EVALUATION OF EPIDEMIOLOGICAL CHARACTERISTICS, RISK FACTORS AND ANTIFUNGAL SENSITIVITY OF CANDIDEMIA CASES IN A TERTIARY-CARE HOSPITAL

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1 Acta Medica Mediterranea, 2017, 33: 815 EVALUATION OF EPIDEMIOLOGICAL CHARACTERISTICS, RISK FACTORS AND ANTIFUNGAL SENSITIVITY OF CANDIDEMIA CASES IN A TERTIARY-CARE HOSPITAL DUYGU MERT¹, GÜL RUHSAR YILMAZ¹, SABAHAT ÇEKEN¹, GÜLŞEN İSKENDER¹, AYLA YENIGÜN², MUSTAFA ERTEK¹ 1 Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Infectious Diseases and Clinical Microbiology Clinic, Ankara - 2 Dr.Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Medical Microbiology Laboratory, Ankara ABSTRACT Introduction: Blood circulation infections due to Candida species have an increasing prevalence among nosocomial infections. These infections cause significant morbidity and mortality. In this study, it is aimed to evaluate the epidemiologic features, risk factors and antifungal susceptibility of candidemia cases in a tertiary-care hospital. Materials and methods: Between January 1, 2012 and March 1, 2016, the data of patients with candidemia were recorded in a previously prepared form in a tertiary-care hospital. In the same period, cases without candidemia were taken as control group. Candidemia cases and control group were compared in terms of epidemiological characteristics and possible risk factors. SPSS 16.0 program was used for statistical analysis. Results: The mean age of 60 patients diagnosed with candidemia was 57.3 ± 18.3, 37 (61.7%) were males and 23 (38.3%) were females. The mean age of the 60 patients in the control group was 58.6 ± 16.6, 35 (58.3%) were male and 25 (41.7%) were female. The most common isolated Candida species were C.albicans (48,3%), C. glabrata (13,3%), C.parapsilosis (10,0%), C.crusei (8% 3), C. tropicalis (8,3%), Candida spp. (5%), C. lipolytica (1.7%) and C. famota (1.7%). Amphotericin B resistance rate was 10.40% for C.albicans, 9.7% for non-albicans, fluconazole resistance rate was 3.5% for C. albicans, 19.4% for non-albicans, voriconazole resistance rate was 7,00% for C. albicans. No resistance was found in non-albicans species. There was no resistance to caspofungin, itraconazole and micafungin. According to the results of antifungal susceptibility, there was no increased resistance among Candida species compared to previous years. Conclusions: In this study, total parenteral nutrition and the use of piperacillin-tazobactam, meropenem and imipenem were the most frequent risk factors for Candida-associated bloodstream infections. The most frequently isolated species was Candida albicans. The proportion of total non-albicans species was high as a result. Keywords: Candidemia, epidemiology, risk factors, antifungal susceptibility. DOI: / _2017_5_121 Received November 30, 2016; Accepted May 20, 2017 Introduction Candidiasis is an important nosocomial infection that occurs in hospitalized patients (1). In the United States, it is the fourth most common cause of bloodstream infection and the seventh in Europe (2,3). Factors such as the use of broad spectrum antibiotics, invasive procedures, and prolonged life span increase the incidence of candidiasis (4,5). The age, abdominal surgery, total parenteral nutrition, neutropenia, acute renal insufficiency, hemodialysis, malnutrition, corticosteroid therapy, diabetes mellitus, invasive mechanical ventilation, and malignancy are risk factors for candidiasis (6,7). Candida albicans is the most frequently isolated species in candidemia, non-albicans species such as Candida glabrata, Candida parapsilosis and Candida krusei are commonly observed in recent studies (8). This study was retrospective case-control study. The aim of this study which included adult patients was to determine the epidemiology of candidemia and to evaluate risk factors for the devel-

