Abstract
Candida krusei is well known as a fungal pathogen for patients with hematologic malignancies and for transplant recipients. Using the ARTEMIS Antifungal Surveillance Program database, we describe geographic and temporal trends in the isolation of C. krusei from clinical specimens and the in vitro susceptibilities of 3,448 isolates to voriconazole as determined by CLSI (formerly NCCLS) disk diffusion testing. In addition, we report the in vitro susceptibilities of bloodstream infection isolates of C. krusei to amphotericin B (304 isolates), flucytosine (254 isolates), anidulafungin (121 isolates), caspofungin (300 isolates), and micafungin (102 isolates) as determined by CLSI broth microdilution methods. Geographic differences in isolation were apparent; the highest frequency of isolation was seen for the Czech Republic (7.6%) and the lowest for Indonesia, South Korea, and Thailand (0 to 0.3%). Overall, 83% of isolates were susceptible to voriconazole, ranging from 74.8% in Latin America to 92.3% in North America. C. krusei was most commonly isolated from hematology-oncology services, where only 76.7% of isolates were susceptible to voriconazole. There was no evidence of increasing resistance of C. krusei to voriconazole from 2001 to 2005. Decreased susceptibilities to amphotericin B (MIC at which 90% of isolates were inhibited [MIC90], 4 μg/ml) and flucytosine (MIC90, 16 μg/ml) were noted, whereas 100% of isolates were inhibited by ≤2 μg/ml of anidulafungin (MIC90, 0.06 μg/ml), micafungin (MIC90, 0.12 μg/ml) or caspofungin (MIC90, 0.25 μg/ml). C. krusei is an uncommon but multidrug-resistant fungal pathogen. Among the systemically active antifungal agents, the echinocandins appear to be the most active against this important pathogen.
Candida krusei has been recognized as a potentially multidrug-resistant (MDR) fungal pathogen, due to its intrinsic fluconazole resistance combined with reports of decreased susceptibility to both flucytosine and amphotericin B (1, 2, 3, 6, 20, 22, 23, 26, 37, 39, 47, 61). Several authors have reported breakthrough infections due to C. krusei among patients receiving fluconazole or amphotericin B (1, 11, 19, 21, 31, 34, 61), and Goldman et al. (9) found that response rates of C. krusei infection were significantly better for patients who had received amphotericin B in doses of ≥1 mg/kg of body weight per day than for those who had received lower doses. Furthermore, amphotericin B exhibits markedly delayed killing kinetics against C. krusei compared with that against Candida albicans (4, 19).
The MDR phenotype exhibited by C. krusei poses a therapeutic dilemma when one is considering treatment choices for neutropenic and critically ill patients, especially for those with prior exposure to fluconazole (32, 54, 56, 57). Despite intrinsic resistance to fluconazole, C. krusei usually remains susceptible in vitro to voriconazole due to the more effective binding of voriconazole to the cytochrome P-450 isoenzyme of C. krusei (7, 48). Furthermore, voriconazole has been used successfully to treat some patients infected with C. krusei (16, 29). In addition, the echinocandins have been used based on their fungicidal activity and excellent in vitro activity against C. krusei (41, 42, 56, 57). Whereas echinocandin antifungals such as caspofungin have been used successfully to treat several different infections involving C. krusei (21, 28, 31, 34, 50), there have been recent troubling reports of caspofungin failure in the treatment of C. krusei infections (10, 15, 33). Notably, Hakki et al. (10) reported a strain of C. krusei from a leukemic patient that displayed reduced susceptibilities to caspofungin, anidulafungin, and micafungin. The strain emerged during therapy with caspofungin and subsequently was shown to contain a heterozygous mutation in the FKS1 gene resulting in altered sensitivity of the glucan synthesis enzyme complex to inhibition by echinocandin drugs (15). These findings emphasize the plasticity of C. krusei with respect to the development of resistance to a broad array of antifungals. Along with Candida glabrata, C. krusei must be considered an important indicator species that should be monitored for the development of antifungal resistance (15, 47).
