Abstract
Candida rugosa is a fungus that appears to be emerging as a cause of infection in some geographic regions. We utilized the extensive database of the ARTEMIS DISK Antifungal Surveillance Program to describe the geographic and temporal trends in the isolation of C. rugosa from clinical specimens and the in vitro susceptibilities of 452 isolates to fluconazole and voriconazole. C. rugosa accounted for 0.4% of 134,715 isolates of Candida, and the frequency of isolation increased from 0.03% to 0.4% over the 6.5-year study period (1997 to 2003). C. rugosa was most common in the Latin American region (2.7% versus 0.1 to 0.4%). Decreased susceptibility to fluconazole (40.5% susceptible) was observed in all geographic regions; however, isolates from Europe and North America were much more susceptible (97 to 100%) to voriconazole than those from other geographic regions (55.8 to 58.8%). C. rugosa was most often isolated from blood and urine in patients hospitalized at the Medical and Surgical inpatient services. Notably, bloodstream isolates were the least susceptible to both fluconazole and voriconazole. C. rugosa should be considered, along with the established pathogens Candida krusei and Candida glabrata, as a species of Candida with reduced susceptibility to the azole antifungal agents.
Although quite rare as a cause of invasive fungal infections (9), Candida rugosa has recently been cited as a possible “emerging” fungal pathogen (6). Fungemia due to this species of Candida was unrecognized prior to 1985, when catheter-related fungemia was reported in two different institutions in the United States (15, 21). Subsequently, Dube et al. (3) reported 15 episodes of candidemia due to C. rugosa in burn patients receiving topical nystatin treatment in a U.S. hospital. No obvious source of the infections was found; however, the isolates were shown to be resistant to nystatin and to have reduced susceptibility to both amphotericin B and fluconazole. More recently, a cluster of six episodes of candidemia caused by C. rugosa was reported in Brazil (2). Two of the episodes represented breakthrough infections in patients receiving amphotericin B treatment, and all four patients treated with this agent died. Follow-up surveillance revealed that C. rugosa was a frequent colonizer of high-risk patients and accounted for 44% of 32 consecutive episodes of fungemia at one Brazilian tertiary care center (17). Those reports suggest that C. rugosa may exhibit decreased susceptibility to both polyenes and fluconazole, may cause catheter-related fungemia in seriously ill patients, may be transmitted from patient to patient in the hospital setting, and may be endemic in certain institutions (6).
Aside from these few observations, there is a paucity of information regarding the epidemiology, frequency of occurrence, and antifungal susceptibility profile of this uncommon species of Candida (9). In the present study, we have taken advantage of the extensive database compiled by the ARTEMIS DISK Antifungal Surveillance Program (11) to describe the geographic and temporal trends in the isolation of C. rugosa from clinical specimens collected from 127 medical centers between 1997 and 2003, the types of specimens and clinical services in which C. rugosa infections are recognized, and the in vitro susceptibilities of 452 clinical isolates, including 74 bloodstream infection (BSI) isolates, of this species to both fluconazole and voriconazole as determined by standardized disk diffusion testing. This report will serve as the largest study of C. rugosa isolates to date.
MATERIALS AND METHODS
Organisms and test sites.
A total of 134,715 isolates of Candida spp. from 127 different medical centers in Asia (23 sites), Latin America (16 sites), Europe (74 sites), the Middle East (2 sites), and North America (12 sites) were isolated and identified between June 1997 and December 2003. All Candida spp. considered pathogens by the respective attending physicians from all body sites (e.g., blood, normally sterile body fluids, deep-tissue biopsy, genital tract, gastrointestinal tract, respiratory tract, skin, and soft tissue) and isolates from all in-hospital and outpatient locations during the study period were tested. Data for C. rugosa 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 clinical infection, 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.
Susceptibility test methods.
Disk diffusion testing of fluconazole and voriconazole was performed as described previously (10-12) and in accordance with Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS) document M44-A (5). Agar plates (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 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 the BIOMIC image analysis plate reader system (version 5.9; Giles Scientific, Santa Barbara, Calif.) (4, 10-12).