2 816 Duygu Mert, Gül Ruhsar Yilmaz et Al opment of candidemia and antifungal susceptibility at a tertiary-care education hospital over a 5-year period. Materials and methods In this retrospective study, study group included patients over 17 years old who had increase in fever due to candidemia between 1 January 2012 and 1 March 2016 in a tertiary-care education hospital. The control group was selected among patients who had no signs and symtomps of candidemia and had negative blood cultures during the study period. The patients in case and control groups followed in the same service and the period in the hospital. The data of the patients and the control group were obtained by reviewing the electronic medical records and microbiology laboratory reports. Demographic and clinical informations of the patients included age, gender, place of admission, date of admission, reason for admission, location (hospital, service, home), intensive care unit stay (> 10 days), intubation in intensive care unit (> 3 days), Glasgow coma scale score in intensive care unit, central venous catheter, urinary catheter (>3 days), total parenteral nutrition (TPN), underlying disease, renal failure, hemodialysis, the presence of diabetes (use of insulin and oral anti-diabetic agent), hematologic malignancy, solid organ malignancy, neutropenia (duration), operation history (abdominal-upper GIS surgery under general anesthesia and extension or repetition of operation within the last 30 days) chemotherapy during the last 30 days, radiotherapy during the last 30 days, (steroid use> 1mg/kg, antibiotic use, antifungal prophylaxis before candidemia, positive culture results before candidemia within the last 30 days (blood, urine, wound, drain, other), candidiasis in central venous catheter, peripheral blood culture, wound/organspace, antifungal susceptibility (amphotericin B, fluconazole, flucytosine, voriconazole, itraconazole, caspofungin, micafungin). These datas were recorded in a previously prepared form. In the same period and in the same service, cases without candidemia were evaluated as control group. The data were recorded in the same form candidemia cases and control group were compared in terms of epidemiological features and possible risk factors. This study was made with approval of Ankara Oncology Education and Research Hospital Ethics Committee. A diagnosis of candidemia was made on the basis of 1 blood cultures growing Candida spp. and the presence of relevant clinical symptomps and signs in patients. The patients had clinical findings of bloodstream infection such as fever or hypotension. Neutropenia was defined as having an absolute neutrophil count of <500/mm³. Blood samples were inoculated into a BACTEC Blood Culture System (Becton Dickinson Diagnostic Instrument Systems, Towson, MD, USA) for blood cultures. C. albicans were separated by using the germ tube test for typing. The nonalbicans species were typed with the VITEK 2 Compact System (biomerieux, France). Amphotericin B, fluconazole, flucytosine, voriconazole, caspofungin, itraconazole sensitivity tests were performed with the VITEK 2 Compact System (biomerieux, France). CLSI (Clinical and Laboratory Standards Institute) criteria were used in the antifungal susceptibility test. Statistics analysis Quantitative results were given as mean ± standard deviation (SS) and categorical results in number and percentage (%). Student t test was used for normal distribution and Mann-Whitney U test was used for non-normal distribution in comparison of quantitative variables. Categorical variables were analyzed by using chi-square Fisher's exact test and 95% confidence interval was calculated by odds ratio. All significance tests were two-sided and P <0.05 was considered as a criterion in two-way analysis for the statistical significance. Multivariate analysis (logistic regression method) was used to determine the risk factors for candidemia (p <0,10), which were determined by univariate analysis. Backward Conditional was performed in logistic regression method analysis. SPSS 16.0 Windows program (SPSS Inc. Chicago, IL, USA) was used for statistical analysis. Results Between January 1, 2012 and March 1, 2016, 60 adult patients were determined to have Candida spp. with at least one positive blood culture result in the hospital. All of the cases had hospitalacquired Candida infections. A total of 39 (65%) patients had candidemia associated with SVC. The mean age of 60 patients diagnosed with candidemia was 57.3 ± 18.3, 37 (61.7%) were males and 23 (38.3%) were females. The mean age