Despite the MDR phenotype exhibited by C. krusei, few studies have addressed the global epidemiology and antifungal susceptibility profile of C. krusei (23). Most of the available information regarding C. krusei comes from single institutions (1) or represents a limited geographic region (23). In the current study, we use the extensive database provided by the ARTEMIS DISK Antifungal Surveillance Program (49) to describe geographic and temporal trends in the isolation of C. krusei from clinical specimens collected from 124 medical centers between 2001 and 2005, as well as the in vitro susceptibilities of 3,448 clinical isolates, including 326 bloodstream infection (BSI) isolates, of this species to voriconazole, as determined by standardized disk diffusion testing. The in vitro susceptibilities of BSI isolates to amphotericin B, flucytosine, anidulafungin, caspofungin, and micafungin were also determined using either Etest (for amphotericin B; AB Biodisk, Solna, Sweden) or Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) broth microdilution methods. This report will serve as the largest study of C. krusei isolates to date.
MATERIALS AND METHODS
Organisms and test sites.
A total of 137,487 isolates of Candida spp., including 3,448 isolates of C. krusei from 124 different medical centers in the Asia-Pacific region (23 sites), Latin America (16 sites), Europe (64 sites), the Africa/Middle East region (11 sites), and North America (10 sites) were collected and tested against voriconazole between January 2001 and December 2005. All Candida spp. considered pathogens from all body sites (e.g., blood, normally sterile body fluids [NSBF], deep tissue, genital tract, urine, respiratory tract, skin and soft tissue) and isolates from all in-hospital and outpatient locations during the study period from 2001 through 2005 were tested. Of the 326 BSI isolates of C. krusei collected, 304 were sent to the University of Iowa for testing against amphotericin B and other antifungal agents.
Data for C. krusei were stratified by year of isolation, geographic region, clinical service (hospital location), and specimen type. Candida spp. considered by the local site investigator to be colonizers, that is, not associated with pathology, were excluded, as were duplicate isolates (the same species and the same susceptible-resistant biotype profile within any 7-day period). Isolates were identified in accordance with each site's routine methods (49).
Susceptibility test methods.
Disk diffusion testing of voriconazole was performed as described previously (49) and in accordance with CLSI document M44-A (25). Agar plates (diameter, 90, 100, or 150 mm) 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. Voriconazole (1 μg) disks (Becton Dickinson, Sparks, MD) were placed on 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. Zone diameter end points were read at 80% growth inhibition by using a BIOMIC image analysis plate reader system (Giles Scientific, Santa Barbara, CA) (49).
MICs of flucytosine, anidulafungin, caspofungin, and micafungin were determined by broth microdilution as described previously (36, 41-43). All isolates were tested in RPMI broth with a 24-h (anidulafungin, caspofungin, and micafungin) or 48-h (flucytosine) incubation and an end point criterion of a prominent reduction in growth relative to that of the control (represented by ≥50% growth inhibition). The susceptibilities of C. krusei isolates to amphotericin B were determined by using Etest (AB Biodisk) as described previously (38).
The interpretive criteria for the voriconazole disk diffusion tests were those of the CLSI (44), as follows: susceptible (S), zone diameter of ≥17 mm; susceptible dose dependent (SDD), zone diameters of 14 to 16 mm; resistant (R), zone diameters of ≤13 mm. The corresponding MIC breakpoints (44) are as follows: S, MIC of ≤1 μg/ml; SDD, MIC of 2 μg/ml; R, MIC of ≥4 μg/ml.
The interpretive criteria for all three echinocandins were those recently assigned by the CLSI (minutes of June 2007 CLSI meeting). Isolates for which the MIC is ≤2 μg/ml are designated S. A category of R has not been established for the echinocandins due to a paucity of “resistant” isolates treated with an echinocandin. Those isolates for which an echinocandin MIC is >2 μg/ml are to be designated “nonsusceptible.”
The interpretive criteria for flucytosine were those recommended by the CLSI (24): S, MIC of ≤4 μg/ml; intermediate (I), MIC of 8 to 16 μg/ml; R, MIC of ≥32 μg/ml. Interpretive breakpoints have not been established for amphotericin B.
