JAC Advance Access originally published online on June 6, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):474-477; doi:10.1093/jac/dkl241
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Effect of fluconazole consumption on long-term trends in candidal ecology
1 Department of Intensive Care, Ghent University Hospital De Pintelaan 185, 9000 Ghent, Belgium 2 Health Care Department, Hogeschool Gent ‘Vesalius’ 9000 Ghent, Belgium 3 Department of Microbiology, Ghent University Hospital De Pintelaan 185, 9000 Ghent, Belgium 4 Hospital Pharmacy, Ghent University Hospital De Pintelaan 185, 9000 Ghent, Belgium 5 Department of Infectious Diseases, Ghent University Hospital De Pintelaan 185, 9000 Ghent, Belgium
*Correspondence address. Department of Intensive Care, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Tel: +32 9240 62 16; Fax: +32 9240 49 95; E-mail: stijn.blot{at}UGent.be
Received 2 January 2006; returned 14 February 2006; revised 15 May 2006; accepted 16 May 2006
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Abstract |
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Background: Fluconazole is an antifungal agent that is widely used for the treatment of Candida infection. Because of its favourable safety profile it is extensively used for prophylaxis in patient populations with a substantial risk for Candida infection. At the individual patient level, exposure to fluconazole selects for Candida non-albicans strains such as Candida glabrata and Candida krusei, with reduced susceptibility or intrinsic resistance to fluconazole. The effect of the volume of consumption of fluconazole on candidal ecology, however, is poorly investigated.
Objectives: The long-term effect of fluconazole consumption on distribution of species causing candidaemia was investigated in a university hospital during an 11 year period (1994–2004).
Methods: In a historical cohort the incidence of nosocomial candidaemia (expressed per 100 000 patient days) was linked with volume consumption of fluconazole [expressed as defined daily doses (DDDs) per 100 000 patient days] and evaluated over time.
Results: During the study period 308 episodes of candidaemia occurred (63.3% caused by Candida albicans). The incidence of candidaemia varied from 6.0 to 13.8 per 100 000 patient days. The percentage candidaemia caused by Candida non-albicans spp. varied between 21% and 50%. No trends in the number of candidaemias or in the proportion of C. albicans versus Candida non-albicans spp. were observed. Fluconazole consumption was high but stable ranging from 5013 to 6807 DDDs per 100 000 patient days. No relationship could be demonstrated between volume of fluconazole consumption and Candida spp. distribution (Pearson's correlation coefficient: –0.083; P = 0.808).
Conclusions: Despite long-term exposure to fluconazole, no change in candidal ecology was observed.
Keywords: Candida species , candidaemia , antifungals , nosocomial , exposure
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Introduction |
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Candida spp. are a frequent cause of nosocomial infection. During the 1980s the incidence of life-threatening Candida infections increased dramatically, urging the need for prophylaxis.1 Fluconazole is a particularly attractive drug for antifungal prophylaxis because of its high bioavailability and favourable safety profile. Since the early 1990s fluconazole has become the drug of choice for most severe Candida infections and is used extensively for prophylaxis in patients undergoing bone marrow transplantation, solid organ transplantation and major abdominal surgery.2,3 During the 1990s, it appeared that further increase of nosocomial Candida infections had stopped and it has been suggested that this observation resulted from the use of fluconazole.4,5 Together with the increasing use of fluconazole, however, changes in the aetiology of Candida infections were reported. A relative decrease was observed in the proportion of Candida albicans, with a shift towards Candida non-albicans spp., mostly Candida glabrata and Candida krusei.6,7 This may be clinically relevant in view of reduced susceptibility of most strains of C. glabrata and the intrinsic resistance of C. krusei to fluconazole. The association between prior exposure to fluconazole and subsequent isolation of Candida non-albicans spp. with reduced susceptibility to this agent has been repeatedly described. This can be explained by the mechanism of selection pressure introduced in an individual patient exposed to fluconazole. However, many more patients receive fluconazole than patients develop Candida infection. The influence of the volume of fluconazole consumption on local candidal ecology has been poorly investigated.
The objective of the present study was to investigate the relationship between fluconazole consumption and species distribution (C. albicans versus Candida non-albicans) in nosocomial candidaemia, isolated in a large university hospital over an 11 year period (1994–2004).
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Methods |
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The present study was conducted at the 1060 bed Ghent University Hospital. Since 1992 all nosocomial bloodstream infections have been prospectively collected by the infection control team. This laboratory-based surveillance programme was used for the search for all patients who developed candidaemia when hospitalized during the period 1992–2004. Candidaemia is defined as the presence of at least one blood culture positive for Candida spp. in the presence of clinical signs and symptoms of infection. Candidaemia was considered nosocomial when diagnosed >48 h after hospital admission. Throughout the study period susceptibility testing for candidal isolates was performed with a disc diffusion test (Neosensitab, Rosco, Daastrub, Denmark). Neosensitabs were used according to the manufacturer's instructions: for zone diameters the breakpoints used were 22 and 14 mm, corresponding to breakpoints of 8 mg/L for susceptibility and 64 mg/L for resistance.
