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J Clin Microbiol. Jun 2007; 45(6): 1735–1745.
Published online Apr 18, 2007. doi:  10.1128/JCM.00409-07
PMCID: PMC1933070

Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2005: an 8.5-Year Analysis of Susceptibilities of Candida Species and Other Yeast Species to Fluconazole and Voriconazole Determined by CLSI Standardized Disk Diffusion Testing[down-pointing small open triangle]

M. A. Pfaller,1,* D. J. Diekema,1,2 D. L. Gibbs,3 V. A. Newell,3 J. F. Meis,4 I. M. Gould,5 W. Fu,6 A. L. Colombo,7 E. Rodriguez-Noriega,8 and and the Global Antifungal Surveillance Group

Abstract

Fluconazole in vitro susceptibility test results for 205,329 yeasts were collected from 134 study sites in 40 countries from June 1997 through December 2005. Data were collected for 147,776 yeast isolates tested with voriconazole from 2001 through 2005. All investigators tested clinical yeast isolates by the CLSI M44-A disk diffusion method. Test plates were automatically read and results recorded with a BIOMIC image analysis system. Species, drug, zone diameter, susceptibility category, and quality control results were collected quarterly. Duplicate (same patient, same species, and same susceptible-resistant biotype profile during any 7-day period) and uncontrolled test results were not analyzed. Overall, 90.1% of all Candida isolates tested were susceptible (S) to fluconazole; however, 10 of the 22 species identified exhibited decreased susceptibility (<75% S) on the order of that seen with the resistant (R) species C. glabrata and C. krusei. Among 137,487 isolates of Candida spp. tested against voriconazole, 94.8% were S and 3.1% were R. Less than 30% of fluconazole-resistant isolates of C. albicans, C. glabrata, C. tropicalis, and C. rugosa remained S to voriconazole. The non-Candida yeasts (8,821 isolates) were generally less susceptible to fluconazole than Candida spp. but, aside from Rhodotorula spp., remained susceptible to voriconazole. This survey demonstrates the broad spectrum of these azoles against the most common opportunistic yeast pathogens but identifies several less common yeast species with decreased susceptibility to antifungal agents. These organisms may pose a future threat to optimal antifungal therapy and emphasize the importance of prompt and accurate species identification.

Although the list of opportunistic fungi causing serious, life-threatening infection increases every year (1, 6, 17, 24, 30, 44), without question the single most important cause of opportunistic mycoses worldwide remains Candida species (34). Despite fewer infections, the opportunistic yeasts other than Candida species, led by Cryptococcus neoformans, also cause disastrous infections in the most fragile immunocompromised patients (3, 24, 44).

More than 20 different species of Candida have been reported as etiologic agents of invasive candidiasis in humans (8, 24). Although more than 90% of invasive infections due to Candida spp. can be attributed to five species, C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei, the list of reported species continues to grow as laboratories are pushed to provide an identification to the species level as an aid in optimizing therapy of candidal infections (20, 31, 32, 34, 41). Likewise, the diverse array of opportunistic yeasts and yeast-like fungi and their variable susceptibilities to both new and established antifungal agents has made the need for prompt identification of noncandidal yeasts from clinical material much more compelling (24, 40, 44). Our understanding of the frequency of occurrence and the antifungal susceptibility of both Candida and non-Candida yeasts has been enhanced in recent years through the efforts of several large surveillance programs conducted throughout the world (2, 7, 9, 13, 19, 23, 26, 34, 37, 45).

Among the fungal surveillance programs, the ARTEMIS Global Antifungal Surveillance Program is the largest and most comprehensive in that it includes both Candida and non-Candida yeasts, is both longitudinal (>8 years in duration, 1997-present) and global (134 institutions in 40 countries) in scope, employs standardized in vitro susceptibility testing methods used for “routine” testing in participating laboratories and for “reference” testing in a central reference laboratory, uses electronic data capture and storage in a central database, and conducts external validation of the data generated by the participating laboratories (9, 13, 25-27, 31, 32). In 2005, we reported the results from the ARTEMIS DISK Global Antifungal Surveillance Program in which species identification and the fluconazole and voriconazole antifungal susceptibility profiles were determined for 134,715 consecutive clinical isolates of Candida and 6,052 isolates of noncandidal yeasts collected from cases of mucosal and invasive fungal infections in 127 medical centers in 39 countries over a 6.5-year period (1997 through 2003) (26). In the present study, we expand the ARTEMIS database to include the time period from June 1997 through December 2005 and a total of 205,329 yeast isolates (196,508 isolates of Candida and 8,821 isolates of noncandidal yeasts) from 134 study sites in 40 countries. We provide comparative susceptibility data for fluconazole and voriconazole for 147,766 isolates collected from 2001 to 2005 and include an analysis of resistance rates by year, geographic region, hospital location, and clinical specimen type for selected species.

