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Invasive candidiasis in intensive care units in China: Risk factors and prognoses of Candida albicans and non–albicans Candida infections
ARTICLE IN PRESS American Journal of Infection Control ■■ (2015) ■■–■■
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American Journal of Infection Control
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Original Research Article
Invasive candidiasis in intensive care units in China: Risk factors and prognoses of Candida albicans and non–albicans Candida infections Xiaoying Gong MD a, Ting Luan MD a, Xingmao Wu MD a, Guofu Li MD a, Haibo Qiu MD b, Yan Kang MD c, Bingyu Qin MD d, Qiang Fang MD e, Wei Cui MD f, Yingzhi Qin MD g, Jianguo Li MD h, Bin Zang MD a,* a
Department of Intensive Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China Department of Intensive Care Medicine, Nanjing Zhongda Hospital, Southeast University School of Medicine, Nanjing, China Department of Intensive Care Medicine, West China Hospital, Sichuan University, Chengdu, China d Department of Intensive Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, China e Department of Intensive Care Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China f Department of Intensive Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medcine, Hangzhou, China g Department of Intensive Care Medicine, Tianjin Third Central Hospital, Tianjin, China h Department of Intensive Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China b c
Key Words: Candida albicans non-albicans infection risk factor intensive care unit China
Background: To investigate the risk factors and prognoses of patients with invasive Candida albicans and non–albicans Candida (NAC) infection in intensive care units (ICUs) in China. Methods: Between November 2009 and April 2011, we performed a prospective study of critically ill patients with invasive Candida infection from 67 ICUs across China to compare the risk factors and mortality between patients with C albicans and NAC infection. Results: There were 306 patients with proven invasive Candida; 244 cases (a total 389 Candida isolates) were sent to laboratory for strain identification (C albicans, 40.1%; NAC, 59.9%). More patients admitted for surgery or trauma had NAC infection than C albicans infection. C albicans infection was more common in patients with subclavian vein catheters or peritoneal drainage tubes. Compared with patients with C albicans infection, patients with NAC infection had longer antifungal therapy (P < .001), longer ICU (P = .004) or hospital stay (P = .002), and slightly higher mortality (38.4% vs 29.6%), but the difference was not significant (P = .17). Conclusions: C albicans remains the most common pathogen in candidiasis in critical care patients. However, the number of NAC infections exceeded C albicans infections. Compared with patients with C albicans infection, patients with NAC infection had heavier disease burdens. © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
Invasive Candida infection is very common in intensive care units (ICUs); the mortality rate is high. This is true especially in immunosuppressed patients or patients with severe diseases, in whom the mortality rate is 35%-80%.1-4 Although difficult to diagnose, invasive Candida infection remains the third leading cause of ICU infections,5 causing (responsible for) 17% of all ICU infections.6 The major risk factors in critically ill patients with invasive fungal in-
* Address correspondence to Bin Zang, MD, Department of Intensive Care Medicine, Shengjing Hospital of China Medical University, Sanhao St No 36, Heping District, Shenyang, China 110004. E-mail address: [email protected] (B. Zang). Conflicts of Interest: This work was supported by Merck Sharp & Dohme China, who sponsored the study. Medical writing and editing assistance were supported by Merck & Co., Inc., Whitehouse Station, NJ, USA.
