JAC Advance Access originally published online on May 29, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 71-77
© 2003 The British Society for Antimicrobial Chemotherapy
Stable susceptibility of Candida blood isolates to fluconazole despite increasing use during the past 10 years
Departments of 1 Internal Medicine and 3 Laboratory Medicine, National Taiwan University Hospital No. 7, Chung-Shan South Road, Taipei; Departments of 2 Medicine and 4 Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Received 30 September 2002; returned 5 January 2003; revised 8 January 2003; accepted 2 April 2003
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Abstract |
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The prevalence of drug-resistant bacterial pathogens is very high in Taiwan. Accordingly, there was great concern that the introduction of fluconazole would result in rapid emergence of drug-resistant yeasts. Thus, we recommended in 1991 that fluconazole be used for treatment only. To explore the impact of this policy fluconazole susceptibility of Candida species blood culture isolates and outcome of patients with nosocomial candidaemia were monitored prospectively at National Taiwan University Hospital during 1994–2000. The MICs of fluconazole were determined by the disc diffusion method. There were 1095 episodes of nosocomial candidaemia during 1994–2000. Candida albicans was the most common species (50.4%), followed by Candida tropicalis (20.5%), Candida parapsilosis (14.2%) and Candida glabrata (12.0%). There were 0–2 isolates of Candida krusei per year. The incidence of nosocomial candidaemia and the proportion of C. glabrata peaked in 1996 and decreased thereafter. Fluconazole susceptibility was determined for 552 Candida blood isolates. Only 0.7% of blood isolates were resistant to fluconazole. Fluconazole susceptibility was 94.0% in 1994–1995 and 97.9% in 1999–2000 (P = 0.06). Attributable mortality for patients with nosocomial candidaemia was 43.2% in 1994–1995 and was 25% in 2000 (P = 0.005). Despite an increase in the incidence of nosocomial fungal infection and increased consumption of fluconazole from 1994 to 2000, there was no significant change in the susceptibility to fluconazole for bloodstream isolates of Candida species. These findings appear to be attributed to several factors. These include low prevalence of C. krusei and C. glabrata, changing patterns of use of antifungal drugs and broad-spectrum antibiotics, and efforts to improve the rational use of antifungal agents at our hospital.
Keywords: Candida, nosocomial infection, antifungal susceptibility testing, outcome
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Introduction |
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The incidence of nosocomial fungal infection has increased substantially over the past several decades.1–4 Candida species are among the leading causes of nosocomial bloodstream infection at the National Taiwan University Hospital (NTUH).5 Nosocomial Candida infection is an independent poor prognostic factor for critically ill patients6 and nosocomial candidaemia is associated with a high mortality rate.7 NTUH has a high incidence of resistant strains for many common pathogenic bacteria.8 This is due to an increasing population of patients undergoing intense treatment for severe underlying diseases and concomitant extensive use of antibiotics.6,9 A prior study from our hospital demonstrated that the MICs of fluconazole for Candida albicans blood isolates collected during 1994–1995 were higher than other series.10 We therefore recommended more judicious use of antifungal agents in the hope of preventing the emergence of resistant strains. Special emphasis was given to fluconazole (Table 1). To explore the impact of these policies we prospectively monitored the incidence of C. albicans and other Candida species and their susceptibility to fluconazole during 1994–2000. We also compared the attributable mortality for patients with nosocomial candidaemia for the period 1994–1995 to 2000.
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Materials and methods |
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Study population
NTUH is a major teaching hospital in Taiwan. The number of beds increased from 1500 in 1994 to 2000 beds in 2000. Annual discharges were 45 358 in 1994 and 69 421 in 2000. Prospective, hospital-wide nosocomial infection surveillance was initiated in 1981. Data on nosocomial infections were collected, analysed and reported to the hospital infection control committee monthly and published annually.