MATERIALS AND METHODS

Organisms and test sites.

A total of 196,508 isolates of Candida spp. and 8,821 isolates of noncandidal yeasts obtained from 134 different medical centers in the Asia-Pacific region (28 sites), Latin America (16 sites), Europe (66 sites), the Africa/Middle East region (11 sites), and North America (13 sites) were collected and tested against fluconazole between June 1997 and December 2005. In addition, a total of 147,766 isolates (141,229 isolates of Candida spp. and 6,379 other yeasts) from 124 study sites in 35 countries were tested against voriconazole between 2001 and 2005. Approximately 80% of the study sites participated in the survey for 3 or more years (average duration of participation, 4.2 years; range, 1 to 8 years).

All yeasts considered pathogens from all body sites (e.g., blood, normally sterile body fluids, deep tissue, genital tract, gastrointestinal tract, respiratory tract, and skin and soft tissue) and isolates from patients in all in-hospital locations during the study period were tested. Yeasts considered by the local site investigator to be colonizers, that is, not associated with an obvious pathology, were excluded, as were duplicate isolates from a given patient (same species and same susceptible-resistant biotype profile within any 7-day period). The identification of isolates was performed locally in accordance with each site's routine methods. The majority (76%) of the study sites employed one or more commercially available yeast identification systems (API, Vitek, and/or MicroScan) supplemented by classical biochemical and morphological methods, and the remainder used the classical methods alone (8, 9).

Susceptibility test method.

Disk diffusion testing of fluconazole and voriconazole was performed as described by Hazen et al. (9) and in CLSI (formerly NCCLS) document M44-A (16). Agar plates (90-, 100-, or 150-mm diameter) containing Mueller-Hinton agar (obtained locally at all sites) supplemented with 2% glucose and 0.5 μg of methylene blue per ml at a depth of 4.0 mm were used. The agar surface was inoculated by using a swab dipped in a cell suspension adjusted to the turbidity of a 0.5 McFarland standard. Fluconazole (25 μg) and voriconazole (1 μg) disks (Becton Dickinson, Sparks, MD) were placed onto the surfaces of the inoculated plates, and the plates were incubated in air at 35 to 37°C and read at 18 to 24 h. Slowly growing isolates, primarily members of the genus Cryptococcus, were read after 48 h of incubation. Zone diameter endpoints were read at 80% growth inhibition by using a BIOMIC image analysis plate reader system (Giles Scientific, Santa Barbara, CA) (9, 25-27).

The interpretive criteria for the fluconazole and voriconazole disk diffusion tests were those of the CLSI (16, 28, 29): susceptible (S), zone diameters of ≥19 mm (fluconazole) and ≥17 mm (voriconazole); susceptible dose dependent (SDD), zone diameters of 15 to 18 mm (fluconazole) and 14 to 16 mm (voriconazole); and resistant (R), zone diameters of ≤14 mm (fluconazole) and ≤13 mm (voriconazole). The corresponding MIC breakpoints (16, 28, 29) are as follows: S, MICs of ≤8 μg/ml (fluconazole) and ≤1 μg/ml (voriconazole); SDD, MICs of 16 to 32 μg/ml and 2 μg/ml (voriconazole); and R, MICs of ≥64 μg/ml (fluconazole) and ≥4 μg/ml (voriconazole).

QC.

Quality control (QC) was performed in accordance with CLSI document M44-A (16) by using Candida albicans ATCC 90029 and C. parapsilosis ATCC 22019. A total of 14,484 and 10,146 QC results were obtained for fluconazole and voriconazole, respectively, of which more than 99% were within the acceptable limits.

Analysis of results.

All yeast disk test results were read by electronic image analysis and interpreted and recorded with the BIOMIC plate reader system (Giles Scientific, Inc.). Test results were sent by e-mail to Giles Scientific for analysis. The zone diameter, susceptibility category (S, SDD, or R), and QC test results were all recorded electronically. Patient and doctor names, duplicate test results (same patient, same species, and same biotype results), and uncontrolled results were automatically eliminated by the BIOMIC system prior to analysis. In the present study, fluconazole and voriconazole S, SDD, and R results for each yeast species were stratified by year of collection, geographic region, clinical specimen type, and hospital location.