fections include age, underlying diseases,7-12 multisite Candida colonization, invasive procedures,13-16 medication, upper abdominal surgery,13-16 and immunosuppressive diseases.17-20 Candida albicans is one of the most common pathogens of invasive fungal infections, with an incidence of 40%-82%.4,21-23 C albicans infections account for 50%-70% of ICU infections in the United States;2,24 in Asia, South America, and Northern Europe, the incidence of non– albicans Candida (NAC) infection is higher.3 In the last 20 years, C albicans has been the most common strain isolated from hospitalized patients; however, there is currently a growing trend of NAC infection. In many countries, Candida glabrata infections account for 15%-20% of Candida infections.1,25 Fungal resistance has changed, and there is decreased fluconazole susceptibility in some Candida spp. Compared with C albicans, approximately 60% of NAC is less fluconazole-sensitive.26-28 The rate of mortality caused by NAC
0196-6553/© 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2015.11.028
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infection is higher than that caused by C albicans.1-4,26-28 Therefore, diagnosing Candida infections early, screening pathogens into C albicans or NAC, and early appropriate empirical therapy are crucial, especially for selecting NAC antifungal drugs. To our knowledge, the risk factors or large-scale surveys and analysis of C albicans and NAC infection prognoses in mainland China have not been reported. This was a prospective multicenter study of critically ill Chinese patients with invasive candidiasis in ICUs. The study has important implications and identifies empirical treatment strategies for clinicians. METHODS Patient identification and data collection We conducted a multicenter, prospective, observational study between November 2009 and April 2011 that involved 67 ICUs across China (China-SCAN). We enrolled patients who were aged ≥18 years, with clinical signs of infection (in the treating physician’s opinion) and at least 1 of the listed diagnostic criteria: (1) confirmation through histopathology, cytopathology, or direct microscopy of yeast cells in a needle aspiration or biopsy specimen from a normally sterile site (other than mucous membranes); (2) at least 1 Candidapositive peripheral blood culture; and (3) a Candida-positive culture from a sample obtained by a sterile technique from a normally sterile site (eg, cerebrospinal, pleural, peritoneal, peritoneal abscess fluid). The attending physicians, who also acted as the investigators for the study, managed the patients at their discretion; patients were followed until discharge or death, whichever occurred first. Demographic information, ICU type, clinical patient characteristics (admission diagnosis, ICU admission diagnosis, Acute Physiology and Chronic Health Evaluation score, sepsis-related organ failure assessment score) (Table 1), and medical interventions (total parenteral nutrition, surgery, mechanical ventilation, arterial and venous catheters, body cavity drainage tubes, catheters, antibiotics and antifungal treatment within 2 weeks before diagnosis) (Table 2) were recorded when the patients were admitted to the ICUs. Investigators evaluated both clinical and microbiologic outcomes for invasive candidiasis. Regarding clinical outcome, we defined complete cure as the disappearance of signs and symptoms caused by Invasive Candida Infections and infectious lesions on radiologic examination, partial cure as partial relief of clinical signs and symptoms and improved radiologic findings, and clinical ineffectiveness as persistent or worsened signs, symptoms, and radiologic lesions. The details have been described previously.29 ICU or hospital stay duration and outcome were recorded. Pathogen identification Specimens were sent to the China-SCAN Central Laboratory (Peking University First Hospital) for pathogen detection. We used chromogenic medium (CHROMagar, Paris, France) and API 20C AUX yeast identification kit (bioMérieux, Marcy l’Etoile, France) for species identification. We used the large subunit (26S) ribosomal DNA gene D1/D2 sequences when necessary.30,31 Statistical analysis We performed statistical analysis using SAS 9.1 software (SAS Institute, Cary, NC). Categorical variables were described using frequencies and 95% confidence intervals. Skewed distribution was described using medians, interquartile ranges, and maximums and minimums. The significance threshold was 0.05. Based on the pathogen detection results, the fungal isolates were classified as C albicans alone or NAC (non-albicans infection, mixed non-albicans
