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Epidemiology of candidemia and antifungal susceptibility in invasive Candida species in the Asia-Pacific region He Wang1,2, Ying-Chun Xu*,1 & Po-Ren Hsueh**,3 In the Asia-Pacific region, Candida albicans is the predominant Candida species causing invasive candidiasis/candidemia in Australia, Japan, Korea, Hong Kong, Malaysia, Singapore and Thailand whereas C. tropicalis is the most frequently encountered Candida species in Pakistan and India. Invasive isolates of C. albicans, C. parapsilosis complex and C. tropicalis remain highly susceptible to fluconazole (>90% susceptible). Fluconazole resistance (6.8–15%), isolates with the non-wild-type phenotype for itraconazole susceptibility (3.9–10%) and voriconazole (5–17.8%), and echinocandin resistance (2.1–2.2% in anidulafungin and 2.2% in micafungin) among invasive C. glabrata complex isolates are increasing in prevalence. Moreover, not all isolates of C. tropicalis have been shown to be susceptible to fluconazole (nonsusceptible rate, 5.7–11.6% in China) or voriconazole (nonsusceptible rate, 5.7–9.6% in China). First draft submitted: 27 May 2016; Accepted for publication: 1 August 2016; Published online: 18 October 2016 Invasive candidiasis/candidemia (ICC) is a leading cause of mortality in patients with hematologic malignancies, those with prolonged neutropenia and in patients in intensive care units (ICUs) [1–3] . Candida albicans remains the predominant etiology of ICC, accounting for 40–50% of all cases, and C. glabrata complex was the most frequently isolated non-C. albicans species in the USA and the UK [1,2] . However, there are important geographical differences in the distribution of Candida species other than C. albicans causing ICC [1–7] . In Asia, a study in 2009 indicated that invasive isolates of Candida species remained highly susceptible to fluconazole (>90% susceptible), although in some Asian countries the rate of resistance to fluconazole among C. glabrata complex isolates was as high as 16% [3] . Voriconazole and echinocandins, however, have been reported to exhibit excellent in vitro activity against invasive Candida isolates [2,3] . The present report summarizes current data from Asia-Pacific region on the etiology of ICC and antifungal susceptibility in invasive Candida species using recently recommended interpretive susceptibility criteria. Mechanisms of azole and echinocandin resistance in several Candida species reported in this region are also reviewed.

Keywords

• antifungal susceptibility • Asia-Pacific region • candidemia • invasive

candidiasis

Epidemiology of ICC in the Asia-Pacific region A recent 12-month (1 July 2010 through 30 June 2011) laboratory-based surveillance study on candidemia in 25 hospitals from China, Hong Kong, India, Singapore, Taiwan and Thailand was conducted

Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China 3 Departments of Laboratory Medicine & Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan *Author for correspondence: Tel.: +886 2 23123456, ext. 65355; Fax: +886 2 23955072; [email protected] **Author for correspondence: [email protected] 1 2

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part of

ISSN 1746-0913

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C. albicans C. guilliermondii complex

C. tropicalis C. krusei

C. papapsilosis complex

C. glabrata complex Others

Proportion of Candida species causing candidaemia (%)

100 90 80 70 60 50 40 30 20 10 0 Australia China 2010–12 2010 (159) (737)

Taiwan Taiwan Taiwan Taiwan Japan Japan Korea 2011–4 2010 2008–12 2009–12 2004–11 2007–11 2006–7 (1,102) (213) (716) (209) (165) (131) (639)

Korea Malaysia Saudi Singapore Thailand Pakistan 2011 2006–8 Arabia 2000–6 2006–1 2013 (450) (159) 2002–9 (279) (62) (188) (252)

C. albicans

C. tropicalis

C. glabrata complex

C. parapsilosis complex

C. guilliermondii

C. krusei

India SENTRY 2011 (100)

% of Candida species causing invasive candidiasis/candidaemia

50 44.7

45

43.5

35

41.4

39.1

40 34.6

30 25

11.3 21.1

20 15

15.1

9.3 17.5 14.8

9.7

11.1 16.5

14.9

20

9.4 19

15.4

15

10 5

1.52.2

1.31.3

1.2 1.5

2 0.9

2.6 1.3

0 2010 (814/12)

