Open Access

Epidemiology and antifungal resistance in invasive candidiasis

European Journal of Medical Research201116:187

DOI: 10.1186/2047-783X-16-4-187

Received: 7 March 2011

Accepted: 20 March 2011

Published: 28 April 2011

Abstract

The epidemiology of Candida infections has changed over the last two decades: The number of patients suffering from such infections has increased dramatically and the Candida species involved have become more numerous as Candida albicans is replaced as an infecting agent by various non-C. albicans species (NAC). At the same time, additional antifungal agents have become available. The different Candida species may vary in their susceptibility for these various antifungals. This draws more attention to in vitro susceptibility testing. Unfortunately, several different test methods exist that may deliver different results. Moreover, clinical breakpoints (CBP) that classify test results into susceptible, intermediate and resistant are controver- sial between CLSI and EUCAST. Therefore, clinicians should be aware that interpretations may vary with the test system being followed by the microbiological laboratory. Thus, knowledge of actual MIC values and pharmacokinetic properties of individual antifungal agents is important in delivering appropriate therapy to patients

Introduction

In 2001, McNeil et al. reported that (in the USA) "from 1980 through 1997, the annual number of deaths in which an invasive mycosis was listed on the death certificate (multiple-cause mortality) increased from 1557 to 6534" (Table 1, Figure 1) [1]. Augmentation of fungal infections had been published earlier i.e. by Beck-Sague and Jarvis [2] and Edmond et al. [3] for the USA and by Lamagni et al. [4] for England and Wales (Figure 2). There are several possible reasons for this change. An important one might be the increase in lifespan in the populations of the developed world and the age related loss of immune-competence. An increase of systemic fungal infections is probably also due to more intensive treatment schemes for hematological and oncological patients causing prolonged neutropenic phases. Finally, more effective antibacterial treatments allow patients with infections to survive longer without necessarily overcoming the underlying diseases and thus leaving them susceptible to other opportunistic infections. Eggimann et al. [5] summarized prior surgery, acute renal failure, previous yeast colonization, neutropenia, antibacterial therapy, parenteral nutrition, and central venous catheters as risk factors for invasive Candidia infections.
Table 1

Ranking of underlying causes of deaths due to infectious diseases in the united states in 1980 and 1997 [1].

 

1980

1997

Rank

Type of infection

No. of deaths

Type of infection

No. of deaths

1

Respiratory tract

56,966

Respiratory tract

87,181

2

Septicemia

9,438

Septicemia

22,396

3

Kidney/utl

8,006

HIV/AIDS

16,524

4

Heart

2,486

Kidney/UTI

13,413

5

Tuberculosis

2,333

Heart

5,577

6

Bacterial meningitis

1,402

Hepatobiliary

4,596

7

Gastrointestinal

1,377

Mycoses

2,370

8

Hepatobiliary

1,277

Tuberculosis

1,259

9

Perinatal

1,035

Gastrointestinal

1,053

10

Mycoses

828

Perinatal

820

Categories of infectious diseases identified by anatomic site rather than by causative microorganism did not have any microorganism specified in the death-certificate data. UTI = urinary tract infedtion.

Figure 1

Mortality in the united states, 1980-1997, 'due to candidiasis, and other mycoses in persons infected and persons not infected with HIV [1].

Figure 2

Annual rates of candidosis laboratory reports, by sex (England and Wales: 1990-9) [4].

Change in Epidemiology

The increase in incidence of Candida infections barely preceded the introduction of fluconazole in 1990. This azole agent combined good activity against Candida albicans with reduced toxicity as compared to i.e. polyene anti-fungals. It is orally and parentally available and has a reliable that means linear pharmacokinetic profile [6], which makes it easy to handle. Not surprisingly, fluconazole became the agent of choice for many fungal infections as well as for prophylactic purposes, at that time often being applied in rather low doses. Although there is inconclusive evidence, many experts in the field believe that it was the selective pressure exerted by this therapeutic concept that caused changes in the epidemiology [7]. While in earlier years, C. albicans was responsible most of the invasive fungal infections (Table 2) [8], gradually more and more non-C. albicans species (NAC) were found as offending agents (Table 3) [916]. While the data show similar tendencies in the prevalence of various Candida ssp. worldwide, considerable differences can be observed as well. However, these do not lend themselves to further interpretation since significant differences in the demographics of the patients observed seem to be obvious. This change in prevalence of various Candida spp. is nevertheless of clinical importance, since individual species vary in their susceptibility to various antifungal agents. While national and international surveillance is important to recognize trends in epidemiology it is, however, of utmost importance to gain knowledge about the local epidemiology as this information should guide the empiric therapy of patients.
Table 2

Species distribution of Candida from cases of invasive candidiasisa [8].