Table 1 Characterization of patients with Candida albicans and NAC infection Risk factor Age (y) Sex Female Male Weight (kg) ICU type Medical Surgical Integrated Others Diagnosis for hospitalization Infection Organ failure Single organ Multiple organ Surgery and trauma Surgery Trauma Diagnosis for ICU admission Infection Organ failure Single organ Multiple organ Surgery and trauma Surgery Trauma APACHE II score SOFA score Underlying disease Solid tumor Hematologic malignancy Diabetes COPD Chronic liver dysfunction Chronic renal insufficiency Chronic heart failure Neutropenia within 2 wk (<500/mm3) Digestive dysfunction
C albicans
NAC
P value
62.2 ± 17.26
61.4 ± 21.36
.7644
37 (37.8) 61 (62.2) 61.8 ± 10.27
40 (27.4) 106 (72.6) 64.0 ± 11.78
.0937
1 (1.0) 13 (13.3) 77 (78.6) 7 (7.1)
6 (4.1) 16 (11.0) 122 (83.6) 2 (1.4)
.0570
44 (44.9)
56 (38.4)
.3531
13 (8.9) 4 (2.7)
.3700
4 (4.1) 3 (3.1)
.2086
.0283 3 (3.1) 11 (11.2)
18 (12.3) 19 (13.0)
60 (61.2)
76 (52.1)
.1888
14 (14.3) 6 (6.1)
35 (24.0) 9 (6.2)
.1777
20 (20.4) 10 (10.2) 27.2 ± 7.1 10.4 ± 3.4
31 (21.2) 21 (14.4) 26.7 ± 7.1 11.2 ± 3.3
.6239 .0738
17 (17.3) 1 (1.0) 20 (20.4) 14 (14.3) 4 (4.1) 9 (9.1) 19 (19.4) 3 (3.1) 55 (56.1)
29 (19.9) 2 (1.4) 33 (22.6) 19 (13.0) 9 (6.2) 14 (9.6) 30 (20.5) 2 (1.4) 86 (58.9)
.5669 >.9999 .9243 .8492 .5706 .4571 .8189 .3934 .6930
.6158
NOTE. Values are mean ± SD, n (%), or as otherwise indicated. Count data between groups were compared using Fisher exact test. Quantitative data between groups were compared using analysis of variance. Data between groups of chronic heart failure (New York Heart Association classification) were compared using the KruskalWallis rank-sum test. Other indicators were compared by Fisher exact test. APACHE II, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; NAC, non–albicans Candida; SOFA, sepsis-related organ failure assessment.
Table 2 Comparison of medical intervention and treatment in Candida albicans and NAC groups Risk factor
C albicans
NAC
P value
Total parenteral nutrition in recent 2 wk Surgery Mechanical ventilation Noninvasive Invasive Both Intravascular catheter Internal jugular vein Subclavian vein Femoral vein Ductus arteriosus Nonintravascular catheter Chest tube Peritoneal drainage tube Subdural, intradural, or ventricular drainage tube Urine catheter Antibiotic treatment before diagnosis Antifungal treatment before diagnosis
43 (43.9) 40 (40.8)
60 (41.1) 54 (37.0)
.6930 .5923 .3448
2 (2.0) 76 (77.6) 2 (2.0)
6 (4.1) 113 (77.4) —
17 (17.3) 23 (23.5) 12 (12.2) 7 (7.1)
17 (11.6) 18 (12.3) 19 (13.0) 7 (4.8)
.2580 .0351 1.0000 .5759
4 (4.1) 9 (9.2) 1 (1.0)
5 (3.4) 3 (2.1) 3 (2.1)
1.0000 .0154 .6508
15 (15.3) 76 (77.6) 22 (22.4)
19 (13.0) 121 (82.9) 49 (33.6)
.7067 .3234 .0637
NOTE. Values are n (%) or as otherwise indicated. Count data between groups were compared using Fisher exact test. NAC, non–albicans Candida.
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infection, C albicans, and NAC mixed infection). We compared the 2 groups with the Student t test or Mann-Whitney U test according to their distribution. RESULTS Candida spp Of 96,060 ICU patients from 67 centers throughout China, 306 were diagnosed with invasive candidiasis and were included in this study. The incidence rate of invasive Candida infection was 0.32%; the rate of mortality was 36.6%. Of the 244 cases (389 strains) sent for strain identification, C albicans was present in 40.1%, Candida parapsilosis was present in 21.3%, Candida tropicalis was present in 17.2%, C glabrata was present in 12.9%, and other Candida was present in 8.6%. Among these were 98 cases of C albicans infection, 139 cases of NAC infection, 3 cases of NAC mixed infections, and 4 cases of C albicans and NAC mixed infection. Patient characteristics There was no significant difference in age, sex, weight, ICU type, and disease severity score between the C albicans and NAC groups. More surgery or trauma patients were diagnosed with NAC than with C albicans (25.3% vs 14.3%, respectively; P = .028). There was no significant difference between patients with infection, organ failure, or other underlying conditions at hospital admission. On a consolidated basis of diseases, such as solid tumors, blood disorders, diabetes, chronic obstructive pulmonary disease, chronic liver failure, chronic heart failure, chronic renal insufficiency, neutropenia (within 2 weeks, <500/mm3), and digestive dysfunction, there was no significant difference between the C albicans and NAC groups (Table 