RESULTS

Isolation rates by species.

A total of 205,329 yeast isolates were collected and tested at 134 study sites between June 1997 and December 2005 (Table (Table1).1). Candida species accounted for 95.2 to 96.3% of all isolates in each study year (overall, 95.7%). A total of 22 different species of Candida were isolated, of which C. albicans was the most common (overall, 65.6% of all Candida spp.). A decreased rate of isolation of C. albicans was noted when the first 3 years of the study (1997 to 2000, 70.9% of all Candida spp.) were compared with the subsequent 5-year time period (2001 to 2005, 63.5%), although the rates of isolation over the latter time period did not show a continued declining trend. In contrast, slightly increased rates of isolation of C. glabrata (10.2% to 11.4%), C. tropicalis (5.4% to 7.5%), and C. parapsilosis (4.8% to 6.6%) were noted when the time periods 1997 to 2000 and 2001 to 2005 were compared. Similar to that seen with C. albicans, the annual isolation rates for each of these species were relatively stable for the years 2001 to 2005. The rates of isolation of C. krusei, C. guilliermondii, C. lusitaniae, C. kefyr, C. rugosa, and C. famata did not vary significantly over the 8.5-year study period. The rates of isolation of the remaining 12 species remained quite low; however, the increased detection of these species, especially in the last 3 years of the study, is evidence of increased efforts to identify clinical isolates of Candida to the species level in recent years.

TABLE 1.
Species distribution of Candida and other yeast isolates by yeara

Among the noncandidal yeasts, Cryptococcus neoformans (33% of 8,821 isolates), Saccharomyces spp. (11.3%), Trichosporon spp. (10.7%), and Rhodotorula spp. (4.2%) were the most commonly identified species (Table (Table1).1). Unfortunately, 33% of the noncandidal yeast isolates were reported as “other” unidentified yeast species. This indicates a relative shortcoming in the commercial yeast identification systems and/or financial or policy constraints in the clinical laboratories that may need attention in the future.

Fluconazole and voriconazole susceptibilities of Candida spp.

Table Table22 summarizes the in vitro susceptibilities of 141,282 and 137,487 isolates of Candida spp. to fluconazole and voriconazole, respectively, as determined by CLSI disk diffusion testing (16). These isolates were obtained from 124 institutions in 35 countries during the period from 2001 through 2005. The percentages of isolates in each category (S, SDD, and R) were 90.1%, 3.6%, and 6.2% and 94.8%, 2.1%, and 3.1% for fluconazole and voriconazole, respectively. Fluconazole was most active (>90% S) against C. albicans (97.9% S), C. tropicalis (90.4% S), C. parapsilosis (93.3% S), C. lusitaniae (92.6% S), C. kefyr (95.6% S), C. dubliniensis (97.6% S), C. pelliculosa (90.3% S), C. pulcherrima (93.8% S), and C. intermedia (100% S). Decreased susceptibility to fluconazole (<75% S) was seen with C. glabrata (68.9% S), C. krusei (9.2% S), C. guilliermondii (73.9% S), C. rugosa (43.8% S), C. inconspicua (23.4% S), C. norvegensis (48.5% S), C. lipolytica (64.9% S), C. zeylanoides (66.7% S), C. valida (20.0% S), and C. humicola (50.0% S). Thus, despite the fact that ~90% of all clinical isolates of Candida were susceptible to fluconazole, these data demonstrate that 10 of the 22 species identified in this survey exhibit decreased susceptibility on the order of that seen with the well-known resistant species C. glabrata and C. krusei.

TABLE 2.
In vitro susceptibilities of Candida spp. to fluconazole and voriconazole as determined by CLSI disk diffusion testinga

As noted previously (26), voriconazole was more active than fluconazole against most species of Candida with the exception of C. tropicalis (90.4% S to fluconazole versus 88.5% S to voriconazole), C. intermedia (100% S to both), C. haemulonii (87.5% S to both), and C. humicola (50% S to both). Although voriconazole was more active than fluconazole against C. rugosa (64.1% S versus 43.8% S, respectively), C. lipolytica (75.0% S versus 64.9% S, respectively), and C. valida (75.0% S versus 20.0% S, respectively), these species were considerably less susceptible and more resistant (14.6% to 25.1%) to voriconazole than all other species of Candida.