3 Evaluation of epidemiogical characteristic, risk factors and antifungal sensitivity of the 60 patients in the control group was 58.6 ± 16.6, 35 (58.3%) were males and 25 (41.7%) were females. Twenty-six (43.3%) of the patients diagnosed with candidemia were in the intensive care unit and 34 (56.7%) were in other services. Twentyone (35%) of the patients in the control group were in intensive care unit and 39 (65%) were in other services. The demographic and clinical characteristics of the patients with candidemia and control group were shown in table 1. In patients with candidemia, the mean duration of intensive care unit stay (mean day ± SD) was 16.9 ± 26.6 while the mean duration of intensive care unit stay (mean day ± SD) was 4.9 ± 8.2 in the control group. When the duration of stay was prolonged in intensive care unit, the risk of candidiasis development increased (p: 0.001). The duration of neutropenia (mean day ± SD) was 18.1 ± 14.7 in patients with candidiasis while the duration of neutropenia (mean day ± SD) was 13.9 ± 8.2 in control group. No statistically significant difference was found between patients and control group in terms of age, Glascow coma score, and duration of neutropenia in Table 1. Feature Candidiasis (n: 60) Control (n: 60) P Age (mean ± SS) 57,25 ± 18,250 58,620 ± 16,587 0,669 Duration of stay in intensive care unit (mean day ± SS) Glaskow coma score (mean ± SS) Time of neutropenia (mean day ± SS) 16,920 ± 26,612 4,92 ± 8,199 0,001 11,22 ± 3,523 12,35 ± 3,579 0,083 18,14 ± 14,660 13,88 ± 8,202 0,460 Table 1: Demographic and Clinical Characteristics of Patients with Candidemia and Control Groups. Solid organ malignancy was found in 33.9% of 60 patients with candidemia; gastrointestinal system tumor 30.5%, hematological malignancy 22%, cerebrovascular event 5.1%, gastrointestinal system pathology 3.4% and other underlying diseases 5.1%. Gastrointestinal system tumor was found in 35,6% of the 60 patients in the control group, solid organ malignancy in 30,5%, hematologic malignancy in 22%, other underlying diseases in 10.2%, gastrointestinal system pathology in 1.7%. There was no statistically significant difference between the patient and the control group in terms of the underlying disease for the development of candidemia. The risk factors affecting development of candidemia in univariate analysis were as follows: presence of urinary catheter (p: 0,002), antibiotic usage before candidemia (p: 0,000), presence of central venous catheter (p: 0,001), presence of intubation (p: 0,041), use of piperacillin-tazobactam (p: 0,004), use of meropenem (p: 0,041), use of imipenem (p: 0,006), use of tigecycline (p: 0,041), candidemia (p: 0,000), positive culture before the candidemia (p: 0,018), positive other cultures before the candidemia (p: 0,000), presence of Candida in central venous catheter (CVC) (p: 0,000), the presence of Candida in the peripheral blood culture (p: 0,000), the presence of Candida in the urinary system (p: 0,000) and survival (p: 0,000). The variables analyzed as possible risk factors in univariate analysis are shown in Table 2. Risk Factor Candidiasis n: 60 No candidiasis n: 60 P Entubation 32 (53,3) 20 (33,3) 0,027 Presence of central venous catheter 52 (86,7) 34 (56,7) 0,001 Urinary catheter presence 58 (96,7) 45 (75,0) 0,002 Total parenteral nutrition 31(51,7) 9 (15,0) 0,000 Kidney failure 26 (43,3) 12 (20,0) 0,011 Pip.-tazobctam use 20(33,3) 6(10,0) 0,004 Meropenem use 22(36,7) 11(18,3) 0,041 Imipenem use 11(18,3) 1(1,7) 0,006 Tigecycline use 6(10,0) 1(1,7) 0,041 Positive blood culture before candidemia Other positive cultures before candidemia Candida reproductive in CVC Candida reproductive in peripheral blood culture Candida reproductive in urinary system. 25(41,7) 12(20,0) 0,018 25(41,7) 6(10,0) 0,000 39(65,0) 0(0,0) 0, (53,3) 0(0,0) 0,000 18(30,0) 2(3,3) 0,000 Survi 22(36,7) 42(70,0) Exitus 38(63,3) 18(30,0) Table 2: Variables Investigated as Possible Risk Factors in Single Variable Analysis. The use of total parenteral nutrition (p: 0,002), piperacillin-tazobactam (p: 0,006), meropenem (p: 0,011) and imipenem (p: 0,014) were found to be risk factors for the development of candidemia in multivariable logistic regression analysis. The risk factors (multivariate analysis) found as independent variables in the development of candidemia are shown in Table 3.

