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Journal of Clinical Microbiology logoLink to Journal of Clinical Microbiology
. 2008 Jan 16;46(3):842–849. doi: 10.1128/JCM.02122-07

Geographic and Temporal Trends in Isolation and Antifungal Susceptibility of Candida parapsilosis: a Global Assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005▿

M A Pfaller 1,*, D J Diekema 1,2, D L Gibbs 3, V A Newell 3, K P Ng 4, A Colombo 5, J Finquelievich 6, R Barnes 7, J Wadula 8; the Global Antifungal Surveillance Group
PMCID: PMC2268358  PMID: 18199791

Abstract

We examined data from the ARTEMIS DISK Antifungal Surveillance Program to describe geographic and temporal trends in the isolation of Candida parapsilosis from clinical specimens and the in vitro susceptibilities of 9,371 isolates to fluconazole and voriconazole. We also report the in vitro susceptibility of bloodstream infection (BSI) isolates of C. parapsilosis to the echinocandins, anidulafungin, caspofungin, and micafungin. C. parapsilosis represented 6.6% of the 141,383 isolates of Candida collected from 2001 to 2005 and was most common among isolates from North America (14.3%) and Latin America (9.9%). High levels of susceptibility to both fluconazole (90.8 to 95.8%) and voriconazole (95.3 to 98.1%) were observed in all geographic regions with the exception of the Africa and Middle East region (79.3 and 85.8% susceptible to fluconazole and voriconazole, respectively). C. parapsilosis was most often isolated from blood and skin and/or soft tissue specimens and from patients hospitalized in the medical, surgical, intensive care unit (ICU) and dermatology services. Notably, isolates from the surgical ICU were the least susceptible to fluconazole (86.3%). There was no evidence of increasing azole resistance over time among C. parapsilosis isolates tested from 2001 to 2005. Of BSI isolates tested against the three echinocandins, 92, 99, and 100% were inhibited by concentrations of ≤2 μg/ml of anidulafungin (621 isolates tested), caspofungin (1,447 isolates tested), and micafungin (539 isolates tested), respectively. C. parapsilosis is a ubiquitous pathogen that remains susceptible to the azoles and echinocandins; however, both the frequency of isolation and the resistance of C. parapsilosis to fluconazole and voriconazole may vary by geographic region and clinical service.

Candida parapsilosis is the most common non-albicans species of Candida isolated from blood cultures in most regions of the world outside of the United States (2, 3, 8, 12, 24, 37, 44, 45, 50). C. parapsilosis is an exogenous pathogen that may be found on skin rather than mucosal surfaces (3, 5, 10, 18, 36, 56, 58). C. parapsilosis is known for the ability to form biofilms on catheters and other implanted devices (6, 10, 13, 17, 18, 20, 53), for nosocomial spread by hand carriage, and for persistence in the hospital environment (3, 8, 10, 14, 18, 20, 35, 48, 50, 51, 58). It is also well known for causing infections in infants and neonates (10, 15, 18, 21, 22, 45, 49, 51, 52, 59).

The frequency of invasive candidiasis due to C. parapsilosis has increased in recent years (44, 45), most notably in Spain (3) and in Latin America (8, 11, 20, 24, 37, 50). Fortunately, bloodstream infection (BSI) due to this species is associated with a significantly lower mortality rate than are infections due to other common species of Candida (1, 2, 16, 29, 31, 48).

Although C. parapsilosis is not considered prone to developing antifungal resistance (2, 8, 12, 14, 16, 29, 37, 44, 45, 48, 54, 55), several recent reports suggest that decreased susceptibility of C. parapsilosis to azoles and echinocandins may be cause for concern (3, 5, 8-10, 25, 26, 29, 46, 51, 54, 55, 57). As early as 1994, Nguyen et al. (29) noted that C. parapsilosis was the most common non-albicans species of Candida recovered in fluconazole-breakthrough fungemia in a prospective multicenter observational study of candidemia. Two recent outbreaks of C. parapsilosis BSI, one in an adult intensive care unit (ICU) (10) and one in a neonatal ICU (NICU) (51), serve to emphasize the importance of the confluence of patient, organism, and environmental or behavioral factors in perpetuating the spread of this exogenous pathogen. In both instances, extensive use of fluconazole, suboptimal hand hygiene and catheter care, and a seriously ill patient population conspired to generate an epidemic strain of C. parapsilosis with decreased susceptibility to fluconazole that was transmitted throughout the respective ICU environments. It was postulated that the decreased susceptibility of the epidemic strains to fluconazole provided a selective advantage, allowing C. parapsilosis colonization of skin and catheter surfaces with subsequent transmission facilitated by poor handwashing practices (10, 51).