QC.
Quality control (QC) was performed in accordance with CLSI documents M44-A (voriconazole) and M27-A2 (all other agents) by using Candida albicans ATCC 90029, Candida parapsilosis ATCC 22019, and C. krusei ATCC 6258 (24, 25). More than 99% of QC results were within the acceptable limits.
Analysis of results.
All disk zone diameters were read by electronic image analysis and interpreted and recorded with the BIOMIC plate reader system (Giles). 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, voriconazole S, SDD, and R results for C. krusei were stratified by year of collection, geographic region, clinical specimen type, and hospital location. The chi-square test, with Yates' correction, was used to determine the statistical significance of differences in voriconazole isolation or susceptibility according to other categorical variables. Alpha was set at 0.05, and all reported P values are two-tailed.
RESULTS
Isolation rates of C. krusei over time and by geographic region.
A total of 137,487 isolates of Candida spp. were recovered and identified at 124 study sites between January 2001 and December 2005 (49). C. krusei ranked fifth among 22 different species of Candida, accounting for 2.5% of all isolates (Table 1). The frequency of isolation of C. krusei did not change (range, 2.3 to 2.7%) over the course of the study.
TABLE 1.
Geographic differences in the frequency of isolation and in vitro susceptibility of Candida krusei to voriconazolea
| Region and country | Total no. of Candida isolates | Total no. (%) of C. krusei isolates | % of C. krusei isolates in the following category:
|
||
|---|---|---|---|---|---|
| S | SDD | R | |||
| Asia-Pacific | 26,580 | 350 (1.2) | 83.7 | 10.0 | 6.3 |
| Australia | 731 | 27 (3.7) | 100.0 | ||
| China | 7,663 | 142 (1.9) | 83.8 | 7.0 | 9.2 |
| India | 356 | 8 (2.2) | 87.5 | 12.5 | |
| Indonesia | 10 | 0 (0.0) | |||
| Malaysia | 10,510 | 142 (1.3) | 78.9 | 16.2 | 4.9 |
| South Korea | 3,515 | 10 (0.3) | 80.0 | 10.0 | 10.0 |
| Taiwan | 3,083 | 19 (0.6) | 94.7 | 5.3 | |
| Thailand | 632 | 2 (0.03) | 100.0 | ||
| Europe | 75,594 | 2.459 (3.3) | 82.1 | 10.1 | 7.8 |
| Belgium | 5,213 | 182 (3.5) | 97.3 | 1.6 | 1.1 |
| Czech Republic | 6,541 | 498 (7.6) | 74.9 | 15.1 | 10.0 |
| France | 2,363 | 57 (2.4) | 78.9 | 12.3 | 8.8 |
| Germany | 2,489 | 110 (4.4) | 90.9 | 4.5 | 4.5 |
| Greece | 589 | 15 (2.5) | 80.0 | 20.0 | |
| Hungary | 12,655 | 519 (4.1) | 70.9 | 17.9 | 11.2 |
| Italy | 5,172 | 177 (3.4) | 89.8 | 5.1 | 5.1 |
| The Netherlands | 6,422 | 31 (0.5) | 93.5 | 3.2 | 3.2 |
| Norway | 253 | 6 (2.4) | 66.7 | 33.2 | |
| Poland | 1,022 | 61 (6.0) | 98.4 | 1.6 | |
| Portugal | 2,843 | 51 (1.8) | 96.1 | 3.9 | |
| Russia | 5,965 | 203 (3.4) | 86.7 | 7.4 | 5.9 |
| Slovakia | 3,559 | 182 (5.1) | 90.1 | 5.5 | 4.4 |
| Spain | 6,328 | 126 (2.0) | 77.0 | 8.7 | 14.3 |
| Switzerland | 1,706 | 47 (2.8) | 93.6 | 4.3 | 2.1 |
| Turkey | 1,320 | 28 (2.1) | 89.3 | 3.6 | 7.1 |
| United Kingdom | 11,154 | 166 (1.5) | 81.9 | 7.8 | 10.2 |
| Latin America | 19,079 | 206 (1.1) | 74.8 | 9.2 | 16.0 |
| Argentina | 6,347 | 61 (1.0) | 93.8 | 4.7 | 1.6 |
| Brazil | 3,764 | 41 (1.1) | 65.9 | 34.1 | |
| Colombia | 3,679 | 55 (1.5) | 61.8 | 20.0 | 18.2 |