Blood culture isolates
Blood samples were cultured by inoculation into BACTEC fungal medium (Becton-Dickinson Microbiology Systems, Cockeysville, MD, USA) and tested daily for microbial growth by a BACTEC 9240 system (BD Biosciences, Sparks, MD, USA). Organisms were identified by germ tube analysis and morphology on cornmeal-Tween 90 agar11 or, when necessary, by standard biochemical testing with the API 20C system (API bioMérieux Vitek, Inc., Hazelwood, MO, USA). Blood isolates of Candida species were collected weekly during 1994–2000. All the isolates were kept at –70°C and were subcultured at least twice on Sabouraud dextrose agar at 35°C before being tested. A total of 552 isolates were tested for susceptibility to fluconazole in this study.
Antifungal susceptibility testing
The MICs of fluconazole (Pfizer Pharmaceuticals, Inc., NY, USA) were determined by the disc diffusion method as part of the Global Antifungal Surveillance Program.12 This system uses a 25 µg fluconazole disc (Becton-Dickinson) and Mueller–Hinton agar supplemented with 2% glucose and 0.5 mg/L Methylene Blue. Inocula were adjusted to a 0.5 McFarland density standard. Plates were incubated aerobically at 35°C for 24 h and read by electronic image analysis and interpreted and recorded with a BIOMIC Plate Reader System (Giles Scientific Inc., Santa Barbara, CA, USA). Zone inhibition interpretive criteria for fluconazole disc testing were based on zone diameters correlated with NCCLS recommended category breakpoints for the reference macrobroth dilution method.13 Fluconazole breakpoints were: susceptible (≤8 mg/L or ≥19 mm), susceptible-dose-dependent (S-DD) (16–32 mg/L or 13–18 mm) and resistant (≥64 mg/L or ≤12 mm). Quality controls were carried out with each batch of clinical isolates by testing C. albicans ATCC 90028 with a recommended acceptable performance range of 32–43 mm.
Data collection
All patients with nosocomial candidaemia diagnosed and treated at our hospital were observed prospectively until discharge or until death as part of the prospective nosocomial control programme.5,7 The incidence of nosocomial fungal infection and nosocomial candidaemia, the distribution of Candida species causing nosocomial candidaemia and annual consumption of antifungal agents were collected every year during 1981–2000. Data collected during 1981–1993 have been reported.5
Definitions
The Centers for Disease Control and Prevention definitions of nosocomial infections14 were used in order to include clinically significant, hospital-acquired infections and to exclude cultures containing contaminants or colonizing organisms. Candidaemia was defined when Candida species were isolated from blood culture(s) collected from a patient with signs and symptoms of infection. Candidaemia was considered to be the primary cause of death of patients who died within 7 days following a positive blood culture, when no other cause (including the primary disease, other infections and haemorrhage) was identified.7 Candidaemia was considered to be an associated cause of death when it was still present at time of death (as indicated by fever, with or without positive cultures), although another complication (e.g. haemorrhage or a secondary non-fungal infection) or an uncontrolled underlying disease was also present. Attributable mortality included both. Death was considered unrelated to candidaemia when candidaemia was cleared at time of death (by symptoms, signs and blood culture) and there was another likely cause such as the underlying disease.
Statistical analyses
Statistical analyses were carried out with the Statistical Package for the Social Sciences (SPSS, version 10.0) for Windows (SPSS Inc., Chicago, IL, USA). Univariate analysis of categorical variables was done with the 
2 test or Fisher’s exact test. Continuous variables were analysed by the Student’s t-test. All P values were two-tailed, and a P value <0.05 was considered to indicate statistical significance.
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Results |
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Incidence of nosocomial candidaemia
The incidence of nosocomial fungal infections increased gradually from 1981 to 2000 (Figure 1). Nosocomial candidaemia increased rapidly during 1981–1996. There was no significant change in the incidence of nosocomial candidaemia during 1996–2000. Candida species were the leading cause of nosocomial bloodstream infection (including both primary and secondary) during 1993–1999, and were second only to Staphylococcus aureus in 2000 (2.8 and 3.6 episodes per 1000 discharges, respectively). Annual consumption of fluconazole (both parenteral and oral forms) increased gradually from 0.08 g per 1000 patient days in 1991 to 9.82 g per 1000 patient days in 2000 (Figure 2a). The trends for other antifungal drugs are shown in Figure 2(b).