The fact that C. parapsilosis is intrinsically less susceptible to the echinocandin class of antifungal agents relative to that of C. albicans or C. glabrata is well known (30, 38-41, 45, 47) and is supported by the documentation of Fks1 polymorphisms that are characteristic of the species and confer reduced susceptibility to all three echinocandins (anidulafungin, caspofungin, and micafungin) (33, 34). Furthermore, caspofungin has been shown to exhibit markedly delayed killing kinetics against C. parapsilosis compared to C. albicans (4). Although in their phase III clinical trials both caspofungin (25) and micafungin (19) were found to be as effective against C. parapsilosis as amphotericin B deoxychocolate and liposomal amphotericin B, respectively, it is notable that in the subgroup of patients with C. parapsilosis infection, 5 of 20 patients had persistently positive cultures at the end of caspofungin therapy compared to none in the amphotericin B group. Likewise, Reboli et al. reported that anidulafungin had a lower rate than fluconazole (69% versus 88%, respectively) at mediating microbiological eradication of C. parapsilosis invasive infection (46).

Perhaps the most alarming evidence regarding the emergence of echinocandin resistance in C. parapsilosis is that reported by Moudgal et al. (26) and Vazquez et al. (57) from Detroit, MI. In a case report of C. parapsilosis prosthetic valve endocarditis, Moudgal et al. (26) described the emergence of resistance to fluconazole, voriconazole, caspofungin, and micafungin (but not anidulafungin) after initial therapy with fluconazole and caspofungin. Subsequently, Vazquez et al. (57) documented an increase in the recovery of multi-echinocandin, multi-azole-resistant C. parapsilosis from patients in the burn unit of their hospital. The development, and subsequent nosocomial expansion, of echinocandin- and azole-resistant C. parapsilosis has important clinical implications. Continued monitoring for the emergence of this multidrug-resistant phenotype of C. parapsilosis is clearly warranted.

Despite the importance of C. parapsilosis as a nosocomial fungal pathogen, few studies have addressed the global epidemiology and antifungal susceptibility profile of C. parapsilosis (3, 58). Most of the available information regarding C. parapsilosis comes from single institutions (5, 10, 24, 26, 48, 50, 51) or represents a limited geographical region (3, 8, 29) and does not address frequency of isolation or resistance over time and among various clinical services or specimen types. Given the potential for decreased susceptibility of C. parapsilosis to azoles and echinocandins, it seems prudent to gather additional information regarding this opportunistic fungal pathogen. In the present study, we use the extensive database provided by the ARTEMIS DISK Antifungal Surveillance Program (44) to describe geographical and temporal trends in the isolation of C. parapsilosis from clinical specimens collected in 124 medical centers worldwide between 2001 and 2005, the types of specimens and clinical services in which C. parapsilosis infections are recognized, and the in vitro susceptibilities of 9,371 clinical isolates, including 2,834 BSI isolates of this species, to fluconazole and voriconazole, as determined by standardized disk diffusion testing. The in vitro susceptibility of BSI isolates to caspofungin, anidulafungin, and micafungin was also determined by using Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) methods.

MATERIALS AND METHODS

Organisms and test sites.

A total of 141,383 isolates of Candida spp., including 9,371 isolates of C. parapsilosis, from 124 different medical centers in various regions—Asia-Pacific (23 sites), Latin America (16 sites), Europe (64 sites), Africa and the Middle East (11 sites), and North America (10 sites)—were collected and tested against fluconazole and 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 biopsy, genital tract, urine, respiratory tract, skin, and soft tissue) and isolates from all in-hospital and outpatient locations during the study period from 2001 thru 2005 were tested. Of the 2,834 BSI isolates of C. parapsilosis collected, 1,447 were sent to the University of Iowa (Iowa City) for testing against caspofungin; 621 of these isolates were also tested against anidulafungin, and 539 were tested against micafungin based on the availability of the antifungal agents from their respective manufacturers.

Data for C. parapsilosis 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, i.e., 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). Identification of isolates was performed in accordance with each site's routine methods (44).

Susceptibility test methods.

Disk diffusion testing of fluconazole and voriconazole was performed as described previously (44) and in accordance with CLSI document M44-A (28). Agar plates (90, 100, or 150 mm in 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. Zone diameter endpoints were read at 80% growth inhibition by using a BIOMIC image analysis plate reader system (Giles Scientific, Santa Barbara, CA) (44).

