JAC Advance Access originally published online on December 23, 2004
Journal of Antimicrobial Chemotherapy 2005 55(2):194-199; doi:10.1093/jac/dkh548
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JAC vol.55 no.2 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved
In vitro susceptibilities of bloodstream isolates of Candida species to six antifungal agents: results from a population-based active surveillance programme, Barcelona, Spain, 2002–2003
1 Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo Km 2, 28220 Majadahonda, Madrid; 2 Infectious Diseases Division, Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona; 4 Microbiology Department, Hospital Universitari Vall d'Hebron, Barcelona; 5 Microbiology Department, Hospital Clínic-IDIBAPS, Barcelona; 6 Infectious Diseases Division, Hospital Clínic-IDIBAPS, Barcelona; 7 Microbiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona; 8 Microbiology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona; 9 Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona; 10 Hospital del Mar, Barcelona, Spain; 3 Mycotic Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Diseases Control and Prevention, Atlanta, GA, USA
* Corresponding author. Tel: +34-91-5097961; Fax: +34-91-5097966; Email: mcuenca-estrella{at}isciii.es
Received 25 August 2004; returned 20 October 2004; revised 22 November 2004; accepted 23 November 2004
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Abstract |
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Objectives:
The antifungal drug susceptibilities of 351 isolates of Candida species, obtained through active laboratory-based surveillance in the period January 2002–December 2003, were determined (Candida albicans 51%, Candida parapsilosis 23%, Candida tropicalis 10%, Candida glabrata 9%, Candida krusei 4%).
Methods:
The MICs of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and caspofungin were established by means of the broth microdilution reference procedure of the European Committee on Antibiotic Susceptibility Testing.
Results and conclusions:
Amphotericin B and flucytosine were active in vitro against all strains. A total of 24 isolates (6.8%) showed decreased susceptibility to fluconazole (MIC 
16 mg/L) and 43 (12.3%) showed decreased susceptibility to itraconazole (MIC 0.25 mg/L). Voriconazole and caspofungin were active in vitro against the majority of isolates, even those that were resistant to fluconazole.
Keywords: fluconazole resistance , caspofungin , voriconazole , EUCAST
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Introduction |
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Candida species now rank as one of the most common causes of hospital-acquired bloodstream infections (BSI).1 Although Candida albicans remains the most frequent cause of Candida BSI, longitudinal surveillance programmes in the USA and Europe have detected an increase in the prevalence of BSI caused by Candida species other than Candida albicans, such as Candida glabrata, Candida krusei and Candida parapsilosis.2–6 Moreover, it appears that marked differences exist in species distributions and antifungal drug susceptibilities between different countries, underscoring the need for continued surveillance, to monitor trends in pathogen distribution and drug susceptibilities.3,7,8
Over the last decade, treatment of Candida BSI has been enhanced by the introduction of fluconazole. Because of its extensive usage in many countries, concern has arisen about the possible development of fluconazole resistance. This has been documented among Candida species isolated from human immunodeficiency virus-infected persons with recurrent oropharyngeal candidiasis,9 but it appears to be uncommon among North American and European bloodstream isolates.3,8,10–13 Of several new triazole and echinocandin agents, voriconazole and caspofungin appear to be highly active against all Candida species, including those that are less susceptible or resistant to fluconazole and/or itraconazole.8,14–16 To date, however, few prospective surveillance studies of the activity of these agents against Candida bloodstream isolates have been reported.
During 2002–2003, we conducted prospective population-based surveillance for Candida BSI in Barcelona, Spain, to determine the distribution of species involved in these infections and the proportion of antifungal drug resistance among the isolates. This report describes the antifungal drug susceptibility profiles of these isolates to various antifungal agents including voriconazole and caspofungin.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Isolates
A total of 351 incident bloodstream isolates of Candida species were obtained as part of a population-based active surveillance programme conducted in Barcelona and the greater Barcelona area in the period 1 January 2002–31 December 2003. These organisms had been recovered from 345 cases; in six cases, two different Candida species were identified. In 16 cases, a second isolate was recovered after antifungal therapy was started and in four cases, a third consecutive isolate was obtained. In each case, the time interval between the serial isolates was at least 5 days.