A total of 8,545 isolates encompassing 21 different species of Candida were found to be resistant to fluconazole (Table (Table3).3). Whereas voriconazole was active (≥75% S) against fluconazole-resistant isolates of C. krusei (79.1% S), C. inconspicua (83.9% S), C. norvegensis (85.7% S), C. dubliniensis (75.0% S), C. sake (100% S), and C. pulcherrima (100% S), activity was quite poor against the remaining 15 species. Notably, less than 30% of fluconazole-resistant isolates of C. albicans (28.8% S), C. glabrata (17.3% S), C. tropicalis (17.7% S), and C. rugosa (26.5% S) remained susceptible to voriconazole. Cross-resistance between fluconazole and voriconazole is clearly more pronounced for some species of Candida than for others, although all are affected to some degree, emphasizing the importance of both species identification and antifungal susceptibility testing in the settings of candidal infection with prior azole exposure (11, 18, 20, 40, 41).

TABLE 3.
In vitro susceptibilities of fluconazole-resistant isolates of Candida spp. to voriconazole as determined by CLSI disk diffusion testinga

Trends in resistance to fluconazole among Candida spp. over an 8.5-year period.

There was no consistent trend towards increasing resistance to fluconazole detected among the common species C. albicans, C. glabrata, or C. tropicalis over the 8.5-year time period (Table (Table4).4). Likewise, consistently high levels of resistance were seen among C. glabrata, C. krusei, C. guilliermondii, C. inconspicua, and C. norvegensis. Resistance remained high among C. rugosa, C. famata, C. lipolytica, and C. zeylanoides for the years 2001 through 2004 but was ≤6% for all four species in 2005. The reasons for such a decrease in resistance are unclear, and the results are likely spurious due to relatively few isolates of these species being tested in 2005.

TABLE 4.
Trends in in vitro resistance to fluconazole among Candida spp. as determined by CLSI disk diffusion testing over an 8.5-year perioda

A slight increase in resistance was noted among C. parapsilosis and C. lusitaniae when the time periods 1997 to 2000 and 2001 to 2005 were compared (2.5% versus 3.7% for C. parapsilosis and 2.9% versus 4.7% for C. lusitaniae). Although the number of isolates was small, both C. pulcherrima (25 to 50% R) and C. valida (50 to 71.4% R) appear to be newly recognized fluconazole-resistant species over the last 3 years (2003 to 2005).

Trends in resistance to voriconazole among Candida spp., 2001 to 2005.

Voriconazole has been tested in the ARTEMIS Global Surveillance Program since its introduction into clinical use in 2001 (Table (Table5).5). Overall, the rates of resistance by year were 2.6%, 3.1%, 3.5%, 3.3%, and 3.0% for the years 2001 to 2005, respectively. Although increases in resistance to voriconazole were observed for several species between 2001 and 2003 (26), this was not sustained for any species over the next 2 years (Table (Table5).5). Thus, resistance to voriconazole among Candida spp. is not negligible but no significant trend towards increasing resistance can be identified over the first 5 years of clinical use.

TABLE 5.
Trends in in vitro resistance to voriconazole among Candida spp. as determined by CLSI disk diffusion testing over a 5-year perioda

Geographic variation in the susceptibilities of C. albicans, C. glabrata, and C. tropicalis to fluconazole and voriconazole.

Table Table66 presents the in vitro susceptibility results for fluconazole and voriconazole tested against the three most common species of Candida, C. albicans, C. glabrata, and C. tropicalis, stratified by geographic region for the time period from 2001 to 2005. Low rates of resistance to both fluconazole and voriconazole were detected among isolates of C. albicans from all regions, although isolates from North America were more resistant than those from other regions.

TABLE 6.
Geographic variation in the in vitro susceptibilities of C. albicans, C. glabrata, and C. tropicalis to fluconazole and voriconazolea

As noted previously (26), the resistance rates for both fluconazole and voriconazole among isolates of C. glabrata varied considerably among the various geographic regions. The lowest rates of resistance to both agents were seen in the Asia-Pacific region and the highest in North America. Although voriconazole was more active than fluconazole against isolates of C. glabrata from all five regions, as resistance to fluconazole increased so did resistance to voriconazole.