The MICs of anidulafungin, caspofungin, and micafungin were determined by BMD as described previously (39-41). All isolates were tested in RPMI broth with 24 h of incubation and a prominent reduction in growth (≥50%) relative to control (MIC-2) endpoint criteria.

The interpretive criteria for fluconazole and voriconazole disk diffusion tests were those of the CLSI (28, 42, 43) and are as follows: 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 (27, 42, 43) are as follows: S, MICs of ≤8 μg/ml (fluconazole) and ≤1 μg/ml (voriconazole); SDD, MICs of 16 to 32 μg/ml (fluconazole) and 2 μg/ml (voriconazole); and R, MICs of ≥64 μg/ml (fluconazole) and ≥4 μg/ml (voriconazole).

The interpretive criteria for all three echinocandins were those recently assigned by the CLSI (June 2007): S, ≤2 μg/ml; a category of R has not been established for the echinocandins due to the paucity of “resistant” isolates treated with an echinocandin. Isolates for which the echinocandin MIC is >2 μg/ml are designated “nonsusceptible” (NS).

QC.

Quality control (QC) was performed in accordance with CLSI documents M44-A (fluconazole and voriconazole) and M27-A2 (all other agents) by using C. albicans ATCC 90029, C. parapsilosis ATCC 22019, and C. krusei ATCC 6258 (27, 28). More than 99% of the QC results were within the acceptable limits (44).

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 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, the fluconazole and voriconazole S, SDD, and R results for C. parapsilosis were stratified by year of collection, geographic region, clinical specimen type, and hospital location.

RESULTS

Isolation rates of C. parapsilosis over time and by geographic region.

A total of 141,383 isolates of Candida spp. were isolated and identified at 124 study sites between January 2001 and December 2005 (44). C. parapsilosis ranked fourth among 22 different species of Candida, accounting for 6.6% of all isolates (Table 1). Although the overall frequency of C. parapsilosis increased from 4.8% in the years 1997 to 2000 to 6.6.% in the years 2001 to 2005 (44), the annual isolation rates were relatively stable during the latter time period ranging from 6.9% in 2001 to 7.3% in 2003 and 5.6% in 2005.

TABLE 1.

Variation in frequency of C. parapsilosis by geographic regiona

Region Total no. of Candida species isolates Total no. (%) of C. parapsilosis isolates
Asia-Pacific 27,845 2,263 (8.1)
Africa and Middle East 6,523 348 (5.3)
Europe 77,268 3,388 (4.4)
Latin America 19,895 1,960 (9.9)
North America 9,852 1,412 (14.3)
Total 141,383 9,371 (6.6)
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a

Data were obtained from the ARTEMIS DISK Global Antifungal Surveillance Program (2001 to 2005). Isolates represent all incident isolates from all sites of infection.

C. parapsilosis was most frequently isolated in North America (14.3% of all Candida isolates) and Latin America (9.9%), although the frequency of isolation varied considerably within each of the five geographic locations, ranging from 0% (Indonesia) to 16.9% (Australia) in the Asia-Pacific region, from 1.3% (Slovakia) to 7.8% (Spain and Turkey) in Europe, and from 1.2% (Ecuador) to 12.8% (Brazil) in Latin America (Tables 1 and 2).

TABLE 2.

Geographic variation in susceptibility of C. parapsilosis to fluconazole and voriconazole

