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Candida glabrata fungaemia in a tertiary centrein Taiwan: antifungal susceptibility and

outcomes

ARTICLE in INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS · MAY 2009

Impact Factor: 4.26 · DOI: 10.1016/j.ijantimicag.2009.02.021 · Source: PubMed

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National Taiwan University

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International Journal of Antimicrobial Agents 34 (2009) 236–239

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / i j a n t i m i c a g

Candida glabrata fungaemia in a tertiary centre in Taiwan: antifungal

susceptibility and outcomes

Sheng-Yuan Ruan a, Yu-Tsung Huang b, Chen-Chen Chu c, Chong-Jen Yu d, Po-Ren Hsueh b,d,∗

a Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwanb Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwanc Department of Pharmacology, National Taiwan University Hospital, Taipei, Taiwand Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

a r t i c l e i n f o

Article history:

Received 18 November 2008

Accepted 13 February 2009

Keywords:

Antifungal susceptibility

Candida glabrata

Candidaemia

Fungaemia

Outcome

a b s t r a c t

The proportion of non-albicans candidaemia has increased during recent decades, especially Candida

glabrata. Weevaluatedthe antifungal susceptibility, clinical featuresand outcome of C. glabrata fungaemia

treated in a tertiary centre in Taiwan. All episodes of C. glabrata fungaemia during 1999–2005 were

identified from microbiology laboratory records and all C. glabrata isolates were subjected to antifungal

susceptibility testing by the broth microdilution method. A total of 177 episodes of C. glabrata fungaemia

were documented, accounting for 30% of the 598 episodes of candidaemia. A dramatic decline of C.

glabrata causing candidaemia from 2003 (46.8%) to 2005 (15.8%) was noted, accompanied by decreased

fluconazole consumption. The most common underlying diseases in these patients were cancer (49%),

diabetes (34%) and renal failure (25%). The most common risk factors were central venous catheter use

(88%), antimicrobial treatment (87%) and parenteral nutrition (51%). The 30-day all-cause mortality was

48.6%, but only 31% of patients were eventually discharged from the hospital. There was no significant

survival difference between patients with C. glabrata and Candida albicans fungaemia. Rates of antifungal

susceptibilitywere 63% for fluconazole, 93%for voriconazole, 96% for caspofungin, 98% for amphotericin B

and 99% for flucytosine. The different levels of susceptibility to fluconazole(susceptible,susceptible-dose

dependent and resistant) were not significantly associated with 30-day mortality.© 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction

A global trend of increasing incidence of invasive candidiasis

and candidaemia has occurred in the past two decades [1–3]. A

trend of an increasing proportion of non-albicans species in Can-

dida bloodstream infection has also been reported [4,5], although it

remains controversial [6,7]. The most important non-albicans Can-

dida species in North America and some other regions is Candida

glabrata [8], accounting for 10–20% of candidaemias [8,9]. Candida

glabrata is unique to other Candia species in biology and genet-

ics, with a smaller morphology and having a haploid genome [10].

Despite these differences between C. glabrata and other Candida

spp., the clinical features of C. glabrata fungaemia are often stud-

ied in the more general context of candidaemias and few studies

have focused solely on C. glabrata fungaemia. In this study, clinical

data and treatment outcomes of C. glabrata fungaemia at National

Taiwan University Hospital over a 7-year period from 1999 to 2005

were retrospectively analysed. In addition, all C. glabrata isolates

∗ Corresponding author. Tel.: +886 2 2312 3456x5355; fax: +886 2 2322 4263.

E-mail address: [email protected] (P.-R. Hsueh).

during this periodwere analysed to determine their antifungal sus-

ceptibility.