The lowest rates of resistance to both azoles among C. tropicalis isolates were seen in the Africa/Middle East region. Although the rates of resistance in North America were higher than those in the Africa/Middle East region, the highest rates of resistance to both azoles were seen in the Asia-Pacific region. In contrast to that seen with virtually all other species of Candida, C. tropicalis isolates were generally more resistant to voriconazole than to fluconazole. This was true in all geographic regions with the exception of the Asia-Pacific and Africa/Middle East regions. At present, we have no mechanistic explanation for this phenomenon, although the differences in resistance rates were generally only 1 to 1.5% in favor of fluconazole.

Variation in the frequency of isolation and the antifungal susceptibility profile of C. albicans, C. glabrata, and C. tropicalis by clinical service.

The clinical services reporting the isolation of C. albicans, C. glabrata, and C. tropicalis from patient specimens included the hematology-oncology service, medical and surgical services, intensive care units (ICUs) (medical, surgical, and neonatal), and dermatology, urology, and outpatient services (Table (Table7).7). Those isolates from services with only a few isolates and those for which a clinical service was not specified were included in the category “other NOS” (not otherwise specified).

TABLE 7.
Susceptibilities of C. albicans, C. glabrata, and C. tropicalis to fluconazole and voriconazole by clinical servicea

C. albicans was isolated most frequently from hospitalized patients from the medical and ICU services and from outpatients and was the least common from the dermatology and urology services. Resistance to both fluconazole and voriconazole was low across all services, with the lowest resistance rates seen among isolates from the outpatient service.

C. glabrata was isolated most frequently from the medical and ICU services, although the highest proportion of Candida isolates that were C. glabrata was seen with the urology service (16% of all Candida isolates). The lowest total number of C. glabrata isolates and the lowest proportion of Candida isolates that were C. glabrata (4%) were seen with the dermatology service. The rates of resistance to both fluconazole and voriconazole were highest among C. glabrata isolates obtained from the hematology-oncology service and lowest among isolates obtained from the urology service.

The largest number of C. tropicalis isolates originated from patients hospitalized in the medical and ICU services. This species accounted for a greater proportion of the Candida isolates obtained from the ICU (10.5%) than from other services (8%; range, 3.4 to 9.8%). C. tropicalis accounted for only 3.4% of all Candida isolates from the dermatology service and 4.8% of all isolates from the outpatient service. The lowest rates of resistance to fluconazole and voriconazole were seen among C. tropicalis isolates obtained from the outpatient service, followed by those obtained from the hematology-oncology and surgical services. The most resistant isolates came from the urology service.

Variation in the frequency of isolation and the antifungal susceptibility profile of C. albicans, C. glabrata, and C. tropicalis by clinical specimen type.

The major specimen types yielding C. albicans, C. glabrata, and C. tropicalis as putative pathogens included blood, normally sterile body fluid (NSBF), urine, respiratory tract, skin and soft tissue, and genital specimens (Table (Table8).8). Those isolates from uncommon specimen types and those for which a specimen type was not recorded were grouped under “miscellaneous NOS.”

TABLE 8.
Susceptibilities of C. albicans, C. glabrata, and C. tropicalis to fluconazole and voriconazole by specimen typea

C. albicans constituted more than 70% of the Candida spp. isolated from respiratory (71%) and genital (79%) tract specimens but accounted for only 43% of Candida sp. isolates obtained from blood cultures. There was very little variation in the rates of resistance of C. albicans to either fluconazole or voriconazole among the different specimen types. Isolates from genital specimens had the lowest frequency of resistance to both agents.

C. glabrata accounted for 14% of all Candida spp. isolated from blood and NSBF and for 19% of those isolated from urine but for less than 10% of isolates from other sites of infection. The resistance rates to fluconazole and voriconazole were highest for isolates from skin and soft tissue specimens and did not vary appreciably across the other specimen types.

C. tropicalis accounted for 12% of all bloodstream isolates of Candida and for 14% of all urinary tract isolates but was less common (<10%) as an agent of candidiasis among other specimen types. The rates of resistance were highest for urinary tract isolates and lowest for respiratory tract isolates.

Activities of fluconazole and voriconazole against other opportunistic yeasts and yeast-like fungi.

Although uncommon, the number and types of noncandidal yeasts isolated from clinical specimens have continued to increase over the duration of this study (Tables (Tables11 and and9).9). Cryptococcus neoformans continues to predominate, but the numbers of isolates of Saccharomyces, Trichosporon, and Rhodotorula species are also substantial. In general, these yeast-like fungi are considerably less susceptible to fluconazole than are Candida spp.