Region or country % by categorya
Fluconazole
Voriconazole
N S SDD R N S SDD R
Asia-Pacific 2,263 90.8 4.6 4.6 2,092 95.3 2.6 2.1
Australia 124 99.2 0.8 124 99.2 0.8
China 121 87.6 4.1 8.3 121 92.6 3.3 4.1
India 32 90.6 6.3 3.1 31 100.0
Malaysia 1,521 89.2 5.5 5.3 1,353 94.6 3.4 2.0
South Korea 186 99.5 0.5 185 99.5 0.5
Taiwan 262 92.0 3.4 4.6 261 94.6 1.6 3.8
Thailand 17 88.2 11.8 17 100.0
Europe 3,388 95.8 1.8 2.4 3,298 98.1 0.8 1.1
Belgium 104 98.1 1.9 103 98.1 1.9
Czech Republic 300 99.0 1.0 283 100.0
France 94 84.0 8.6 7.4 77 96.1 2.6 1.3
Germany 135 99.3 0.7 135 99.3 0.7
Greece 36 83.3 5.6 11.1 36 94.4 2.8 2.8
Hungary 259 90.3 3.5 6.2 237 95.4 1.2 3.4
Italy 374 97.9 1.0 1.1 374 99.2 0.5 0.3
The Netherlands 151 95.4 2.6 2.0 151 96.7 1.3 2.0
Norway 7 100.0 7 100.0
Poland 68 91.2 1.4 7.4 68 95.6 1.5 2.9
Portugal 215 96.7 0.5 2.8 215 97.7 0.4 1.9
Russia 213 87.8 3.7 8.5 213 96.7 1.9 1.4
Slovakia 47 91.5 4.2 4.3 47 93.6 6.4
Spain 496 99.0 0.6 0.4 496 99.6 0.2 0.2
Switzerland 88 98.9 1.1 89 100.0
Turkey 109 96.3 1.9 1.8 93 98.9 1.1
United Kingdom 692 96.8 1.9 1.3 674 97.9 1.2 0.9
Latin America 1,960 93.7 4.0 2.3 1,910 97.8 1.2 1.0
Argentina 715 93.7 4.8 1.5 702 98.4 1.0 0.6
Brazil 500 97.2 1.2 1.6 496 97.8 1.0 1.2
Colombia 465 89.9 5.4 4.7 440 96.4 1.8 1.8
Ecuador 32 87.5 12.5 32 96.9 3.1
Mexico 98 95.9 3.1 1.0 88 98.9 1.1
Venezuela 150 93.3 4.0 2.7 152 98.7 0.6 0.7
Africa and Middle East 348 79.3 5.2 15.5 345 85.8 2.9 11.3
South Africa 256 74.2 5.5 20.3 253 81.0 4.0 15.0
Israel 54 94.4 3.7 1.9 54 100.0
Saudi Arabia 38 92.1 5.3 2.6 38 97.4 2.6
North America 1,412 94.3 1.8 3.9 1,396 97.1 0.9 2.0
Canada 69 97.1 1.5 1.4 69 100.0
United States 1,343 94.2 1.8 4.0 1,327 96.9 0.9 2.2
Total 9,371 93.3 3.0 3.6 9,041 96.8 1.4 1.9
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a

All isolates were tested by the disk diffusion method performed in accordance with CLSI standard M44-A. S, susceptible, with zone diameters of ≥19 mm for fluconazole and ≥17 mm for voriconazole; SDD, susceptible dose dependent, with zone diameters of 15 to 18 mm for fluconazole and 14 to 16 mm for voriconazole; R, resistant, with zone diameters of ≤14 mm for fluconazole and ≤13 mm for voriconazole.

Geographic variation in susceptibility of C. parapsilosis to fluconazole and voriconazole.

Table 2 represents the in vitro susceptibilities of C. parapsilosis to fluconazole and voriconazole stratified by country and geographic region of origin, as determined by CLSI disk diffusion testing. Overall, C. parapsilosis exhibited slightly decreased susceptibility to fluconazole (93.3% S, 3.6% R) compared to that of C. albicans (97.9% S, 1.5% R) (data not shown).

A surprising degree of variation in the susceptibility of C. parapsilosis to fluconazole was observed across the first five broad regions: isolates from Europe were the most susceptible (95.8% S, 2.4% R), and the lowest overall susceptibility was seen among isolates from the Africa and Middle East region (79.3% S, 15.5% R), the latter being largely accounted for by isolates from South Africa (74.2% S, 20.3% R). No other country reported susceptibility rates of less than 80%; however, the susceptibility rates were less than 90% in eight countries: China (87.6%), Malaysia (89.2%), Thailand (88.2%), France (84.0%), Greece (83.3%), Russia (87.8%), Colombia (89.9%), and Ecuador (87.5%). More than 95% of isolates were susceptible to fluconazole in 16 countries: Australia (99.2%), South Korea (99.5%), Belgium (98.1%), the Czech Republic (99.0%), Germany (99.3%), Italy (97.9%), The Netherlands (95.4%), Norway (100%), Portugal (96.7%), Spain (99.0%), Switzerland (98.9%), Turkey (96.3%), the United Kingdom (96.8%), Brazil (97.2%), Mexico (95.9%), and Canada (97.1%).

Voriconazole was always more active against C. parapsilosis than fluconazole, irrespective of geographic region. In contrast to fluconazole, only a slight variation in voriconazole activity was observed across the different countries and regions, ranging from a low of 81% susceptible in South Africa to a high of 100% in India, Thailand, Czech Republic, Norway, Switzerland, Israel, and Canada. More than 98% of isolates in 17 of the 35 countries were susceptible to voriconazole.