2. Materials and methods

2.1. Patients and setting

All episodes of C. glabrata fungaemia during 1999–2005 were

identified from the records of the microbiology laboratory at

National Taiwan University Hospital, a 2000-bed, university-

affiliated medical centre in Taiwan. This hospital provides both

primary and tertiary medical care and has ca. 200 Intensive CareUnit (ICU) beds, including medical, surgical and paediatric ICUs. All

C. glabrata isolates during this periodhad been stored in the mycol-

ogy laboratory at−70 ◦C in trypticase soybroth supplementedwith

15% glycerol. Each isolate was retrieved from storage for antifun-

gal susceptibility testing. The medical records of each episode of C.

glabrata fungaemia were retrospectively reviewed.

2.2. Definitions

Candida glabrata fungaemia was defined as at least one blood

culture positive for C. glabrata. Fungaemia in the same patient

0924-8579/$ – see front matter © 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

doi:10.1016/j.ijantimicag.2009.02.021

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S.-Y. Ruan et al. / International Journal of Antimicrobial Agents 34 (2009) 236–239 237

occurringduring thesame hospital coursewas counted as thesame

episode. The probableportals of entry were determined by medical

records, which mainly reflected the judgement of the primary care

clinicians. ‘Renal failure’ in the analysis of risk factors was defined

as end-stage renal disease or need for dialysis. Liver cirrhosis was

defined as Child-Pugh class B or C. Neutropenia was defined as an

absolute neutrophil count 48 h. Nil per os (NPO)

was defined as withholding of feeding for >48 h for any reason.

Patients who received chemotherapy, systemic steroids or flucona-

zole within 30daysbefore theonsetof fungaemiawereclassified as

positive for each corresponding factor. Thirty-day mortality in this

study included mortality due to any cause. Data on annual con-

sumption of fluconazole (intravenous and oral forms) from 1999 to

2005 were obtained from the pharmacy department of the hospi-

tal.Antibiotic consumption wasexpressedas the number of defined

daily doses/1000 patient-days.

2.3. Antifungal susceptibility testing

Standard powders of the following antifungal agents were

obtained from their respective manufacturers: fluconazole and

voriconazole (Pfizer Inc., New York, NY); flucytosine (Sigma Chem-

ical Co., St Louis, MO); caspofungin (Merck Sharp & Dohme, West

Point, PA); and amphotericin B (Bristol-Myers Squibb Laborato-ries, Princeton, NJ). Prior to testing, isolates were passaged twice

on potato dextrose agar (Difco Laboratories, Detroit, MI) at 35 ◦C.

Antifungal susceptibility testing was performed by the reference

broth microdilution method of the Clinical and Laboratory Stan-

dards Institute (CLSI) [11]. The tested concentrations of the agents

ranged from 0.03g/mL to 64g/mL. Final dilutions were made

in RPMI 1640 medium (Sigma) buffered to pH 7.0 with 0.165 M

morpholinepropanesulfonic acid (MOPS) buffer (Sigma). Following

incubation at 35 ◦C for 48 h, minimum inhibitory concentrations

(MICs) were determined. Two reference strains, Candida parapsilo-

sis ATCC 22019 and Candida krusei ATCC 6258, were used as the

control strains for susceptibility testing. Susceptibilities to flucona-

zole and flucytosine were determined according to CLSI guidelines.

The proposed susceptibility breakpoint of 1g/mL was used forvoriconazole and amphotericin B and 2g/mL was used for caspo-

fungin [12–14].

2.4. Statistical analyses

Categorical variables were analysed using Fisher’s exact test

or 2 test. The probability of survival was estimated using the

Kaplan–Meier method. Pearson’s correlation coefficient was used

to determine the relationship between annual fluconazole con-

sumption and trends in the percentage of C. glabrata among all

Candida spp. causing fungaemia each year. An R-value greater than

0.72 (or less than −0.72) and a P -value 60 years of age. Onset of fun-

gaemia occurred at a median of 27 days after admission. Most of

the patients had several co-morbidities and risk factors (Table 1).