Species identification was performed at the participating laboratories and confirmed by the Mycology Reference Laboratory, National Center for Microbiology, Madrid, Spain, using standard morphological and physiological methods, including fermentation of and growth on carbon sources, growth on nitrogen sources and growth at various temperatures.17 C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were used as quality control organisms for antifungal drug susceptibility testing.
Antifungal drugs
Standard powders of amphotericin B (Sigma Aldrich Quimica S.A., Madrid, Spain), flucytosine (Sigma Aldrich Quimica S.A.), fluconazole (Pfizer S.A., Madrid, Spain), itraconazole (Janssen S.A., Madrid, Spain), voriconazole (Pfizer S.A.) and caspofungin (Merck & Co., Inc., Rahway, NJ, USA) were used. The final concentrations were in the range 16–0.03 mg/L for amphotericin B and caspofungin, 64–0.12 mg/L for flucytosine and fluconazole and 8–0.015 mg/L for itraconazole and voriconazole.
Broth microdilution susceptibility testing method
The MICs of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and caspofungin were determined by the reference procedure proposed by the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing for testing fermentative yeasts (AFST-EUCAST, discussion document 7.1).18 These recommendations are based on the National Committee for Clinical Laboratory Standards (NCCLS) reference procedure described in document M27-A2,19 but include some modifications to allow for automation of the method and to permit the incubation period to be shortened from 48 to 24 h.20 Briefly, testing was performed with RPMI 1640 medium supplemented with 2% glucose; an inoculum size of 105 cfu/mL was used, as were flat-bottom microdilution plates. MIC endpoints were determined spectrophotometrically at 24 and 48 h. For amphotericin B, the MIC endpoint was defined as the lowest drug concentration that resulted in a reduction in growth of 90% or more, compared with that of a drug-free growth control well. For flucytosine and azoles, the MIC endpoint was defined as a 50% reduction in optical density. For caspofungin, the endpoint was defined according to reports recently published (50% or greater inhibition relative to the control), which analysed influences of methodological variables on susceptibility testing of caspofungin against Candida species.21,22
Analysis of results
Interpretive breakpoints proposed by the NCCLS for flucytosine, fluconazole and itraconazole were used.19 Isolates were classified as susceptible or as showing decreased susceptibility. The latter category included the susceptible dose-dependent (SDD), intermediate and resistant categories of the NCCLS. An analysis of the SDD or intermediate and resistant isolates conducted separately showed no statistically significant differences.
The significance of the differences in MICs was determined by Student's t-test (unpaired, unequal variance). In order to approximate a normal distribution, the MICs were transformed to log2 values to establish susceptibility differences between species. A P value of <0.01 was considered significant. Both on-scale and off-scale results were included in the analysis. The off-scale MIC values were converted to the next concentration up. Statistical analysis was performed with Statistical Package for the Social Sciences (SPSS, version 12.0) (SPSS S.L., Madrid, Spain).
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Results |
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Table 1 summarizes the species distribution and in vitro susceptibilities of the 351 incident bloodstream isolates of Candida species to amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and caspofungin. The results are reported as MIC ranges, geometric mean (GM) MIC values and the MICs at which 90% of the isolates were inhibited (MIC90s). C. albicans was the most common isolate (51%), followed by C. parapsilosis (23%), C. tropicalis (10%), C. glabrata (9%) and C. krusei (4%).
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Amphotericin B MICs were in the range 0.03–0.5 mg/L, with isolates of C. krusei demonstrating the highest GM MIC and MIC90 values (0.3 and 0.5 mg/L, respectively). Flucytosine MICs were in the range 0.125–4 mg/L, with isolates of C. krusei again showing the highest GM and MIC90 values (2.43 and 4 mg/L, respectively). With regard to the three azole agents, fluconazole, itraconazole and voriconazole showed good activity against the majority of isolates, with GM MICs of 0.39, 0.03 and 0.02 mg/L, respectively. Caspofungin MICs were in the range 0.015–16 mg/L. Overall, a caspofungin MIC of
1 mg/L was demonstrated for 19 isolates (5.4%).