2011 (1,243/22)

2012 (1,619/22)

2013 (2,687/48)

2014 (3,411/62)

Year (no. of isolates/no. of participating hospitals)

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Figure 1. Distribution of six Candida species causing invasive candidiasis/candidemia. This is shown in (A) selected countries in the Asia-Pacific region and in (B) annual yeast collections in the National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) program from 2010 to 2014 in China. The number of Candida species associated with invasive candidiasis/candidemia and the number of hospitals participating the CHIF-NET program increased with year.

by Tan et al.  [4] . Of the 1601 episodes of candidemia among 1.2 million discharges, the overall incidence was 1.22 per 1000 discharges (0.15 episodes/1000 patient-days) and varied widely among the hospitals (range: 0.16–4.53) and participating countries (range: 0.25–2.93). More than half of the episodes of candidemia occurred in medical (30.3%) or surgical wards (23.7%), 23.1% occurred in ICUs (11.7 episodes/1000 patients) and 10.1% occurred in hemato-oncology wards. Among the 1910 nonduplicate blood isolates identified to the species level, C. albicans was the most frequently isolated (41.3%), followed by C. tropicalis (25.4%), C. glabrata complex (13.9%) and C. parapsilosis complex (12.1%). The proportion of C. tropicalis among blood isolates was significantly higher in hemato-oncology wards than in other wards (33.7 vs 24.5%, p = 0.0058) and the species was more likely to be isolated from patients in tropical Asian countries (e.g., India, Singapore and Thailand) than in temperate countries (46.2 vs 18.9%, p = 0.04) [4] . In China and Singapore, however, C. glabrata complex was the most common, accounting for 26% of isolates from patients with candidemia. A 2-year multicenter prospective observational study on the epidemiology of and mortality associated with invasive fungal disease (IFD, n = 420) among patients with hematological disorders in Asia demonstrated that Candida species was the second (n = 79, 26.7%) most common etiology of probable (n = 158, 38.3%) and proven (n = 138, 33.5%) IFD [5] . The study also showed that progressive chronic renal disease (odds ratio [OR]: 6.677), hematological disorders (OR: 5.192) and ICC (OR: 3.679) were independently associated with overall 30-day mortality of patients with IFD [5] . In Asia-Pacific region, the highest incidence of candidemia was reported in Taiwan, where the aggregate incidence among six hospitals was 2.93 episodes/1000 patients (0.37 per 1000 patient-days) in 2010–2011 (1104 episodes) [4] . Interestingly, the aggregate incidence among nine hospitals in China was only 0.38 per 1000 discharges in 2010–2011 (n = 310) [4] . The distribution of Candida species causing invasive candidiasis and candidemia in several

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selected countries in the Asia-Pacific region is presented graphically in Figure 1A  [8–23] . Data on the epidemiology of invasive candidiasis from the National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) program in 2010–2014 are presented in Figure 1B, and the annual incidence of all candidemia and healthcare-associated (HCA)-candidemia at the National Taiwan University Hospital (NTUH) from 2005 to 2014 are presented in Figure 2A–C . ●●China

The CHIF-NET program is a nationwide, multicenter surveillance network established in July 2009 to provide up-to-date information on the epidemiology of invasive fungal infections in China [9] . Among the 814 invasive yeast isolates collected during the first year (August 2009–July 2010) of the CHIF-NET program, 90.5% were Candida species, 7.7% were Cryptococcus neoformans and the remaining 1.7% belonged to other yeast species [9] . Among the 737 isolates of Candida species, C. albicans (38.2%) was the predominant species, followed by C. parapsilosis complex (23.3%), C. tropicalis (16.7%), C. glabrata complex (12.4%), C. krusei (2.4%), C. guilliermondii (1.6%), C. pelliculosa (1.6%) and C. lipolytica (1.4%) (Figure 1) . Among the 737 isolates of invasive Candida species, 92.3% were isolated from inpatients (40% from ICUs, 30.7% from surgical wards and 18.2% from medical wards), and 7.7% were isolated from outpatient or emergency departments [9] . Figure 1B shows the trend in isolation of the main Candida species causing ICC during 2010–2014 in hospitals participating in the CHIF-NET program [Wang H et al., Unpublished Data]. During November 2009 and April 2011, a multicenter, prospective and observational study in 67 hospital adult ICUs across China was conducted [24] . Incidence of ICC in ICU adult patients was 0.32% (306 patients/96,060 ICU admissions). Among the 306 patients, Candida isolates (n = 389) from 244 patients were collected for further study. C. albicans was the most prevalent single isolate (41.8%), followed by C. parapsilosis (23.8%), C. tropicalis (17.6%) and C. glabrata (12.3%) [24] . First-line