The interpretive criteria for the fluconazole and voriconazole disk diffusion tests were those of the CLSI (5, 13, 14) 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 (5, 13, 14) are as follows: S, MIC of ≤8 μg/ml (fluconazole) and ≤1 μg/ml (voriconazole); SDD, MIC of 16 to 32 μg/ml (fluconazole) and 2 μg/ml (voriconazole); R, MIC of ≥64 μg/ml (fluconazole) and ≥4 μg/ml (voriconazole).
QC.
Quality control (QC) was performed in accordance with CLSI document M44-A (5) by using Candida albicans ATCC 90029 and Candida parapsilosis ATCC 22019. A total of 5,865 and 5,484 QC results were obtained for fluconazole and voriconazole, respectively, more than 99% of which were within the acceptable limits. External quality assurance was performed by testing more than 2,900 isolates from blood and normally sterile-site infections against both fluconazole and voriconazole by ARTEMIS participating laboratories and by the central reference laboratory (10, 12). Excellent agreement was seen between participating and reference laboratories, ensuring the accuracy of the ARTEMIS data.
Analysis of results.
All disk zone diameters were read by electronic image analysis and interpreted and recorded with a BIOMIC Plate Reader system (Giles Scientific). Test results were sent by e-mail to Giles Scientific for analysis. The zone diameter susceptibility categories (S, SDD, or R) and QC test results were all recorded electronically. Patient and doctor names, duplicate test results (the same patient, the same species, and same biotype result), and uncontrolled results were automatically eliminated by the BIOMIC system prior to analysis.
RESULTS
Isolation of C. rugosa over time and by geographic region.
A total of 134,715 isolates of Candida spp. were isolated and identified at 127 study sites between June 1997 and December 2003 (11). C. rugosa ranked ninth among more than 16 species of Candida, accounting for approximately 0.4% of all isolates (11). The frequency of isolation of C. rugosa increased by more than 10-fold over the course of the study (0.03% to 0.4%) (11).
Data for the various sites contributing isolate results to the study were available for the time period of 2001 through 2003 (Table 1). C. rugosa represented 0.6% of the 75,761 isolates collected during this time period and was most common in the Latin American region (Table 1).
TABLE 1.
Variation in the frequency of Candida rugosa by geographic regiona
| Region | Total no. of Candida species isolates | Total no. (%) of C. rugosa isolates |
|---|---|---|
| Asia-Pacific | 17,183 | 83 (0.4) |
| Europe | 41,187 | 54 (0.1) |
| Latin America | 11,280 | 311 (2.7) |
| North America | 6,111 | 4 (0.1) |
| Total | 75,761 | 452 (0.6) |
Data were obtained from the ARTEMIS DISK Global Antifungal Surveillance Program from 2001 to 2003. Isolates represent all incident isolates from all sites of infection.
Geographic variation in susceptibility of C. rugosa to fluconazole and voriconazole.
Table 2 presents the in vitro susceptibilities of C. rugosa to fluconazole and voriconazole, stratified by geographic region of origin, as determined by CLSI disk diffusion testing. These isolates were obtained from 115 institutions in 35 countries. Overall, it is evident that C. rugosa exhibits decreased susceptibility to both fluconazole and voriconazole, with only 40.5% and 61.4% of isolates, respectively, showing susceptibility to these two triazole antifungal agents. Susceptibilities to fluconazole were lowest (<40%) in the Asia-Pacific (34.9%) and Latin American (35.7%) regions and highest in Europe (75.9%).
TABLE 2.
Geographic variation in susceptibilities of Candida rugosa to fluconazole and voriconazole
| Region | Antifungal agent | No. of isolates tested | % of isolatesa
|
||
|---|---|---|---|---|---|
| S | SDD | R | |||
| Asia-Pacific | Fluconazole | 83 | 34.9 | 8.4 | 56.7 |
| Voriconazole | 34 | 58.8 | 23.5 | 17.7 | |
| Europe | Fluconazole | 54 | 75.9 | 13.0 | 11.1 |
| Voriconazole | 46 | 97.8 | 2.2 | ||
| Latin America | Fluconazole | 311 | 35.7 | 8.4 | 55.9 |
| Voriconazole | 310 | 55.8 | 12.9 | 31.3 | |
| North America | Fluconazole | 4 | 50.0 | 25.0 | 25.0 |
| Voriconazole | 4 | 100.0 | |||
| Total | Fluconazole | 452 | 40.5 | 9.1 | 50.4 |
| Voriconazole | 394 | 61.4 | 12.2 | 26.4 | |
All isolates were tested by disk diffusion performed in accordance with CLSI standard M44-A. S, susceptible, with zone diameters of ≥19 mm for fluconazole and ≥17 mm for voriconazole; R, resistant, with zone diameters of ≤14 mm for fluconazole and ≤13 mm for voriconazole; SDD, susceptible-dose dependent, with zone diameters of 15 to 18 mm for fluconazole and 14 to 16 mm for voriconazole.
