Original Articles. Introduction

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1 Medical Mycology April 2013, 51, Original Articles Is the incidence of candidemia caused by Candida glabrata increasing in Brazil? Five-year surveillance of Candida bloodstream infection in a university reference hospital in southeast Brazil MARIA LUIZA MORETTI *, PLINIO TRABASSO *, LUZIA LYRA, RENATA FAGNANI, MARIANGELA RIBEIRO RESENDE *, LUIS GUSTAVO DE OLIVEIRA CARDOSO & ANG É LICA ZANINELLI SCHREIBER * Internal Medicine Department and Clinical Pathology Department, Faculty of Medical Sciences, State University of Campinas, Sao Paulo, and Hospital Epidemiology Service, Hospital and Clinics, State University of Campinas, Sao Paulo, Brazil From 2006 to 2010, a retrospective study was conducted in a university referral tertiary care hospital to study the frequency and distribution of Candida species in different medical specialties. The use of mechanical ventilation, central venous catheter, and urinary catheter were recorded per 1,000 patient-days and the use of antifungals was calculated using defined daily dose (DDD). A total of 313 episodes were identified and the overall incidence was 0.54 ( ) episodes per 1,000 patient-days. Candida albicans caused 44% of the overall episodes, followed by C. tropicalis (21.7%), C. parapsilosis (14.4%), C. glabrata (11.2%), and C. krusei (3.5%). The incidence of C. glabrata significantly increased from (range: %) (P 0.024). Candida glabrata was associated with malignancies ( P 0.004) and C. krusei with hematologic malignancies ( P ). The use of antifungals was higher in the hematology/bone marrow transplant units and represented 40% of all fluconazole prescription in the hospital. There was no correlation with the use of fluconazole and the increasing ratio of C. glabrata (r 0.60). The use of invasive devices was significantly higher in the intensive care units (ICUs) than the medical and surgical emergencies units ( P 0.001). In contrast, the emergencies had higher incidence of candidemia (2 2.1 episodes/1,000 patient-days) than the ICUs (1.6 episodes 1,000 patient-days). Candida glabrata candidemia showed a significant increase in contrast to the current national literature where C. parapsilosis remained the most important non- C. albicans Candida species in Brazilian hospitals. Our findings suggested that the increasing incidence of C. glabrata was not associated with use of fluconazole and other risk factors might play an important role. Keywords candidemia, Brazil, Candida species, antifungal use, invasive devices Introduction Blood stream infections are among the most important causes of death in hospitalized patients and Candida Received 6 February 2012 ; Received in final form 29 May 2012; Accepted 27 June 2012 Correspondence: M. L. Moretti, Internal Medicine Department, Faculty of Medical Sciences, State University of Campinas. Rua: Tess á lia Vieira de Camargo, 126; Cidade Universit á ria Zeferino Vaz ; ZIP: , Campinas, S ã o Paulo, Brazil. mlmoretti@ hc.unicamp.br; moretti.luiza@gmail.com species represent a major problem in hospitals worldwide [1 3] with a high attributable mortality rate despite antifungal therapy [4 7]. The frequency of Candida varies geographically, which might reflect differences among patients, hospitals, health care assistance, and hospital epidemiology [8 11]. Several local publications [12 14] showed that non- C. albicans Candida species caused more candidemia than C. albicans. Candida parapsilosis was indicated as the second most important Candida species, after C. albicans, causing candidemia in Brazilian hospitals, and it has been 2013 ISHAM DOI: /

2 226 M. L. Moretti et al. suggested that the high proportion of C. parapsilosis candidemia might be related to low adherence to infection control practices [15,16]. The increasing use of empiric and prophylactic antifungal drugs has also been cited as causing changes in the epidemiology of Candida species in hospitals [17,18], in particular with C. glabrata. A large Brazilian seven-year study that analyzed the use of antifungals and changes in the epidemiology of Candida species showed an increased incidence of non- C. albicans Candida species directly related to the use of fluconazole; however, C. glabrata represented only 3% of the candidemia episodes [19]. The objective of the present study was to analyze the epidemiology of Candida species, use of invasive devices and the use of antifungal drugs, in our university hospital during five-year surveillance. Materials and methods The study was conducted in Hospital and Clinics of the State University of Campinas-UNICAMP, a 404-bed tertiary-care university hospital that provides all major medical services as the reference hospital for five million inhabitants, except for gynecology-obstetrics and neonates that are cared for in the Women s Hospital (UNICAMP). This retrospective surveillance of candidemia was performed based on the data bank of Candida bloodstream infections from the Clinical Microbiology Laboratory, Department of Clinical Pathology, which stored all