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All Candida species C. glabrata complex

C. albicans C. parapsilosis complex

Incidence of candidaemia (episodes/1000 inpatient-days)

0.45 0.372

0.35

0.339

0.327

0.311

0.323

0.299

0.25

0.228 0.176

0.196

0.18

0.166

0.217 0.155

0.162

0.129

0.15 0.10

0.334

0.285

0.30

0.20

0.424

0.406

0.40

C. tropicalis

0.069

0.119 0.065

0.055

0.083

0.08

0.062 0.046

0.05 0.048

0.03

0.00 2005 (225)

0.046 0.049

2006 (203)

0.085 0.071

0.047

0.046

0.043

2007 (232)

2008 (245)

2009 (305)

0.09 0.066

0.069

0.059

0.037

2010 (284)

2011 (307)

0.067

0.078

0.069 0.069 0.043 0.041

0.042

0.068

2012 (243)

2013 (243)

0.063

2014 (227)

% of candidaemia among all patients with healthcare-associated BSI

Year (no. of patients)

16

15

14 12.7

12 10

11.8

11.3 10.1

12.5

12.3 10

9.6

9.8

8 6 4 2 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 (1842) (1769) (2068) (2318) (2326) (2355) (2038) (2161) (1940) (1527) Year (no. of patients with BSI)

Figure 2. Incidence of candidemia (for part C, see facing page). (A) Incidence (episodes of candidemia/1000 inpatient-days) and trend in candidemia caused by four Candida species at the National Taiwan University Hospital (NTUH) from 2005 to 2014. Episodes of candidemia due to more than one species of Candida were considered one episode of candidemia. (B) Proportion of patients with healthcare-associated (HCA) candidemia among those with HCA-bloodstream infection (HCABSI). (C) Incidence of (cases/10,000 discharges) and trends in HCA candidemia caused by Candida albicans and non-C. albicans species at the NTUH from 2005 to 2014. BSI: Bloodstream infection.

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Incidence (cases/10,000 discharges) of healthcare-associated candidaemia

All Candida species

C. albicans

Review

Non-albicans Candida

40 35

33.6 29.8

30 25

24.2 21.2

21.7

29.2 24.8

24.0

22.2

20 15 10 5

17.2 12.5

11.4

11.7

11.2 10.5

12.8

14.9

15.5

16.4 14.9

14.3

12.6

13.6

11.2

9.0 10.5

8.8

13.7

9.6 4.7

0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 (209) (179) (198) (227) (296) (278) (306) (271) (238) (152) Year (no. of patients)

treatment comprised a single agent in 264/268 (98.5%) patients, most commonly fluconazole (101/268, 37.7%), followed by caspofungin (64/268, 23.9%) and voriconazole (49/268, 18.3%). Overall, triazoles (62.7%) and echinocandins (34.2%) were the most commonly used antifungal agents. The mortality rate was 36.6% (112/306) and was higher in older individuals, those with solid tumors, those with recent mechanical ventilation and those with a higher sequential organ failure assessment score. Susceptibility to first-line antifungals was associated with lower mortality (31.3%) than dosedependent susceptibility (56.3%) or complete resistance (50.0%; p = 0.008) [24] ●●Taiwan

During the 10-year period at the NTUH, the overall incidence (episodes of candidemia/1000 patient-days) of candidemia due to all Candida species decreased significantly from 0.424 in 2011 to 0.299 in 2014 (Figure 2A) . The incidence (episodes of candidemia/1000 patient-days) of candidemia due to C. albicans also decreased significantly with time (p < 0.001), with the highest value in 2009 (0.228) and the lowest value in 2014 (0.119). However, the incidence of candidemia due to C. tropicalis, C. parapsilosis complex and C. glabrata complex remained stable during the study period (Figure 2A) . The incidence (episodes of candidemia/1000 patientdays) of candidemia due to C. guilliermondii ranged from 0.001 in 2005 to 0.008 in 2014