Although voriconazole was always more active against C. rugosa than fluconazole, irrespective of geographic region, the lowest susceptibilities to this agent (55.8 to 58.8%) were also observed in the regions with the lowest susceptibilities to fluconazole (Table 2). In contrast, 97% to 100% of C. rugosa isolates from Europe (97.6%) and North America (100%) were susceptible to voriconazole. These extremes in voriconazole susceptibility among isolates of C. rugosa are important to recognize, especially given previous suggestions (based on very limited data) that this species was highly susceptible to voriconazole (6, 9).
Trends in resistance to fluconazole and voriconazole among C. rugosa isolates over time.
Although resistance to fluconazole among isolates of C. rugosa tested in 2001 was already quite high (31.7%) (Table 3), more resistance was observed in 2002 and 2003, where 66.0% and 61.2% of isolates, respectively, were resistant to fluconazole. Likewise, resistance to voriconazole was low in 2001 (3.1%) and was 10-fold higher (38.0%) in both 2002 and 2003.
TABLE 3.
Trends in in vitro resistance to fluconazole and voriconazole among C. rugosa isolates as determined by CLSI disk diffusion testing over timea
| Antifungal agent | Resistance during yrb:
|
|||||
|---|---|---|---|---|---|---|
| 2001
|
2002
|
2003
|
||||
| No. of isolates | %R | No. of isolates | %R | No. of isolates | %R | |
| Fluconazole | 186 | 31.7 | 150 | 66.0 | 116 | 61.2 |
| Voriconazole | 129 | 3.1 | 149 | 38.0 | 116 | 38.0 |
Data were obtained from the ARTEMIS DISK Surveillance Program, 2001 to 2003.
Zone (≤14 mm [fluconazole] or ≤13 mm [voriconazole]) disk diffusion testing was performed in accordance with CLSI standard M44-A.
Variation in the frequency of isolation and antifungal susceptibility profile of C. rugosa by clinical service.
The clinical services reporting the isolation of C. rugosa from patient specimens included the hematology-oncology service, the medical and surgical services, intensive care units (ICUs) (medical, surgical, and neonatal), and the outpatient service (Table 4). 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, not otherwise specified” (NOS).
TABLE 4.
Susceptibility of Candida rugosa to fluconazole and voriconazole by clinical service
| Clinical service (total no. of isolates)a | Antifungal agent | No. of isolates tested (%)b | % of isolates from servicec | % of isolates
|
||
|---|---|---|---|---|---|---|
| S | SDD | R | ||||
| Hematology-oncology (4,635) | Fluconazole | 14 (3.1) | 0.3 | 71.4 | 21.4 | 7.1 |
| Voriconazole | 11 (2.8) | 90.0 | 9.1 | |||
| Medical (17,408) | Fluconazole | 179 (39.6) | 1.0 | 31.8 | 3.9 | 64.2 |
| Voriconazole | 158 (40.1) | 44.9 | 19.0 | 36.1 | ||
| Surgical (5,126) | Fluconazole | 145 (32.1) | 2.8 | 40.0 | 9.7 | 50.3 |
| Voriconazole | 140 (35.5) | 67.1 | 10.0 | 22.9 | ||
| ICU (10,052) | Fluconazole | 24 (5.3) | 0.2 | 41.7 | 12.5 | 45.8 |
| Voriconazole | 10 (2.5) | 80.0 | 10.0 | 10.0 | ||
| Outpatient (6,414) | Fluconazole | 17 (3.8) | 0.3 | 70.6 | 17.6 | 11.8 |
| Voriconazole | 17 (4.3) | 88.2 | 5.9 | 5.9 | ||
| Other, NOS (32,136) | Fluconazole | 73 (16.1) | 0.2 | 49.3 | 15.1 | 36.6 |
| Voriconazole | 58 (14.8) | 75.9 | 3.4 | 20.7 | ||
Total number of Candida isolates from each service.