A total of 24 isolates (6.8%) showed decreased susceptibility to fluconazole (MIC 16 mg/L) (Table 2). Six isolates were classified as resistant to this compound (MIC 64 mg/L) and 18 were SDD (MIC, 16–32 mg/L). Although 25 of 31 incident C. glabrata isolates were classified as fluconazole-susceptible, MICs of 4–8 mg/L were demonstrated for these isolates. Overall, itraconazole MICs of 0.25 mg/L were demonstrated for 43 of 351 isolates (12.3%); 34 were classified as SDD (MIC 0.25–0.5 mg/L) and nine as resistant (MIC 1 mg/L). Notably, most of the isolates for which fluconazole MICs were 16 mg/L showed decreased susceptibility to itraconazole (P < 0.01). Interpretative breakpoints for susceptibility testing of voriconazole have not been established, but voriconazole MICs of 1 mg/L were demonstrated for only three isolates (0.85%) (one each of Candida tropicalis, C. glabrata and C. krusei).
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A total of 20 serial isolates were obtained from 16 cases of Candida BSI: seven cases were due to C. albicans, six to C. parapsilosis, two to C. tropicalis and one to C. krusei. Most of these patients were treated with fluconazole for several weeks, but the MICs of fluconazole for the first and successive isolates were comparable. No significant differences in susceptibility were demonstrated for any of the antifungal agents tested between the initial and subsequent isolates (P > 0.01).
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Discussion |
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This report provides the first population-based description of the species distribution and in vitro drug susceptibilities of bloodstream isolates of Candida species from Spain. It provides more representative information than previous reports, which were based only on selected hospitals or particular groups of hospitalized patients. Our findings indicate that the distribution of Candida species causing BSI in Spain is similar to that documented in recent reports from several other European countries. C. albicans was the predominant organism, accounting for 51% of isolates, followed by C. parapsilosis (23%), C. tropicalis (10%), C. glabrata (9%) and C. krusei (4%). Although several previous reports from Spain have indicated that almost 40% of cases of Candida BSI were due to C. parapsilosis,23–27 the lower proportion reported here (23%) is more consistent with recently reported rates of 15%–16% from France and Italy.28,29 It is, however, higher than the rates of 1%–10% reported for C. parapsilosis from England and Wales, Finland, Iceland and Switzerland.12,30–32 These differences in rates might be attributable to differences in the representativeness of the populations studied, but variations in healthcare practices could also be an important factor. It has been suggested that the higher prevalence of C. parapsilosis in some institutions might be related to poor catheter care or infection control practices, but ecological and climatological factors could also be involved.26,33
In this study, C. glabrata and C. krusei accounted for 9% and 4%, respectively, of bloodstream isolates. C. glabrata, a species that easily acquires azole drug resistance, is represented in European surveillance data of the 1990s at proportions in the range 9%–16%, depending on the geographic location.12,28–32 The low proportion of Candida BSI due to C. krusei, a species that is intrinsically resistant to fluconazole, is also consistent with reports from other European countries12,28–31 and the USA.10,11,34,35
Our findings confirm the negligible proportions of fluconazole resistance among C. albicans bloodstream isolates that have been reported elsewhere.8,10–13,30,36 Our susceptibility results for Candida species other than C. albicans are also consistent with those of other studies8,10–13,30,36 in showing a low level of fluconazole resistance among C. tropicalis and C. parapsilosis, and the expected high level of resistance in C. krusei. A total of 43 isolates (12.3%) demonstrated decreased susceptibility to itraconazole (MIC > 0.25 mg/L), a similar proportion to that reported elsewhere.8,23,36 Of these less-susceptible strains, 28 were identified as C. glabrata, eight as C. krusei and two as C. tropicalis.