Species

% of total casesb

 

1997-1998

1999

2000

2001

2002

2003

C. albicans

73.3

69.8

68.1

65.4

61.4

62.3

C. glabrata

11.0

9.7

9.5

11.1

10.7

12.0

C. tropicalis

4.6

5.3

7.2

7.5

7.4

7.5

C. parapsilosis

4.2

4.9

5.6

6.9

6.6

7.3

C. krusei

1.7

2.2

3.2

2.5

2.6

2.7

C. guilliermondii

0.5

0.8

0.8

0.7

1.0

0.8

C. lusitaniae

0.5

0.5

0.5

0.6

0.5

0.6

C. kefyr

0.2

0.4

0.5

0.4

0.4

0.5

C. rugosa

0.03

0.03

0.2

0.7

0.6

0.4

C. famata

0.08

0.2

0.5

0.2

0.4

0.3

C. inconspicua

  

0.08

0.1

0.2

0.3

C. novegensis

  

0.08

0.1

0.07

0.1

C. dubliniensis

  

0.01

0.08

0.1

0.05

C. lipolytica

  

0.06

0.06

0.06

0.08

C. zeylanoides

  

0.03

0.08

0.02

0.04

C. pelliculosa

   

0.06

0.05

0.04

Canida spp.

3.9

6.0

3.7

3.3

7.9

4.9

Total no. of cases

22,533

20,998

11,698

21,804

24,680

33,002

a Data compiled from the ARTEMIS DISK surveillance Program, 1997 to 2003 (221).

b Includes all specimen types and all hospitals from a total of 127 different institutions in 39 countries.

c Candida species not otherwise identified.

Table 3

Species distribution of Candida in blood stream infections in various studies.

Reference

9 Artemis

10 Sentry

11 Horn

12 Ostrosky

13 Cisterna

14 Arendrup

15 Fleck

16 Borg

Year

2005-2007

2008-2009

2004-2008

1995/1999

2008-2009

2004-2009

2004-2006

2004-2005

Location

worldwide

worldwide

USA

USA

Spain

Denmark

Germany

Germany

n

88647

1354

2019

2000

984

2901

512

561

C. albicans

65

48.4

45.6

36.7

49.1

57.1

43

58.5

C. glabrata

11.7

18.2

26

22.9

13.6

21.1

31.3

19.1

C. tropicalis

8

10.6

8.1

15.4

10.8

4.8

11.7

7.5

C. parapsilosis

5.6

17.1

15.6

19.6

20.7

3.7

5.7

8

C. krusei

2.5

2

2.5

2.5

2.1

4.1

3.7

1.4

C. guilliermondii

0.6

 

0.3

    

1.1

C. lusitaniae

0.6

 

0.8

1

  

≤1

0.2

C. kefyr

0.6

     

≤1

 

C. inconspicua

0.3

     

≤1

1.1

C. famata

0.3

     

≤1

0.7

C. rugosa

0.2

      

0.2

C. dubliniensis

0.2

 

0.4

0.9

 

2.6

 

1.1

C. norvegensis

0.1

      

0.4

C. lipolytica

0.06

     

≤1

 

C. sake

0.08

     

≤1

 

C. pelliculosa

0.05

       

C. apicola

0.06

       

C. zeylanoides

0.02

       

C. valida

0.01

     

≤1

 

C. intermedia

0.01

     

≤1

0.4

C. pulcherrima

< 0.01

       

C. haemulonii

< 0.01

       

C. stellatoidea

< 0.01

       

C. utilis

< 0.01

     

≤1

0.4

C. humicola

< 0.01

       

C. lambica

< 0.01

       

C. ciferrii

< 0.01

       

C. colliculosa

< 0.01

     

≤1

0.4

C. holmii

< 0.01

       

C. marina

< 0.01

       

C. sphaerica

< 0.01

       

Candida spp.

