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Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008–2009)
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Diagnostic Microbiology and Infectious Disease 68 (2010) 278 – 283 www.elsevier.com/locate/diagmicrobio
Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008–2009) Michael A. Pfallera , Mariana Castanheiraa,⁎, Shawn A. Messera , Gary J. Moeta , Ronald N. Jonesa,b a
b
JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, Massachusetts, 02111, USA Received 24 April 2010; accepted 26 June 2010
Abstract The variation in Candida spp. causing bloodstream infection (BSI) and the frequency of resistance to fluconazole by patient age have been previously described. However, similar data have been shown for neither the echinocandins nor the newer triazoles. We analyzed the 24-h reference MIC data from the SENTRY Antimicrobial Surveillance Program to compare the antifungal resistance profiles and species distribution of Candida BSI isolates according to patient age. MIC results were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole, and voriconazole, and recently revised Clinical and Laboratory Standards Institute breakpoints were applied. A total of 1239 Candida BSI isolates were obtained from 79 medical centers in 2008 to 2009: 50.0%, 17.4%, 17.4%, 9.8%, and 1.8% were Candida albicans (Ca), Candida glabrata (Cg), Candida parapsilosis (Cp), Candida tropicalis (Ct), and Candida krusei (Ck), respectively. Ca was most common in the 60- to 79-year age group (52.3%) and least common in the 80- to 99-year age group (46.7%), whereas Cg was most common in the 80- to 99-year age group (28.6%) and least common in the 0- to 19-year age group (2.0%). Cp and Ct were most common in the 0- to 19-year age group (28.5% and 12.9%, respectively), and Ck was most common among the patients in the 20- to 39-year age group (3.5%). No resistance to echinocandins was detected among isolates of Ca, Cp, and Ct from all age groups. Likewise, no resistance to posaconazole or voriconazole was observed in isolates of Ca, Cp, or Ck from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of Cg with the highest resistance rates to echinocandins (16.7%), fluconazole (16.7%), posaconazole (5.0%), and voriconazole (11.1%) among isolates from the 20- to 39-year age group. Both species distribution and antifungal resistance patterns vary markedly with patient age. Cg BSI isolates may show lower susceptibility rates to both azoles and echinocandins with the highest rates of resistance detected in 20- to 59-year-old patients. © 2010 Elsevier Inc. All rights reserved. Keywords: Candida; Antifungal resistance; Bloodstream infections; SENTRY Program
1. Introduction Invasive candidiasis (IC) (candidemia and other deepseated infections including disseminated candidiasis, hepatic candidiasis, endocarditis, and meningitis) is associated with considerable morbidity and mortality (Falagas et al., 2006; Labelle et al., 2008; Pfaller and Diekema, 2010; Slavin et al.,
⁎ Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address: [email protected] (M. Castanheira). 0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2010.06.015
2010). Rapid initiation of appropriate antifungal therapy is essential for the management of IC and has been shown to reduce mortality (Garey et al., 2006; Labelle et al., 2008; Morrell et al., 2005; Parkins et al., 2007). The guidelines for the management of IC published by the Infectious Diseases Society of America (IDSA) (Pappas et al., 2009) recommend that initial antifungal therapy should be directed by the species identification of the organism and the local epidemiology (occurrences) of IC including the antifungal susceptibility patterns. Due to the spectrum and fungicidal potency against Candida spp., an echinocandin antifungal agent (anidulafungin, caspofungin, and micafungin) is
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recommended as first-line therapy for most patients with IC with de-escalation to fluconazole based on the susceptibility of the infecting organism to fluconazole (Pappas et al., 2009). Although much is known regarding the geographic variation in the species of Candida causing IC and the associated susceptibility of these isolates to fluconazole (Pfaller and Diekema, 2007; Pfaller and Diekema, 2010; Pfaller et al., 2010a), considerably less is understood regarding the variation in the infecting species and their susceptibilities to the newer azoles (posaconazole, voriconazole) and echinocandins according to patient age (Arendrup et al., 2008; Panizo et al., 2009; Pfaller et al., 2002; Pfaller et al., 2009; Sandven et al., 2006; Tortorano et al., 2004). Given the fact that some of the highest rates of IC have been observed among patients over the age of 70 years (Zaoutis et al., 2005; Zilberberg et al., 2008), it is notable how little attention has been paid to these issues in the older patient population (Kauffman, 2001). The SENTRY Antimicrobial Surveillance Program (antifungal objective) has been active since 1997 and has reported the frequency of pathogen occurrence and the susceptibilities of the various species to fluconazole and other agents according to patient age for the years 1997 to 2000 (Pfaller et al., 2002). In the present study, we update this information using the SENTRY Program database from 2008 to 2009, including species variation according to patient age and the associated resistance profiles for the contemporary echinocandin and azole antifungal agents.