fungal strains and recorded all invasive mycoses in our hospital. The clinical data were obtained from the Infection Control Division data bank. Nosocomial candidemia was defined according to the Centers for Disease Control and Prevention (CDC) criteria [20]. Only one episode per patient was included. All episodes of candidemia from were analyzed. Blood cultures and yeast identification were performed by automated microbiological systems BacT/ALERT 3D FA and PF bottles and Vitek 2 YST card (biom é rieux, Inc. Durham, NC, USA). All isolates were stored in sterile distilled water and for the purpose of this study, isolates were inoculated on CHROMagar Candida (Becton Dickinson, Sparks, MD, USA) to check purity. The use of mechanical ventilation, central venous catheter and urinary catheter were recorded per 1,000 patientdays, in the medical and surgical emergencies and intensive care units (ICUs). The use of antifungal therapy was calculated using the defined daily dose (DDD), defined as the assumed average maintenance dose per day for a drug used for its main indication in adults [21]. DDDs for the following antifungal drugs were: fluconazole: 0.2 g; voriconazole: 0.4 g; caspofungin: 50 mg, and amphotericin B: 35 mg. To evaluate if the antifungal use was related to any particular distribution of non- C. albicans Candida species, in particular C. glabrata, the antifungal DDD was recorded in the ICUs, medical and surgical emergencies, hematology/bone marrow transplant (BMT) units, and the hospital as a whole. Statistical analysis: the data were analyzed using Epi Info version software and OpenEpi version [22] Descriptive analyses of the numeric variables such as mean, median, and standard variation of the rate of use of the invasive devices were compared using the Kruskal- Wallis test. Linear regression was used to study the association of fluconazole use and the ratio of C. glabrata. Results From , 313 episodes of candidemia were analyzed (Table 1). Candida albicans was responsible for 138 (44%) of all episodes in the 5-year study. Non- C. albicans Candida species had the following distribution: C. tropicalis : 68 (21.7%); C. parapsilosis : 45 (14.4%); C. glabrata : 35 (11.2%), and C. krusei : 11 (3.5%) (Table 1). During the study period, candidemia per 1,000 patient-days was 0.54 varying from and candidemia per 100 admissions varied from The incidence of C. parapsilosis was significantly lower in 2009 than in the other years, when comparing with all other Candida species ( P 0.020) or with all other non- C. albicans (p 0.025). Of note, the incidence of C. glabrata increased remarkably from (Table 1). The distribution of Candida species related to medical specialties and underlying diseases is shown in Tables 2 and 3, respectively. Candida glabrata was significantly associated with patients with malignancies ( P 0.004) and these patients were mainly hospitalized in the gastroenterology ward, surgical and medical emergencies, ICUs and Internal Medicine. Candida tropicalis was not associated with patients with malignancies ( P 0.59) or hematologic malignancies ( P 0.26) and these patients were mainly assisted in the ICUs and medical wards. In this latter group of patients, non- C. albicans Candida spp. were significantly higher than patients with any other underlying diseases ( P ) and represented 88% of 34 candidemia episodes. Candida parapsilosis was not particularly associated with any underlying condition and was isolated in different wards of our hospital. Candida krusei was significantly more isolated in patients with hematologic diseases ( P ) than any other underlying conditions. The main underlying diseases of 313 patients and the distribution of Candida species are summarized in Table 3. Malignancies were present in 77 (24.6%) patients; 34 (10.3%) had hematologic malignancies, including the hematologic transplant recipients. We had 25 (7.9%) episodes in the pediatric population ( 1 14-year-old) and

3 Five-year surveillance of Candida bloodstream infection 227 Table 1 Distribution of Candida species isolated from patients with candidemia from n (%) 2007 n (%) 2008 n (%) 2009 n (%) 2010 n (%) Total n (%) Candida albicans 25 (38.4) 19 (36.5) 34 (54.8) 39 (46.9) 21 (41.2) 138 (44) C. tropicalis 15 (23) 12 (23) 12 (19.3) 21 (25.3) 8 (15.7) 68 (21.7) C. parapsilosis 13 (20) 10 (19.2) 9 (14.5) 3 (3.6) 10 (19.6) 45 (14.4) C. glabrata 8 (12.3) 5 (9.6) 3 (4.8) 7 (8.4) 12 (23.5) 35 (11.2) C. krusei 3 (4.6) 3 (5.7) 1 (1.6) 4 (4.8) 11 (3.5) C. guilliermondii 2 (3.8) 2 (2.4) 4 (1.3) C. kefyr 1 (1.6) 3 (3.6) 4 (1.3) C. lipolytica 1 (1.6) 1 (0.3) C. rugosa 1 (1.2) 1 (0.3) C. dubliniensis 1 (1.6) 1 (0.3) C. spp. * 1 (1.5) 1 (1.9) 3 (3.6) 5 (1.6) Total No. candidemias per 1,000 patient-days * Five Candida isolates were unidentified. C. albicans represented 40% of all candidemia, followed by C. parapsilosis (seven episodes), C. tropicalis (seven episodes) and one isolate of C. glabrata. The use of antifungal drugs was analyzed by DDD/1,000 patient-days from Fluconazole, amphotericin B (amphotericin deoxycholate lipid formulation), caspofungin, and