Data concerning fluconazole consumption, either orally or intravenously, were retrieved from the hospital pharmacy department for the period 1994–2004 and are described in defined daily doses (DDDs). According to the Anatomical Therapeutic Chemical classification and DDD assignment, one DDD of fluconazole represents 200 mg.8 Exposure to fluconazole prior to the onset of candidaemia was considered to be any dose of fluconazole administered prior to the date of blood sampling of the subsequent positive culture. Incidence figures for candidaemia and fluconazole consumption are described per 100 000 patient days. Pearson's correlation coefficient was used to assess the relationship between Candida spp. distribution and fluconazole consumption. The Candida spp. distribution is expressed as the ratio of Candida non-albicans spp. to Candida spp. per 100 000 patient days. In addition, because of the greater resistance in C. glabrata and C. krusei, the correlation between the proportion of these particular species and fluconazole consumption was explored. The 
2 test was used as appropriate. The study was approved by the Ethics Committee of the Ghent University Hospital.
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Results |
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During the period 1992–2004, 368 episodes of nosocomial candidaemia occurred (9.35/100 000 patient days). Throughout the study period the incidence of candidaemia varied from 6.0 per 100 000 patient days in 2000 to 13.8 in 2003. Yet, no trend could be determined (Figure 1). Of all episodes, 63.3% were caused by C. albicans (n = 233). The most frequently isolated Candida non-albicans spp. were C. glabrata (n = 62; 18.8%), Candida parapsilosis (n = 41; 11.1%) and Candida tropicalis (n = 18; 4.9%). C. krusei, Candida guillermondii and Candida lusitaniae each caused three episodes of candidaemia. One episode was caused by Candida kefyr. For four episodes no species identification was performed; these isolates were excluded from further analysis. C. albicans was more frequently fluconazole-susceptible than Candida non-albicans spp. (98.5% versus 61.8%; P < 0.001). Over the study period, the percentage of candidaemia caused by Candida non-albicans spp. varied between 21% (in 1998) and 50% (in 1997 and 2002). Yet, no trends in the proportion of C. albicans versus Candida non-albicans spp. were observed (Figure 1). Because pharmacy data on fluconazole consumption could only be retrieved from 1994 onwards, only cases of candidaemia that occurred between 1994 and 2004 (n = 308) were used to investigate the relationship between fluconazole and Candida spp. distribution.
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During the period 1994–2004 consumption of fluconazole varied between 5014 DDDs (in 1998) and 6807 DDDs (in 1995) per 100 000 patient days, but no trend in time could be demonstrated. During the study period the percentage of patients receiving fluconazole, as well as the mean number of DDD/patient administered, remained stable (Table 1).
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Figure 2 illustrates the relationship between the proportion of Candida non-albicans spp. and fluconazole consumption between 1994 and 2004. Volume of fluconazole consumption did not correlate with either Candida spp. distribution (Pearson's correlation coefficient: –0.083; P = 0.808) or proportion of candidaemia caused by C. glabrata and C. krusei (Pearson's correlation coefficient: –0.422; P = 0.196). At the individual patient level, however, fluconazole use prior to the onset of candidaemia increased the likelihood of infection with Candida non-albicans spp. (58.6% versus 40.8%; P = 0.001).
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Discussion |
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In this historical cohort study over an 11 year period in a university hospital, the volume of fluconazole consumption did not correlate with the proportion of Candida non-albicans spp. causing nosocomial candidaemia or with bloodstream infection due to C. glabrata or C. krusei.
Some reasons might explain the lack of correlation between fluconazole consumption and candidal ecology. First, in contrast with antibiotics, only a limited fraction of the total hospital population is exposed to fluconazole. Therefore these results should not be generalized to high-risk areas, where there is a high consumption of fluconazole as well as a high incidence of invasive candidiasis. Unfortunately, lack of study power precluded us from meaningful subgroup analyses in areas of particular interest such as haematology and intensive care units. Second, it can be questioned whether an 11 year exposure time is long enough to observe significant changes in candidal ecology. However, with an absolute absence of any correlation between consumption and ecology it appears that such assumptions are rather frail. Third, although there certainly is evidence for horizontal spread or cross-infection of Candida,9 cases of candidaemia are generally presumed to arise from endogenous sources. This is in contrast with bacteria, where horizontal spread resulting in colonization and infection is much better documented. An endogenous source of Candida infection should favour a relationship between fluconazole consumption (as an evident indicator or measure of selective pressure) and C. glabrata or C. krusei candidaemia. A hypothesis we could confirm only at the individual patient level. We assume that the extent of horizontal spread of Candida spp. is too low to affect the candidal ecology at the hospital level.