Percentage of all C. rugosa isolates tested.
C. rugosa as a percentage of all isolates from that clinical service.
C. rugosa was isolated most frequently from hospitalized patients from the medical and surgical services and was less common from the hematology-oncology, ICU, and outpatient services. Likewise, isolates from the medical and surgical services were the least susceptible to both fluconazole (31.8% and 40.0%, respectively) and voriconazole (44.9% and 67.1%, respectively), whereas the isolates that were the most susceptible to both agents were seen in the hematology-oncology and outpatient services (Table 4).
Variation in the frequency of isolation and antifungal susceptibility profile of C. rugosa by clinical specimen type.
The major specimen types yielding C. rugosa as a putative pathogen included blood, urine, respiratory, skin, soft tissue, and genital specimens (Table 5). Those isolates from uncommon specimen types and those for which a specimen type was not recorded were grouped under “miscellaneous (Misc.), NOS.”
TABLE 5.
Susceptibility of Candida rugosa to fluconazole and voriconazole by specimen type
| Specimen type/site (total no. of isolates)a | Antifungal agent | No. of isolates tested (%)b | % of isolates from sitec | % of isolates
|
||
|---|---|---|---|---|---|---|
| S | SDD | R | ||||
| Blood (8,256) | Fluconazole | 74 (16.4) | 0.9 | 28.4 | 6.8 | 64.9 |
| Voriconazole | 59 (15.0) | 35.6 | 20.3 | 44.1 | ||
| Urine (9,722) | Fluconazole | 99 (21.9) | 1.0 | 39.4 | 6.1 | 54.5 |
| Voriconazole | 83 (21.1) | 61.4 | 15.7 | 22.9 | ||
| Respiratory (20,274) | Fluconazole | 41 (9.1) | 0.2 | 46.3 | 12.2 | 41.5 |
| Voriconazole | 36 (9.1) | 63.9 | 2.8 | 33.3 | ||
| Skin/soft tissue (4,986) | Fluconazole | 23 (5.1) | 0.5 | 47.8 | 13.0 | 39.1 |
| Voriconazole | 21 (5.3) | 66.7 | 9.5 | 23.8 | ||
| Genital (15,831) | Fluconazole | 20 (4.4) | 0.1 | 75.0 | 10.0 | 15.0 |
| Voriconazole | 12 (3.0) | 100.0 | ||||
| Misc., NOS (16,692) | Fluconazole | 195 (43.1) | 1.2 | 40.0 | 10.3 | 49.7 |
| Voriconazole | 183 (46.5) | 66.1 | 10.9 | 23.0 | ||
Total number of Candida isolates from each specimen type.
Percentage of all C. rugosa isolates tested.
C. rugosa as a percentage of all isolates of that specimen type.
Aside from the Misc., NOS category, more C. rugosa isolates were found in blood and urine specimens than in respiratory, skin, soft tissue, and genital specimens (Table 5). Thus, C. rugosa most often causes infection in sites common to other Candida spp. Importantly, isolates of C. rugosa from blood were considerably less susceptible to both fluconazole (28.4%) and voriconazole (35.6%) than those from any other specimen type (Table 5).
DISCUSSION
The results from this large study of C. rugosa both confirm previous observations regarding this species and refute others (6, 9). First of all, it does appear, as suggested previously by Colombo et al. (2) and Nucci and Marr (6), that the frequency of C. rugosa as a cause of candidal infections is increasing and that these infections are especially common in Latin America (Table 1). Although the apparent “emergence” of C. rugosa may simply reflect an increasing tendency for clinical laboratories to identify isolates of Candida species, one cannot discount the possibility that given the increased numbers of immunocompromised individuals worldwide, an ever-increasing number of previously rare species, such as C. rugosa, are truly emerging as opportunistic pathogens (6, 9). Furthermore, C. rugosa does appear to exhibit decreased susceptibility to fluconazole, and this pattern varies by geographic region (Table 2). Decreased susceptibility to both polyenes and fluconazole has been noted previously (1-3, 9), even though data were based on the testing of relatively few isolates.
