Epidemiology, Species Distribution, Antifungal Susceptibility, and Outcome of Candidemiaacross ...

18 Pages·2013·0.48 MB·English

JCM Accepts, published online ahead of print on 9 October 2013
J. Clin. Microbiol. doi:10.1128/JCM.01998-13
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
1 Epidemiology, Species Distribution, Antifungal Susceptibility, and Outcome of
2 Candidemiaacross five sites in Italy and Spain
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4 Matteo Bassetti 1, Maria Merelli 1, Elda Righi 1, Ana Diaz-Martin 2, Eva Maria Rosello 3 , Roberto
5 Luzzati 4 , Anna Parra 5, Enrico Maria Trecarichi 6 , Maurizio Sanguinetti 7, Brunella Posteraro 8, D
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6 Jose Garnacho-Montero 2, Assunta Sartor 9, Jordi Rello 10, Mario Tumbarello 6 w
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8 1 Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy d
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9 2 Critical Care and Emergency Clinical Unit. Virgen del Rocio University Hospital, Seville, Spain m

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10 3 Microbiology Department, Vall d'Hebron University Hospital, Barcelona, Spain tt
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11 4 Infectious Diseases Unit, University Hospital of Trieste, Trieste, Italy /jc
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12 5 Critical Care Department, Vall d'Hebron University Hospital, Barcelona, Spain .a
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13 6 Institute of Infectious Diseases, Università Cattolica del Sacro Cuore, Rome, Italy m
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14 7 Institute of Microbiology, Università Cattolica del Sacro Cuore, Rome, Italy rg
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15 8 Institute of Public Health (Section of Hygiene), Università Cattolica del Sacro Cuore, Rome, Italy n

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16 9 Microbiology Unit, Santa Maria Misericordia University Hospital, Udine, Italy o
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17 10 Critical Care Department, Vall d'Hebron University Hospital, CIBERES, Universitat autonoma de m
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18 Barcelona, Barcelona, Spain r

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20 Running title: Epidemiology and susceptibility of candidemia in Europe 1
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21 Contact information b
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23 Matteo Bassetti, MD, PhD u
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24 Clinica Malattie Infettive s
25 Azienda Ospedaliera Universitaria Santa Maria della Misericordia t
26 Piazzale Santa Maria della Misericordia 15
27 33100 Udine
28 Italy
29 Phone [phone]
30 Fax [phone]
31 Email: [email protected]
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32 Abstract
33 Candidemia has become an important bloodstream infection that frequently associates a high rate of
34 mortality and morbidity, its growing incidence being related to complex medical and surgical
35 procedures. We conducted a multicentric study in five tertiary care teaching hospitals in Italy and
36 Spain evaluating epidemiology, species distribution, antifungal susceptibility and outcome of D
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37 candidemia episodes. In the period 2008-2010, 995 episodes of candidemia were identified. The w
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38 overall incidence was 1.55 cases per 1,000 admissions and remained stable during the three years a
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39 analysed. Candida albicans was the leading agent (58.4%), followed by Candida parapsilosis d
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40 complex (19.5%), C. tropicalis (9.3%), and C. glabrata (8.3%). The majority of the candidemia m

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41 episodes were found in internal medicine department (49.6%), followed by surgery, ICU and tt
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42 hemato-oncology. Out of 955 evaluable patients, 381 (39.9%) died within 30 days from the onset jc
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43 of candidemia. Important differences in 30 days- mortality were noted between institutions: lowest a
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44 mortality in Barcelona and highest in Udine (33.6% vs 51%, respectively, P 0.0005). Overall, 5.1 .o
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45 % of the 955 isolates tested were resistant or SDD to fluconazole with minor differences between /
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46 Italy and Spain (5.7% vs 3.5%, P 0.2). Higher MICs for caspofungin were found, especially in C. N
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47 parapsilosis complex (MIC90 1 (cid:541)g/mL). Amphotericin B has shown the lowest values of MICs. e
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48 This report shows that candidemia is a significant source of morbidity in Europe, with a substantial e
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49 burden of disease and mortality. 2
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51 Key words: Candida, bloodstream infection, fungemia, antifungal susceptibility 1
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64 Introduction
65 Candida is an important cause of bloodstream infections (BSI), causing significant mortality and
66 morbidity in health care settings. The incidence of candidemia is growing with the increasing
67 complexity of surgical procedures, the existence of patient populations at higher risk of infection,
68 and the changes in patient demographic characteristics. Its overall incidence raised fivefold in the D
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69 past ten years and Candida spp. is currently between the fourth and the sixth most common
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70 nosocomial bloodstream isolate in American and European studies (1,2). However, candidemia a
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71 rates vary geographically. For example, an increasing incidence of candidemia in Iceland was d
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72 reported for the period between 1980 and 1999 (3), but the same was not observed in Switzerland, m