TABLE 9.
In vitro susceptibilities of non-Candida yeasts to fluconazole and voriconazole as determined by CLSI disk diffusion testinga

Among the species of Cryptococcus, it is important to note the rather poor activity of fluconazole against isolates of C. gattii (Table (Table9).9). This species has long been noted to be an important opportunistic pathogen in tropical and subtropical climates and has recently gained importance due to an outbreak of C. gattii on Vancouver Island, BC, Canada (10, 15, 39). The decreased susceptibility of this species of Cryptococcus to fluconazole is similar to that observed by other investigators (14, 42, 43), although a recent report from Africa found low MICs to fluconazole and other azoles (15). Both C. gattii and C. neoformans were very susceptible to voriconazole in the present study (Table (Table99).

Both Saccharomyces cerevisiae and various species of Trichosporon appear to be moderately susceptible to fluconazole. It is interesting that T. mucoides, T. inkin, and T. ovoides appear to be considerably more susceptible to fluconazole than T. asahii and T. beigelii/T. cutaneum. Voriconazole exhibited very good activity against both Saccharomyces and Trichosporon species with the exception of T. beigelii/T. cutaneum.

Rhodotorula spp., including R. rubra/mucilaginosa and R. glutinis, are often resistant to both fluconazole and voriconazole. Amphotericin B continues to be the antifungal agent of choice for the treatment of infections due to this opportunistic yeast (5).

Fluconazole has only modest activity against isolates of Blastoschizomyces capitatus and Pichia (Hansenula) spp. Voriconazole appears to be active against these yeasts, although clinical experience in treating infections due to these rare yeasts is lacking (24, 44).

Similar to that seen with the Candida species, isolates of non-Candida yeasts that are resistant to fluconazole also show increased resistance to voriconazole (Table (Table10).10). These organisms could be quite problematic when encountered in an immunocompromised host given the fact that, in addition to the acquired azole resistance, they also exhibit intrinsic resistance to the echinocandin class of antifungal agents (24, 40).

TABLE 10.
In vitro susceptibilities of fluconazole-resistant isolates of non-Candida yeasts to voriconazole as determined by CLSI disk diffusion testinga

DISCUSSION

In this most recent summary of the data from the ARTEMIS DISK Global Surveillance Program, we report fluconazole and voriconazole susceptibility results for more than 200,000 clinical isolates of Candida and other opportunistic yeast pathogens from throughout the world. The value of such a large database is that for the more common species of Candida, we can assess trends in resistance over time (Tables (Tables44 and and5),5), by geographic region (Table (Table6),6), by clinical service (Table (Table7),7), and by specimen type (Table (Table8).8). Of greater potential value is the data pertaining to the less common species of Candida and other yeasts (Tables (Tables11 to to3,3, ,9,9, and and10).10). These relatively rare pathogens are unlikely to be familiar to both clinicians and microbiologists, and there is little or no data regarding prognosis or optimal treatment strategies (17, 24, 31, 32, 40, 44). Given the ubiquitous use of azoles in prophylaxis, empirical, and directed therapies (4, 20, 40, 41), it is important to know the activities of the systemically active agents, such as fluconazole and voriconazole, against these organisms (40, 41, 44). The fact that the less common species of Candida exhibit decreased susceptibility to fluconazole, and in some instances to voriconazole (Table (Table2),2), is important, as these organisms could emerge as pathogens in immunocompromised patients who have already been receiving an azole (24, 31, 32). In this regard, it is also important to understand what to expect with regard to susceptibility to voriconazole among Candida species found to break through fluconazole therapy (Table (Table3)3) (21). Species such as C. krusei, C. inconspicua, and C. norvegensis may emerge during fluconazole therapy due to their intrinsic resistance to fluconazole yet remain susceptible to voriconazole (Table (Table3).3). Unfortunately, most other species of Candida that exhibit acquired resistance to fluconazole also appear to be significantly less susceptible to voriconazole than their “fluconazole-naïve” counterparts (Table (Table3)3) and are less likely to respond optimally to treatment with this agent (11, 18, 20, 40, 41).