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Species distribution
During 1994–2000, a total of 1095 episodes of nosocomial candidaemia occurred. C. albicans was the leading species (50.4%), followed by Candida tropicalis (20.5%), Candida parapsilosis (14.2%) and Candida glabrata (12.0%). There were only six episodes of Candida krusei during the 7 year period. The proportion of non-albicans Candida species reached its peak in 1996 (62.5%) and did not change significantly thereafter (51.1% in 2000) (Figure 3). Parallel to this trend, the proportion of C. glabrata increased gradually to 19.4% in 1996 and decreased thereafter to 9.0% in 2000.
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In vitro activity of fluconazole
The MICs of fluconazole were determined for 552 Candida blood isolates. This included 188 isolates of C. albicans, 155 isolates of C. parapsilosis, 116 isolates of C. tropicalis, 85 isolates of C. glabrata and eight isolates of Candida guillermondii. Fluconazole susceptibility was 94.0% in 1994–1995 and 97.9% in 1999–2000 (P = 0.06) (Table 2). The proportion of fluconazole-resistant strains was low (0.7%) and did not change significantly during the study period for any species (Table 2). The frequency of resistant or dose-dependent susceptible strains was greater for C. glabrata (5.9%) and C. tropicalis (7.7%) than C. albicans (2.1%) and C. parapsilosis (1.3%) (P = 0.016).
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Outcome of patients with nosocomial candidaemia
Out of 188 patients with nosocomial candidaemia in 2000, 65 (34.6%) died within 14 days from the onset of candidaemia and 81 (43.1%) died within 30 days. The overall mortality at discharge was 60.6% (114/188). This was similar to mortality observed during 1994–1995 (59.3%, 70/118)7 (P > 0.05). Attributable mortality in 2000 was 25% (47/188). This was lower than that of 1994–1995 (43.2%, 51/118)7 (P = 0.005).
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Discussion |
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Emergence of resistance of Candida species to fluconazole and other azoles is of great concern,15–17 particularly because of the well-known relationship between antimicrobial use and resistance.18–20 The greatest fear is that increased use of fluconazole will lead to a shift toward intrinsically resistant Candida species such as C. glabrata and C. krusei and lead to emergence of resistant strains of C. albicans.15,16 Shifts in distribution of Candida species and antifungal susceptibility have been reported in several countries.20–24 A similar trend was noted at our hospital during 1981–19935 and 1994–1996.
Despite these fears, the current study at NTUH demonstrates that the percentage of fluconazole-resistant blood isolates remains quite low, and did not appear to be increasing despite increased use of fluconazole. This trend appears to be due in part to a decrease in C. glabrata and increase in fluconazole susceptibility in C. tropicalis. A possible explanation for these findings is that we were able to decrease cross-resistance to fluconazole by restricting the use of other azoles such as ketoconazole and itraconazole.15–17 The decrease in the proportion of C. glabrata from 19% in 1996 to 9% in 2000 at NTHU differs from reports from Europe,23,25 Canada23,24 and the USA22,23,26 (Table 3). Furthermore, the proportion of fluconazole-susceptible Candida species of 97.9% at our hospital during 1999–2000 was greater than reported elsewhere (Table 4).12,22–24,27–30 We doubt that these differences can be accounted for by methods in fluconazole susceptibility testing since we used the Global Antifungal Surveillance Group disc diffusion method,12 which has been shown to generate the same results as the broth microdilution method.23,28,29,31
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Restriction or judicious use of antifungal use should be balanced between antimicrobial resistance and patient outcome. The present study showed that not only did the incidence of nosocomial candidaemia not increase since 1996, but also attributable mortality of candidaemia decreased from 43.2% during 1994–1995 to 25.0% in 2000. In addition, the 30 day mortality in this study was similar to those in multicentre studies.25,32 A possible explanation for the decreased incidence of nosocomial candidaemia is the decrease in annual consumption of potent broad-spectrum antibacterial agents at NTUH after implementation of the National Health Insurance Program in 1995.33 Broad-spectrum antibacterial agents have been shown to be a major risk factor for candidaemia.34,35 Increase in empirical and/or pre-emptive use of fluconazole for presumed invasive candidiasis might also account for this changing epidemiology. Furthermore, cross-transmission does not appear to account for the high prevalence of invasive candidiasis at NTUH.36
When comparing data collected in different geographical regions (Table 3), the percentage of C. tropicalis was higher at NTUH (23%) and in Argentina (20%)37 than in other countries. Our previous study showed that C. tropicalis was more frequently isolated from patients with neutropenia than those without.7 Abi-Said et al.21 suggested the absence of fluconazole prophylaxis as an independent predictor of C. tropicalis fungaemia in patients with cancer. At our hospital, fluconazole was not used for prophylaxis except in bone marrow transplant recipients. This might be the reason that C. tropicalis was the second most common species of Candida causing fungaemia at NTUH (Figure 3). On the other hand, the impact of geographical variation and/or environmental sources was unknown. Furthermore, the incidence of S-DD isolates was relatively high. Only 86.1% of C. tropicalis collected during 1996–1997 were susceptible to fluconazole and 100% during 1999–2000. This unique trend could not be explained by the contribution of fluconazole use alone34,38 and is possibly due to a decrease in the use of other azoles.