Previously reported data regarding the susceptibility of C. rugosa to voriconazole suggested that this agent was very active against this species (6, 7, 9). Again, this conclusion was based on the testing of very small numbers of isolates obtained primarily from North America and Europe. The data presented herein indicate that C. rugosa should be considered to have decreased susceptibility to voriconazole as well as fluconazole (Table 2). This pattern of decreased susceptibility was most prominent in the Asia-Pacific and Latin American regions (Table 2). Voriconazole appeared to be considerably more active against C. rugosa isolates from Europe and North America. The reasons for these geographic differences in azole susceptibility are not known; however, the most conservative approach to dealing with infections caused by C. rugosa would be to assume decreased susceptibility (e.g., resistance) until proven otherwise by standardized antifungal susceptibility testing (16). Very few isolates of C. rugosa have been tested against the echinocandins (7, 9). The few isolates that have been tested all appear to be susceptible to these agents at clinically achievable concentrations (i.e., <2 μg/ml).
In addition to the apparent emergence of C. rugosa as a cause of clinical infection, there also seems to be a trend towards the emergence of resistance to fluconazole and voriconazole over time (Table 3) (11). Resistance to fluconazole increased from a baseline rate of ∼30% to more than 60% over the course of the study (Table 3). Similarly, resistance to voriconazole increased from 3.1% in 2001 to 38.0% in 2002 and 2003 (Table 3). These parallel increases in resistance provide further support for a strong degree of cross-resistance among the azole class of antifungals. Although little is known about resistance mechanisms specific to C. rugosa, mechanisms described for other Candida species include the alteration of the 14-α-demethylase target (19) along with the induction of efflux pump mechanisms (18, 22).
As suggested previously by Colombo et al. (2) and by Rosas et al. (17), infections due to C. rugosa were most common among patients hospitalized in the medical and surgical services of the participating hospitals (Table 4). Likewise, resistance to both fluconazole and voriconazole was highest among isolates from these two services. Interestingly, the most susceptible isolates to both agents were found in the hematology and oncology services, where one might expect azole drug pressure to be greatest. Thus, the in vitro susceptibility of this species to the azole antifungals is not entirely predictable, suggesting that, as with C. glabrata (9), antifungal susceptibility testing may play a useful role in optimizing the antifungal therapy for this organism (8, 20).
Finally, it is important that C. rugosa is most often detected in bloodstream and urinary tract infections (Table 5). Furthermore, the isolates obtained from blood cultures demonstrated the highest level of resistance to both agents. This finding reinforces previously published opinions regarding the importance of identifying isolates of Candida obtained from blood and normally sterile-site infections to the species level (8, 9, 16, 20). It should be noted that although isolates of C. rugosa from blood are clearly pathogenic, the isolation of this or any other species of Candida from nonsterile sites (e.g., urine, respiratory, and genital specimens) may simply represent colonization rather than infection. We have included isolates of C. rugosa from sites other than blood based on the clinical assessment of the local-site investigators that the isolate was associated with clinical pathology in the respective patient.
In summary, we have used the extensive and validated database of the ARTEMIS DISK Antifungal Surveillance Program (11) to address several gaps in our knowledge of C. rugosa as an opportunistic pathogen. Our findings suggest that not only is this species emerging as an agent of invasive fungal infection, it also appears to be developing increased resistance to azole antifungal agents, especially in certain geographic regions. C. rugosa appears to fill the same clinical niche as other more common species of Candida in that it most often causes BSI and urinary tract infections in patients hospitalized in the medical and surgical inpatient services. Notably, BSI isolates of this species are the least susceptible to both fluconazole and voriconazole. Thus, C. rugosa joins the established pathogens C. glabrata and C. krusei as a species of Candida with reduced susceptibility to the azole antifungal agents. These data provide significant new information regarding a relatively uncommon cause of opportunistic fungal infection and underscore the value of longitudinal global surveillance studies such as ARTEMIS.
Acknowledgments
Linda Elliott provided excellent support in the preparation of the manuscript.
The ARTEMIS DISK Surveillance Program is supported by grants from Pfizer.