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73 where a national surveillance study showed that the incidence of candidemia had remained tt
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74 unchanged during the period of 1991 to 2000 (2). Therefore it seems that differences do exist in the jc
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75 epidemiology of candidemia between different countries, underscoring the need for continuous a
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76 surveillance to monitor trends in incidence, species distribution, and antifungal drug susceptibility .o
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77 profiles. The epidemiology of candidemia has been studied extensively in the United States, /
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78 Europe, and some countries in South America (4-16) N
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79 Candidemia remains associated with high crude and attributable mortality rates and with increased e
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80 costs of care and duration of hospitalization. Attributable mortality has been reported to range from e
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81 5% to 71%, and crude mortality rates have been reported to be as high as 81% (4-6,14,17-19). In 2
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82 terms of species of Candida, recently, a shift towards non-albicans species was reported by some 0
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83 authors especially in haematological, transplanted and intensive care unit (ICU) patients (12,20,21). b
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84 A reduced antifungal susceptibility in non-albicans species and a correlation with routine u
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85 fluconazole prophylactic use has been suggested (15). Intrinsic and emerging resistance to azoles t
86 actually represents a major challenge for empirical therapeutic and prophylactic strategies (5).
87 This study was performed to evaluate contemporary epidemiology, species distribution, antifungal
88 susceptibility and outcome of candidemia in five big teaching hospitals in Italy and Spain.
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89 Methods
90 The study was conducted in five tertiary care teaching hospitals in Italy and Spain: 1) Trieste
91 University Hospital (700 beds), Trieste, Italy; 2) Santa Maria Misericordia University Hospital
92 (1200 beds), Udine, Italy; 3) Policlinico Gemelli (1500 beds), Roma, Italy; 4) Val d’Hebron
93 Hospital (1150 beds), Barcelona, Spain, 5) Virgen Del Rocio University Hospital (851 beds), D
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94 Seville, Spain. All patients admitted to these five hospitals who developed candidemia in the period
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95 January 2008-December 2010 were included in the study and prospectively followed. Patients with a
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96 at least one positive blood culture for Candida spp. and a compatible clinical illness were identified d
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97 through the microbiological laboratory database and all information was recorded in an electronic m

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98 database. For each patient, only the first episode of candidemia was recorded. Patients whose tt
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99 cultures grew >1 species of Candida were excluded from the analysis. Patients with candidemia jc
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100 were followed prospectively for 30 days or until their discharge from the hospital. Outcome was a
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101 recorded only for patients with at least 30 days follow-up after the initial episode of candidemia. .o
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102 During the study period there were no changes in microbiological laboratory techniques in the five /
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103 hospitals. Candida species were isolated from blood using BACTEC 860 system (Becton N
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104 Dickinson, Inc., Sparks, MD). The species were identified using API ID 32C system (bioMérieux, e
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105 Marcy l’Etoile, France) or Vitek 2 system (bioMérieux). In the case of inconclusive results by both e
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106 the systems, isolates were definitively identified using supplemental tests, e.g., presence or absence 2
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107 of well-formed pseudohyphae on cornmeal-Tween 80 agar and growth at 42 to 45°C. The last test 0
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108 was also required to differentiate isolates of Candida albicans from those of Candida dubliniensis. b
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109 Antifungal susceptibility testing to amphotericin B, caspofungin, fluconazole, itraconazole, and u
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110 voriconazole was performed using the Sensititre YeastOne colorimetric plate (Trek Diagnostic t
111 Systems, Cleveland, OH). Minimum inhibitory concentration (MIC) results were interpreted
112 according to species-specific clinical breakpoints as established by the Clinical and Laboratory
113 Standards Institute (CLSI) for amphotericin B, caspofungin, fluconazole, itraconazole (only with C.
114 albicans), and voriconazole (22, 23).
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115 The Chi-square-test or the Fisher Exact-test were used to compare categorical variables. Differences
116 between groups were considered to be significant for variables yielding a p value < 0.05.
117 The study was approved by the local institutional review boards and written patient consent was not
118 required because of the observational nature of this study.
119 Results D
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120 A total of 995 episodes of candidaemia were identified during the study period (January 2008-
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121 December 2010). The median age was 66.2 years old and 57 % were males. The demographic and a
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122 clinical characteristics of the patients are summarized in table 1. The majority of patients (93.1%) d
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123 had one or more comorbidity at the time of the diagnosis of candidaemia. Four hundred and forty- m