4 818 Duygu Mert, Gül Ruhsar Yilmaz et Al Risk factor P OR %95 GA TPB 0,002 15,5 2,5-72,2 PTZ 0,006 16,2 2,2-119,5 Meropenem 0,011 9,5 1,7-53,9 Imipenem 0,014 34,3 2,0-580,4 Table 3: Candidemia Risk Factors (Multivariate Analysis). Candida albicans (48,3%) was the most frequently isolated type in 60 patients with candidemia. The other species were C. glabrata (13,3%), C.parapsilosis (10,0%), C.crusei (8,3%), C. tropicalis (8,3%), Candida spp. (5%), C. lipolytica (1.7%) and C. famata (1.7%). The types of isolated candida are shown in Table 4. Specimens and Culture positivity isolated species n (%) Blood culture (n = 60) Number of patients with candidemia C.albicans 48,3 29 C.glabrata 13,3 8 C. parapsilosis 10,0 6 C.crusei 8,3 5 C.tropicalis 8,3 5 C.lipolytica 1,7 1 Candidaspp. 5,0 3 C.famata 1,7 1 More than one species 3,3 2 Table 4: Culture outcomes in cases with candidemia and the source of candidemia. Amphotericin B resistance rates were 10.3% for C. albicans and 9.7% for non-albicans. All isolates of C.parapsilosis and C.glabrata were sensitive to amphotericin B. The voriconazole resistance rate was 6.9% for C. albicans, voriconazole resistance was not detected for non-albicans species. Other Candida species were voriconazole sensitive. Fluconazole resistance rates were 3.4% for C. albicans and 14.3% for non-albicans. Fluconazole resistance was not observed in C. parapsilosis. All isolates of C. krusei were fluconazole resistant. Candida albicans and non-albicans isolates were susceptible to caspofungin. Caspofungin, itraconazole and micafungin resistance was not detected in Candida spp. 38 patients (63.3%) with candidemia died. Discussion Candidiasis is an important nosocomial infection in hospitalized patients (1). In most hospitals, most episodes of candidiasis are seen in patients in intensive care units. Especially trauma and burn patients in surgical units, newborns in newborn units have increasing incidence of Candida infections. Other risk factors besides age, trauma and burns include central venous catheter, total parenteral nutrition, broad spectrum antibiotic use, high APACHE score, especially acute renal failure accompanying hemodialysis, surgical intervention especially abdominal surgery, gastrointestinal system perforation and anastomotic leakage (9,10). Patients with impaired immune system are also included in the specific risk group for candidiasis. Patients with hematologic malignancy, solid organ or hematopoietic stem cell transplant recipients, patients with chemotherapeutic agents, especially patients with gastrointestinal system mucosal damage are at high risk. Steroid use in transplant recipients and neutropenia, broad-spectrum antibiotics and central venous catheter use are other risk factors (10, 11). In a study conducted by Tadec et al., the presence of central venous catheters and the use of broad-spectrum antibiotics were the most common risk factors for the development of candidiasis (12). One study by Yenigün Koçak and colleagues found that the presence of central venous catheters and the length of stay in the hospital were the most common risk factors in univariate analysis when candidemia and control group were compared. In multivariate analysis, the presence of central venous catheter was found to be an independent risk factor for the development of candidemia (13). In one study by Erdem et al., the use of carbapenem antibiotics, the use and duration of central venous catheter, and total parenteral nutrition were found to be the most important risk factors in the development of candidiasis in the candidemia group. In multivariate analysis total parenteral nutrition was found to be an independent risk factor (14). The most frequent risk factors in univariate analysis for the development of candidemia in this study were presence of urinary catheter (p: 0.002), use of broad spectrum antibiotic before candidiasis (p: 0,000), presence of central venous catheter (p: 0.001), intubation (p: 0,027), total parenteral nutrition (p: 0,000), renal failure (p: 0,011), use of piperacillin-tazobactam (p: 0,004), use of meropen-