We express our appreciation to all ARTEMIS participants. Participants contributing to this study included Jorge Finquelievich, Buenos Aires University, and Nora Tiraboschi, Hospital Escuela Gral., Buenos Aires, Argentina; David Ellis, Women's and Children's Hospital, N. Adelaide, Australia; Dominique Frameree, CHU de Jumet, Jumet, Annemarie van den Abeele, St. Lucas Campus Heilige Familie, Gent, and Jean-Marc Senterre, Hôpital de la Citadelle, Liege, Belgium; Arnaldo Colombo, Escola Paulista de Medicina, Sao Paulo, Brazil; Robert Rennie, University of Alberta Hospital, Edmonton, and Steve Sanche, Royal University Hospital, Saskatoon, Canada; Bijie Hu, Zhong Shan Hospital, Shanghai, Yingchun Xu, Peking Union Medical College Hospital, Beijing, Yingyuan Zhang, Hua Shan Hospital, Shanghai, and Nan Shan Zhong, Guangzhou Institute of Respiratory Diseases, Guangzhou, China; Pilar Rivas, Inst. Nacional de Cancerología, Bogotá, Angela Restrepo and Catalina Bedout, CIB, Medellin, and Ricardo Vega and Matilde Mendez, Hospital Militar Central, Bogotá, 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, A. Haase, RWTH Aachen, Aachen, G. 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; Erzsébet Puskás, BAZ County Institute, Miskolc, Ilona Doczi, University of Szeged, Szeged, 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, Giacomo Fortina, Ospedale di Novara, Novara, Gian Piero Testore, Univerrsita di Roma Tor Vergata, Rome, Domenico D'Antonio, Pescara Civil Hospital, Pescara, Giorgio Scalise, Instituto di Malattie Infettive, Ancona, Pietro Martino, Dept. di Biotechnologie, Rome, and Graziana Manno, Università di Genova, Genova, Italy; Kee Peng, University Malaya, Kuala Lumpur, Malaysia; Celia Alpuche and Jose Santos, Hospital General de Mexico, Mexico City, Eduardo Rodriguez Noriega, Universidad de Guadalajara, Guadalajara, and Mussaret Zaidi, Hospital General O'Horan, Merida, Mexico; Jacques F. G. M. Meis, Canisius Wilhemina 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, 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 Laboratory 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, Riyadh, Saudi Arabia; Jan Trupl, National Cancer Center, Leon Langsadl, NUTaRCH, Alena Vaculikova, Derer University Hospital, and Hupkova Helena, St. Cyril and Metod Hospital, Bratislava, Slovak Republic; Denise Roditi, Groote Schuur Hospital, Cape Town, Anwar Hoosen, GaRankuwa Hospital, Medunsa, H. H. Crewe-Brown, 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; Malai Vorachit, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Deniz Gur, Hacettepe University Children's Hospital, Ankara, and Volkan Korten, Marmara Medical School Hospital, Istanbul, Turkey; John Paul, Royal Sussex County Hospital, Brighton, Brian Jones, Glasgow Royal Infirmary, Glasgow, F. Kate Gould, Freeman Hospital, Newcastle, Chris Kibbler, Royal Free Hospital, London, Nigel Weightman, Friarage Hospital, Northallerton, Ian M. Gould, Aberdeen Royal Hospital, Aberdeen, Ruth Ashbee, General Infirmary, P.H.L.S., Leeds, and Rosemarie Barnes, University of Wales College of Medicine, Cardiff, United Kingdom; Jose Vazquez, Harper Hospital, Wayne State University, Detroit, Mich., Ed Chan, Mt. Sinai Medical Center, New York, N.Y., Davise Larone, Cornell Medical Center NYPH, New York, N.Y., Ellen Jo Baron, Stanford Hospital and Clinics, Stanford, Calif., Mahmoud A. Ghannoum, University Hospitals of Cleveland, Cleveland, Ohio, Mike Rinaldi, University of Texas Health Science Center, San Antonio, Tex., Kevin Hazen, University of Virginia Health Systems, Charlottesville, Va., and Elyse Foraker, Christiana Care, Wilmington, Del.; and Heidi Reyes, Gen del Este Dr. Domingo Luciani, and Axel Santiago, Universitario de Caracas, Caracas, Venezuela.
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