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and that of C. krusei candidemia varied from 0.006 in 2005, 0 in 2008, 0.008 in 2009 and 2013, and 0.004 in 2014. During the 10-year period from 2005 to 2014, a total of 20,344 patients with HCAbloodstream infection (HCA-BSI) were treated at the NTUH (Figure 2B) . Of the 20,344 patients with HCA-BSI during 2005–2014 at the hospital, 12.6% (n = 2354) had candidemia. The proportion of HCA-BSI patients with candidemia ranged from 9.6% (198/2068) in 2007 to 15.0% (306/2038) in 2011 (Figure 2B) . The incidence of HCA candidemia (patients with candidemia/10,000 discharges) was highest in 2010 (33.6) and lowest in 2014 (13.7) (Figure 2C) . The incidence of HCA candidemia (patients with candidemia/10,000 discharges) due to nonC. albicans was higher than that of candidemia due to C. albicans in all years with the exception of 2005 (11.7 and 12.5, respectively) and 2009 (14.9 and 14.9, respectively) (Figure 2C) . The reason why an increase of incidence of HCA candidemia in 2010 was unknown. Molecular epidemiology study on Candida isolates found in 2010 should be conducted to investigate the possible nosocomial outbreak of candidemia at the NTUH. In contrast to the data from the NTUH showing a decrease in incidence of candidemia, data from the Mackay Memorial Hospital in Taipei reveal that there was a significant increase (p = 0.002) in overall incidence of candidemia from 2008 (0.21/1000 patient-days) to 2012

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Review  Wang, Xu & Hsueh (0.30/1000 patient-days) [25] . At that hospital, C. albicans (49.0%) was the most frequently isolated species, followed by C. tropicalis (15.5%), C. glabrata complex (15.2%) and C. parapsilosis complex (10.8%) (Figure 1A) . There was no significant increase in incidence per year of individual Candida species. Similar data on the distribution of Candida species causing candidemia were also found at a teaching hospital in central Taiwan  [13] . In contrast, data on the distribution of Candida species isolated from patients with candidemia reported in the TSARY study in 2010 (23 participating hospitals) showed that C. parapsilosis complex (16.4%) was the second most commonly isolated species after C. tropicalis (19.2%) (Figure 1A) [12] . ●●Other countries in the Asia-Pacific region

C. albicans is the predominant Candida species causing ICC in Australia, Japan, Korea, Hong Kong (China), Malaysia, Saudi Arabia, Singapore and Thailand [8–21] . However, in Pakistan and India, C. tropicalis is the most frequently encountered Candida species causing ICC [22,23] . The most commonly isolated nonC. albicans species associated with ICC in the Asia-Pacific are C. tropicalis in Saudi Arabia, Singapore and Thailand; C. parapsilosis complex in Japan, Korea, Malaysia and Singapore; and C. glabrata complex in Australia (Figure 1) [8–20] . Of all Candida isolates causing ICC, C. krusei represented 4% in Saudi Arabia, 6% in Japan and 9% in India (Figure 1)  [14–15,19,23] . In an 8-year surveillance study on candidemia at a medical center in Saudi Arabia, Al Thaqafi et al. reported that 166 (65.9%) of the 252 cases of candidemia were caused by non-C. albicans species and 45 (17.9%) of the Candida species were unspecified  [19] . In addition, malignancy was shown to be independently associated with the development of candidemia due to non-C. albicans species (OR: 3.24) [19] . Specifically, the incidence rates of fungaemia due to C. albicans (34.5%) and C. glabrata complex (27.6%) were higher among patients with solid malignancies than in those with hematological malignancies (26.2 and 4.9%, respectively). In contrast, the incidence of candidemia due to non-C. albicans species was higher among patients with hematological malignancies than solid malignancies, with C. tropicalis (21.3 vs 17.2%), C. parapsilosis complex (13.1 vs 10.3%), C. krusei (13.1 vs 0.0%) and C. famata (8.2 vs 0.0%) being the most commonly isolated species [19] .