2. Materials and methods 2.1. Organisms and study sites Between January 2008 and December 2009, a total of 2085 bloodstream infection (BSI) isolates of Candida spp. from 79 medical centers throughout the world were submitted to JMI Laboratories (North Liberty, IA) for species identification and antifungal susceptibility testing with fluconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The isolates represented consecutive incident isolates from patients with candidemia treated at hospitals in the Asia-Pacific (16 centers, 51 isolates), European (25 centers, 750 isolates), Latin American (10 centers, 348 isolates), and North American (28 centers, 936 isolates) regions. Patient ages were provided for 1239 (59%) isolates of Candida. The isolates were identified by standard methods and stored as water suspensions until used in the study. Before testing, each isolate was passaged on Sabouraud dextrose agar (Remel, Lenexa, KS) and CHROMagar (Beckton Dickinson, Sparks, MD) to ensure purity and viability. 2.2. Susceptibility test methods Broth microdilution testing was performed in accordance with the guidelines in the Clinical and Laboratory Standards
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Institute (CLSI, 2008a) document M27-A3. MICs were determined visually after 24 h of incubation for the echinocandins and fluconazole and after 48 h for posaconazole and voriconazole as the lowest concentration of each drug that caused a significant diminution (≥50%) of growth below control levels. We used the recently revised CLSI breakpoints to identify strains resistant to the echinocandins and fluconazole (Pfaller et al., 2010a; Pfaller et al., 2010c): anidulafungin, caspofungin, and micafungin MICs at N0.5 μg/mL were considered resistant for Candida albicans, Candida tropicalis, and Candida krusei, and MIC results at N4 μg/mL were defined as resistant for Candida parapsilosis; anidulafungin and caspofungin MICs at N0.5 μg/mL and micafungin MICs at N0.12 μg/mL were considered resistant for Candida glabrata; fluconazole MIC values N4 μg/mL were considered resistant for C. albicans, C. parapsilosis, and C. tropicalis, and MICs at N32 μg/mL were called resistant for C. glabrata. All isolates of C. krusei were declared as resistant to fluconazole. The CLSI-resistant breakpoint for voriconazole (MIC, N2 μg/mL) was also defined as resistant for posaconazole for all species (CLSI, 2008b; Pfaller et al., 2006). Quality control was performed by testing CLSI-recommended strains C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 (CLSI, 2008b) 3. Results and discussion 3.1. Isolates rates according to patient age Among the 1239 Candida BSI isolates, 620 (50%) were C. albicans, 215 (17.4%) were C. glabrata, 215 (17.4%) were C. parapsilosis, 122 (9.8%) were C. tropicalis, 22 (1.8%) were C. krusei, and 45 (3.6%) were miscellaneous species including Candida dubliniensis (13 isolates), Candida guilliermondii (8 isolates), Candida kefyr (6 isolates), Candida famata (3 isolates), Candida lipolytica (3 isolates), Candida rugosa (2 isolates), C. sake (2 isolates), Candida pelliculosa (2 isolates), and 1 isolate each of Candida lambica, Candida utilis, Candida haemulonii, Candida norvegensis, and Candida inconspicua (Table 1). Comparing the frequency of isolation of different species by age group, we found identical rank orders for the groups 40 to 59, 60 to 79, and 80 to 99 years of age: C. albicans N C. glabrata N C. parapsilosis N C. tropicalis N C. krusei. The dominant causes of Candida BSI in the pediatric and adolescent age groups (0–19 years) were C. albicans and C. parapsilosis, and very few infections were due to C. glabrata and C. krusei. C. parapsilosis was detected more frequently than C. glabrata in the 20 to 39 years of age group. Although C. albicans was the most common species in all age groups, the proportions of BSIs due to this species was ≥50% in the groups 0 to 19 (50.0%), 20 to 39 (51.7%), and 60 to 79 (52.3%) years of age and b50% in the groups 40 to 59 (47.5%) and 80 to 99 (46.7%) years of age. Consistent with other studies (Arendrup et al., 2008; Malani et al., 2005; Panizo et al., 2009; Pfaller et al., 2009; Sandven et al., 2006;
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Table 1 Species distributions of Candida bloodstream isolates stratified by patient age group, SENTRY Antimicrobial Surveillance Program (2008–2009) Species
C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Miscellaneousa
% by age (years) (no. of isolates tested) 0–19 (256)
20–39 (116)
40–59 (326)
60–79 (436)
80–99 (105)
Total (1239)
50.0 2.0 28.5 12.9 0.8 5.8
51.7 15.5 16.4 10.4 3.5 2.5
47.5 21.8 15.3 9.5 2.1 3.8
52.3 20.9 12.6 9.6 1.4 3.2
46.7 28.6 17.1 3.8 2.9 0.9
50.0 17.4 17.4 9.8 1.8 3.6
a
Miscellaneous species including C. dubliniensis (13 isolates), C. guilliermondii (8 isolates), C. kefyr (6 isolates), C. famata (3 isolates), C. lipolytica (3 isolates), C. rugosa (2 isolates), C. sake (2 isolates), C. pelliculosa (2 isolates), and 1 isolate each of C. lambica, C. utilis, C. haemulonii, C. norvegensis, and C. inconspicua.
Tortorano et al., 2004), the proportion of BSI isolates of Candida that were C. glabrata increased with patient age; the lowest proportion (2.0%) was noted in the 0- to 19-year age group (0.5% in the b10-year-old subgroup), and the
highest proportion (28.6%) was seen in the 80- to 99-year age group. C. tropicalis was most common in the 0- to 19year age group (12.9%) and least common in the 80- to 99year age group (3.8%), whereas C. krusei was most common in the 20- to 39-year age group (3.5%) and least common in the 0- to 19-year age group (0.8%). 3.2. Differences in susceptibilities among isolates from individuals in different age groups to azole and echinocandin antifungal agents Although in vitro susceptibility testing is often used to select antimicrobial agents that are most likely to be active clinically, the most important role of testing in a surveillance network such as the SENTRY Program is for detecting resistance (e.g., establishing those agents that will not work) (Turnidge and Paterson, 2007). The revision of the clinical breakpoints for fluconazole and the echinocandins was undertaken to provide a more accurate separation between wild-type (WT) strains that do not exhibit acquired or intrinsic resistance mechanisms from those non-WT strains
Table 2 Frequency of antifungal resistance among Candida BSI isolates by patient age group, SENTRY Antimicrobial Surveillance Program (2008–2009) Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