voriconazole were prescribed for our hospitalized patients (Table 4). Hematology/BMT units consumed 40% of the total amount of fluconazole in our hospital; however, it was prescribed mainly for prophylaxis. Hematology/BMT also had the highest consumption of all classes of antifungal drugs (Table 4), and use of fluconazole was approximately six times higher than in emergencies, 3.7 times higher than in the ICUs, and 8.4 times higher than in all the other comprised units in the hospital. Of note, of the 22 episodes of candidemia that occurred in the hematology/bmt, C. albicans was isolated in only one episode, whereas C. tropicalis, C. parapsilosis, and C. krusei were isolated in eight, five, and four episodes, respectively, suggesting that extensive use of fluconazole might lead to the predominance of non- C. albicans Candida species. The use of fluconazole was not associated with the increasing incidence of C. glabrata (r 0.60) in our hospital. Device use was recorded, per 1,000 patient-days, in the medical and surgical emergencies and ICUs, during all the study period. For analysis, all ICUs were included except pediatric and neonatal. Device use varied according to the clinics and the mean rates of use, from , of central venous catheter, indwelling urinary catheter, and mechanical ventilation are shown in Table 5. ICUs had a significantly higher incidence density of all devices use ( P 0.001) compared to clinical and surgical emergencies. However, the incidence of candidemia in ICUs was lower (1.55 episodes per 1,000 patient-days) than the other two specialties (1.92 and 2 per 1,000 patient-days in surgical and clinical emergencies, respectively). Discussion In Brazil, the National Health System provides free access for patients to primary, secondary, and tertiary care assistance. Public hospitals are responsible for Table 2 Distribution of Candida species according to medical specialties. ICUs Gastroenterology Surgical Medical Pediatrics Hematology/ BMT Internal medicine All others Total Candida albicans C. tropicalis C. parapsilosis C. glabrata C. krusei C. guilliermondii C. kefyr C. rugosa 1 1 C. dubliniensis 1 1 C. lipolytica 1 1 C. spp. * Total No. candidemias per 1,000 patient-days * Five Candida isolates were unidentified.

4 228 M. L. Moretti et al. Table 3 Distribution of Candida species according to main underlying condition. Number of isolates Underlying condition Candida albicans Non- C. albicans Candida spp. 1 C. tropicalis C. parapsilosis 2 C. glabrata 3 C. krusei *Other Candida spp. Total (%) Malignancies (24.6) Hematologic malignancies (10.8) Liver disease (9) Acute trauma (8.3) Pediatric patients (8) Infection/sepsis (6) Abdominal/intestinal (5.4) Cardiac insufficiency (5.8) Diabetes (4.1) Renal failure (3.8) Neurological disease (2.2) Others (4.1) AIDS (2) COPD (2) Crohn s disease (2) Rheumatic disease (2) Total (100) *Other Candida spp.: C. guilliermondii : 4; C. kefyr : 4; C.lipolytica : 1; C. rugosa : 1; C. dubliniensis : 1; Candida spp.: 5. Non-C. albicans Candida spp. were significantly higher in patients with hematologic malignancies ( P ). 1 C. tropicalis was not associated with malignancies ( P 0.59) or hematologic malignancies ( P 0.26). 2 C. glabrata was significantly more prevalent in patients with malignancies ( P 0.004). 3 C. krusei was significantly higher in patients with hematologic disease ( P ). 7 8 hospitalizations per 100 inhabitants [23]. Several variables are associated with the different candidemia rates in Brazil. Most data on candidemia from Brazil were from patients hospitalized in public hospitals [12 15,24]. Our hospital is a reference hospital and the patients that are referred to it have more complex and advanced diseases Table 4 DDD/1,000 patient-days of antifungal use in the hospital from Cumulative from Hematology/Bone marrow transplant Fluconazole Amphotericin B Caspofungin Voriconazole Medical and surgical emergencies Fluconazole Amphotericin B Caspofungin Voriconazole Intensive care units Fluconazole Amphotericin B Caspofungin Voriconazole All other units Fluconazole Amphotericin B Caspofungin Voriconazole and lower social/educational level compared to the ones assisted in private hospitals. Candidemia in our hospital varied from cases per 1,000 patient-days, during the five-year study. Comparing to previous studies, our rates were similar to the ones observed by Colombo et al. [12] in the largest multicenter prospective study that included 11 Brazilian hospitals, but higher than most publications from other countries [25 28]. In our study, non- C. albicans Candida species were more frequently isolated, in blood cultures, than C. albicans, except in 2008 (Table 1) and the frequency of isolation of C. albicans and non -C. albicans Candida spp. did not change during the study period ( P 0.23). In Brazil, C. parapsilosis has been cited as the second cause of candidemia after C. albicans, followed by C. tropicalis and C. glabrata. In our hospital, the proportion of C. tropicalis (21.7%) was higher than C. parapsilosis (14.4%) and, although not statistically significant, C. tropicalis was frequently isolated in patients with cancer (15 of 68 cases) and hematologic malignancies (10 of 68 cases) (Table 3) similar to a previous Brazilian study [29]. Of note, candidemia caused by C. glabrata significantly increased from (P 0.021). The incidence of C. glabrata, in Brazilian candidemia studies, varied from 3 9% [13,14,19,24]. Of note, one publication [24] with 9% of C. glabrata prevalence studied a very limited number of candidemia cases. The high prevalence of C. glabrata, in our hospital, was mainly found in surgical and medical