4

 

0.7

 

3.6

5.1

4.7

 

Susceptibility Testing

Some of the already cited and many other studies have also reported on the in-vitro susceptibility of Candida spp. For various reasons it is difficult to assess the various results. There are currently several test methods for performing these assays. Standardized methods have been published by the Clinical and Laboratory Standards Institute (CLSI) of the USA [17, 18] and by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [19]. The two broth dilution methods are not identical as methodological differences include glucose concentration, inoculum size, shape of microtitration wells (flat or round), and end-point reading (visual or spectrophotometric). However, it appears that they result in similar MIC levels for polyenes, azoles and echinocandins for identical isolates with a few noted exceptions [2023]. This is especially true if isolates with defined resistance mechanisms are being tested [22, 23]. However, some "drug/bug" combinations seem to offer particular test problems i.e. caspofungin and C. glabrata [22]. Moreover, EUCAST (and for that matter Etest) results have a tendency for one to two dilution steps lower MIC values [20, 23]. There are also some commercially available test devices that have been tested in their performance. A high degree of correlation with the reference methods was found for the Etest by various authors [22, 23]. The percentage of strains classified as resistant in vitro by the EUCAST procedure and as susceptible in vitro by the VITEK 2 system was 2.6%, and as resistant by the CLSI method and as susceptible by the VITEK 2 was 1.6% (very major error) [24]. The difference observed for the Vitek 2 results and CLSI and EUCAST is driven by the fact that there are differences in clinical breakpoints (CBP) suggested by the two organizations. However these results indicate that although the CBP of EUCAST and CLSI are significantly different, currently only few strains are affected by this difference.

CBP are used to classify MIC results into susceptible (S), intermediate (I) (CLSI for some strange reason "susceptible dose dependent"; S-DD), and resistant (R), respectively. This has complicated to assess and compare studies were only percentages of S, I and R are published. The same is true for published MIC50/90 values, as very different MIC distributions might be behind these numbers. To illustrate this further, two very different fictitious distributions resulting in the same MIC50/90 values are given with Figure 3. Therefore, meaningful surveillance data should be published as MIC distributions. That allows for evaluation of the results even at a later date when i.e. CBP had been changed as has happened in the past. To circumvent the problem with differences in CBP published by various organizations, it has been suggested to use epidemiological cut -off values to distinguish between wild type (WT) organisms without any resistance mechanisms and non-wild type (N-WT) strains with higher MIC values that are thought or known to possess a resistance mechanism [22, 25]. This would put in vitro test results on the safe side as long as the particular species is a target for the antifungal agent in question. Obviously, CBP should not divide WT distributions as this will cause arbitrary test results. Monitoring the development of N-WT strains in surveillance studies allows one to analyze the spread of resistance mechanisms.
Figure 3

Two very different fictitious MIC distributions result- ing in the same MIC50/90 values: 2 and 32 mg/L.

Resistance Mechanisms

A number of different resistance mechanisms have been described in Candida spp. Often, several of these mechanisms are combined to result in a stepwise development of clinically relevant resistance. Resistance to i.e. fluconazole can be caused i.e. by alterations in sterol biosynthesis, by mutations in the drug target enzyme, sterol 14α-demethylase, which lowers its affinity for fluconazole, by increased expression of the ERG11 gene encoding for this enzyme, or by overexpression of genes coding for membrane transport proteins of the ABC transporter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies [26].

Similarly Candida isolates were found with reduced susceptibility to echinochandins that showed mutations in selected regions of fks1, the gene encoding the echinocandin target enzyme 1-3-b-D-glucan synthase [27]. In particular, mutations of the serine at position 645 and also, in some cases, at position 641 have been associated with decreased susceptibility to echinochandins [28].

It should be noted that there is at least for fluconazole a clear relation between MIC values, pharmacokinetics (expressed in serum AUC) and outcome (Figure 4) [29]. Since resistance development against i.e. echinocandines so far is very limited, it is obviously very difficult to establish such a correlation. This problem is further aggravated by the fact that current antifungals still leave much to be desired as they i.e. do not reach the cure rates of antibacterial agents for susceptible bacteria. Moreover, the described resistance mechanisms were at least in individual cases associated with clinical failure of the involved patients [3035]. This has raised concern over the CBP as suggested by the CLSI. For a discussion of this subject see [36, 37].
Figure 4

Mortality rate stratified by tertiles and fluconazole Auc/Mic at 24 h (P = 0.09 using logistic regression controlling for time to initiation of fluconazole therapy) [29].