| Ecuador | 2,607 | 13 (0.5) | 76.9 | 15.4 | 7.7 |
| Mexico | 889 | 11 (1.2) | 63.6 | 36.4 | |
| Venezuela | 1,793 | 22 (1.2) | 72.7 | 13.6 | 13.6 |
| Africa/Middle East | 6,452 | 108 (1.7) | 88.0 | 6.5 | 5.5 |
| South Africa | 5,286 | 84 (1.6) | 86.9 | 7.1 | 6.0 |
| Israel | 814 | 19 (2.3) | 94.7 | 5.3 | |
| Saudi Arabia | 352 | 5 (1.4) | 80.0 | 20.0 | |
| North America | 9,782 | 325 (3.3) | 92.3 | 3.4 | 4.3 |
| Canada | 913 | 16 (1.8) | 93.8 | 6.3 | |
| United States | 8,869 | 309 (3.5) | 92.2 | 3.2 | 4.5 |
| Total | 137,487 | 3,448 (2.5) | 82.9 | 9.3 | 7.8 |
Isolates were obtained from 124 institutions. Voriconazole disk testing was performed in accordance with CLSI document M44-A (25). The interpretive breakpoints (zone diameters) were as follows: susceptible (S), ≥17 mm; susceptible dose dependent (SDD), 14 to 16 mm; resistant (R), ≤13 mm.
C. krusei represented 3.3% of all Candida spp. isolated in both Europe and North America (3.5% in the United States, 1.8% in Canada) (Table 1). In Europe, C. krusei was isolated most frequently (≥5% of all Candida sp. isolates) in the Eastern European countries of the Czech Republic (7.6%), Poland (6.0%), and Slovakia (5.1%) and was distinctly uncommon (<1%) in The Netherlands (0.5%). C. krusei was also quite uncommon in the Asia-Pacific region (1.3%) and Latin America (1.7%). Fewer than 1% of all Candida strains isolated in Indonesia (0%), South Korea (0.3%), Taiwan (0.6%), Thailand (0.3%), and Ecuador (0.5%) were identified as C. krusei (Table 1).
Geographic differences in the susceptibility of C. krusei to voriconazole.
Table 1 presents the in vitro susceptibility of C. krusei to voriconazole stratified by country and geographic region of origin, as determined by CLSI disk diffusion testing. Overall, C. krusei exhibited decreased susceptibility to voriconazole (82.9% S, 7.8% R) compared to that of C. albicans (98.4% S, 1.2% R) (data not shown).
Considerable differences in the susceptibility of C. krusei to voriconazole were observed across the five broad regions: isolates from North America were the most susceptible (92.3% S, 4.3% R), while the lowest overall susceptibility was seen among isolates from Latin America (74.8% S, 16.0% R; P < 0.001 for the difference between North America and Latin America in the proportion of C. krusei isolates that were susceptible to voriconazole). The lowest susceptibilities to voriconazole (<70%) were seen in the Latin American countries of Brazil (65.9% S, 34.1% R), Colombia (61.8% S, 18.2% R), and Mexico (63.6% S, 36.4% R). No other country reported susceptibility rates of less than 70%. In contrast, susceptibility rates exceeded 90% in 14 countries: Australia (100%), Taiwan (94.7%), Thailand (100%), Belgium (97.3%), Germany (90.9%), The Netherlands (100%), Poland (98.4%), Portugal (96.1%), Slovakia (90.1%), Switzerland (93.6%), Argentina (93.8%), Israel (94.7%), Canada (93.8%), and the United States (92.2%). These extreme differences in the susceptibility of C. krusei to voriconazole are important to understand and monitor, and they emphasize the importance of antifungal susceptibility testing of this species if voriconazole is considered a therapeutic option.