The most commonunderlying diseases were cancer (49%),diabetes

(34%) and renal failure (25%). The most common risk factors were

central venous catheter use (88%), antibacterial treatment (87%)

and parenteral nutrition (51%).

The probable portals of entry for C. glabrata fungaemia are

shown in Table 2. The probable portalof entry could be determined

retrospectively from the medical records in only 130 (73%) of 177

Table 2

Probable portals of entry of Candida glabrata fungaemia.

Probable portals of entry (N = 130) No. of episodes (%)

Central venous catheter 79 (61)

Urinary tract 20 (15)

Intra-abdominal 18 (14)

Airway or lung 3 (2)

Surgical wound 4 (3)

Other 6 (5)

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238 S.-Y. Ruan et al. / International Journal of Antimicrobial Agents 34 (2009) 236–239

Table 3

In vitro susceptibilities of Candida glabrata isolates to five antifungal agents.

Antifungal MIC (g/mL) Susceptible (%)a

Range MIC50 MIC90

Fluconazole 2 to >64 8 32 63

Voriconazole 0.06–64 0.25 1 93

Caspofungin 0.25 to >64 0.5 1 96

Flucytosine 0.06 to >64 0.06 0.12 99

Amphotericin B 0.25–2 1 1 98

MIC,minimum inhibitory concentration;MIC50/90 , MIC atwhich50%and 90% ofthe

isolates are inhibited, respectively.a Susceptibility breakpoints were defined as ≤8g/mL for fluconazole and

≤4g/mLfor flucytosine,and presumptivelyidentified as≤1g/mLfor voriconazole

and amphotericin B and ≤2g/mL for caspofungin.

fungaemic episodes. The most commonly identified portal of entry

was a central venous catheter (61%), followed by the urinary tract

(15%) and intra-abdominal (14%).

3.2. Antifungal susceptibility testing

The MICs of the C. glabrata isolates to five antifungal agents are

shown in Table 3. The susceptibility rate was 63% for fluconazole,

93% for voriconazole, 96% for caspofungin, 99% for flucytosine and98% for amphotericin B. The proportion of isolates with flucona-

zole resistance (MIC > 32g/mL) was 7% and with susceptible-dose

dependence was 30% (MIC = 16–32g/mL). The different levels of

susceptibility to fluconazole (susceptible, susceptible-dose depen-

dent and resistant) were not significantly associated with 30-day

mortality (P = 0.09).

3.3. Treatment and outcomes

Of the 177 C. glabrata fungaemia episodes, 21 (11.9%) were not

treated with antifungal agents. Lack of antifungal treatment was

most often due to death of the patient before the time of diag-

nosis. Of the 156 treated episodes, the mean interval between

culture and the start of empirical antifungal treatment was 2.3days, and 78% of patients were treated within 3 days. Early anti-

fungal treatment, starting


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S.-Y. Ruan et al. / International Journal of Antimicrobial Agents 34 (2009) 236–239 239

rather than fluconazole susceptibility or treatment agents [26–28].

Amphotericin B is an important therapeutic agent for infection

caused by azole-resistant Candida spp. The guidelines of the Infec-

tious Diseases Society of America (IDSA) suggest treating serious C.

glabrata infections with amphotericin B or high-dose fluconazole

[29]. In this study, patients treated with amphotericin B-containing

regimens had a lower mortality rate than those treated with non-

amphotericin B regimens, but this difference was not significant

(42% vs. 50%; P = 0.34). However, because the majority of patients

who received amphotericin B-containing regimens were treated

with fluconazole prior to amphotericin B, the lack of difference

in mortality between the two regimens might have been due to

patients receiving inappropriate initial therapy.

Candida glabrata fungaemia is associated with poor outcome

and the 30-day mortality rate ranged from 25% to 50% in previ-

ous reports [20,21,30]. In this study, the 30-day all-cause mortality

rate was 48.6%, and only 31% of patients could be discharged from

hospital. Early antifungal treatment, starting

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