% of isolates resistanta to each antifungal by patient age group (years) Antifungal agent
0–19
20–39
40–59
60–79
80–99
Total
n
%
n
%
n
%
n
%
n
%
n
%
Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Posaconazole Voriconazole
128 128 128 128 128 128 5 5 5 5 5 5 73 73 73 73 73 73 33 33 33 33 33 33 2 2 2 2 2
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
60 60 60 60 60 60 18 18 18 18 18 18 19 19 19 19 19 19 12 12 12 12 12 12 4 4 4 4 4
0.0 0.0 0.0 0.0 0.0 0.0 16.7 16.7 16.7 16.7 5.6 11.1 0.0 0.0 0.0 15.8 0.0 0.0 0.0 0.0 0.0 16.7 0.0 16.7 0.0 0.0 0.0 0.0 0.0
155 155 155 155 155 155 71 71 71 71 71 71 50 50 50 50 50 50 31 31 31 31 31 31 7 7 7 7 7
0.0 0.0 0.0 0.0 0.0 0.0 7.0 7.0 4.2 11.3 4.2 5.6 0.0 0.0 0.0 10.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 14.3 0.0 0.0 0.0
228 228 228 228 228 228 91 91 91 91 91 91 55 55 55 55 55 55 42 42 42 42 42 42 6 6 6 6 6
0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.2 0.0 3.3 2.2 2.2 0.0 0.0 0.0 1.8 0.0 0.0 0.0 0.0 0.0 2.4 2.4 2.4 0.0 0.0 0.0 0.0 0.0
49 49 49 49 49 49 30 30 30 30 30 30 18 18 18 18 18 18 4 4 4 4 4 4 3 3 3 3 3
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 25.0 0.0 25.0 0.0 0.0 0.0 0.0 0.0
620 620 620 620 620 620 215 215 215 215 215 215 215 215 215 215 215 215 122 122 122 122 122 122 22 22 22 22 22
0.0 0.0 0.0 0.0 0.0 0.0 3.7 4.7 2.8 6.5 3.3 3.7 0.0 0.0 0.0 4.2 0.0 0.0 0.0 0.0 0.0 3.3 0.8 3.3 0.0 0.5 0.0 0.0 0.0
a Resistance (R) defined as an MIC at N0.5 μg/mL for anidulafungin, caspofungin, and micafungin versus C. albicans, C. tropicalis, and C. krusei and as an MIC of N4 μg/mL versus C. parapsilosis; R defined as an MIC at N0.5 μg/mL for anidulafungin and caspofungin and as an MIC at N0.12 μg/mL for micafungin versus C. glabrata; R defined as an MIC of N4 μg/mL for fluconazole versus C. albicans, C. tropicalis, and C. parapsilosis and as an MIC N32 μg/mL versus C. glabrata; and R defined as an MIC of N2 μg/mL for posaconazole and voriconazole for all species.
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that do possess resistance mechanisms and simultaneously to provide a useful means for selecting the optimal treatment of patients with Candida BSI (Pfaller et al., 2010a; Pfaller et al., 2010c). As shown in Table 2, no resistance to anidulafungin, caspofungin, or micafungin was detected among isolates of C. albicans, C. parapsilosis, or C. tropicalis from all age groups. Likewise, complete susceptibility to posaconazole and voriconazole was observed among isolates of C. albicans, C. parapsilosis, and C. krusei from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of C. glabrata with the highest resistance rates to anidulafungin (16.7%), caspofungin (16.7%), micafungin (16.7%), fluconazole (16.7%), posaconazole (5.6%), and voriconazole (11.1%) found in isolates from the 20- to 39-year age group. Previously, we had demonstrated that although the proportion of BSI isolates of Candida that were C. glabrata increased with patient age in the United States, the rate of fluconazole resistance declined (Pfaller et al., 2009). An identical trend was seen in the present geographically diverse study; although 28.6% of Candida BSI in patients in the 80- to 99-year age group was due to C. glabrata, none were fluconazole resistant compared to 16.7% resistance in the 20- to 39-year age group (Table 2). In addition to C. glabrata, resistance to fluconazole was observed among isolates of C. parapsilosis from the 20- to 39- (15.8%), 40- to 59- (10.0%), and 60- to 79-year (1.8%) age groups and among C. tropicalis from the 20- to 39(16.7%), 60- to 79- (2.4%), and 80- to 99-year (25.0%) age groups. Cross-resistance between fluconazole and voriconazole was observed in isolates of C. tropicalis from the 20- to 39- (16.7%), 60- to 79- (2.4%), and 80- to 99-year (25.0%) age groups. No resistance to the echinocandins was found in isolates of C. krusei with the exception of a single caspofungin-resistant strain in the 40- to 59-year age group. There are several notable findings in this survey of contemporary Candida BSI isolates. First, the variation in species distribution noted by others is confirmed, especially the trend toward an increase in the proportion of BSI isolates of Candida that were C. glabrata with increasing patient age (Arendrup et al., 2008; Malani et al., 2005; Panizo et al., 2009; Pfaller et al., 2009; Sandven et al., 2006; Tortorano et al., 2004). Second, the lack of antifungal resistance to both echinocandins and azoles among isolates of Candida from all age groups is confirmed, with the exception of C. glabrata from the 20- to 39- and 40- to 59-year age groups. Third, the finding of azole- and echinocandin-resistant strains of C. glabrata localized among patients in the 20to 39-year age group is confirmed. The WT susceptibility of C. glabrata to the echinocandins is well documented (Pagano et al., 2010; Pfaller et al., 2010b; Pound et al., 2010; Sipsas et al., 2009); however, reports of sporadic resistance in strains with acquired fks mutations have been reported (Chapeland-Leclerc et al., 2010; Cleary et al., 2008; Dodgson et al., 2005; Thompson et al., 2008). The generally excellent WT susceptibility to the echinocandins
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coupled with broadening azole resistance has driven the use of echinocandins for C. glabrata treatment (Pappas et al., 2009) and, at the same time, has generated selection pressure for the resistant organisms (Chapeland-Leclerc et al., 2010; Pfeiffer et al., 2010). Although the increased use of echinocandins and the newer triazoles (posaconazole and voriconazole) has been associated with a decrease in the frequency of BSI due to C. glabrata at certain medical centers (Forrest et al., 2008; Sendid et al., 2006; Sipsas et al., 2009), a recent report of 5 episodes of breakthrough fungemia in patients treated with micafungin involving strains of C. glabrata with fks mutations and elevated MIC values (4 to N8 μg/mL) to all echinocandins suggests that this specie bears watching with respect to both azole and echinocandin emerging resistance (Pfeiffer et al, 2010). Multidrug resistance (MDR) in C. glabrata involving amphotericin B and caspofungin has been described (Krogh-Madsen et al., 2002), and recently, Chapeland-Leclerc et al. (2010) reported the acquisition of flucytosine, azole, and caspofungin resistance in a strain of C. glabrata from a hematopoietic stem cell transplant recipient with candidemia. Point mutations in C. glabrata FUR1 and Cg FKS2 and overexpression of Cg CDR1 and Cg CDR2 were observed in resistant isolates demonstrating the high propensity