Trends in resistance to fluconazole and voriconazole among C. parapsilosis isolates over time.

There was no evidence of increasing resistance to the azoles among C. parapsilosis isolates tested between 2001 and 2005. Resistance to fluconazole ranged from 4.2% in 2001 to 3.1% in 2003 and was 4.2% in 2005. Resistance to voriconazole was 1.9% in 2001, peaked at 2.3% in 2002, and was 1.9% in 2005.

Variation in the frequency of isolation and antifungal susceptibility profile of C. parapsilosis by clinical service.

The clinical services reporting the isolation of C. parapsilosis from patient specimens included the hematology-oncology service, medical and surgical services, intensive care units (medical, surgical, and neonatal), the dermatology service, the urology service, and the outpatient service (Table 3). 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 (NOS)”.

TABLE 3.

Susceptibility of C. parapsilosis to fluconazole and voriconazole by clinical service

Clinical service (total no. of isolates)a Antifungal agent No. of isolates tested % of isolates from serviceb % of isolatesc
S SDD R
Hematology-oncology (8,432) Fluconazole 305 3.6 94.8 2.6 2.6
Voriconazole 301 98.7 0.7 0.7
Medical (33,681) Fluconazole 2,144 6.4 93.7 2.6 3.7
Voriconazole 2,100 96.7 1.4 2.0
Surgical (8,869) Fluconazole 561 6.3 93.9 3.0 3.0
Voriconazole 547 96.9 1.3 1.8
ICU (18,691) Fluconazole 1,119 6.0 91.3 3.6 5.1
Voriconazole 1,083 95.3 1.4 3.3
Dermatology (2,519) Fluconazole 527 20.9 93.0 4.0 3.0
Voriconazole 502 97.2 1.2 1.6
Urology (1,293) Fluconazole 61 4.7 91.8 4.9 3.3
Voriconazole 60 96.7 3.3
Outpatient (11,621) Fluconazole 811 7.0 95.2 2.8 2.0
Voriconazole 797 98.4 0.8 0.9
Other, NOSd (38,649) Fluconazole 3,843 9.9 93.2 3.1 3.7
Voriconazole 3,653 96.5 1.6 1.9
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a

That is, the total number of Candida isolates from each service.

b

C. parapsilosis as a percentage of all isolates from that clinical service.

c

S, SDD, and R are as defined in Table 2, footnote a.

d

Other, NOS, other, not otherwise specified.

Candida parapsilosis was isolated most frequently from patients on the Dermatology service (20.9%) and least frequently from patients on the Hematology-Oncology service (3.6%). Only 6% of the Candida spp. isolated from ICU patients in the present study were C. parapsilosis. However, C. parapsilosis was isolated much more frequently from patients in the NICU (15.4% of all Candida spp. from NICU).

There was little variation in susceptibility to either triazole across the different services. More than 90% of isolates were susceptible to both fluconazole and voriconazole irrespective of the different clinical services.

Variation in the frequency of isolation and antifungal susceptibility profile of C. parapsilosis by clinical specimen type.

The major specimen types yielding C. parapsilosis as a putative pathogen included blood, NSBF, urine, respiratory, skin and soft tissue, and genital specimens (Table 4). The isolates from uncommon specimen types and those for which a specimen type was not recorded were grouped under the category “Misc., NOS” (miscellaneous, not otherwise specified).

TABLE 4.

Susceptibility of C. parapsilosis to fluconazole and voriconazole by specimen type

Specimen type/site (total no. of isolates)a Antifungal agent No. of isolates tested % of isolates from siteb % of isolatesc
S SDD R
Blood (14,887) Fluconazole 2,834 19.0 93.1 2.7 4.2
Voriconazole 2,755 96.8 1.0 2.2
NSBF (6,055) Fluconazole 373 6.2 94.1 2.7 3.2
Voriconazole 368 97.3 0.5 2.2
Urine (18,168) Fluconazole 806 4.4 91.1 4.5 4.5
Voriconazole 771 96.1 1.8 2.1
Respiratory (39,523) Fluconazole 1,008 2.6 94.2 3.4 2.4
Voriconazole 979 97.3 1.2 1.5
Skin or soft tissue (8,290) Fluconazole 1,220 14.7 95.1 3.0 1.9
Voriconazole 1,196 97.9 1.2 0.9
Genital (31,157) Fluconazole 1,009 3.2 95.7 2.3 2.0
Voriconazole 926 97.3 1.3 1.4
Misc. NOS (23,303) Fluconazole 2,121 9.1 91.7 3.3 5.0
Voriconazole 2,046 95.7 2.0 2.3
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a

That is, the total number of Candida isolates from each specimen type. Misc. NOS, miscellaneous, not otherwise specified.

b

C. parapsilosis as a percentage of all isolates from that specimen type.

c

S, SDD, and R are as defined in Table 2, footnote a.