The present study had several limitations.39 First, the impact of use of antibacterial drugs on the emergence of nosocomial candidaemia was not included in this study. Secondly, we are unable to assess the effect of the recent restriction of over-the-counter sales of azoles in Taiwan. Thirdly, we did not conduct a formal study of prescribing practices of fluconazole at NTUH to confirm that our recommendations were implemented. Fourthly, these findings are limited to the experience of a single centre study. Nevertheless NTUH is very similar to other major medical centres in that it has a heavy concentration of immunocompromised patients and clustered critically ill patients6,7 and a high prevalence of antibacterial resistance.8,9 Furthermore, the disc method does not do well in distinguishing susceptible from S-DD categories and may contribute to the discrepancy between the proportions of C. tropicalis in the S-DD category during 1994–1995 using the disc method or broth microdilution method (12.1% and 0%, respectively) (Table 4).
Global trends in fluconazole resistance to Candida species make it increasingly more important to select antifungal agents for empirical use based on ongoing surveillance of local patterns of the prevalence of the various Candida species and their susceptibility to antifungal drugs.40 The rational use of antifungal drugs will become even more important as new agents are introduced. Furthermore, comparison between different antifungal agents, using resistance as an endpoint in addition to patient outcome, may reveal how to avoid losing the azoles as promising antifungal agents.41–43
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Acknowledgements |
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We thank Dr Calvin Kunin for critical review and useful comments prior to submission. We also thank Ms Mei-Ling Chen and Ms Shiou-Hwa Wang for retrieval of data from the Nosocomial Control Program of our hospital, and Ms Hui-Ming Tai for technical assistance with the antifungal susceptibility test. This work was supported partially by grants (NSC87-2314-B-002-094, NSC88-2314-B-002-068) to Y.-C.C. from the National Science Council, Taiwan, and partially by a grant to S.-C.C. from Pfizer Pharmaceuticals, Inc. The funding sources were not involved in study design, data collection, laboratory work, statistical analysis and paper preparation.
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Footnotes |
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* Corresponding author. Tel: +886-2-2312-3456, ext. 5401; Fax: +886-2-2397-1412; E-mail: sc4030{at}ha.mc.ntu.edu.tw
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M. A. Pfaller, A. Espinel-Ingroff, and R. N. Jones Clinical Evaluation of the Sensititre YeastOne Colorimetric Antifungal Plate for Antifungal Susceptibility Testing of the New Triazoles Voriconazole, Posaconazole, and Ravuconazole J. Clin. Microbiol., October 1, 2004; 42(10): 4577 - 4580. [Abstract] [Full Text] [PDF]
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M. A. Pfaller, S. A. Messer, L. Boyken, S. Tendolkar, R. J. Hollis, and D. J. Diekema Geographic Variation in the Susceptibilities of Invasive Isolates of Candida glabrata to Seven Systemically Active Antifungal Agents: a Global Assessment from the ARTEMIS Antifungal Surveillance Program Conducted in 2001 and 2002 J. Clin. Microbiol., July 1, 2004; 42(7): 3142 - 3146. [Abstract] [Full Text] [PDF]
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