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Antimicrobial Agents and Chemotherapy, July 2001, p. 2129-2133, Vol. 45, No. 7
Infectious Diseases Service, Department of
Medicine, Memorial Sloan-Kettering Cancer Center and Department of
Medicine, Weill Medical College of Cornell
University,1 and The Public Health
Research Institute,3 New York, and
Mycology Laboratory, Axelrod Institute, New York State
Department of Health, Albany,2 New York
Received 24 July 2000/Returned for modification 20 January
2001/Accepted 11 April 2001
Since most nosocomial systemic yeast infections arise from the
endogenous flora of the patient, we prospectively evaluated the species
stratification and antifungal susceptibility profile of
Candida spp. associated with heavy colonization and
systemic infection in patients at Memorial Sloan-Kettering Cancer
Center in New York. A total of 349 Candida isolates were
obtained from 223 patients during the later half of 1998. Cancer was
the most common underlying disease, occurring in 91% of the patients,
including 61.8% with organ and 23.7% with hematological malignancies;
4.4% of the patients had AIDS. Candida albicans was the
predominant species (67.3%); among 114 non-albicans
Candida spp., C. glabrata (45.6%) was the most
frequent, followed by C. tropicalis (18.4%), C. parapsilosis (16.6%), and C. krusei
(9.6%). The overall resistance to triazole-based agents among
all yeast isolates was 9.4 and 10.8% for fluconazole and
itraconazole, respectively. A total of 5% of C. albicans
strains were resistant to triazole antifungals, whereas 30.8 and 46.2%
of C. glabrata strains were resistant to fluconazole
(MIC Systemic candidiasis in hospitalized
patients has increased steadily over the past four decades and
represents a significant cause of morbidity and mortality among
severely ill individuals (2, 7, 8, 16, 17, 24, 30). A
nationwide increase of 1.8 fungal infections per 1,000 discharges was
reported from 1980 to 1990, and 86% were due to Candida
spp. (5). Candidemia is the fourth most prevalent cause of
bloodstream infections (4, 5, 32), although its
attributable mortality (~40%) exceeds that of bacteremia (19,
32, 40). This rise in fungal infections is exacerbated by the
increasing population of immunocommpromised patients, the prevalence of
treatment with multiple broad-spectrum antibiotics, and the common use
of indwelling intravascular devices (10, 14, 16, 32).
In recent years, this problem has been magnified by an increase in the
prevalence of Candida spp. such as Candida
glabrata and C. tropicalis, with reduced susceptibility
to triazole antifungals, and C. krusei, which is
intrinsically resistant to fluconazole and itraconazole (1, 11,
15, 27, 41). In addition, the development of de novo triazole
resistance among C. albicans and other normally susceptible
species further limits therapeutic options (3, 35, 36). A
growing association has been proposed between prior exposure to
triazole-based antifungal drugs and development of resistance (1,
22, 42). Recent studies have highlighted important geographic
variations in the distribution of Candida species and
differences in the prevalence of resistance (26-28).
Given the extensive use of triazoles in hospitals with large
populations of cancer patients, it is important to understand changing
trends in species distribution and azole susceptibility patterns among
Candida spp. In addition, since fungemia due to Candida spp. largely arise from the endogenous flora of the
patient, mostly the gastrointestinal and genitourinary tract floras
(18, 30, 34, 37, 39), it is important to assess these
parameters among the colonizing organisms. We therefore performed a
prospective evaluation of Candida associated with prominent
colonization and infection in 223 patients at a comprehensive cancer
hospital in New York City.
(The results of this study were presented in part at the 9th
International Congress on Infectious Diseases, Buenos Aires, Argentina,
April 2000.)
Study design.
All clinical isolates that were submitted to the
mycology laboratory at Memorial Sloan-Kettering Cancer Center (MSKCC)
were screened from 1 July to 31 December 1998. Specimens from sterile body sites and those with prominent colonization ( Organism identification.
On identification of yeasts, a germ
tube test was performed for presumptive identification of C. albicans. Organisms that failed to form a germ tube were further
tested by the auxanographic plate method (BBL Microbiology System,
Cockeysville, Md., and Difco Laboratories, Detroit, Mich.). The species
not identified by the above methods were subjected to additional
standard testing (38). Five to ten colonies were obtained
from the primary culture and transported on Trypticase agar slants
(Becton Dickinson Microbiology Systems, Cockeysville, Md.) for species
reidentification and antifungal susceptibility testing (under code).
Susceptibility testing.
All Candida samples were
maintained on Sabouraud dextrose agar media plates (Becton Dickinson
Microbiology Systems) at an ambient temperature. A broth
microdilution method was performed on the basis of the proposed
guidelines of the National Committee for Clinical Laboratory
Standards (NCCLS) (20). Antifungal drugs (amphotericin B,
flucytosine, ketoconazole, fluconazole, and itraconazole) were obtained
from their respective manufacturers. Quality control was performed by
testing American Type Culture Collection-designated strains. The
interpretative criteria for susceptibility and breakpoints for
antifungal drugs were referenced as described by the NCCLS (20).
Statistical analysis.
The association between categorical
variables was determined by using Fisher's exact test. A
two-sided P value of less than 0.05 was considered
statistically significant.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.7.2129-2133.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Prospective Study of Candida Species in
Patients at a Comprehensive Cancer Center

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ABSTRACT
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Abstract
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64 µg/ml) and itraconazole (MIC
1 µg/ml), respectively. A significant association was observed between prior treatment with triazole and isolation of fluconazole-resistant C. albicans (P = 0.005, OR 36), although this
relationship was not seen in C. glabrata isolates
(P = 0.4). This study reinforces the importance
of periodic, prospective surveillance of clinical fungal isolates to
determine appropriate prophylactic, empiric, and preemptive antifungal
therapy for the highly susceptible patient population.