Resistance surveillance

Among the worldwide largest and long run surveillance systems is the ARTEMIS program. In a recent publication [9], comparative susceptibility data for fluconazole and voriconazole for more than 190,000 isolates collected from 2001 to 2007 were provided and analysis of resistance rates by year, geographic location, hospital location, and specimen type for selected species were included. The data were collected employing the CLSI disk diffusion method and are summarized in Table 4. They show that fluconazole resistance has to be expected especially in C. glabrata, krusei, guillermondii, famata, inconspicua, rugosa, norvegensis and some other rarer species. There seem to be some but no complete crossresistance with voriconazole which leaves the latter as an option in appropriate cases. A trend toward increased resistance over the most recent 3 years (2005 to 2007) was observed for voriconazole and some species with low prevalence such as C. famata (1.1% to 5.7%), C. norvegensis (0.0% to 6.9%), C. lipolytica (0.0% to 11.1%), and C. pelliculosa (14.3% to 16.7%). However, there was no trend toward increased resistance to voriconazole among the fluconazole-resistant species C. glabrata, C. krusei, C. guilliermondii, C. rugosa, and C. inconspicua.
Table 4

In vitro susceptibilities of Candida spp. to fluconazole and voriconazole as determined by CLSI disk diffusion testinga [9].

  

Fluconazoleb

  

Voriconazoleb

 

Species

No. of isolates

% S

% R

No. of isolates

% S

% R

C. albicans

128,625

98.0

1.4

125,965

98,5

1.2

C. glabrata

23,305

68.7

15.7

22,968

82.9

10.0

C. tropicalis

15,546

91.0

4.1

15,198

89.5

5.4

C. parapsilosis

12,788

93.2

3.6

12,453

97.0

1.8

C. krusei

5,079

8.6

78.3

5,005

83.2

7.6

C. guilliermondii

1,410

73.5

11.4

1,375

90.5

5.7

C. lusitaniae

1,233

92.1

5.4

1,215

96.7

2.0

C. kefyr

1,044

96.5

2.7

1,032

98.7

0.9

C. inconspicua

566

22.6

53.2

563

90.6

3.9

C. famata

622

79.1

10.3

606

90.3

5.0

C. rugosa

603

49.9

41.8

580

69.3

21.2

C. dubliniensis

310

96.1

2.6

308

98.4

1.0

C. norvegensis

248

41.9

40.7

247

91.5

4.0

C. lipolytica

130

66.2

28.5

128

77.3

14.1

C. sake

87

85.1

11.5

87

92.0

6.9

C. pelliculosa

87

89.7

6.9

86

94.2

4.7

C. apicola

57

98.2

1.8

57

98.2

1.8

C. zeylanoides

70

67.1

24.3

67

85.1

6.0

C. valida

21

23.8

61.9

22

81.8

13.6

C. intermedia

24

95.8

4.2

25

100.0

0.0

C. pulcherrima

14

100.0

0.0

14

100.0

0.0

C. haemulonii

9

88.9

11.1

9

88.9

11.1

C. stellatoidea

7

85.7

0.0

7

85.7

14.3

C. utilis

6

83.3

0.0

7

100.0

0.0

C. humicola

6

50.0

50.0

6

50.0

33.3

C. lambica

5

0.0

80.0

5

40.0

20

C. ciferrii

2

50.0

50.0

2

50.0

0.0

C. colliculosa

2

100.0

0.0

2

100.0

0.0

C. holmii

1

100.0

0.0

1

100.0

0.0

C. marina

1

0.0

0.0

1

100.0

0.0

C. sphaerica

1

100.0

0.0

1

100.0

0.0

Candida spp.

9,744

86.2

8.9

9,577

93.6

4.1

a Isolates were obtained from 133 istitutions, 2001 tp 2007.

b Fluconazole and voriconazole disk diffusion testing was performed in accordance with CLSI document M44-a (7). the interpretive breakpoint (zone diameters) were as follows: s, ≥19 mm (fluconazole) and ≥ 17 min (voriconazole); R, ≤14 mm (fluconazole) and = 13 mm (voriconazole).

c Candida species, not otherwise specified.