of C. glabrata to mutate in vivo in a single patient (Chapeland-Leclerc et al., 2010). It is suggested that expression of resistance to echinocandins and other classes of antifungal agents in C. glabrata is facilitated by the haploid nature of the genome (Chapeland-Leclerc et al., 2010; Pfeiffer et al., 2010). These reports emphasize the importance of antifungal susceptibility testing in patients with breakthrough fungemia. The findings in the present study also focus attention on the 20- to 39-year age group as one where this problem may be concentrated. The IDSA recommends that patients with IC due to C. parapsilosis be treated with either a lipid formulation of amphotericin B or fluconazole rather than an echinocandin due in large part to the relatively high WT echinocandin MIC values that are characteristic of this species (Pappas et al., 2009). Reports of increased BSI due to C. parapsilosis in individual hospitals (Forrest et al., 2008; Sipsas et al., 2009) and in a US population-based surveillance (Ahlquist et al., 2009) in the current echinocandin era add to these concerns. Breakthrough infections due to C. parapsilosis in patients treated with caspofungin have been reported, and this species may account for more than 50% of such infections in certain care settings (Kabbara et al., 2008; Pfeiffer et al., 2010; Sipsas et al., 2009). Most recently, Pfeiffer et al. (2010) reported breakthrough fungemias due to C. parapsilosis in patients treated with micafungin. The micafungin MIC results were N2 μg/mL in 5 of 6 isolates tested; however, none of the isolates were found to have fks hot spot mutations beyond the naturally occurring polymorphism characteristic of this species. In the present study, we found no evidence of echinocandin resistance among 215 isolates of C. parapsilosis, whereas 15.8% of isolates in the 20- to 39-year age group were resistant to fluconazole
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(Table 2) (Krogh-Madsen et al., 2006; Panizo et al., 2009; Pfaller et al., 2010d). In summary, we provide additional information relating to the importance of patient age in considering the potential species and resistance profile among BSI isolates of Candida. Whereas resistance to the systemically active echinocandin and azole antifungal agents is distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, and C. krusei isolates from all age groups, resistance to both classes of agents is evident in C. glabrata isolates from the 20- to 39- and 40- to 59-year age groups. Although prolonged exposure to antifungal agents may account for resistance in C. glabrata isolates from patients in these age groups, the true cause is likely multifactorial (Pfaller et al., 2009; Pfeiffer et al., 2010). The emergence of MDR in C. glabrata is a real concern given the fact that neither the newer azoles nor amphotericin B are an optimal approach for therapy for C. glabrata infection (Alexander et al., 2005; ChapelandLeclerc et al., 2010; Krogh-Madsen et al., 2006; Pappas et al., 2009). The haploid nature of C. glabrata makes it particularly adept at acquiring resistance mutations, and the emergence of MDR phenotypes, especially in the 20- to 39year age group, bears close watching. In addition to fluconazole resistance, one must be aware of the potential of this species to develop resistance to the echinocandins in patients receiving or having previously been exposed to these agents. These findings also point to the importance of antifungal susceptibility testing in both surveillance programs and for patient cases. Acknowledgments The authors acknowledge the excellent assistance of Ashley Small and Patty Strabala in the preparation of the manuscript. This study was supported in part by an educational/research grant from Astellas (Deerfield, IL) and Pfizer (New York, NY) that included reagent antifungal agents. They also thank all of the global surveillance centers who contributed isolates to this study. References Ahlquist A, Farley MM, Harrison LH, Baughman W, Siegel B, Hollick R, Lockhart SR, Magill SS, Chiller T (2009) Epidemiology of candidemia in metropolitan Atlanta and Baltimore City and County: prelilminary results of population-based active, laboratory surveillance—2008–2009. 49th ICAAC, September 12–15, 2009. pp.Abstr. M-1241. San Francisco, California, USA: Antimicrob. Agents Chemother. Alexander BD, Schell WA, Miller JL, Long GD, Perfect JR (2005) Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole. Transplantation 80:868–871. Arendrup MC, Fuursted K, Garn-Hansen B, Schonheyder HC, Knudsen JD, Jensen IM, Bruun B, Christensen JJ, Johansen HK (2008) Semi-national surveillance of fungaemia in Denmark 2004–2006: increaseing incidence of fungaemia and numbers of isolates with reduced azole susceptibility. Clin Microbiol Infect 14:487–494. Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, Ribaud P, Lacroix C (2010) Acquisition of flucytosine, azole, and
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M.A. Pfaller et al. / Diagnostic Microbiology and Infectious Disease 68 (2010) 278–283 Pfaller MA, Diekema DJ, Jones RN, Messer SA, Hollis RJ (2002) Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000. J Clin Microbiol 40:852–856. Pfaller MA, Diekema DJ, Rex JH, Espinel-Ingroff A, Johnson EM, Andes D, Chaturvedi V, Ghannoum MA, Odds FC, Rinaldi MG, Sheehan DJ, Troke P, Walsh TJ, Warnock DW (2006) Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol 44:819–826. Pfaller MA, Messer SA, Hollis RJ, Boyken L, Tendolkar S, Kroeger J, Diekema DJ (2009) Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007. J Clin Microbiol 47:3185–3190. Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D, the CLSI Subcommittee for Antifungal Testing (2010a) Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug Resist Updat in press. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Jones RN, Turnidge J, Diekema DJ (2010b) Wild-type MIC distributions and epidemiological cutoff values (ECVs) for the echinocandins and Candida spp. J Clin Microbiol 48:52–56. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Motyl M, Perlin DS, the CLSI Subcommittee for Antifungal Testing (2010c) Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat in press. Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Ellis D, Tullio V, Rodloff A, Fu W, Ling TA (2010d) Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J Clin Microbiol 48:1366–1377. Pfeiffer CD, Garcia-Effron G, Zaas AK, Perfect JR, Perlin DS, Alexander BD (2010) Breakthrough invasive candidiasis on micafungin. J Clin Microbiol 48:2373–2380.