Trends in resistance to voriconazole among C. krusei isolates over time.
There was no evidence of increasing resistance to voriconazole among C. krusei isolates tested between 2001 and 2005. Resistance to voriconazole ranged from 8.0% in 2001 to 7.9% in 2005 (overall range, 6.1 to 8.3) (data not shown).
Differences in the frequency of isolation and the voriconazole susceptibility profile of C. krusei by clinical service.
The clinical services reporting the isolation of C. krusei from patient specimens included the hematology-oncology service, medical and surgical services, intensive care units (medical, surgical, and neonatal), the dermatology service, the obstetrics and gynecology (ObGyn) service, the urology service, and the outpatient service (Table 2). Those strains from services with only a few isolates and those for which a clinical service was not specified were included in the category “other, not otherwise specified” (other, NOS).
TABLE 2.
Susceptibility of Candida krusei to voriconazole by clinical service
| Clinical service (total no. of Candida isolates) | No. of C. krusei isolates | % C. krusei isolatesa | % of C. krusei isolates in the following category:
|
||
|---|---|---|---|---|---|
| S | SDD | R | |||
| Hematology-oncology (8,262) | 514 | 6.2 | 76.7 | 13.4 | 9.9 |
| Medical (32,872) | 752 | 2.3 | 82.7 | 8.4 | 8.9 |
| Surgical (8,673) | 218 | 2.5 | 82.6 | 10.1 | 7.3 |
| Intensive care unit (18,215) | 445 | 2.4 | 81.8 | 11.0 | 7.2 |
| Dermatology (2,450) | 25 | 1.0 | 68.0 | 24.0 | 8.0 |
| ObGyn (17,013) | 220 | 1.3 | 77.3 | 14.5 | 8.2 |
| Urology (1,270) | 26 | 2.0 | 73.1 | 15.4 | 11.5 |
| Outpatient (11,438) | 149 | 1.3 | 81.2 | 7.4 | 11.4 |
| Other, NOS (37,294) | 1,099 | 2.9 | 88.5 | 5.9 | 5.6 |
C. krusei isolates as a percentage of all Candida isolates from the indicated clinical service.
As expected, C. krusei represented a higher proportion of Candida strains isolated from patients hospitalized in hematology-oncology services than from all other services combined (6.2% versus 2.3%; P < 0.001). C. krusei was especially uncommon among Candida isolates from the dermatology, ObGyn, and outpatient services. Voriconazole was least active against isolates from the dermatology (68.0%) and urology (73.1%) services and most active against isolates from the medical (82.7%) and surgical (82.6%) services and from the unspecified (other, NOS) group (88.5%). Fewer than 80% of isolates from the hematology-oncology service were susceptible to voriconazole (76.7%).
Differences in the frequency of isolation and the voriconazole susceptibility profile of C. krusei by clinical specimen type.
The major specimen types yielding C. krusei as a putative pathogen included blood, NSBF, urine, respiratory, general, and skin/soft tissue specimens (Table 3). Those isolates from uncommon specimen types and those for which a specimen type was not recorded were grouped under the category “miscellaneous, NOS.”
TABLE 3.
Susceptibility of Candida krusei to voriconazole by specimen type
| Specimen type or site (total no. of Candida isolates) | No. of C. krusei isolates | % C. krusei isolatesa | % of C. krusei isolates in the following category:
|
||
|---|---|---|---|---|---|
| S | SDD | R | |||
| Blood (14,583) | 326 | 2.2 | 89.0 | 3.7 | 7.4 |
| NSBF (5,940) | 151 | 2.5 | 81.5 | 11.9 | 6.6 |
| Urine (17,693) | 368 | 2.1 | 76.6 | 12.0 | 11.4 |
| Respiratory (38,578) | 1,164 | 3.0 | 81.4 | 10.0 | 8.6 |
| Genital (30,009) | 426 | 1.4 | 81.5 | 10.6 | 8.0 |
| Skin/soft tissue (8,078) | 178 | 2.2 | 85.4 | 7.9 | 6.7 |
| Misc.,b NOS (22,606) | 835 | 3.7 | 86.0 | 8.6 | 5.4 |
C. krusei isolates as a percentage of all isolates from the indicated body site or specimen type.
Misc., miscellaneous.