1). Intervention factors between patients infected with C albicans or NAC More patients with subclavian vein catheter (23.5% vs 12.3%, respectively; P = .035) or peritoneal drainage tube (9.2% vs 2.1%, respectively; P = .009) had NAC infection than C albicans infection 2 weeks before diagnosis. There was no significant difference between other types of central venous catheter or drainage. There was also no difference between other risk factors, such as total parenteral nutrition (>2 weeks), mechanical ventilation, and surgery in the 2 groups (Table 2). Compared with C albicans and 3 common NACs (C glabrata, C parapsilosis, and C tropicalis), the proportion of patients who received total parenteral nutrition within 2 weeks before invasive candidiasis diagnosis was lowest in patients infected with C parapsilosis (C albicans, C glabrata, C parapsilosis, and C tropicalis were 43.9%, 51.9%, 25.5%, and 48.8% of such patients, respectively). A slightly higher proportion of patients receiving antibiotic therapy before diagnosis had NAC infection than C albicans infection (82.9% vs 77.6%, respectively; P = .32). However, among patients who received antibiotics before diagnosis, there were significantly more with C parapsilosis infection than patients with other Candida infection (there was C albicans, C glabrata, C parapsilosis, and C tropicalis infection in 77.6%, 74.6%, 98.2%, and 65.9% of such patients, respectively). The proportion of C parapsilosis infection diagnosed before antifungal treatment was received was the highest among the NAC infections (38.2%) and was significantly higher than that of C albicans (P = .041). Most patients received triazole drug monotherapy as C albicans and NAC antifungal therapy. The most commonly used drugs were triazole, echinocandin, and polyenes, which were used to treat 64.7%,
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31.8%, and 0% of patients with C albicans infection and 62.8%, 34.1%, and 2.3% of NAC patients, respectively (P = .38). On treatment timing, more patients with NAC infection received empirical therapy (30.2% vs 24.7%), whereas more patients with C albicans infection received targeted therapy (68.2% vs 56.6%), which may be associated with the more serious condition of the former, but the difference was not significant (P = .19). Treating patients with NAC infection was more difficult, reflected by longer treatment durations (20.4 vs 12.85 days, P < .001), and more patients with NAC infection required treatment adjustment (52.7% vs 30.6%, P = .002), which included alterations to dosage (33.3% vs 16.3%), administration route (6.1% vs 5.0%), drug replacement (36.4% vs 66.3%), single to multiple drugs (15.2% vs 3.8%), and multiple to single drug (0% vs 1.3%). Evaluation of treatment and prognostic factors At the end of the treatment, the clinical and microbiologic evaluations yielded similar results for both groups. In the C albicans group, there was complete cure in 28.6%, partial cure in 40.5%, and clinical ineffectiveness in 31%; in the NAC group, there was complete cure, partial cure, and clinical ineffectiveness in 35.9%, 38.3%, and 25.8%, respectively (P = .50). There was 41.2% and 54.3% clearance in the C albicans and NAC group, respectively; 10.6% and 7.8% of patients in the C albicans and NAC group, respectively, had persistent infection (P = .17). The mortality rate in the NAC and C albicans groups was 38.4% and 29.6%, respectively, which was not statistically significant (P = .17). The analysis of the 244 patients showed that they had single Candida infections and that C parapsilosis and C glabrata infections caused the highest mortality (41.8% and 40.7%, respectively), followed by C tropicalis (36.6%). The mortality rate after C albicans infection was 29.6%, and the mortality rate after other NAC infections was 26.67%. Seven patients had ≥2 Candida infections. Two of the 4 cases with C albicans and NAC mixed infections died, and 1 of the 3 cases with NAC mixed infection died. After 2.1 and 6.3 days, a few patients in the C albicans and NAC groups, respectively, had relapse or reinfection (2.5% vs 1.6%, P = .65). The median ICU stay of the C albicans and NAC groups was 18 and 29 days, respectively; the median duration of hospitalization of the C albicans and NAC groups was 32 and 44 days, respectively. The difference in ICU and hospital stay was statistically significant between the 2 groups (ICU: P = .004; hospitalization: P = .002). DISCUSSION C albicans infection accounts for the largest proportion of candidemia, but an increasing number of studies