In a population-based surveillance programme in the USA, conducted during 1998–2000, Hajjeh et al.11
documented amphotericin B Etest MICs in the range 0.002–12 mg/L, with MICs of 0.38 mg/L for 10% of isolates, 1 mg/L for 1.7% and 2 mg/L for 0.4%. In this study, we documented amphotericin B MICs in the range 0.03–0.5 mg/L, with MICs of >0.25 mg/L for 10% of isolates. These results are consistent with those of reports from other European countries.12,30
The decreased susceptibility of C. krusei to amphotericin B (MIC90, 0.5 mg/L) is consistent with previous reports for this organism.11,34,35
Pfaller et al.37
reported the in vitro activities of flucytosine against > 8000 incident isolates of Candida spp. obtained from blood and other deep sites at more than 200 hospitals worldwide. Only 3% of C. albicans and 1% of C. glabrata were resistant to this agent in vitro (MIC 32 mg/L). More recently, Hajjeh et al.11
reported that 4.3% of North American C. albicans bloodstream isolates were resistant to flucytosine, compared with <1% of C. parapsilosis and C. tropicalis isolates and no C. glabrata isolates. In this study, we documented flucytosine MICs in the range 0.125–4 mg/L, with MICs of >0.5 mg/L for 10% of isolates. Again, our results are consistent with those of reports from other European countries.12,30,38
Although no established interpretative breakpoints are available for the new triazole agents and echinocandins, both voriconazole and caspofungin were active in vitro against the majority of bloodstream isolates of Candida species tested in this study, even those strains resistant to other agents. However, as has been noted elsewhere,14
the activity of voriconazole was reduced among isolates that showed decreased susceptibility to fluconazole and/or itraconazole. Our findings confirm those of Pfaller et al.15
who tested 351 clinical isolates of Candida species resistant to fluconazole against caspofungin and observed that 99% were inhibited by caspofungin at an MIC of 
2 mg/L.
In conclusion, the results of this population-based surveillance study indicate that the majority of strains causing Candida BSI are still susceptible to fluconazole (93%) and itraconazole (88%). Our results indicate that fluconazole is a reasonable alternative for empirical treatment of candidaemia. However, 13% of cases were due to organisms that were either intrinsically resistant to fluconazole (C. krusei) or possessed the ability to develop fluconazole resistance rapidly (C. glabrata). Prompt identification of isolates causing Candida BSI is important in selecting the most appropriate antifungal therapy.
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Footnotes |
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Contributed equally to this work. 
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Acknowledgements |
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This study was supported by research grants from Pfizer S.A. and Gilead S.A., and by a medical grant from the Spanish Society for Infectious Diseases and Clinical Microbiology.
Other members of the Barcelona Candidemia Project Study Group are: Scott Fridkin, Rana Hajjeh, Benjamin Park, (Centers for Disease Control and Prevention:, Atlanta, GA, USA), Francesc Marco Reverter and C. Melcion Soler (Microbiology Department, Hospital-Clinic-IDIBAPS, Barcelona, Spain), P. Saballs (Internal Medicine Department, Hospital del Mar, Barcelona, Spain), Amadeu Gener (Microbiology Department, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain), Dionisia Fontanals (Microbiology Department, Hospital Parc Taulí, Sabadell, Barcelona, Spain), Mariona Xercavins (Microbiology Department, Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain), Lluis Falgueras (Internal Medicine Department, Hospital General de Catalunya, Sant Cugat del Valles, Barcelona, Spain), Marta de Ramon (Microbiology Deparment, Hospital General de Catalunya, Sant Cugat del Valles, Barcelona, Spain) Maria Teresa Torroella (Microbiology Deparment, Hospital General de Catalunya, Sant Cugat del Valles, Barcelona, Spain), Carles Alonso (Microbiology Department, Hospital Creu Roja, Hospitalet de Llobregat, Barcelona, Spain), Montserrat Sierra (Microbiology Department, Hospital de Barcelona, Barcelona, Spain), Joaquin Martinez-Montauti (Internal Medicine Department, Hospital de Barcelona, Barcelona, Spain), Maria Antonia Morera (Microbiology Department, Hospital de Terrassa, Terrassa, Barcelona, Spain), and Jordi de Otero (Internal Medicine Department, Hospital Creu Roja, Barcelona, Spain).
