia (J. A. Robledo); Instituto Nacional de la Nutricion, Mexico City, Mexico (J. S. Osornio); Laboratorio Medico Santa Luzia, Florianopolis, Brazil; Instituto DE Doencas Infecciosas-IDIPA, Sao Paulo, Brazil (H. S. Sader); Centro Medico De Caracas, San Bernadino, Caracas, Venezuela (M. Guzman); Chru De Lille Hopital Calmette, Lille, Cedex, France (M. Roussel-Delvallez); National University of Athens Medical School, Athens, Greece (N. Legakis); Sheba Medical Center, Tel-Hashomer, Israel (N. Keller); University Hospital V. de Macarena, Sevilla, Spain (E. J. Perea); Hospital de Bellvitge, Barcelona, Spain (J. Linares); Hospital Ramon y Cajal, Madrid, Spain (R. Canton); Unite de Bacteriologie, Lausanne, Switzerland (F. Praplan); Hacettepe Universitaesi Tip Fakultesi, Ankara, Turkey (D. Gur); Universita degli Studi di Genova, Genova, Italy (E. Debbia); Azienda Policlinico Univ. Catania, Catania, Italy (G. Nicoletti); Policlinico Agostino Germelli, Rome, Italy (G. Fadda); Universitat Bonn, Bonn, Germany (K. P. Schaalb); J.-W.-Goethe Universitat, Frankfurt, Germany (P. Shah); University Hospital, Linkoping, Sweden (H. Hanberger); Sera & Vaccines Central Research Lab, Warsaw, Poland (W. Hryniewicz); St. Thomas Hospital, London, United Kingdom (G. French); Univ. Libre de Bruxelles-Hopital Erasme, Brussels, Belgium (M. J. Struelens); Marmara Universitesi Tip Fakultesi, Istanbul, Turkey (V. Korten).

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