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124 one patients (46%) had undergone a surgical intervention, 285 (30%) had solid tumor, 275 (28.8%) tt
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125 had cardiovascular diseases, 242 (25.3%) were diabetic, 60 (6.3%) had haematological jc
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126 malignancies, 33 (3.4%) received a solid organ transplantation and 19 (2 %) had human a
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127 immunodeficiency virus (HIV) infection. The overall incidence was 1.55 cases per 1,000 .o
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128 admissions and remained stable during the three years analysed. As shown in Table 2, the incidence /
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129 differed across hospitals, with the highest incidence in Roma-Italy (2.53 cases per 1,000 N
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130 admissions) and the lowest in Udine-Italy (0.8 per 1,000 admissions). e
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131 Candida albicans was the leading agent (58.4%), followed by C. parapsilosis complex (19.5%), C. e
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132 tropicalis (9.3%), and C. glabrata (8.3%). C. albicans accounted for more than 50% in all the 3 2
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133 Italian hospitals and in a Spanish one, only in Seville non-albicans species represented more that 0
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134 50% of the isolates. The distribution of albicans and non-albicans strains differed according to the b
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135 type of patient population and risk factors, as shown in Figure 1. In hemato-oncology patients, C. u
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136 albicans was isolated in 41.8 % of the cases, C. tropicalis in 20% and C. glabrata in 16.4%; in t
137 internal medicine, ICU and surgery C. albicans accounted for around 60% of the cases.
138 The majority of the candidemia episodes were found in internal medicine department (49.6%),
139 followed by surgery, ICU and hemato-oncology (table 3).
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140 Crude mortality stratified by hospital and type of units are reported in table 3. Out of 955 evaluable
141 patients, 381 (39.9%) died within 30 days from the onset of candidemia. Important differences in 30
142 days-mortality were noted between institutions: lowest mortality in Barcelona and highest in Udine
143 (33.6% vs 51%, respectively, P 0.0005).
144 Regarding the crude mortality in the different units, patients in hemato-oncology wards had the D
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145 highest mortality rate (56.9%), followed by patients in ICU (46%) and in internal medicine (45.9%).
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146 Patients in general surgery show the lowest mortality in all the centres with a mean of 18.7 %. a
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147 Table 4 shows the results of the in vitro activity of 5 systemically active antifungal agents tested d
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148 against 955 BSI isolates of Candida spp. based on CLSI breakpoints (23). The rate of susceptibility m

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149 to fluconazole was 98.6 % for C. albicans and 97.3 % for C. parapsilosis complex. Decreased tt
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150 susceptibility to fluconazole was mostly seen with C. glabrata (54.4%) and C. tropicalis (94.9%). jc
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151 Overall, 5.1 % of the 955 isolates tested were resistant, intermediate or susceptible dose dependant a
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152 (SDD) to fluconazole. Higher MICs for caspofungin were found in C. albicans, C. glabrata and, .o
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153 especially, in C. parapsilosis complex (MIC90 1 (cid:541)g/ml) with 5 resistant strains (2.7%). . o/
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154 Amphotericin B has shown the lowest values of MICs. Some minor differences were found for N
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155 fluconazole resistance in all Candida species between Italy and Spain (5.7% vs 3.5%, P 0.2). e
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156 Discussion e
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157 Several studies have shown a substantial increase in the incidence of candidemia in the past 2 2
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158 decades. Our data show that in the 5 analysed hospitals the incidence of candidemia has increased 0
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159 steadily in two institutions (Rome Catholic Hospital and Seville Hospital) and has remained stable b
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160 in the other three. The mean rates are higher than those reported for centres in the Northern u
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161 Hemisphere, including the United States (0.42 cases per 1,000 admissions) (24), Canada (0.45 per t
162 1,000 admissions) (25) and some European countries (0.20 to 1.09 case per 1,000 admissions) (26)
163 and much higher than those reported in Finland ( 0.026 to 0.03 case per 1,000 admission (27). The
164 differences in candidemia rates between countries may reflect differences in representativeness and
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165 age distributions of the study populations, variations in health care practices, patterns using blood
166 cultures, and antibiotic usage as well as the resistance situation.
167 Over the past 10 years, some studies have reported a shift in the etiology of candidemia. While C.
168 albicans is still considered the most common species causing candidemia, increasing rates of
169 candidemia caused by C. tropicalis, C. parapsilosis species complex, C. glabrata, and C. krusei D
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170 have been reported worldwide (28-31). The reasons for the emergence of C. non-albicans species
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171 are not completely understood, but some medical conditions may consistently impact the risk of a
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172 developing candidemia due to non-C. albicans species: C. parapsilosis complex fungemia has been d
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173 associated with vascular catheters and parenteral nutrition (28). C. tropicalis candidemia is m