Among the non-Candida yeasts, there is even less information to guide antifungal therapy (24, 26, 44). These organisms generally appear to be less susceptible to fluconazole than Candida spp. (Table (Table9)9) but, aside from Rhodotorula spp., remain susceptible to voriconazole (Table (Table9).9). Unfortunately, as with Candida, fluconazole-resistant isolates of these noncandidal yeasts also exhibit decreased susceptibility to voriconazole (Table (Table10).10). Given their intrinsic resistance to the echinocandins and their variable response to amphotericin B, these yeasts may pose considerable problems in the future (5, 12, 24, 44).

Overall, the ARTEMIS database can serve as a look into the future of clinical mycology. At present, the azoles fluconazole and voriconazole appear to be adequate in their coverage of the most common species of Candida (Table (Table2).2). However, the weaknesses of both of these agents, as well as posaconazole and the echinocandins (34), can be seen as we look at the less common species of Candida and the other opportunistic yeasts (24). Although any one of these unusual pathogens may never truly “emerge” to become a major threat in and of itself, in aggregate these organisms could pose problems among patients with prior azole exposure. Furthermore, the lack of any meaningful activity of the echinocandin class against the non-Candida yeasts and the increasing use of this class of antifungal agents suggest that these organisms may be prime candidates to “emerge” as new mycotic threats (12).

The potential value of large antifungal surveillance databases such as that of ARTEMIS is considerable; however, the value of such information for clinical purposes is weakened substantially without knowledge of the species identification of the infecting organism. Thus, it is imperative that clinical laboratories strive to provide rapid and accurate identification of Candida and other opportunistic yeasts. Although antifungal susceptibility testing of fluconazole and voriconazole is becoming more accessible (22, 25, 27, 33, 35, 36), in most instances the species identification alone, coupled with survey data such as that of ARTEMIS, is sufficient to guide the selection of initial antifungal therapy. Specific antifungal susceptibility testing may help to optimize therapy in instances where a suboptimal response is observed to what would ordinarily be considered adequate therapy (20, 38, 41).

Acknowledgments

The ARTEMIS DISK Surveillance Program is supported by grants from Pfizer.