has shown a growing proportion of NAC infection. The incidence of NAC infection differs greatly between regions, and the reasons for this are unclear.26 Furthermore, the incidence of Candida infection is associated with species, which differ according to the study population.32,33 There remains a lack of large-scale data on Candida infections in critically ill patients in mainland China. This study is the first large-scale, prospective, clinical multicenter study in mainland China. The ICUs involved were comprehensive, medical, and surgical ICUs. C albicans accounted for up to 40.1% infections, followed by C parapsilosis (21.3%), C tropicalis (17.2%), and C glabrata (12.9%). The incidence of C albicans infection was consistent with that of other domestic reports,22,23,34-37 but it was lower than that reported by the ARTEMIS DISK Global Antifungal Surveillance Study (64%-67%).38 The rate of NAC infection was 51.4%, which is higher than that in other reports (eg, 32% in the ARTEMIS DISK study,38 39% in the study by Holley et al23). The age, sex, weight, and ICU type between the populations infected with C albicans and NAC were not significantly different. Holley
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et al reported that women are high risk when infected with NAC,23 which differs from our findings. In terms of diagnosis and underlying diseases, there was a higher incidence of NAC infection in hospitalized patients admitted with surgery or trauma than C albicans infection. Holley et al also considered surgery or trauma risk factors for NAC infection.23 We found no significant differences between C albicans and NAC infection in patients with other infections and organ failure. NAC infection may be associated with malignant hematologic disease, allogeneic hepatocyte transplantation, severe illness, and immune suppression.32,39-42 A study in Taiwan showed that in patients infected with NAC, neutropenia is more common and positive Candida urine culture is less common.43 However, in our study, there was no difference in hematologic malignances and neutropenia (in the recent 2 weeks) between patients with C albicans or NAC infection. This may have been because there were very few cases of blood disorders (n = 3; progressive: n = 2 [0.8%]; nonprogressive: n = 1 [0.4%]) and neutropenia (5/244, 2%): in the C albicans group, there were 3 patients (3.1%), and in the NAC group there were 2 patients (1.4%). However, this study was not limited to non-neutropenic ICU patients. C albicans infection was more common than NAC infection in patients with indwelling peritoneal drainage tubes (9.6% vs 2.1%, respectively). Among the enrolled patients, 38.2% underwent surgical procedures within 2 weeks; abdominal surgery was the most common (25.2%), suggesting that indwelling peritoneal drainage may be a C albicans infection risk factor. Similarly, the Gruppo Italiano per lo Studio In Vitro degli Antifungini (GISIA-1) study found that C albicans infection was more common than NAC infection in surgical patients.44 Previous studies have reported a higher incidence of NAC infection than C albicans infection in patients with longterm indwelling central venous catheters and parenteral nutrition.23,32,40 One study reported that indwelling central venous catheters are the only risk factor for NAC infection.42 In our study, C albicans infection was more common than NAC infection in patients with subclavian vein catheters (P = .035); there was no difference in patients with jugular vein or femoral vein catheters. Second to C albicans, C parapsilosis infection accounted for 21.3% of infections; previous studies have suggested that central venous catheters may be a C parapsilosis infection risk factor.23,32,40 We found no difference between C albicans and NAC infection in patients who received total parenteral nutrition or with mechanical ventilation 2 weeks before diagnosis, even though others have reported that these medical interventions potentially act as NAC infection risk factors. Because all patients enrolled in the study were diagnosed with invasive fungal infections, we did not include risk factor analysis for NAC infection, which could be studied in the future. More patients with NAC infection (32.9%) were diagnosed before antifungal therapy than with C albicans (22.4%); however, the difference was not significant. Triazole is one of the most common antifungal drugs. It is generally believed that azole drugs increase NAC infections, which may be associated with improper treatment of asymptomatic bacteriuria and inappropriate