MIC distributions for echinocandins have been published by Pfaller et al. (Table 5) [39]. The results of this study demonstrate the comparable spectrum and potency of all three available echinocandin antifungals against a large collection of clinically important Candida spp. It also highlights the fact that species such as C. parapsilosis and C. guilliermondii exhibit decreased susceptibilities to all three echinocandins. The clinical relevance of these elevated MICS currently remains doubtful.
Table 5

In vitro susceptibilities of 5,346 clinical isolates of Candida spp. to anidulafungin, caspofingin, and micafungin [38].

Organism

No. of isloates

tested

Antifungal

agent

 

Cumulative % of isolates susceptible at a MIc (μg/ml) ofa

  
   

0.007

0.015

0.03

0.06

0.12

0.25

0.5

1

2

4

≥8

C. albicans

2,869

Anidulafungin

6.2

33.5

69.5

92.4

99.1

99.5

99.5

99.6

100.0

  
  

Caspofungin

1.7

26.7

74.2

97.1

99.3

99.9

100.0

    
  

Micafungin

11.9

80.6

96.4

99.3

99.4

99.5

99.6

100.0

   

C. parapsilosis

759

Anidulafungin

  

0.3

0.3

0.3

1.4

4.7

27.9

92.5

100.0

 
  

Caspofungin

 

0.1

0.5

3.3

10.7

52.2

89.5

98.6

99.9

100.0

 
  

Micafungin

 

0.1

0.3

0.3

0.5

6.1

24.4

79.3

100.0

  

C. glabrata

747

Anidulafungin

 

0.4

7.8

62.4

93.6

99.4

99.7

99.9

99.9

100.0

 
  

Caspofungin

 

7.0

65.2

95.3

98.4

99.2

99.7

99.9

99.9

99.9

100.0

  

Micafungin

13.7

91.4

97.9

98.9

99.5

99.9

99.9

100.0

   

C. tropicalis

625

Anidulafungin

3.2

24.2

75.7

95.0

98.4

99.4

99.5

99.5

100.0

  
  

Caspofungin

1.3

31.0

79.7

97.3

99.0

99.7

99.7

99.8

99.8

99.8

100.0

  

Micafungin

4.0

39.5

77.6

96.3

98.6

99.5

99.7

100.0

   

C. krusei

136

Anidulafungin

 

2.9

47.1

90.4

99.3

99.3

100.0

    
  

Caspofungin

 

0.7

0.7

41.9

75.7

94.9

99.3

100.0

   
  

Micafungin

 

2.2

13.2

85.3

96.3

100.0

     

C. guilliermondii

61

Anidulafungin

    

3.3

6.6

13.1

57.4

90.2

100.0

 
  

Caspofungin

  

1.6

4.9

11.5

39.3

80.3

95.1

95.1

95.1

100.0

  

Micafungin

 

3.3

3.3

6.6

11.5

21.3

65.6

98.4

100.0

  

C. lusitaniae

58

Anidulafungin

   

1.7

13.8

43.1

96.6

100.0

   
  

Caspofungin

  

3.4

6.9

44.8

89.7

96.6

100.0

   
  

Micafungin

  

1.7

8.6

63.8

96.6

98.3

100.0

   

C. kefyr

37

Anidulafungin

 

2.7

10.8

56.8

100.0

      
  

Caspofungin

13.5

97.3

100.0

        
  

Micafungin

 

5.4

40.5

100.0

       

C. famata

24

Anidulafungin

 

4.2

16.7

20.8

20.8

20.8

25.0

50.0

100.0

  
  

Caspofungin

 

4.2

12.5

20.8

37.5

70.8

70.8

95.8

100.0

  
  

Micafungin

 

4.2

16.7

16.7

20.8

33.3

75.0

91.7

100.0

  

Candida spp.

30

Anidulafungin

3.3

30.0

50.0

63.3

63.3

73.3

86.7

93.3

96.7

96.7

100.0

  

Caspofungin

 

16.7

43.3

63.3

73.3

96.7

100.0

    
  

Micafungin

 

20.0

53.3

66.7

66.7

86.7

100.0

    

Total

5,246

Anidulafungin

3.7

21.1

48.9

72.6

82.0

83.4

84.7

88.7

98.8

99.9

100.0

  

Caspofungin

1.2

19.7

59.4

79.6

84.0

91.9

98.1

99.7

99.9

99.9

100.0

  

Micafungin

8.8

60.9

75.6

81.3

83.3

85.0

88.5

97.0

100.0

  

a Values corresponding to MIcs at which at least 90% of isolates are inhibited are listed in bold types.