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Candida auris, first isolated from the external ear canal of a Japanese patient, is phylogenetically related to C. haemulonii and was described as a new species in 2009 [26–28] . This organism has been recognized as an emerging multidrugresistant yeast that can cause a wide spectrum of infections, ranging from fungaemia to deepseated infections, especially in intensive care settings. C. auris is frequently misidentified as C. haemulonii, C. famata and Rhodotorula glutinis by commercial identification systems, such as the Vitek 2 and API20C-AUX systems, and exhibits a unique susceptibility profile [26–30] . Isolates of C. auris recovered from patients with otitis media in India and those isolated from patients with fungaemia in Korea were shown to be clonal in origin [26–30] . Resistance profiles of Candida species This review only evaluated studies that used susceptibility methods and interpretive criteria with species-specific clinical breakpoints (CBPs) recommended by the Clinical and Laboratory Standards Institute (CLSI) [31] or the European Committee on Antimicrobial Susceptibility Testing of yeasts to test susceptibilities of Candida species to antifungal agents [32,33] . In addition, species-specific epidemiological cut-off values (ECVs) were used to define wild-type (WT) and non-WT isolates if no CBPs were available from the CLSI. Isolates with a non-WT phenotype for susceptibility to an indicated agent likely contain a resistance mutation [2,31,32,34–36] . In addition to reviewing studies that determined minimum inhibitory concentrations (MICs) using the broth microdilution method recommended by the CLSI [31] , this review also included studies that determined MICs by the Sensititre YeastOne YO10 (SYO, Sensititre; Thermo Scientific, OH, USA) system for nine antifungal agents using current CBPs/ECVs to assign susceptibility phenotypes (WT or nonWT) and the CLSI M44-A2 disc diffusion method (CLSI DDM) to determine susceptibility to fluconazole and voriconazole [37] . Studies that used the Etest for susceptibility testing of yeast isolates are also reviewed. Importantly, ECVs to interpret MIC values are method dependent and species specific. Although the commercial broth microdilution SYO method recommends the use of CLSI interpretive criteria for interpretation of MIC results, species-specific ECVs of azoles and echinocandins have been proposed to some

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Epidemiology & resistance in invasive candidiasis  Candida species for susceptibility testing by the SYO method [11,38,39] . The agreement of the SYO method and reference CLSI method with 24-h MICs was reported to be 95–99% for all Candida species and antifungal agents, however, these methods may fail to give identical results on certain occasions [11,38,39] . Moreover, the CBPs have not been established for the SYO methods. Although the CLSI provides CBP and ECV for itraconazole (Table 1)  [2] , ECV to interpret susceptibility to itraconazole is used in this review  [34] . The CLSI CBPs of itraconazole for isolates of C. albicans were assigned based entirely on MICs and clinical outcomes of patients with oropharyngeal candidiasis, not ICC, who were treated with oral itraconazole (capsule and/or solution) and in whom serum concentrations of itraconazole were commonly less than 0.5 mg/l [2] . The existing CLSI CBPs (MICs ≤0.12 mg/l) for itraconazole should provide an optimal means for detecting decreased susceptibility (non-WT susceptibility, ECV of >0.12 mg/l) among isolates of C. albicans [2] . The CLSI CBPs for itraconazole are not appropriate for any species other than C. albicans [2,31] . Susceptibility interpretive criteria for caspofungin against the six main Candida species are the same as those for anidulafungin with the exception of C. guilliermondii (≤2 mg/l for WT susceptibility) (Table 1) [2] ; however, susceptibility results were not evaluated in this review. This is because that significant interlaboratory discrepancies in caspofungin MICs against C. albicans, C. glabrata complex, C. tropicalis and C. krusei are present by using the CLSI-recommended methods. As a result, interpretation of MICs using the CLSI species-specific caspofungin CBPs may exaggerate the rates nonsusceptibility to caspofungin among Candida species, especially among C. glabrata complex and C. krusei isolates [11,31] . Interpretive criteria for susceptibility of Candida species to eight other antifungal agents are summarized in Table 1. Many investigators from countries in the Asia-Pacific region, including Australia, China, India, Indonesia, Iran, Japan, Korea, Malaysia, Pakistan, the Philippines, Saudi Arabia, Singapore, Taiwan, Thailand and Turkey, have reported antifungal susceptibilities among isolates causing ICC [8–13,17,22,38,40–45] . However, only studies on the susceptibility for selected Candida species causing ICC in Asia-Pacific region that used currently recommended