C. krusei was isolated from 2 to 3% (each) of blood, NSBF, urine, respiratory, and skin/soft tissue specimens. It was isolated infrequently from genital specimens. Interestingly, C. krusei isolates from blood were more likely to be susceptible to voriconazole than those from urine (89.0 versus 76.6%, respectively; P < 0.001). This pattern was similar to that reported previously for another uncommon species of Candida, Candida guilliermondii (45).
Activities of amphotericin B, flucytosine, and the echinocandins against bloodstream isolates of C. krusei.
Among the 326 BSI isolates of C. krusei collected during this survey, 304 isolates were sent to the University of Iowa for further testing against amphotericin B (304 isolates), flucytosine (254 isolates), anidulafungin (121 isolates), caspofungin (300 isolates), and micafungin (102 isolates) (Table 4). Our broth dilution antifungal susceptibility testing panels changed during the 5-year span of the study, which explains why the numbers of isolates tested against each of the agents differ somewhat (e.g., anidulafungin and micafungin were added to the panel, and flucytosine was dropped, in the latter years of the study).
TABLE 4.
In vitro activities of amphotericin B, flucytosine, and the echinocandins against bloodstream isolates of Candida krusei
| Antifungal agenta | No. of isolates tested | Cumulative % of C. krusei isolates inhibited at a MIC (μg/ml) of:
|
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | ||
| Amphotericin B | 304 | 4 | 4 | 5 | 7 | 24 | 51 | 85 | 98 | 99 | 100 | ||
| Flucytosine | 254 | 1 | 1 | 1 | 1 | 2 | 5 | 8 | 26 | 93 | 99 | 99 | |
| Anidulafungin | 121 | 49 | 92 | 99 | 99 | 100 | |||||||
| Caspofungin | 300 | 1 | 40 | 69 | 90 | 98 | 99 | 100 | |||||
| Micafungin | 102 | 12 | 84 | 99 | 100 | ||||||||
Amphotericin B MICs were determined by Etest after 24 h of incubation. Echinocandin MICs were determined using RPMI 1640 broth with 24 h of incubation and an end point criterion of a prominent reduction in growth (MIC-2).
Among the BSI isolates tested, decreased susceptibilities to amphotericin B (MIC at which 90% of isolates were inhibited [MIC90], 4 μg/ml) and flucytosine (MIC90, 16 μg/ml; 8% S) were noted. By comparison, the MIC90s of amphotericin B and flucytosine tested against C. albicans were 0.5 μg/ml and 1.0 μg/ml, respectively (data not shown). All isolates of C. krusei were susceptible to the three echinocandins at the CLSI breakpoint concentration of ≤2 μg/ml: MIC90s were 0.06 μg/ml for anidulafungin, 0.12 μg/ml for micafungin, and 0.25 μg/ml for caspofungin.
DISCUSSION
The results from this extensive survey of C. krusei both confirm and extend previous observations concerning this species (1, 3, 6, 22, 23, 39, 40, 47, 52). C. krusei remains a relatively uncommon clinical isolate throughout the world (Table 1). Most notable is the very low frequency of isolation in both the Asia-Pacific and Latin American regions as opposed to the higher frequency observed in several Eastern European countries. This could represent geographic differences in the ecology of Candida species or in the use of cytotoxic drugs and antimicrobial agents (22). C. krusei is most common among patients with hematologic malignancies and recipients of blood and marrow transplants (1, 2, 12, 20, 26, 61). Whether this observation is a direct result of fluconazole administration remains controversial, since others have reported infections due to this species before the introduction of fluconazole (14, 22, 60). In addition, several centers have reported no increased incidence of infections with C. krusei, despite the widespread use of fluconazole (8, 17, 18, 51, 55). As reported in several smaller studies (5, 6, 10, 23, 30, 34, 37, 39, 55), C. krusei was generally susceptible to voriconazole, although considerable geographic differences were seen (Table 1), like those seen with C. glabrata (49) and Candida rugosa (46).