5 Five-year surveillance of Candida bloodstream infection 229 Table 5 Candidemia per 1,000 patient-days and the cumulative mean rate of use of urinary catheter, central venous catheter and mechanical ventilation in patients hospitalized in high-risk areas from High risk area Candidemia 1,000 patient-days Mean rate of use from Indwelling urinary catheter Central venous catheter Mechanical ventilation Surgical Clinical ICUs P value Device use was calculated as incidence density ( device-days/ patientdays 1000). P value was calculated by Kruskal-Wallis test for comparing the rates of use of invasive devices among the three units. emergencies, ICUs, and gastroenterology (surgical and medical) but not in hematology and BMT units. Of note, 45.7% of all C. glabrata candidemia occurred in patients with malignancies ( P 0.004). Several studies documented an increase in C. glabrata candidemia associated with fluconazole use [30,31] ; however, some authors found an association with age over 60 years [32], use of broad spectrum antibiotics [33], and stay in ICU [34,35] to be more important than the use of fluconazole. In our study, the increasing number of C. glabrata candidemia was seen in patients with malignancies, and might reflect the type of patient referred to our hospital. The use of fluconazole, except in 2007, has been increasing in all main medical specialties, such as ICUs, hematology/bmt, and emergencies units (Table 4). Conversely, amphotericin B use has decreased in all units (Table 5) and these data might be explained by the introduction of new antifungals such as caspofungin and voriconazole. Interestingly, the highest use of fluconazole was in hematology/bmt units (821 DDD per 1,000 patientdays), comprising 40% of all fluconazole used in our hospital. In these units, we had 20 candidemia episodes and only two were caused by C. albicans with none due to C. glabrata, suggesting that other variables may be associated with the increased number of C. glabrata episodes in our hospital, such as the patients underlying conditions. ICU units have been pointed out as the hospital units with the highest risk for the acquisition of candidemia [34,35]. The use of invasive devices, such as indwelling urinary catheters, central venous catheters, and mechanical ventilation are well-established risk factors associated with candidemia and invasive candidiasis [36,37]. The use of invasive devices was analyzed in the emergencies (medical and surgical) and ICU units and we observed that emergencies had a significantly lower rate of use of indwelling urinary catheters ( P 0.001), central venous catheters ( P 0.001), and mechanical ventilation ( P 0.001) than ICUs, but higher rates of candidemia and lower use of antifungal drugs than the ICUs. In our hospital, a high rate of candidemia was found in non-critical and non-icus wards, such as the gastroenterology (one case per 1,000 patient-days) and the surgical and medical emergencies wards (two cases per 1,000 patient-days). These data suggested that other risk factors might have contributed to the epidemiology of candidemia such as underlying medical conditions [9,38 40]. In this article, we described the current epidemiology of candidemia in our hospital that is a reference hospital in the State of Sao Paulo, Brazil, highlighting the significant increase of C. glabrata as an important causative agent of candidemia. Our findings suggested that the increasing incidence of C. glabrata was not associated with high use of fluconazole and other risk factors, such as underlying conditions, seemed to play an important role. Additional studies are necessary to understand factors other than use of antifungal drugs, to explain epidemiology of non- C. albicans candidemia in our hospital. Acknowledgements This project was approved by the Ethical Committee of the Faculty of Medical Sciences, State University of Campinas No. 039/2011 on 22 February We are grateful to the Hospital & Clinics; the Faculty of Medical Sciences of the State University of Campinas, Sao Paulo, Brazil, and JST (Japan Science and Technology Agency)/JICA (Japan International Cooperation Agency), SATREPS (Science and Technology Research Partnership for Sustainable Development) for the financial support. The grant number for financial aid is 02P Unicamp. Declaration of interest : The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. References 1 Pfaller MA, Dikema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. 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