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Review

interpretive criteria (CBPs and ECVs) for reporting susceptibility are summarized. For studies that did not present susceptibility results using currently recommended CLSI CBPs/ECVs, susceptibility results were analyzed based on the current CLSI CBPs/ECVs criteria only if the details of the MIC results of the isolates tested were available. These results are summarized in Table 2 [8–13,17,22,38,40,41] . Among the tested isolates of the six main Candida species causing ICC, nearly all were found to be WT for susceptibility to amphotericin B (MICs of ≤2 mg/l) (Table 2) . For C. albicans isolates, rates of resistance to fluconazole were low in nine countries participating in the SENTRY study and in recent studies from China and Taiwan [8–13] . The rate of non-WT susceptibility to itraconazole was highest in Pakistan (23.7%) and lowest (1.3%) in Taiwan [11,22] . For C. parapsilosis complex isolates, rates of resistance to fluconazole ranged from 0% in Pakistan to 1.5% in China (C. parapsilosis sensu stricto [1.5%] and C. metapsilosis [2.3%]) to 5.7% in countries participating in the SENTRY study [8,10,22] . In Australia, 0.4% of C. parapsilosis complex isolates were resistant to micafungin and 0.5% were resistant to anidulafungin [38] . Regarding C. tropicalis isolates, the highest rates of resistance to fluconazole and voriconazole were found in China, 8.2 and 5.7%, respectively [9,10] . The percentages of C. tropicalis isolates with the non-WT phenotype for susceptibility to posaconazole were 31.7% in Australia and 62.2% in Taiwan [11,38] . The highest rate of resistance to fluconazole among C. glabrata complex isolates was found in Pakistan (15%) and 17.8% of C. glabrata complex isolates were of the nonWT phenotype for voriconazole in China [9,22] . All C. krusei isolates tested in Australia, China, Korea and Pakistan had the non-WT phenotype for susceptibility to fluconazole [9–10,17,22,38] . However, in Taiwan, Huang et al. reported that 11.1% (1/9) of C. krusei isolates exhibited the WT phenotype to fluconazole and Yang et al. reported that 100% (18/18) of isolates had the WT phenotype [11,12] . All C. krusei isolates tested in China, Pakistan and Taiwan had the WT phenotype for susceptibility to itraconazole, posaconazole and 5-flucytotsine [9–11,22] . In China, 15.7% of the isolates tested were not susceptible to voriconazole (Table 2) [9] . In Iran, 67 Candida isolates were collected from various clinical specimens from patients

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    ≤32   ≥64  

  ≤2 4   ≥8  

  ≤2 4   ≥8  

Fluconazole

         

  ≤2 4   ≥8            

          ≤0.5

          ≤2

          ≤0.5

          ≤0.12

Itraconazole

  ≤0.5 1   ≥2

  ≤0.12 0.25–0.5   ≥1  

          ≤0.5

  ≤0.12 0.25–0.5   ≥1  

  ≤0.12 0.25–0.5   ≥1  

Voriconazole

         

          ≤0.25

          ≤2

          ≤0.12

          ≤0.06

Posaconazole

         

          ≤0.5

          ≤0.5

          ≤0.5

          ≤0.5

5-Flucytosine

Value for the agent (mg/l)

  ≤0.25   0.5 ≥1

  ≤2   4 ≥8  

  ≤0.06   0.12 ≥0.25  

  ≤0.25   0.5 ≥1  

  ≤0.25   0.5 ≥1  

Micafungin

  ≤0.25   0.5 ≥1

  ≤2   4 ≥8  

  ≤0.12   0.25 ≥0.5  

  ≤0.25   0.5 ≥1  

  ≤0.25   0.5 ≥1  

Anidulafungin

ECVs were used if no CBPs were available from the CLSI (12, 14, 15, 17–19, 21). CBP: Clinical breakpoint; CLSI: Clinical and Laboratory Standards Institute; ECV: Epidemiological cut-off value; I: Intermediate; R: Resistant; S: Susceptible; S-DD: Susceptible-dose dependent.