C. parapsilosis was isolated most frequently from blood and skin and soft tissue specimens and was isolated infrequently from urine, respiratory, and genital tract specimens. Both fluconazole and voriconazole were quite active (>90% S) against isolates of C. parapsilosis irrespective of specimen type.

Activity of echinocandin antifungal agents against bloodstream isolates of C. parapsilosis.

Previously, we and others have shown that echinocandin MICs are consistently higher for C. parapsilosis than for C. albicans when tested by BMD methods (30, 39-41). When tested against anidulafungin, caspofungin, and micafungin using the CLSI BMD method, 93.2, 99.6, and 100% of the BSI isolates of C. parapsilosis were susceptible to the three echinocandins, respectively, at the recently assigned (June 2007) CLSI breakpoint concentration of ≤2 μg/ml (Table 5). The differences in potency among the three agents are best reflected by the modal MICs: caspofungin (0.25 to 0.5 μg/ml), micafungin (1.0 μg/ml), and anidulafungin (2.0 μg/ml). This pattern was unchanged across the different geographic regions (data not shown). Importantly, we did not observe a multi-echinocandin, multi-azole-resistant phenotype such as that reported by Moudgal et al. (26) and Vazquez et al. (57). Among nine isolates that were found to be resistant to fluconazole (MIC, ≥64 μg/ml), all were susceptible (MIC, ≤2 μg/ml) to anidulafungin (range, 1 to 2 μg/ml), caspofungin (range, 0.25 to 2 μg/ml), and micafungin (range, 1 to 2 μg/ml). Likewise, the Detroit phenotype for echinocandin resistance (i.e., caspofungin- and micafungin-resistant, anidulafungin-susceptible) was not detected among 539 isolates tested against all three echinocandins.

TABLE 5.

In vitro activity of anidulafungin, caspofungin, and micafungin against bloodstream isolates of C. parapsilosisa

Antifungal agent No. tested Cumulative % of isolates at an MIC (μg/ml) of:
0.015 0.03 0.06 0.12 0.25 0.5 1 2 4
Anidulafungin 621 0.3 0.8 0.8 0.8 1.9 4.7 29.3 93.2 100
Caspofungin 1,447 0.3 0.9 3.7 12.4 49.9 89.4 98.8 99.6 100
Micafungin 539 0.2 0.2 0.2 0.6 5.2 22.5 75.3 100
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a

Isolates were tested in RPMI 1640 broth with 24 h of incubation and a prominent reduction endpoint criterion (MIC-2).

DISCUSSION

The results of this extensive survey of C. parapsilosis both confirm and extend previous observations regarding this species (1, 3, 8, 15, 29, 48, 50, 58). We have demonstrated that the frequency of isolation of C. parapsilosis varies considerably among countries, clinical services, and specimen types and confirm the increased frequency in Latin America, neonatal ICUs, and blood and dermatologic specimens. Likewise, we confirm the general susceptibility of C. parapsilosis to both fluconazole and voriconazole and yet document an unusual pocket of azole resistance in South Africa.

Although fluconazole is well known to have good activity against C. parapsilosis, it is clear from this survey that decreased susceptibility may occur in certain geographic regions and in select institutions (10, 26, 51, 57), suggesting that monitoring of local susceptibility profiles may be useful. Decreased susceptibility to fluconazole among C. parapsilosis may be enhanced by the proclivity of this species to form extensive biofilms on catheters and other devices (13, 17, 18, 20). Because the source of C. parapsilosis fungemia is a vascular catheter in more than 50% of cases and such infections occur commonly in patients who had received prior antifungal treatment (3), an adequate response to fluconazole alone may not be achieved, and administration of this agent should be coupled with prompt removal of the catheter to ensure an optimal response (32). Furthermore, despite excellent overall activity of voriconazole against C. parapsilosis, it must be recognized that only 36.7% of fluconazole-resistant isolates of C. parapsilosis retain susceptibility to voriconazole (44).