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O. Lortholary, E. Dannaoui, D. Raoux, D. Hoinard, A. Datry, A. Paugam, J.-L. Poirot, C. Lacroix, F. Dromer, and the YEASTS Group In Vitro Susceptibility to Posaconazole of 1,903 Yeast Isolates Recovered in France from 2003 to 2006 and Tested by the Method of the European Committee on Antimicrobial Susceptibility Testing Antimicrob. Agents Chemother., September 1, 2007; 51(9): 3378 - 3380. [Abstract] [Full Text] [PDF]
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 M. B.-v. Zepelin, L. Kunz, R. Ruchel, U. Reichard, M. Weig, and U. Gross Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005 J. Antimicrob. Chemother., August 1, 2007; 60(2): 424 - 428. [Abstract] [Full Text] [PDF]
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 M. A. Pfaller and D. J. Diekema Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem Clin. Microbiol. Rev., January 1, 2007; 20(1): 133 - 163. [Abstract] [Full Text] [PDF]
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C. Girmenia, G. Pizzarelli, F. Cristini, F. Barchiesi, E. Spreghini, G. Scalise, and P. Martino Candida guilliermondii Fungemia in Patients with Hematologic Malignancies. J. Clin. Microbiol., July 1, 2006; 44(7): 2458 - 2464. [Abstract] [Full Text] [PDF]
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B. Almirante, D. Rodriguez, M. Cuenca-Estrella, M. Almela, F. Sanchez, J. Ayats, C. Alonso-Tarres, J. L. Rodriguez-Tudela, A. Pahissa, and the Barcelona Candidemia Project Study Group Epidemiology, Risk Factors, and Prognosis of Candida parapsilosis Bloodstream Infections: Case-Control Population-Based Surveillance Study of Patients in Barcelona, Spain, from 2002 to 2003. J. Clin. Microbiol., May 1, 2006; 44(5): 1681 - 1685. [Abstract] [Full Text] [PDF]
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M. A. Pfaller, D. J. Diekema, and D. J. Sheehan Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing Clin. Microbiol. Rev., April 1, 2006; 19(2): 435 - 447. [Abstract] [Full Text] [PDF]
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S. S. Magill, C. Shields, C. L. Sears, M. Choti, and W. G. Merz Triazole Cross-Resistance among Candida spp.: Case Report, Occurrence among Bloodstream Isolates, and Implications for Antifungal Therapy J. Clin. Microbiol., February 1, 2006; 44(2): 529 - 535. [Abstract] [Full Text] [PDF]
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M. Marine, C. Serena, B. Fernandez-Torres, F. J. Pastor, and J. Guarro Activities of Flucytosine, Fluconazole, Amphotericin B, and Micafungin in a Murine Model of Disseminated Infection by Candida glabrata Antimicrob. Agents Chemother., November 1, 2005; 49(11): 4757 - 4759. [Abstract] [Full Text] [PDF]
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K. B. Laupland, D. B. Gregson, D. L. Church, T. Ross, and S. Elsayed Invasive Candida species infections: a 5 year population-based assessment J. Antimicrob. Chemother., September 1, 2005; 56(3): 532 - 537. [Abstract] [Full Text] [PDF]
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M. A. Pfaller, L. Boyken, R. J. Hollis, S. A. Messer, S. Tendolkar, and D. J. Diekema In Vitro Susceptibilities of Clinical Isolates of Candida Species, Cryptococcus neoformans, and Aspergillus Species to Itraconazole: Global Survey of 9,359 Isolates Tested by Clinical and Laboratory Standards Institute Broth Microdilution Methods J. Clin. Microbiol., August 1, 2005; 43(8): 3807 - 3810. [Abstract] [Full Text] [PDF]
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