CBPs S S-DD I R

Candida krusei

CBPs S S-DD I R ECV

Candida parapsilosis complex

CBPs S S-DD I R ECV

Candida glabrata complex

CBPs S S-DD I R ECV

Candida tropicalis

CBPs S S-DD I R ECV

Candida albicans

 

Candida species and susceptibility category

Table 1. Clinical breakpoints and epidemiologic cut-off values of Candida species to eight antifungal agents.

         

          ≤2

          ≤2

          ≤2

          ≤2

Amphotericin B

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  ≤2   4 ≥8 ≤2           ≤1           ≤0.5           ≤0.25           ≤1           ≤8 CBPs S S-DD I R ECV

Candida guilliermondii complex

≤64 ECV

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ECVs were used if no CBPs were available from the CLSI (12, 14, 15, 17–19, 21). CBP: Clinical breakpoint; CLSI: Clinical and Laboratory Standards Institute; ECV: Epidemiological cut-off value; I: Intermediate; R: Resistant; S: Susceptible; S-DD: Susceptible-dose dependent.

          ≤2   ≤2   4 ≥8 ≤4

≤2  

Anidulafungin Micafungin

  ≤32

5-Flucytosine Posaconazole

≤0.5  

Fluconazole  

Itraconazole

Voriconazole

Value for the agent (mg/l) Candida species and susceptibility category

Table 1. Clinical breakpoints and epidemiologic cut-off values of Candida species to eight antifungal agents (cont.).

≤1

Amphotericin B

Epidemiology & resistance in invasive candidiasis 

Review

hospitalized in ICUs at a single medical center in 2013 [45] . All isolates had the WT phenotype for susceptibility to amphotericin B as determined by the Etest. For C. glabrata complex (n = 32) isolates, the voriconazole MICs ranged from 0.032 to 32 mg/l and the posaconazole MICs ranged from 0.047 to >32 mg/l. Several isolates of C. albicans (n = 19; MIC ranges: 0.023–0.38 mg/l) and C. tropicalis (n = 5; MIC ranges: 0.064–0.38 mg/l) were susceptible dosedependent (S-DD) to voriconazole. One of the two C. krusei isolates had the non-WT phenotype for susceptibility to amphotericin B (MIC of 4 mg/l) [45] . At a single institution in Japan, researchers used the Antifungal Susceptibility Test for Yeast (Kyokuto Pharmaceutical Industrial Co., Japan) to test for susceptibility of 77 blood isolates of Candida species to a number of antifungal agents and found that more than 10% of C. glabrata complex (n = 21) isolates were resistant to fluconazole (MIC ranges: 8 to >64 mg/l; MIC90 : 64 mg/l), 14.3% had the non-WT phenotype for susceptibility to voriconazole (MIC ranges: 0.25–8 mg/l; MIC90 : 1 mg/l) and 100% of C. parapsilosis complex isolates were susceptible to micafungin (MIC ranges: 0.25–2 mg/l) [15] . More than 50% of C. glabrata complex (n = 21) isolates were resistant to fluconazole (MIC ranges: 1 to >64 mg/l; MIC50 : 8 mg/l) or S-DD to voriconazole (MIC ranges: 0.12–0.5 mg/l; MIC50 : 0.25 mg/l) [15] . In Singapore, SYO-5/6 panels were used for susceptibility testing of 279 Candida isolates causing BSI in three hospitals [20] . All Candida isolates tested had the WT phenotype for susceptibility to amphotericin (MIC ranges: 0.06–1 mg/l). Wide MIC distributions were found for several of the tested antifungal agents, including caspofungin (0.008–1 mg/l), posaconazole (0.008–16 mg/l) and voriconazole (0.008–16 mg/l). All C. albicans isolates (n = 107) were susceptible to voriconazole, 15.5% of C. glabrata complex (n = 45) isolates had the non-WT phenotype for susceptibility to that agent, and 17.3% of C. tropicalis isolates (n = 75) and 2.5% of C. parapsilosis complex isolates (n = 40) were S-DD. When tested against posaconazole, 1.8% of C. albicans isolates (n = 55) were shown to have the non-WT phenotype for susceptibility and all C. glabrata complex (n = 28) isolates had the WT phenotype for susceptibility. The non-WT phenotype was found in 42.2% of C. tropicalis isolates (n = 45) and in