We express our appreciation to all ARTEMIS participants. Currently active participants contributing to this study include Jorge Finquelievich, Buenos Aires University, and Nora Tiraboschi, Hospital Escuela Gral., Buenos Aires, Argentina; David Ellis, Women's and Children's Hospital, North Adelaide, Australia; Dominique Fameree, CHU de Jumet, Jumet, Anne-Marie van den Abeele, St. Lucas Campus Heilige Familie, Gent, and Jean-Marc Senterre, Hôpital de la Citadelle, Liege, Belgium; Arnaldo Lopez Colombo, Federal University of Sao Paulo, Sao Paulo, Brazil; Robert Rennie, University of Alberta Hospital, Edmonton, and Stephen Sanche, Royal University Hospital, Saskatoon, Canada; Hu Bijie, Zhong Shan Hospital, Shanghai, Yingchun Xu, Peking Union Medical College Hospital, Beijing, Wang Fu, Hua Shan Hospital, Shanghai, and Nan Shan Zhong, Guangzhou Institute of Respiratory Disease, Guangzhou, China; Pilar Rivas, Instituto Nacional de Cancerología, Bogota, Catalina de Bedout, CIB, Medellin, and Matilde Mendez and Ricardo Vega, Hospital Militar Central, Bogota, Colombia; Nada Mallatova, Hospital Ceske Budejovice, Ceske, and Stanislava Dobiasova, Zdravotni ustav se sidlem Ostrave, Ostrava, Czech Republic; Julio Ayabaca, Hospital FF. AA HG1, Quito, and Jeannete Zurita, Hospital Vozandes, Quito, Ecuador; M. Mallie, Faculte de Pharmacie, Montpellier, and E. Candolfi, Institut de Parasitologie, Strasbourg, France; W. Fegeler, Universitaet Muenster, Münster, G. Haase, RWTH Aachen, Aachen, A. C. Rodloff, Inst. F. Med. Mikrobiologie, Leipzig, W. Bar, Carl-Thiem Klinikum, Cottbus, and V. Czaika, Humaine Kliniken, Bad Saarow, Germany; George Petrikos, Laikon General Hospital, Athens, Greece; Puskás Erzsébet, BAZ County Institute, Miskolc, and Elisabeth Nagy, University of Szeged, Hungary; Mestyan Gyula, Medical University of Pecs, Pecs, and Radka Nikolova, Szt. Laszlo Hospital, Budapest, Hungary; Uma Banerjee, All India Institute of Medical Sciences, New Delhi, India; Nathan Keller, Sheba Medical Center, TelHashomer, Israel; Vivian Tullio, Università degli Studi di Torino, Torino, Gian Carlo Schito, University of Genoa, Genoa, Domenico D'Antonio, Pescara Civil Hospital, Pescara, and Pietro Martino, Dept. di Biotechnologia, Rome; N. G Kee Peng, University Malaya, Kuala Lumpur, Malaysia; Celia Alpuche and Jose Santos, Hospital General de Mexico, Mexico City, Rayo Morfin Ortero, Universidad de Guadalajara, Guadalajara, and Mussaret Zaidi, Hospital General O'Horan, Merida, Mexico; Jacques F. Meis, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; Egil Lingaas, Rikshospitalet, Oslo, Norway; Danuta Dzierzanowska, Children's Memorial Health Institute, Warsaw, and Waclaw Pawliszyn, Pracownia Bakteriologii, Krakow, Poland; Mariada Luz Martins, Inst. de Higiene e Medicina Tropical, Lisboa, Luis Albuquerque, Centro Hospitalar de Coimbra, Coimbra, Laura Rosado, Instituto Nacional de Saude, Lisboa, Rosa Velho, Hosp da Universidade de Coimbra, Coimbra, and Jose Amorim, Hospital de Santo Antonio, Porto, Portugal; Vera N. Ilina, Novosibirsk Regional Hospital, Novosibirsk, Olga I. Kretchikova, Institute of Antimicrobial Chemotherapy, Smolensk, Galina A. Klyasova, Hematology Research Center, Moscow, Sophia M. Rozanova, City Clinical Hospital No. 40, Ekaterinburg, Irina G. Multykh, Territory Center of Lab Diagnostics, Krasnodar, Nikolay N. Klimko, Medical Mycology Research Inst., St. Petersburg, Elena D. Agapova, Irkutsk Regional Childrens Hospital, Irkutsk, and Natalya V. Dmitrieva, Oncology Research Center, Moscow, Russia; Abdul Mohsen Al-Rasheed, Riyadh Armed Forces Hospital, and Atef Shibl, King Saud University, Riyadh, Saudi Arabia; Jan Trupl, National Cancer Center, and Hupkova Helena, St. Cyril and Metod Hospital, Bratislava, Slovak Republic; Anwar Hoosen, GaRankuwa Hospital, Medunsa, Jeannette Wadula, Baragwanath Hospital, Johannesburg, M. N. Janse van Rensburg, Pelanomi Hospital, UOFS, Bloemfontein, and Adriano Duse, Johannesburg General Hospital, Johannesburg, South Africa; Kyungwon Lee, Yonsei University College of Medicine, and Mi-Na Kim, Asan Medical Center, Seoul, South Korea; A. del Palacio, Hospital 12 De Octobre, and Aurora Sanchez-Sousa, Hospital Ramon y Cajal, Madrid, Spain; Jacques Bille, Institute of Microbiology CHUV, Lausanne, and K. Muhlethaler, Universitat Bern, Bern, Switzerland; Shan-Chwen Chang, National Taiwan University Hospital, Taipei, and Jen-Hsien Wang, China Medical College Hospital, Taichung, Taiwan; Deniz Gur, Hacettepe University Children's Hospital, Ankara, and Volkan Korten, Marmara Medical School Hospital, Istanbul, Turkey; John Paul, Royal Sussex County Hospital, Brighton, Derek Brown, Addenbrooke's Hospital, Cambridge, Chris Kibbler, Royal Free Hospital, London, Nigel Weightman, Friarage Hospital, Northallerton, Ian M. Gould, Aberdeen Royal Hospital, Aberdeen, Claire Rennison, Royal Victoria Hospital, Newcastle, Richard Barton, General Infirmary, P.H.L.S, Leeds, and Rosemary Barnes, University of Wales College of Medicine, Cardiff, United Kingdom; Jose Vazquez, Henry Ford Hospital, Detroit, MI; Davise Larone, Cornell Medical Center NYPH, New York, NY; Mike Rinaldi, University of Texas Health Science Center, San Antonio, TX; and Heidi Reyes, Gen del Este Domingo Luciani, and Axel Santiago, Universitario de Caracas, Caracas, Venezuela.

Footnotes

[down-pointing small open triangle]Published ahead of print on 18 April 2007.

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