Given that C. parapsilosis is well known as a superficial colonizer of cutaneous surfaces and as a cause of onychomycosis (5, 7, 23, 56), it is not surprising that we found it to be isolated commonly from skin and soft tissue infections in patients on the Dermatology service. Bonassoli et al. (5) found a high frequency of C. parapsilosis colonization of the hands of healthy volunteers and health care workers and noted that these colonizing strains exhibited the same potential virulence characteristics as those isolated from sites of infection. Thus, hand colonization with virulent strains of C. parapsilosis coupled with poor hand washing and catheter care may serve as a nosocomial threat to seriously ill patients (10, 18).

Although C. parapsilosis is often reported to cause infections among patients hospitalized in the ICU (1, 3, 10, 51), only 6% of the Candida spp. isolated from ICU patients in the present study were C. parapsilosis. However, C. parapsilosis was isolated much more frequently from patients in the NICU (15.4% of all Candida spp.) than from those in the medical (5.8%) or surgical (3.4%) ICU. This finding supports previous observations regarding candidiasis in the NICU (15, 21, 22, 49, 51, 52, 58, 59).

Although the role of C. parapsilosis as a pathogen when isolated from nonsterile sites such as the respiratory, urinary, and genital tracts is debated, isolation from blood and NSBF must be considered significant. Thus, it is worth noting that the single most common specimen to yield C. parapsilosis in culture was blood (Table 4). Prior colonization of mucosal sites is rare among patients with C. parapsilosis fungemia, further confirming the exogenous nature of this pathogen (3).

Perhaps the most encouraging information from this survey is the lack of any multi-azole, multi-echinocandin-resistant strains of C. parapsilosis. Although this species is innately less susceptible to the echinocandins than many other species of Candida, the vast majority of isolates remain susceptible to all three echinocandins (Table 5). Specifically, the epidemic phenotype reported from Detroit, MI (57), was not detected. Potency differences among the three echinocandins were detected; however, previous studies have found that such differences in vitro were normalized by the addition of serum to the test medium and did not prove to be important in vivo (34). Nevertheless, the experience in Detroit (26, 57) and the less-than-stellar results against C. parapsilosis in clinical trials (25, 46, 54) suggest that this species should be carefully monitored with respect to emerging echinocandin resistance.

In summary, we have used the extensive and validated database of the ARTEMIS DISK Antifungal Surveillance Program (44) to increase our understanding of C. parapsilosis as an opportunistic pathogen. Our findings confirm that this species is an emerging pathogen in Latin America and is also important in North America. This species may exhibit decreased susceptibility to fluconazole in some geographic locations and is generally susceptible to voriconazole and the echinocandins. It is most likely to be isolated from blood and is often associated with intravascular catheters and parenteral nutrition. The detection of BSIs with C. parapsilosis should raise a “red flag” regarding breaks in catheter care and infection control procedures, since it usually signifies the exogenous introduction of the offending pathogen into an already compromised host (3, 10, 44, 58).

Acknowledgments

Linda Elliot and Tara Schroder provided excellent support in the preparation of the manuscript.

This study was supported in part by grants from Pfizer, Astellas, and Merck.