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174 associated with cancer and neutropenia (32), and C. krusei and C. glabrata fungemias are tt
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175 associated with previous exposure to azoles (15). The findings of our surveillance are not jc
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176 supportive of these reports. We observed a predominance of C. albicans (around 60 %). In our a
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177 study C .parapsilosis complex surpassed the other non-albicans to become the most common .o
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178 species isolated after C.albicans. Our series clearly consolidates the concept that C. parapsilosis /
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179 complex accounts for the large majority of non-albicans Candida species in southern Europe. The N
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180 high incidence of C. parapsilosis complex candidemia has been previously reported in South e
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181 American and Italian hospitals (11,16). Of note the frequency of C. glabrata candidemia is lower e
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182 than that reported in the Northern Hemisphere (33) and its frequency has been surpassed by C. 2
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183 tropicalis. We did not observed important differences across countries regarding the species 0
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184 distribution in the different departments. C. albicans dominated in our study in internal medicine, b
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185 surgery and ICU, while non-albicans Candida occurs frequently among haemato-oncologial u
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186 patients, confirming previous observations (28). On the other hand, C. tropicalis candidemia was t
187 more frequent in elderly patients, as reported elsewhere (34).
188 Interesting differences emerged in the profiles of patients with candidal BSI between our data and
189 those previously described. Latin-American and European figures (31identified that 56.5% and
190 44.4% of episodes of nosocomial fungaemia respectively, occurred in patients in ICU. In contrast,
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191 only 19.6 %% of episodes in our study arose in ICU patients; this proportion being only a small
192 amount lower than that which arose from patients in the surgical units (24.6%). In our study in
193 contrast with other experiences, an unusually large proportion (49.7%) occurred among patients in a
194 general internal medicine services, especially in the Italian hospitals. We hypothesise that this
195 variety of patterns reflects differences in the organisation and resourcing of healthcare delivery in D
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196 various countries rather than significant differences in the characteristics of the different
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197 populations studied. a
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198 Our proportion of fluconazole-resistant or SDD (5.1%) was similar the rates observed with d
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199 European (6.3%) and North American (6.6%) isolates (9,35). Differences in the susceptibility to m

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200 fluconazole were observed between Italy and Spain with an higher proportion in Italy, but lower tt
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201 than the rates recently reported in a tertiary-care Italian hospital (12). Voriconazole was the azole jc
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202 which exhibited the best in vitro antifungal activity. As reported by others (36) caspofungin a
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203 demonstrated excellent activity for all the Candida species, except for C. parapsilosis complex .o
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204 where higher MICs were observed. The clinical relevance of these findings is unknown because the /
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205 correlation between MIC and the outcome is still uncertain. N
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206 Retrospective cohort studies involving patients with candidemia and varying underlying diseases e
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207 have revealed worldwide crude and attributable mortality rates of 30%–81% and 5%–71%, e
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208 respectively (10). The severity of candidemia is confirmed by the high crude mortality rate found in 2
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209 the ECMM survey (38%) (37-39) as well as in Finland (35%) (40) and in the Barcelona area 0
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210 (44%).(8). In our series, patients with candidemia had a crude 30 days mortality rate of 39.9%. A b
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211 major finding of the present study is the high mortality rate for candidemia in patients admitted to u
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212 hemato-oncology and internal medicine compared with other wards (44.4% vs 35.4%, p=0.002). t
213 Several factors may have impacted the outcome, i.e. the high APACHE II score, the age, and the
214 presence of multiple comorbidities. Therefore, it is reasonable to assume that these factors have
215 played a major role in favouring poor outcomes in internal medicine compared to other wards.
216 Thus, factors potentially prone to intervention should be explored in future studies.
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217 Certainly the severity of the underlying medical condition greatly influences the crude mortality
218 rate in these patient populations, however for the patient in internal medicine wards inappropriate
219 therapy could represent an important variable – consisting mostly of omission of initial empirical
220 therapy and an inadequate choice of antifungals – which has been associated with increased
221 mortality (41). D
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222 Finally, the current study has several limitations that should be borne in mind when interpreting the
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223 results. All five sites analysed were located in teaching institutions and our observations may not a
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224 be generalizable to all patients with candidemia. Important intra-hospital differences may be d
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225 observed in large hospitals. Another limitation of our study is that although 5 centres from 2 m

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226 European countries participated, this may not be representative of each country. tt
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227 This report shows that candidemia is a significant source of morbidity in Italy and Spain, with a jc
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228 substantial burden of disease, mortality, and likely high associated costs. Determining factors a
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229 associated with high rates of candidemia may lead to identifying measures that can help to prevent .o
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230 disease. /
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231 Transparency declarations N
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232 MB serves on scientific advisory boards for Pfizer Inc., MSD, Gilead and Astellas Pharma Inc.; has e
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233 received funding for travel or speaker honoraria from Pfizer Inc., MSD, Gilead Sciences, and e
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234 Astellas Pharma Inc. MT have been speakers or consultants for Gilead Sciences, MSD and Pfizer. 2
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235 The other authors declare that they have no competing interests. 0
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236 Funding statement. b
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237 The work was carried out as part of the regular work of the hospital and university departments. u
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238 t
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