The data collected by the SENTRY surveillance program were published as MIC50/90 values and interpreted results according to CLSI, only [39, 40]. However, this study included most important antifungals. An excerpt for C. parapsilosis is given with Table 6. German data were published in the same way [15], not offering significant differences to the SENTRY results with the exception of a high degree of flucytosine resistance in C. krusei and C. tropicalis. Finally, susceptibility data for rare Candida isolates have been collected by Diekema et al. [41] (Table 7) and chen et al. [42] that might help to guide therapy in these cases.
Table 6

In vitro antifungal agent susceptibilities of Candida and Cryptococcus isolates collected by the SENTRY Program in 2006 to 2007 [39].

Species (no. of isolates) and drug

MIC50/MIC90 (μg/ml)

MIC range (μg/ml)

 

% by categorya

 
   

S

SDD

R b

C. parapsilosis (238)

     

Anidulafungin

2/2

0.03-4

95.4

-

4.6

Caspofungin

0.5/1

0.06-4

99.6

-

0.4

Amphotericin B

1/1

0.25-1

99.6

-

0.4

5-FC

≤0.5/≤0.5

≤0.5- > 64

98.7

(0.0)

1.3

Fluconazole

1/4

≤0.5-32

96.6

3.4

0.0

Itraconazole

0.25/0.25

≤0.015-2

40.8

57.1

2.1

Posaconazole

0.12/0.25

≤0.06-1

-

-

-

Voriconazole

≤0.06/0.12

≤0.06-2

99.6

0.4

0.0

Table 7

Antifungal susceptibilities of rare Candida bloodstream isolates [41].

Species

No. of isolates

Antifungal agent

No. inhibited at MIC (μg/ml) of:

   

0.007

0.015

0.03

0.06

0.12

0.25

0.5

1

2

4

8

16 b

32

64 c

≥128

C. lasitaniae

171

Amphotericin a

   

3

18

74

66

7

1

0

1

1

   
 

171

Fluconazole

    

20

52

64

20

5

3

1

1

3

2

 
 

171

Posaconazole

2

25

63

58

15

4

1

3

       
 

171

Voriconazole

123

33

3

4

2

3

2

1

       
 

96

Anidulafungin

   

5

13

36

40

2

       
 

166

Caspofungin

 

1

4

6

68

66

17

3

0

1

     
 

80

Micafungin

1

0

4

8

44

21

1

1

       

C. guilliermondii

174

Amphotericin

1

0

1

8

63

62

24

6

2

1

1

0

0

5

 
 

175

Fluconazole

     

1

4

4

69

68

13

7

2

3

4

 

175

Posaconazole

 

1

9

10

44

73

25

3

4

0

0

6

   
 

175

Voriconazole

2

11

19

83

43

8

1

0

2

0

0

6

   
 

107

Anidulafungin

 

1

 

2

6

5

7

37

41

8

     
 

156

Caspofungin

  

2

9

21

33

58

21

4

2

2

4

   
 

96

Micafungin

 

3

1

4

10

13

33

27

4

0

0

1

   

C. orthopsilosis

102

Amphotericin

     

7

29

35

23

8

     
 

102

Fluconazole

     

6

28

45

9

8

4

1

0

1

 
 

102

Posaconazole

 

1

12

40

30

8

11

        
 

102

Voriconazole

1

24

40

24

1

10

1

1

       
 

52

Anidulafungin

     

3

12

28

9

      
 

91

Caspofungin

1

0

3

17

37

25

8

        
 

51

Micafungin

    

2

25

21

3

       

C. kefyr

74

Amphotericin

      

20

43

10

0

0

0

0

1

 
 

74

Fluconazole

    

11

44

12

6

1

      
 

74

Posaconazole

1

3

17

21

23

8

1

        
 

74

Voriconazole

50

18

4

2

           
 

58

Anidulafungin

 

1

5

31

21

          
 