prevention of cryptococcal infection in HIV-infected patients. Similar incidences of C albicans and NAC infections have also been reported under appropriate empirical treatment.45 On the timing of treatment, more NAC patients received empirical therapy, whereas more C albicans patients received treatment when the diagnosis was confirmed. These results may suggest that patients with NAC infection are in worse clinical conditions, which make the clinicians prone to starting antifungal therapy earlier. During treatment, more regimens for treating NAC patients were adjusted primarily to replace the antifungal drugs. Using in vitro susceptibility testing, our previously published data demonstrated a significant difference between C albicans and NAC,46 especially fluconazole resistance. NAC fluconazole susceptibility is
much lower than that of C albicans, whereas triazole is the most commonly used antifungal drug for treating both C albicans and NAC infections. Lack of sensitivity to initial treatment may be the main reason for changing strategies in NAC treatment. Slow replication in addition to antifungal therapy resistance result in longer-lasting treatment for NAC infection. In addition, both ICU and hospital stay for patients with NAC infection were significantly longer than that for C albicans–infected patients. Our previous data show that the mortality of patients with isolates sensitive to initial therapy is significantly lower than that of patients with intermediate sensitivity or resistant isolates and that they have higher rates of full clinical recovery and fungal elimination.46 Therefore, antifungal therapy in patients with NAC infection lasts longer, they have longer ICU and hospital stays, and their treatment is more difficult and accompanied by higher mortality compared with patients with C albicans infection, which is all caused by the combined effect of pathogens and the choice of initial antifungal agents. CONCLUSIONS Although C albicans is one of the most common pathogens in ICU patients with invasive fungal infections, NAC infection incidence exceeded that of C albicans. The proportion of NAC infection in patients with surgery or trauma when admitted to hospital is higher than that with C albicans infection. C albicans infection is more common than NAC infection in patients with indwelling subclavian vein catheters and peritoneal drainage tubes. Patients with NAC infection receive longer but less effective antifungal therapy and have longer ICU and hospital stays and higher mortality. References 1. Méan M, Marchetti O, Calandra T. Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care 2008;12:204. 2. Kett D, Azoulay E, Echeverria P, Vincent JL; Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 2011;39:665-70. 3. Falagas M, Roussos N, Vardakas K. Relative frequency of albicans and non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis 2010;14:e954-66. 4. Horn DL, Neofytos D, Anaissie EJ, Fishman JA, Steinbach WJ, Olyaei AJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009;48:1695-703. 5. Concia E, Azzini AM, Conti M. Epidemiology, incidence and risk factors for invasive candidiasis in high-risk patients. Drugs 2009;69(Suppl):5-14. 6. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9. 7. Craven DE, Barber TW, Steget KA, Montecalvo MA. Nosocomial pneumonia in the 1990: update of epidemiology and risk factors. Semin Respir Infect 1990;5:157. 8. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infect Dis 2001;33:1824-33. 9. Rees JR, Pinner RW, Hajjeh RA, Brandt ME, Reingold AL. The epidemiological features of invasive mycotic infections in the San Francisco Bay area, 1992-1993: results of population-based laboratory active surveillance. Clin Infect Dis 1998;27:1138-47. 10. Borzotta AP, Beardsley K. Candida infections in critically ill trauma patients: a retrospective case-control study. Arch Surg 1999;134:657-64, discussion 664-5. 11. Hoerauf A, Hammer S, Muller-Myhsok B, Rupprecht H. Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality. Crit Care Med 1998;26:2010-5. 12. de Vera F, Martinez JF, Clara Verdu R, López MM, Gómez A. Pancreatic abscess caused by Candida following wide-spectrum antibiotic treatment. Gastroenterol Hepatol 1998;21:188-90. 13. Leon C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J, Alvarez-Lerma F, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006;34:730-7. 14. Kourkoumpetis T, Manolakaki D, Velmahos G, Chang Y, Alam HB, De Moya MM, et al. Candida infection and colonization among non-trauma emergency surgery patients. Virulence 2010;1:359-66.