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Diagnostic Microbiology and Infectious Disease 68 (2010) 278 – 283 www.elsevier.com/locate/diagmicrobio
Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008–2009) Michael A. Pfallera , Mariana Castanheiraa,⁎, Shawn A. Messera , Gary J. Moeta , Ronald N. Jonesa,b a
b
JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, Massachusetts, 02111, USA Received 24 April 2010; accepted 26 June 2010
Abstract The variation in Candida spp. causing bloodstream infection (BSI) and the frequency of resistance to fluconazole by patient age have been previously described. However, similar data have been shown for neither the echinocandins nor the newer triazoles. We analyzed the 24-h reference MIC data from the SENTRY Antimicrobial Surveillance Program to compare the antifungal resistance profiles and species distribution of Candida BSI isolates according to patient age. MIC results were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole, and voriconazole, and recently revised Clinical and Laboratory Standards Institute breakpoints were applied. A total of 1239 Candida BSI isolates were obtained from 79 medical centers in 2008 to 2009: 50.0%, 17.4%, 17.4%, 9.8%, and 1.8% were Candida albicans (Ca), Candida glabrata (Cg), Candida parapsilosis (Cp), Candida tropicalis (Ct), and Candida krusei (Ck), respectively. Ca was most common in the 60- to 79-year age group (52.3%) and least common in the 80- to 99-year age group (46.7%), whereas Cg was most common in the 80- to 99-year age group (28.6%) and least common in the 0- to 19-year age group (2.0%). Cp and Ct were most common in the 0- to 19-year age group (28.5% and 12.9%, respectively), and Ck was most common among the patients in the 20- to 39-year age group (3.5%). No resistance to echinocandins was detected among isolates of Ca, Cp, and Ct from all age groups. Likewise, no resistance to posaconazole or voriconazole was observed in isolates of Ca, Cp, or Ck from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of Cg with the highest resistance rates to echinocandins (16.7%), fluconazole (16.7%), posaconazole (5.0%), and voriconazole (11.1%) among isolates from the 20- to 39-year age group. Both species distribution and antifungal resistance patterns vary markedly with patient age. Cg BSI isolates may show lower susceptibility rates to both azoles and echinocandins with the highest rates of resistance detected in 20- to 59-year-old patients. © 2010 Elsevier Inc. All rights reserved. Keywords: Candida; Antifungal resistance; Bloodstream infections; SENTRY Program
1. Introduction Invasive candidiasis (IC) (candidemia and other deepseated infections including disseminated candidiasis, hepatic candidiasis, endocarditis, and meningitis) is associated with considerable morbidity and mortality (Falagas et al., 2006; Labelle et al., 2008; Pfaller and Diekema, 2010; Slavin et al.,
⁎ Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address: [email protected] (M. Castanheira). 0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2010.06.015
2010). Rapid initiation of appropriate antifungal therapy is essential for the management of IC and has been shown to reduce mortality (Garey et al., 2006; Labelle et al., 2008; Morrell et al., 2005; Parkins et al., 2007). The guidelines for the management of IC published by the Infectious Diseases Society of America (IDSA) (Pappas et al., 2009) recommend that initial antifungal therapy should be directed by the species identification of the organism and the local epidemiology (occurrences) of IC including the antifungal susceptibility patterns. Due to the spectrum and fungicidal potency against Candida spp., an echinocandin antifungal agent (anidulafungin, caspofungin, and micafungin) is
M.A. Pfaller et al. / Diagnostic Microbiology and Infectious Disease 68 (2010) 278–283
recommended as first-line therapy for most patients with IC with de-escalation to fluconazole based on the susceptibility of the infecting organism to fluconazole (Pappas et al., 2009). Although much is known regarding the geographic variation in the species of Candida causing IC and the associated susceptibility of these isolates to fluconazole (Pfaller and Diekema, 2007; Pfaller and Diekema, 2010; Pfaller et al., 2010a), considerably less is understood regarding the variation in the infecting species and their susceptibilities to the newer azoles (posaconazole, voriconazole) and echinocandins according to patient age (Arendrup et al., 2008; Panizo et al., 2009; Pfaller et al., 2002; Pfaller et al., 2009; Sandven et al., 2006; Tortorano et al., 2004). Given the fact that some of the highest rates of IC have been observed among patients over the age of 70 years (Zaoutis et al., 2005; Zilberberg et al., 2008), it is notable how little attention has been paid to these issues in the older patient population (Kauffman, 2001). The SENTRY Antimicrobial Surveillance Program (antifungal objective) has been active since 1997 and has reported the frequency of pathogen occurrence and the susceptibilities of the various species to fluconazole and other agents according to patient age for the years 1997 to 2000 (Pfaller et al., 2002). In the present study, we update this information using the SENTRY Program database from 2008 to 2009, including species variation according to patient age and the associated resistance profiles for the contemporary echinocandin and azole antifungal agents.