We express our appreciation to all ARTEMIS participants. Contributing participants from 2001 to 2005 include Jorge Finquelievich, Buenos Aires University, Buenos Aires, Argentina; 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, Belgium; Anne-Marie van den Abeele, St. Lucas Campus Heilige Familie, Gent, Belgium; 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, Alberta, Canada; Stephen Sanche, Royal University Hospital, Saskatoon, Saskatchewan, Canada; Hu Bijie, Zhong Shan Hospital, Shanghai, China; Yingchun Xu, Peking Union Medical College Hospital, Beijing, China; Wang Fu, Hua Shan Hospital, Shanghai, China; Nan Shan Zhong, Guangzhou Institute of Respiratory Disease, Guangzhou, China; Pilar Rivas, Institut Nacional de Cancerología, Bogota, Colombia; Catalina de Bedout, CIB, Medellin, Colombia; Matilde Mendez and Ricardo Vega, Hospital Militar Central, Bogota, Colombia; Nada Mallatova, Hospital Ceske Budejovice, Ceske, Czech Republic; Stanislava Dobiasova, Zdravotni ustav se sidlem Ostrave, Ostrava, Czech Republic; Julio Ayabaca, Hospital FF, AA HG1, Quito, Ecuador; Jeannete Zurita, Hospital Vozandes, Quito, Ecuador; M. Mallie, Faculte de Pharmacie, Montpellier, France; E. Candolfi, Institut de Parasitologie, Strasbourg, France; W. Fegeler, Universitaet Muenster, Münster, Germany; P. D. G. Haase, RWTH Aachen, Aachen, Germany; A. Rodloff, Institut F. Med. Mikrobiologie, Leipzig, Germany; W. Bar, Carl-Thiem Klinikum, Cottbus, Germany; V. Czaika, Humaine Kliniken, Bad Saarow, Germany; George Petrikos, Laikon General Hospital, Athens, Greece; Erzsébet Puskás, BAZ County Institute, Miskolc, Hungary; Ilona Dóczi, University of Szeged, Szeged, Hungary; Gyula Mestyan, University of Pecs, Pecs, Hungary; 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, Italy; Gian Carlo Schito, University of Genoa, Genoa, Italy; Domenico D'Antonio, Pescara Civil Hospital, Pescara, Italy; Pietro Martino, Departamento di Biotechnologia, Rome, Italy; N. G. Kee Peng, University Malaya, Kuala Lumpur, Malaysia; Celia Alpuche and Jose Santos, Hospital General de Mexico, Mexico City, Mexico; Rayo Morfin Ortero, Universidad de Guadalajara, Guadalajara, Mexico; 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, Poland; Waclaw Pawliszyn, Pracownia Bakteriologii, Krakow, Poland; Mariada Luz Martins, Institut de Higiene e Medicina Tropical, Lisboa, Portugal; Luis Albuquerque, Centro Hospitalar de Coimbra, Coimbra, Portugal; Laura Rosado, Instituto Nacional de Saude, Lisboa, Portugal; Rosa Velho, Hosp. da Universidade de Coimbra, Coimbra, Portugal; Jose Amorim, Hospital de Santo Antonio, Porto, Portugal; Vera N. Ilina, Novosibirsk Regional Hospital, Novosibirsk, Russia; Olga I Kretchikova, Institute of Antimicrobial Chemotherapy, Smolensk, Russia; Galina A. Klyasova, Hematology Research Center, Moscow, Russia; Sophia M. Rozanova, City Clinical Hospital No. 40, Ekaterinburg, Russia; Irina G. Multykh, Territory Center of Lab Diagnostics, Krasnodar, Russia; Nikolay N. Klimko, Medical Mycology Research Institute, St. Petersburg, Russia; Elena D. Agapova, Irkutsk Regional Childrens Hospital, Irkutsk, Russia; Natalya V. Dmitrieva, Oncology Research Center, Moscow, Russia; Abdul Mohsen Al-Rasheed, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia; Atef Shibl, King Saud University, Riyadh, Saudi Arabia; Jan Trupl, National Cancer Center, Bratislava, Slovak Republic; Hupkova Helena, St. Cyril and Metod Hospital, Bratislava, Slovak Republic; Anwar Hoosen, GaRankuwa Hospital, Medunsa, South Africa; Jeannette Wadula, Baragwanath Hospital, Johannesburg, South Africa; M. N. Janse van Rensburg, Pelanomi Hospital, UOFS, Bloemfontein, South Africa; Adriano Duse, Johannesburg General Hospital, Johannesburg, South Africa; Kyungwon Lee, Yonsei University College of Medicine, Seoul, South Korea; Mi-Na Kim, Asan Medical Center, Seoul, South Korea; A. del Palacio, Hospital 12 De Octobre, Madrid, Spain; Aurora Sanchez-Sousa, Hospital Ramon y Cajal, Madrid, Spain; Jacques Bille, Institute of Microbiology CHUV, Lausanne, Switzerland; K. Muhlethaler, Universitat Bern, Berne, Switzerland; Shan-Chwen Chang, National Taiwan University Hospital, Taipei, Taiwan; Jen-Hsien Wang, China Medical College Hospital, Taichung, Taiwan; Deniz Gur, Hacettepe University Children's Hospital, Ankara, Turkey; Volkan Korten, Marmara Medical School Hospital, Istanbul, Turkey; John Paul, Royal Sussex County Hospital, Brighton, United Kingdom; Derek Brown, Addenbrooke's Hospital, Cambridge, United Kingdom; Chris Kibbler, Royal Free Hospital, London, United Kingdom; Nigel Weightman, Friarage Hospital, Northallerton, United Kingdom; Ian M. Gould, Aberdeen Royal Hospital, Aberdeen, United Kingdom; Claire Rennison, Royal Victoria Hospital, Newcastle, United Kingdom; Richard Barton, General Infirmary, P.H.L.S, Leeds, United Kingdom; 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; Heidi Reyes, Gen. del Este Domingo Luciani, Caracas, Venezuela; and Axel Santiago, Universitario de Caracas, Caracas, Venezuela.

Footnotes

▿

Published ahead of print on 16 January 2008.

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