There was less variability in voriconazole susceptibility across the different clinical services (Table 2) and specimen types (Table 3). Notably, BSI isolates of C. krusei exhibited the greatest susceptibility to voriconazole. Although isolates of C. krusei from blood and NSBF are clearly pathogenic, the isolation of this organism from nonsterile sites (e.g., urine, respiratory, and genital specimens) may simply represent colonization rather than infection. That said, colonization with C. krusei precedes infection in approximately 70% of patients (1, 9, 13, 26, 35, 53, 59), and colonizing strains of C. krusei have been shown to be indistinguishable from BSI isolates obtained from the same patient, supporting the role of this species as an endogenous pathogen (3, 27, 58). Thus, the isolation of C. krusei from nonsterile sites may have direct bearing on the selection of antifungal therapy.
We document a pattern of decreased susceptibility of C. krusei to amphotericin B and flucytosine that, along with intrinsic resistance to fluconazole, results in an MDR phenotype. As seen previously (41, 43), the echinocandins were all active against BSI isolates of C. krusei. The activity of this class of antifungal agents against this MDR pathogen is encouraging; however, the reports of resistance developing to caspofungin during the treatment of C. krusei infection must be kept in mind. The reduced susceptibility to caspofungin in both cases was associated with the onset of clinically apparent fungal infection involving anatomic sites, such as the eye (10) or the central nervous system (33), where adequate free drug levels cannot be readily obtained. In such instances, the availability of an agent such as voriconazole, with both activity against the infecting organism and good penetration into ocular and central nervous system sites, may be vital to a successful outcome (33). Continued monitoring of the susceptibility of C. krusei to voriconazole and the echinocandins is clearly warranted.
In summary, we have used data from the ARTEMIS DISK Antifungal Surveillance Program (49) to increase our understanding of C. krusei as an opportunistic fungal pathogen. Our findings demonstrate considerable geographic diversity both in its occurrence and in its susceptibility to the expanded-spectrum triazole voriconazole. In addition to resistance to fluconazole, this species clearly exhibits decreased susceptibility to amphotericin B and flucytosine. Given the variable activity of voriconazole against this species, demonstrated here, and recent reports of acquired resistance to echinocandins, testing of the susceptibility of C. krusei to these potentially useful antifungal agents may be warranted to help guide therapeutic decisions.
Acknowledgments
Tara Schroder provided excellent support in the preparation of this article.
The ARTEMIS DISK Surveillance Program is supported by grants from Pfizer.
We express our appreciation to all ARTEMIS participants. Contributing participants during 2001 to 2005 include Jorge Finquelievich (Buenos Aires University) and Nora Tiraboschi (Hospital Escuela General), 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) 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), P. D. G. Haase (RWTH Aachen, Aachen), A. C. Rodloff (Institut für Medizinische Mikrobiologie, Leipzig), W. Bar (Carl-Thiem Klinikum, Cottbus), and V. Czaika (Humaine Kliniken, Bad Saarow), Germany; George Petrikos (Laikon General Hospital, Athens), Greece; Erzsébet Puskás (BAZ County Institute, Miskolc), Ilona Dóczi (University of Szeged, Szeged), Gyula Mestyan (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, Tel Hashomer), 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 (Dipartimento di Biotechnologia, Rome), Italy; Ng 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 (Instituto de Higiene e Medicina Tropical, Lisboa), Luis Albuquerque (Centro Hospitalar de Coimbra, Coimbra), Laura Rosado (Instituto Nacional de Saude, Lisboa), Rosa Velho (Hospital 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 Institute, 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 Ki, (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—New York Presbyterian Hospital, New York, NY), and Mike Rinaldi (University of Texas Health Science Center, San Antonio, TX); Heidi Reyes (Hospital General del Este Domingo Luciani) and Axel Santiago (Universitario de Caracas), Caracas, Venezuela.
Footnotes
Published ahead of print on 12 December 2007.
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