2. Materials and methods 2.1. Organisms and study sites Between January 2008 and December 2009, a total of 2085 bloodstream infection (BSI) isolates of Candida spp. from 79 medical centers throughout the world were submitted to JMI Laboratories (North Liberty, IA) for species identification and antifungal susceptibility testing with fluconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The isolates represented consecutive incident isolates from patients with candidemia treated at hospitals in the Asia-Pacific (16 centers, 51 isolates), European (25 centers, 750 isolates), Latin American (10 centers, 348 isolates), and North American (28 centers, 936 isolates) regions. Patient ages were provided for 1239 (59%) isolates of Candida. The isolates were identified by standard methods and stored as water suspensions until used in the study. Before testing, each isolate was passaged on Sabouraud dextrose agar (Remel, Lenexa, KS) and CHROMagar (Beckton Dickinson, Sparks, MD) to ensure purity and viability. 2.2. Susceptibility test methods Broth microdilution testing was performed in accordance with the guidelines in the Clinical and Laboratory Standards
279
Institute (CLSI, 2008a) document M27-A3. MICs were determined visually after 24 h of incubation for the echinocandins and fluconazole and after 48 h for posaconazole and voriconazole as the lowest concentration of each drug that caused a significant diminution (≥50%) of growth below control levels. We used the recently revised CLSI breakpoints to identify strains resistant to the echinocandins and fluconazole (Pfaller et al., 2010a; Pfaller et al., 2010c): anidulafungin, caspofungin, and micafungin MICs at N0.5 μg/mL were considered resistant for Candida albicans, Candida tropicalis, and Candida krusei, and MIC results at N4 μg/mL were defined as resistant for Candida parapsilosis; anidulafungin and caspofungin MICs at N0.5 μg/mL and micafungin MICs at N0.12 μg/mL were considered resistant for Candida glabrata; fluconazole MIC values N4 μg/mL were considered resistant for C. albicans, C. parapsilosis, and C. tropicalis, and MICs at N32 μg/mL were called resistant for C. glabrata. All isolates of C. krusei were declared as resistant to fluconazole. The CLSI-resistant breakpoint for voriconazole (MIC, N2 μg/mL) was also defined as resistant for posaconazole for all species (CLSI, 2008b; Pfaller et al., 2006). Quality control was performed by testing CLSI-recommended strains C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 (CLSI, 2008b) 3. Results and discussion 3.1. Isolates rates according to patient age Among the 1239 Candida BSI isolates, 620 (50%) were C. albicans, 215 (17.4%) were C. glabrata, 215 (17.4%) were C. parapsilosis, 122 (9.8%) were C. tropicalis, 22 (1.8%) were C. krusei, and 45 (3.6%) were miscellaneous species including Candida dubliniensis (13 isolates), Candida guilliermondii (8 isolates), Candida kefyr (6 isolates), Candida famata (3 isolates), Candida lipolytica (3 isolates), Candida rugosa (2 isolates), C. sake (2 isolates), Candida pelliculosa (2 isolates), and 1 isolate each of Candida lambica, Candida utilis, Candida haemulonii, Candida norvegensis, and Candida inconspicua (Table 1). Comparing the frequency of isolation of different species by age group, we found identical rank orders for the groups 40 to 59, 60 to 79, and 80 to 99 years of age: C. albicans N C. glabrata N C. parapsilosis N C. tropicalis N C. krusei. The dominant causes of Candida BSI in the pediatric and adolescent age groups (0–19 years) were C. albicans and C. parapsilosis, and very few infections were due to C. glabrata and C. krusei. C. parapsilosis was detected more frequently than C. glabrata in the 20 to 39 years of age group. Although C. albicans was the most common species in all age groups, the proportions of BSIs due to this species was ≥50% in the groups 0 to 19 (50.0%), 20 to 39 (51.7%), and 60 to 79 (52.3%) years of age and b50% in the groups 40 to 59 (47.5%) and 80 to 99 (46.7%) years of age. Consistent with other studies (Arendrup et al., 2008; Malani et al., 2005; Panizo et al., 2009; Pfaller et al., 2009; Sandven et al., 2006;
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Table 1 Species distributions of Candida bloodstream isolates stratified by patient age group, SENTRY Antimicrobial Surveillance Program (2008–2009) Species
C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Miscellaneousa
% by age (years) (no. of isolates tested) 0–19 (256)
20–39 (116)
40–59 (326)
60–79 (436)
80–99 (105)
Total (1239)
50.0 2.0 28.5 12.9 0.8 5.8
51.7 15.5 16.4 10.4 3.5 2.5
47.5 21.8 15.3 9.5 2.1 3.8
52.3 20.9 12.6 9.6 1.4 3.2
46.7 28.6 17.1 3.8 2.9 0.9
50.0 17.4 17.4 9.8 1.8 3.6
a
Miscellaneous species including C. dubliniensis (13 isolates), C. guilliermondii (8 isolates), C. kefyr (6 isolates), C. famata (3 isolates), C. lipolytica (3 isolates), C. rugosa (2 isolates), C. sake (2 isolates), C. pelliculosa (2 isolates), and 1 isolate each of C. lambica, C. utilis, C. haemulonii, C. norvegensis, and C. inconspicua.