Thorough comparison with other studies is difficult because of differences in methodological approach. Other investigators compared general trends in fluconazole use with trends in the distribution of Candida species.2,4,10 Our approach is characterized by a year-by-year appraisal of fluconazole use and species distribution, merged in a scatter plot to allow correlation calculation. Despite methodological differences, our results are in line with those of others. Over a 12 year period (1989–2000) Garbino et al.10 found an incidence of candidaemia of 2.0–4.6 per 100 000 patient days in a single centre study performed in a university hospital. About 66% of episodes were caused by C. albicans. Despite a significant increase in fluconazole use during the study period, these investigators also did not observe a shift towards more Candida non-albicans spp. Similarly, in 17 Swiss university or university-affiliated hospitals the incidence of candidaemia remained stable, without a shift to resistant species, between 1991 and 2000, whereas the consumption of fluconazole increased significantly.4 Berrouane et al.2 reported a more prominent incidence of C. glabrata along with an increase in the use of fluconazole but the overall proportion of Candida non-albicans spp. did not increase.
During the study period fluconazole consumption was stable but high in comparison with other centres. Between 1993 and 1994 Berrouane et al.2 described a fluconazole use in a university hospital of 3.23 g/1000 patient days, which corresponds to 1615 DDDs per 100 000 patient days. In the multicentre study by Marchetti et al.,4 the fluconazole use increased steadily from 14 g in 1994 to 30 g/10 000 patient days in 2000, which corresponds to 700–1500 DDDs per 100 000 patient days. Compared with these studies, fluconazole expenditure in our hospital is three to five times higher, approximately between 5000 and 6800 DDDs per 100 000 patient days, yet stable over the study period. We have no direct explanation for the high fluconazole use in our institution. This may be multifactorial and include preference of fluconazole over other antifungals, use of higher daily dosages and a case-mix with a high proportion of patients at risk for invasive fungal infection (high activity in intensive care, solid organ transplantation, digestive surgery and haematology). Anyhow, the remarkable high utilization of fluconazole in our hospital underscores the study findings: fluconazole consumption does not affect candidal ecology despite long-term, high volume exposure.
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None of the authors has any conflict of interest to disclose.
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Acknowledgements |
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We would like to thank Professor Dr G. Verschraegen, MD, and Mr J. De Schuijmer, RN, MA, of the infection control team, Ghent University Hospital, Ghent Belgium, for continuous efforts in collecting data on nosocomial bloodstream infection. This study was performed without specific financial support. This work was presented in part at the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005.
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1 Jarvis WR and Martone WJ. (1992) Predominant pathogens in hospital infections. J Antimicrob Chemother 29:Suppl A, 19–24.
2
Berrouane YF, Herwaldt LA, Pfaller MA. (1999) Trends in antifungal use and epidemiology of nosocomial yeast infections in a university hospital. J Clin Microbiol 37:531–7.
3 Blot S and Vandewoude K. (2004) Management of invasive candidiasis in critically ill patients. Drugs 64:2159–75.[CrossRef][Web of Science][Medline]
4 Marchetti O, Bille J, Fluckiger U, et al. (2004) Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991–2000. Clin Infect Dis 38:311–20.[CrossRef][Web of Science][Medline]
5 Trick WE, Fridkin SK, Edwards JR, et al. (2002) Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis 35:627–30.[CrossRef][Web of Science][Medline]
6 Nguyen MH, Peacock JE Jr, Morris AJ, et al. (1996) The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. Am J Med 100:617–23.[CrossRef][Web of Science][Medline]
7 Snydman DR. (2003) Shifting patterns in the epidemiology of nosocomial Candida infections. Chest 123:500–3S.
8 Hartstein AI, Denny MA, Morthland VH, et al. (1995) Control of methicillin-resistant Staphylococcus aureus in a hospital and an intensive care unit. Infect Control Hosp Epidemiol 16:405–11.[Web of Science][Medline]
9 Taylor BN, Harrer T, Pscheidl E, et al. (2003) Surveillance of nosocomial transmission of Candida albicans in an intensive care unit by DNA fingerprinting. J Hosp Infect 55:283–9.[CrossRef][Web of Science][Medline]
10 Garbino J, Kolarova L, Rohner P, et al. (2002) Secular trends of candidemia over 12 years in adult patients at a tertiary care hospital. Medicine (Baltimore) 81:425–33.[CrossRef][Medline]
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