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TEXT
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Abstract
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50 colonies of
Candida) from nonsterile sources were included in the study. More than one isolate from a single patient was included if multiple species or different (genotypic) Candida strains were
identified, if the specimens were obtained from separate body sites, or
if they resulted from recurrent infection. Demographic information and
laboratory data were retrieved from patient charts and from the
computerized hospital data system. All specimens were initially processed at the MSKCC Microbiology Laboratory, which isolated and
identified Candida spp. Species reidentification (under
code) and determination of susceptibility to a panel of antifungal
agents were conducted at the New York State Department of Health
Mycology Laboratory. All molecular genotyping was carried out at the
Public Health Research Institute, New York.
TABLE 1.
Characteristics of patients with Candida
colonization or infection
|
0.5 µg/ml). The overall
triazole resistance to fluconazole and itraconazole was 9.4 and
10.8%, respectively. A total of 95% of C. albicans
isolates were susceptible to fluconazole (MIC
8 µg/ml)
and itraconazole (MIC
0.25 µg/ml), while resistance was 3.4%
to fluconazole (MIC
64 µg/ml) and 4% to itraconazole (MIC
1 µg/ml). Eight isolates (3.4%) were resistant to
flucytosine, and 2% showed in vitro resistance to ketoconazole.
Resistance among C. glabrata isolates to fluconazole and
itraconazole was 30.7 and 46.2%, respectively, whereas 19% of
C. tropicalis isolates were resistant to fluconazole and
21% were resistant to itraconazole. All antifungal agents were
effective against C. parapsilosis. The MIC for 90% of
isolates (MIC90) of fluconazole ranged from 1 µg/ml for
C. albicans to
64 µg/ml for C. glabrata, C. tropicalis, and C. krusei (Table 2). The itraconazole MIC90 was higher for C. tropicalis (16 µg/ml)
C. glabrata (4 µg/ml), and C. krusei (0.5 µg/ml). The antifungal susceptibility profile among the bloodstream
infection isolates was similar to that of the total isolate population
reported in Table 2.
Of 22 C. glabrata isolates for which the fluconazole MIC was
32 µg/ml, 10 (45.4%) were isolated from patients with prior exposure to triazole-based antifungals for a duration of >7 days in the preceding 12 weeks. On the other hand, only 7 of 33 fluconazole-susceptible (
16 µg/ml) C. glabrata
isolates (21.8%) were obtained from triazole-experienced patients (P = 0.4). For fluconazole-resistant C. albicans isolates, 85.7% were obtained from patients with prior
triazole exposure (P < 0.005) (Table
3). Molecular genotyping (by random
amplification of polymorphic DNA) confirmed that the resistant isolates
of C. albicans and C. glabrata were distinct
strains (data not shown), indicating that they were not transmitted
from common progenitor strains.
|
16 µg/ml and that 83% showed reduced
susceptibility to itraconazole (Table 2). Recently, an increase in the
prevalence of C. krusei infections has been reported from
several institutions (6, 13, 24, 41), although the
prevalence of this species remained <5% among all clinical
Candida isolates at MSKCC (Table 2).
The level of triazole resistance in C. albicans (3%
fluconazole resistance and 4% itraconazole resistance) at our
institution compares favorably with 5.5% fluconazole resistance
reported from institutions in the northeastern United States during
1995 to 1996 (25). The susceptibility profiles of
C. parapsilosis and C. tropicalis were
consistent with findings from other institutions (21, 27).
Interestingly, all C. lusitaniae (5) isolates were susceptible to amphotericin B (MIC90, 0.25 µg/ml), a
finding inconsistent with other reports (41, 42).
There is evidence linking prior exposure to triazoles and subsequent
emergence of drug resistance in Candida spp. (1,
42). It was expected that such an association would be found for
C. glabrata, given the high prevalence of triazole
resistance in this study. Nonetheless, we report no significant
association between prior fluconazole or itraconazole prophylaxis or
treatment and high-level resistance among C. glabrata
strains (P = 0.4; Table 3). The fact that resistance
among C. glabrata isolates was observed independently of
triazole exposure may reflect a selection of resistant isolates from
the environmental pool, most probably within the community.
Alternatively, it may relate to a rapid acquisition of resistance
traits in colonizing strains due to the haploid nature of the organism
and its ability to mutate rapidly (9). In contrast,
C. albicans isolates displaying resistance (<5%) to
fluconazole and itraconazole were isolated predominantly from patients
with prior triazole exposure (P = 0.005) (Table 3).
These results emphasize the dynamic nature of Candida spp.
in the compromised host and the complexity of factors promoting drug
resistance. Furthermore, they emphasize the need for ongoing surveillance of antifungal susceptibility patterns and an evaluation of
factors influencing the introduction of resistance among clinically significant yeasts in highly susceptible patients. Interval
surveillance of this type is an essential component in developing
institutional guidelines for prophylaxis and empiric or preemptive
therapy for these life-threatening infections.
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ACKNOWLEDGMENTS |
|---|
This study was supported by a grant from the New York State Department of Health to The Public Health Research Institute, New York, N.Y.
We are grateful to Dennis Leung and Larry Leon for expert statistical assistance and to Timothy Kiehn, Susan Shuptar, Kathleen Gilhuley, Fitzroy Edwards, and May Wong for their support in the collection and analysis of Candida isolates.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: The Public Health Research Institute, 455 First Ave., New York, NY 10021. Phone: (212) 578-0820. Fax: (212) 578-0804. E-mail: perlin{at}phri.nyu.edu.
Present address: Division of Infectious Diseases, Department of
Medicine, University of South Carolina School of Medicine, Columbia,
S.C.
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