Tortorano et al., 2004), the proportion of BSI isolates of Candida that were C. glabrata increased with patient age; the lowest proportion (2.0%) was noted in the 0- to 19-year age group (0.5% in the b10-year-old subgroup), and the
highest proportion (28.6%) was seen in the 80- to 99-year age group. C. tropicalis was most common in the 0- to 19year age group (12.9%) and least common in the 80- to 99year age group (3.8%), whereas C. krusei was most common in the 20- to 39-year age group (3.5%) and least common in the 0- to 19-year age group (0.8%). 3.2. Differences in susceptibilities among isolates from individuals in different age groups to azole and echinocandin antifungal agents Although in vitro susceptibility testing is often used to select antimicrobial agents that are most likely to be active clinically, the most important role of testing in a surveillance network such as the SENTRY Program is for detecting resistance (e.g., establishing those agents that will not work) (Turnidge and Paterson, 2007). The revision of the clinical breakpoints for fluconazole and the echinocandins was undertaken to provide a more accurate separation between wild-type (WT) strains that do not exhibit acquired or intrinsic resistance mechanisms from those non-WT strains
Table 2 Frequency of antifungal resistance among Candida BSI isolates by patient age group, SENTRY Antimicrobial Surveillance Program (2008–2009) Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
% of isolates resistanta to each antifungal by patient age group (years) Antifungal agent
0–19
20–39
40–59
60–79
80–99
Total
n
%
n
%
n
%
n
%
n
%
n
%
Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Fluconazole Posaconazole Voriconazole Anidulafungin Caspofungin Micafungin Posaconazole Voriconazole
128 128 128 128 128 128 5 5 5 5 5 5 73 73 73 73 73 73 33 33 33 33 33 33 2 2 2 2 2
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
60 60 60 60 60 60 18 18 18 18 18 18 19 19 19 19 19 19 12 12 12 12 12 12 4 4 4 4 4
0.0 0.0 0.0 0.0 0.0 0.0 16.7 16.7 16.7 16.7 5.6 11.1 0.0 0.0 0.0 15.8 0.0 0.0 0.0 0.0 0.0 16.7 0.0 16.7 0.0 0.0 0.0 0.0 0.0
155 155 155 155 155 155 71 71 71 71 71 71 50 50 50 50 50 50 31 31 31 31 31 31 7 7 7 7 7
0.0 0.0 0.0 0.0 0.0 0.0 7.0 7.0 4.2 11.3 4.2 5.6 0.0 0.0 0.0 10.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 14.3 0.0 0.0 0.0
228 228 228 228 228 228 91 91 91 91 91 91 55 55 55 55 55 55 42 42 42 42 42 42 6 6 6 6 6
0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.2 0.0 3.3 2.2 2.2 0.0 0.0 0.0 1.8 0.0 0.0 0.0 0.0 0.0 2.4 2.4 2.4 0.0 0.0 0.0 0.0 0.0
49 49 49 49 49 49 30 30 30 30 30 30 18 18 18 18 18 18 4 4 4 4 4 4 3 3 3 3 3
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 25.0 0.0 25.0 0.0 0.0 0.0 0.0 0.0
620 620 620 620 620 620 215 215 215 215 215 215 215 215 215 215 215 215 122 122 122 122 122 122 22 22 22 22 22
0.0 0.0 0.0 0.0 0.0 0.0 3.7 4.7 2.8 6.5 3.3 3.7 0.0 0.0 0.0 4.2 0.0 0.0 0.0 0.0 0.0 3.3 0.8 3.3 0.0 0.5 0.0 0.0 0.0
a Resistance (R) defined as an MIC at N0.5 μg/mL for anidulafungin, caspofungin, and micafungin versus C. albicans, C. tropicalis, and C. krusei and as an MIC of N4 μg/mL versus C. parapsilosis; R defined as an MIC at N0.5 μg/mL for anidulafungin and caspofungin and as an MIC at N0.12 μg/mL for micafungin versus C. glabrata; R defined as an MIC of N4 μg/mL for fluconazole versus C. albicans, C. tropicalis, and C. parapsilosis and as an MIC N32 μg/mL versus C. glabrata; and R defined as an MIC of N2 μg/mL for posaconazole and voriconazole for all species.
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that do possess resistance mechanisms and simultaneously to provide a useful means for selecting the optimal treatment of patients with Candida BSI (Pfaller et al., 2010a; Pfaller et al., 2010c). As shown in Table 2, no resistance to anidulafungin, caspofungin, or micafungin was detected among isolates of C. albicans, C. parapsilosis, or C. tropicalis from all age groups. Likewise, complete susceptibility to posaconazole and voriconazole was observed among isolates of C. albicans, C. parapsilosis, and C. krusei from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of C. glabrata with the highest resistance rates to anidulafungin (16.7%), caspofungin (16.7%), micafungin (16.7%), fluconazole (16.7%), posaconazole (5.6%), and voriconazole (11.1%) found in isolates from the 20- to 39-year age group. Previously, we had demonstrated that although the proportion of BSI isolates of Candida that were C. glabrata increased with patient age in the United States, the rate of fluconazole resistance declined (Pfaller et al., 2009). An identical trend was seen in the present geographically diverse study; although 28.6% of Candida BSI in patients in the 80- to 99-year age group was due to C. glabrata, none were fluconazole resistant compared to 16.7% resistance in the 20- to 39-year age group (Table 2). In addition to C. glabrata, resistance to fluconazole was observed among isolates of C. parapsilosis from the 20- to 39- (15.8%), 40- to 59- (10.0%), and 60- to 79-year (1.8%) age groups and among C. tropicalis from the 20- to 39(16.7%), 60- to 79- (2.4%), and 80- to 99-year (25.0%) age groups. Cross-resistance between fluconazole and voriconazole was observed in isolates of C. tropicalis from the 20- to 39- (16.7%), 60- to 79- (2.4%), and 80- to 99-year (25.0%) age groups. No resistance to the echinocandins was found in isolates of C. krusei with the exception of a single caspofungin-resistant strain in the 40- to 59-year age group. There are several notable findings in this survey of contemporary Candida BSI isolates. First, the variation in species distribution noted by others is confirmed, especially the trend toward an increase in the proportion of BSI isolates of Candida that were C. glabrata with increasing patient age (Arendrup et al., 2008; Malani et al., 2005; Panizo et al., 2009; Pfaller et al., 2009; Sandven et al., 2006; Tortorano et al., 2004). Second, the lack of antifungal resistance to both echinocandins and azoles among isolates of Candida from all age groups is confirmed, with the exception of C. glabrata from the 20- to 39- and 40- to 59-year age groups. Third, the finding of azole- and echinocandin-resistant strains of C. glabrata localized among patients in the 20to 39-year age group is confirmed. The WT susceptibility of C. glabrata to the echinocandins is well documented (Pagano et al., 2010; Pfaller et al., 2010b; Pound et al., 2010; Sipsas et al., 2009); however, reports of sporadic resistance in strains with acquired fks mutations have been reported (Chapeland-Leclerc et al., 2010; Cleary et al., 2008; Dodgson et al., 2005; Thompson et al., 2008). The generally excellent WT susceptibility to the echinocandins