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Review  Wang, Xu & Hsueh 55.6% of C. parapsilosis complex isolates (n = 18) [20] . At a tertiary care hospital in northern Taiwan, susceptibility of 77 blood isolates of C. parapsilosis complex to eight antifungal agents was tested using the SYO method and the results showed that 100% of isolates were susceptible to amphotericin B, 100% were susceptible to voriconazole and 95.5% were susceptible to fluconazole. The rate of resistance to fluconazole was 3% [25] . Interestingly, the MIC50 /MIC90 of anidulafungin was 1/2 mg/l and that of micafungin was 1/2 mg/l, indicating that more than 50% of C. parapsilosis complex isolates tested were resistant to both agents [25] . In Turkey, of the 201 clinical isolates of C. albicans (sources not specified) isolated from blood cultures from hospitalized patients at a single institution, all were susceptible to anidulafungin and amphotericin B (MICs of ≤2 mg/l). The rates of resistance to fluconazole (MICs of ≥8 mg/l) and voriconazole (MICs of ≥1 mg/l) were 34 and 14%, respectively [45] . Only three (1.5%) of the isolates were classified as dose dependently susceptible to fluconazole [46] . Two studies on C. auris were available for review, one from India involving 12 isolates from patients with candidemia and the other from Korea involving 15 isolates from patients with otitis media. The MIC values (MIC90 ) for fluconazole ranged from 16 to 64 mg/l (64 mg/l) and from 2 to 128 mg/l (128 mg/l), respectively; for voriconazole, the ranges were 0.125–1 (1) and 0.03–2 (2) mg/l, respectively; and for micafungin, the MIC value range was 0.06–0.125 and 0.03–0.06 (0.03) mg/l, respectively  [26,30] . The posaconazole MIC range and MIC90 value among the 12 C. auris isolates from Indian patients with candidemia were 0.06–0.25 and 0.25 mg/l, respectively, and the anidulafungin MIC range and MIC90 value were 0.125–0.5 and 0.5 mg/l, respectively [26,30] . Mechanisms of resistance to azoles & echinocandins in Candida species In Candida species, the most important mechanism associated with decreased susceptibility or resistance of Candida to azoles is induction of efflux pumps. Upregulation of efflux pumps encoded by either MDR or CDR genes is associated with azole resistance in C. albicans (MDR1, CDR1, CDR2), C. glabrata (CgCDR1, CgCDR2) and C. dubliniensis (CdMDR1, CdCDR1) [47–51] . Another common mechanism

10.2217/fmb-2016-0099

Future Microbiol. (Epub ahead of print)

of resistance is the acquisition of point mutations in the gene encoding for the target enzyme (ERG11), resulting in an altered target with reduced affinity for or incapacity to bind azoles [47–51] . However, multiple mechanisms can also coexist in the same fungal cell, particularly in some Candida isolates after long-term exposure to azoles [47,51] . Acquired resistance to echinocandins in Candida species is typically mediated by the acquisition of point mutations in the catalytic Fsk subunit (Fks1 and Fks2) of glucan synthase  [47,49,52] . Resistance to echinocandins is mediated by specific amino acid substitutions in Fks subunits [7] , which result in elevated MIC values (10- to 100-fold) and decreased sensitivity of glucan synthase (IC50) to echinocandins by 50- to 3000-fold [50] . Importantly, the presence of characteristic mutations in FKS genes rather than MIC is an independent risk factor for reduced clinical response of echinocandin therapy among patients with invasive candidiasis caused by C. glabrata [52] . The overall mutation rates among clinical isolates remain low (C. glabrata complex, ∼4%; other species:

Epidemiology of candidemia and antifungal susceptibility in invasive Candida species in the Asia-Pacific region.

In the Asia-Pacific region, Candida albicans is the predominant Candida species causing invasive candidiasis/candidemia in Australia, Japan, Korea, Ho...
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