5 Evaluation of epidemiogical characteristic, risk factors and antifungal sensitivity em ( p:0,041), use of imipenem (p: 0,006), use of tigecycline (p: 0,041), presence of other positive cultures before candidaemia (p: 0,000), Candida growth in the urinary system (p: 0,000). Total parenteral nutrition (p: 0.002), use of piperacillintazobactam (p: 0.006), use of meropenem (p: 0.011) and use of imipenem (p: 0.014) were found to be risk factors for the development of candidemia in multivariate analysis. C.albicans is the most commonly isolated species in candidemia, but recent years non-albicans Candida species have also increased (15,16). In a study conducted by Tsai-YuWang and colleagues, C.albicans (50.9%) was the most commonly detected species, C. tropicalis (19.6%) was detected in candidemia cases (17). In a study carried out by Rajendran and colleagues, C.albicans (41%) was the most frequently isolated species, followed by C.glabrata (35%), C. parapsilosis (11,5%), C. tropicalis (3,6%) and other species (5,3%) (18). In a study by Zhi-Tao Yang and et.al., C.albicans (37.2%) was the most frequently isolated species in candidemia and non-albicans Candida species was detected 62,8% (19). In this study, C. albicans (48.3%) was the most frequently isolated Candida species in 60 patients with candidemia and it was followed by C. glabrata (13,3%), C.parapsilosis (10,0%), C.crusei (8,3%), C. tropicalis (8,3%), Candida spp. (5%), C. lipolytica (1.7%) and C. famata (1.7%). It is important to know the frequency of nonalbicans Candida species because there is variability in susceptibility to antifungal agents among species. For example, all isolates of C. krusei are fluconazole resistant. There is increasing resistance to fluconazole in C. glabrata. Fluconazole-resistant isolates are mostly C. glabrata, and the risk factors for candidemia are neutropenia, chronic kidney disease, chronic pulmonary disease, male sex, and the use of fluconazole and other antifungal agents (20,21). Fluconazole resistance was found in a small proportion of isolates of C. albicans, C. parapsilosis and C. tropicalis (21). Increases in the frequency of echinocandin resistance among C. glabrata isolates from certain centers have been reported (22,23). In the antifungal susceptibility pattern, voriconazole exhibits excellent in vitro activity against all Candida species. Successful rescue treatment with voriconazole has been performed in the treatment of candidemia in other antifungal resistant or intolerant patients (24). In most publication, resistance to triazole antifungals (especially fluconazole, itraconazole and ketoconazole) has been reported for over 10 years. Ketoconazole resistance was observed in 50% of C.albicans and C.parapsilosis cases. Itraconazole resistance was detected in 30.5% of all Candida species and the highest rate of resistance was in C. glabrata (90.9%) (25). In Erdem et al s study, the resistance rate of fluconazole and flucytosine to candida species was found to be 2.6% and 1.7%, respectively, and no resistance was detected against voriconazole. In 4.4% of the isolates, amphotericin B MIC value was found to be 1 μg/ml (14). In the study by Zhi-Tao Yang and et al., antifungal resistance was rarely reported and restricted resistance to azoles except C. tropicalis. Fluconazole resistant C. tropicalis was found to be 27,8% (19). In a study conducted by Chun-Fang Ma et al., antifungal resistance was noteworthy and predominantly fluconazole resistance was detected. Fluconazole resistant isolates (53.9%) were determined in the highest rate (26). In this study, amphotericin B resistance rates were 10.3% for C. albicans and 9.7% for non-albicans. All isolates of C.parapsilosis and C. glabrata were sensitive to amphotericin B. The voriconazole resistance rate for C.albicans was 6.9%, voriconazole resistance was not detected for non-albicans species. Fluconazole resistance rates were 3.4% for C. albicans and 14.3% for non-albicans. All isolates of C. krusei were fluconazole resistant. Fluconazole resistance was not observed in C. parapsilosis. C. albicans and non-albicans were susceptible to caspofungin. No resistance was detected in Candida species for caspofungin, itraconazole and micafungin. In this study, total parenteral nutrition, piperacillin-tazobactam, meropenem and imipenem use were found to be important risk factors in the development of candidemia. C. albicans was the most frequently isolated species among the Candida species, respectively followed by C. glabrata and C. parapsilosis. The proportion of total non-albicans species was high as a result. No increased resistance to antifungal agents was found in Candida albicans and non-albicans. References 1) Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 2003; 3(11): ) Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States

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Voriconazole salvage treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis 2003; 22(11): ) Diekema DJ, Messer SA, Brueggemann AB, Coffman SL, Doern GV, Herwaldt LA, Pfaller MA. Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 2002; 40(4): ) Ma CF, Li FQ, Shi LN, Hu YA, Wang Y, Huang M, Kong QQ. Surveillance study of species distribution, antifungal susceptibility and mortality of nosocomial candidemia in a tertiary care hospital in China. BMC Infect Dis 2013; 13: 337. Corresponding author DUYGU MERT Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Infectious Diseases and Clinical Microbiology Clinic Ankara (Turkey)