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coupled with broadening azole resistance has driven the use of echinocandins for C. glabrata treatment (Pappas et al., 2009) and, at the same time, has generated selection pressure for the resistant organisms (Chapeland-Leclerc et al., 2010; Pfeiffer et al., 2010). Although the increased use of echinocandins and the newer triazoles (posaconazole and voriconazole) has been associated with a decrease in the frequency of BSI due to C. glabrata at certain medical centers (Forrest et al., 2008; Sendid et al., 2006; Sipsas et al., 2009), a recent report of 5 episodes of breakthrough fungemia in patients treated with micafungin involving strains of C. glabrata with fks mutations and elevated MIC values (4 to N8 μg/mL) to all echinocandins suggests that this specie bears watching with respect to both azole and echinocandin emerging resistance (Pfeiffer et al, 2010). Multidrug resistance (MDR) in C. glabrata involving amphotericin B and caspofungin has been described (Krogh-Madsen et al., 2002), and recently, Chapeland-Leclerc et al. (2010) reported the acquisition of flucytosine, azole, and caspofungin resistance in a strain of C. glabrata from a hematopoietic stem cell transplant recipient with candidemia. Point mutations in C. glabrata FUR1 and Cg FKS2 and overexpression of Cg CDR1 and Cg CDR2 were observed in resistant isolates demonstrating the high propensity of C. glabrata to mutate in vivo in a single patient (Chapeland-Leclerc et al., 2010). It is suggested that expression of resistance to echinocandins and other classes of antifungal agents in C. glabrata is facilitated by the haploid nature of the genome (Chapeland-Leclerc et al., 2010; Pfeiffer et al., 2010). These reports emphasize the importance of antifungal susceptibility testing in patients with breakthrough fungemia. The findings in the present study also focus attention on the 20- to 39-year age group as one where this problem may be concentrated. The IDSA recommends that patients with IC due to C. parapsilosis be treated with either a lipid formulation of amphotericin B or fluconazole rather than an echinocandin due in large part to the relatively high WT echinocandin MIC values that are characteristic of this species (Pappas et al., 2009). Reports of increased BSI due to C. parapsilosis in individual hospitals (Forrest et al., 2008; Sipsas et al., 2009) and in a US population-based surveillance (Ahlquist et al., 2009) in the current echinocandin era add to these concerns. Breakthrough infections due to C. parapsilosis in patients treated with caspofungin have been reported, and this species may account for more than 50% of such infections in certain care settings (Kabbara et al., 2008; Pfeiffer et al., 2010; Sipsas et al., 2009). Most recently, Pfeiffer et al. (2010) reported breakthrough fungemias due to C. parapsilosis in patients treated with micafungin. The micafungin MIC results were N2 μg/mL in 5 of 6 isolates tested; however, none of the isolates were found to have fks hot spot mutations beyond the naturally occurring polymorphism characteristic of this species. In the present study, we found no evidence of echinocandin resistance among 215 isolates of C. parapsilosis, whereas 15.8% of isolates in the 20- to 39-year age group were resistant to fluconazole
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(Table 2) (Krogh-Madsen et al., 2006; Panizo et al., 2009; Pfaller et al., 2010d). In summary, we provide additional information relating to the importance of patient age in considering the potential species and resistance profile among BSI isolates of Candida. Whereas resistance to the systemically active echinocandin and azole antifungal agents is distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, and C. krusei isolates from all age groups, resistance to both classes of agents is evident in C. glabrata isolates from the 20- to 39- and 40- to 59-year age groups. Although prolonged exposure to antifungal agents may account for resistance in C. glabrata isolates from patients in these age groups, the true cause is likely multifactorial (Pfaller et al., 2009; Pfeiffer et al., 2010). The emergence of MDR in C. glabrata is a real concern given the fact that neither the newer azoles nor amphotericin B are an optimal approach for therapy for C. glabrata infection (Alexander et al., 2005; ChapelandLeclerc et al., 2010; Krogh-Madsen et al., 2006; Pappas et al., 2009). The haploid nature of C. glabrata makes it particularly adept at acquiring resistance mutations, and the emergence of MDR phenotypes, especially in the 20- to 39year age group, bears close watching. In addition to fluconazole resistance, one must be aware of the potential of this species to develop resistance to the echinocandins in patients receiving or having previously been exposed to these agents. These findings also point to the importance of antifungal susceptibility testing in both surveillance programs and for patient cases. Acknowledgments The authors acknowledge the excellent assistance of Ashley Small and Patty Strabala in the preparation of the manuscript. This study was supported in part by an educational/research grant from Astellas (Deerfield, IL) and Pfizer (New York, NY) that included reagent antifungal agents. They also thank all of the global surveillance centers who contributed isolates to this study. References Ahlquist A, Farley MM, Harrison LH, Baughman W, Siegel B, Hollick R, Lockhart SR, Magill SS, Chiller T (2009) Epidemiology of candidemia in metropolitan Atlanta and Baltimore City and County: prelilminary results of population-based active, laboratory surveillance—2008–2009. 49th ICAAC, September 12–15, 2009. pp.Abstr. M-1241. San Francisco, California, USA: Antimicrob. Agents Chemother. Alexander BD, Schell WA, Miller JL, Long GD, Perfect JR (2005) Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole. Transplantation 80:868–871. Arendrup MC, Fuursted K, Garn-Hansen B, Schonheyder HC, Knudsen JD, Jensen IM, Bruun B, Christensen JJ, Johansen HK (2008) Semi-national surveillance of fungaemia in Denmark 2004–2006: increaseing incidence of fungaemia and numbers of isolates with reduced azole susceptibility. Clin Microbiol Infect 14:487–494. Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, Ribaud P, Lacroix C (2010) Acquisition of flucytosine, azole, and
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