74

Caspofungin

11

56

6

1

           
 

53

Micafungin

 

4

2

26

1

          

C. pelliculosa

40

Amphotericin

    

3

14

21

2

       
 

40

Fluconazole

       

2

7

24

7

    
 

40

Posaconazole

   

1

1

6

4

14

12

2

     
 

40

Voriconazole

 

1

1

1

21

13

3

        
 

14

Anidulafungin

2

9

2

1

           
 

37

Caspofungin

1

16

17

3

           
 

14

Micafungin

 

5

7

2

           

C. famata

16

Amphotericin

    

1

6

8

0

0

1

     
 

16

Fluconazole

       

1

5

6

1

3

   
 

16

Posaconazole

 

2

0

0

1

5

7

1

2

      
 

16

Voriconazole

  

2

5

4

3

0

1

1

      
 

16

Anidulafungin

   

2

0

0

0

5

9

      
 

16

Caspofungin

  

1

2

2

5

3

2

1

      
 

16

Micafungin

  

1

1

0

2

5

5

2

      

C. metapsilosis

30

Amphotericin

    

1

5

12

9

2

1

     
 

30

Fluconazole

     

1

0

19

9

1

     
 

30

Posaconazole

 

1

7

15

5

1

0

1

       
 

30

Voriconazole

1

4

22

2

1

          
 

11

Anidulafungin

     

5

3

2

1

      
 

24

Caspofungin

  

1

5

14

3

0

1

       
 

11

Micafungin

     

7

3

1

       

C. dubliniensis

18

Amphotericin

   

1

8

7

1

1

       
 

18

Fluconazole

    

8

9

0

0

0

0

1

    
 

18

Posaconazole

 

4

6

7

1

          
 

18

Voriconazole

11

5

2

            
 

11

Anidulafungin

  

7

2

0

2

         
 

17

Caspofungin

 

2

6

9

           
 

9

Micafungin

 

4

3

2

           

C. lipolytica

16

Amphotericin

      

1

5

5

4

1

    
 

16

Fluconazole

      

1

1

6

6

1

0

0

1

 
 

16

Posaconazole

    

2

1

8

4

0

1

     
 

16

Voriconazole

 

1

5

7

2

0

0

1

       
 

10

Anidulafungin

     

3

4

2

1

      
 

15

Caspofungin

    

6

9

         
 

10

Micafungin

     

6

3

1

       

C. rugosa

16

Amphotericin

      

4

3

7

1

0

0

0

1

 
 

16

Fluconazole

      

1

0

4

3

2

4

1

1

 
 

16

Posaconazole

   

6

2

5

3

        
 

16

Voriconazole

2

1

4

3

1

3

2

        
 

16

Anidulafungin

   

3

1

4

3

3

0

0

2

    
 

16

Caspofungin

  

1

1

0

1

2

8

0

1

0

2

   
 

16

Micafungin

  

1

3

3

5

2

0

0

0

0

2

   

a Amphoiericin B MICs were determined by EtesL

b For posaconazole. voriconazole, anidulafungin. caspofungin. and micafungin. isolates for which MICs are reported to be 16 μg/ml encompass all isolates for which MICs were > 8 μg/ml.

c For amphotericin B. isolates for which the MIC is reported to be 64 μg/ml encompass all isolates for which MICs were > 32 μg/ml.

Conclusion

Meanwhile in vitro methods are available to assess reliably the susceptibility of fungal isolates. There are, however, considerable differences in the evaluation of the results, as CLSI and EUCAST breakpoints vary. If isolates with known resistance mechanisms that have been shown to be clinically relevant at least in individual cases shall not be categorized as susceptible, some CLSI CBP need to be reconsidered. Despite the fact that a number of new antifungals are nowadays available, clinical results of antifungal therapy leave much to be desired. Hence, optimization of empiric therapy according to the local epidemiological situation and reevaluation of the therapeutic regimen when susceptibility results become available should carefully be followed. With our expanded knowledge on pharmacokinetics of antifungal compounds, MIC data could be valuable at least when treating invasive fugal infections. More information about MICs of clinical isolates and outcome of the particular patients would be helpful to establish further and validate current CBP.

Authors’ Affiliations

(1)
Institute for Medical Microbiology and Epidemiology of Infectious Diseases, University Hospital of Leipzig

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