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15. Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 2001;33:177-86. 16. Wey SB, Motomi M, Pfaller MA, Woolson RF, Wenzel RP. Risk factors for hospital acquired candidemia. Arch Intern Med 1989;149:2349-53. 17. Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, et al. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clin Infect Dis 2000;30:696-709. 18. Pappas PG, Rex JH, Sobel JD, Filler SG, Dismukes WE, Walsh TJ, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004;38:161-89. 19. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005;18:44-69. 20. Patel R, Portela D, Badley AD, Harmsen WS, Larson-Keller JJ, Ilstrup DM, et al. Risk factors of invasive Candida and non-Candida fungal infections after liver transplantation. Transplantation 1996;62:926-34. 21. Diekema DJ, Messer SA, Brueggemann AB, Coffman SL, Doern GV, Herwaldt LA, et al. Epidemiology of candidemia: 3-year results from the Emerging Infections and the Epidemiology of Iowa Organisms study. J Clin Microbiol 2002;40:1298303. 22. Playford EG, Lipman J, Sorrell T. Management of invasive candidiasis in the intensive care unit. Drugs 2010;70:823-39. 23. Holley A, Dulhunty J, Blot S, Lipman J, Lobo S, Dancer C, et al. Temporal trends, risk factors and outcomes in albicans and non-albicans candidaemia: an international epidemiological study in four multidisciplinary intensive care units. Int J Antimicrob Agents 2009;33:554.e1-7. 24. Vazquez JA. Invasive fungal infections in the intensive care unit. Semin Respir Crit Care Med 2010;31:79-86. 25. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 2007;20:133-63. 26. Pfaller MA, Jones RN, Doern GV, Sader HS, Hollis RJ, Messer SA. International surveillance of bloodstream infections due to Candida species: frequency of occurrence and antifungal susceptibilities of isolates collected in 1997 in the United States, Canada, and South America for the SENTRY Program. The SENTRY Participant Group. J Clin Microbiol 1998;36:1886-9. 27. Cheng MF, Yu KW, Tang RB, Fan YH, Yang YL, Hsieh KS, et al. Distribution and antifungal susceptibility of Candida species causing candidemia from 1996 to 1999. Diagn Microbiol Infect Dis 2004;48:33-7. 28. Yang YL, Ho YA, Cheng HH, Ho M, Lo HJ. Susceptibilities of Candida species to amphotericin B and fluconazole: the emergence of fluconazole resistance in Candida tropicalis. Infect Control Hosp Epidemiol 2004;25:60-4. 29. Guo FM, Yang Y, Kang Y, Zang B, Cui W, Qin B, et al. Invasive candidiasis in intensive care units in China: a multicentre prospective observational study. J Antimicrob Chemother 2013;68:1660-8. 30. Kurtzman CP, Robnett CJ. Identification of clinically important ascomycetous yeasts based on nucleotide divergence in the 5′ end of the large-subunit (26S) ribosomal DNA gene. J Clin Microbiol 1997;35:1216-23. 31. Lu HZ, Jia JH, Wang QM, Bai FY. Candida asparagi sp. nov., Candida diospyri sp. nov. and Candida qinlingensis sp. nov., novel anamorphic, ascomycetous yeast species. Int J Syst Evol Microbiol 2004;54:1409-14.
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32. Apisarnthanarak A, Naknarongkij N, Kiratisin P, Mundy LM. Risk factors and outcomes of Candida albicans and non-albicans Candida species at a Thai tertiary care center. Am J Infect Control 2009;37:781-2. 33. Ha JF, Italiano CM, Heath CH, Shih S, Rea S, Wood FM. Candidemia and invasive candidiasis: a review of the literature for the burns surgeon. Burns 2011;37:8195. 34. Yap HY, Kwok KM, Gomersall CD, Fung SC, Lam TC, Leung PN, et al. Epidemiology and outcome of Candida bloodstream infection in an intensive care unit in Hong Kong. Hong Kong Med J 2009;15:255-61. 35. Li S, An Y. Retrospective analysis of invasive fungal infection in surgical intensive care unit. Zhonghua Yi Xue Za Zhi 2010;90:382-5. 36. Xie GH, Fang XM, Fang Q, Wu XM, Jin YH, Wang JL, et al. Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients. Crit Care 2008;12: R5. 37. Bassetti M, Ansaldi F, Nicolini L, Malfatto E, Molinari MP, Mussap M, et al. Incidence of candidaemia and relationship with fluconazole use in an intensive care unit. J Antimicrob Chemother 2009;64:625-9. 38. Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Ellis D, Tullio V, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J Clin Microbiol 2010;48:1366-77. 39. Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999;28:10719. 40. Wingard JR. Importance of Candida species other than C. albicans as pathogens in oncology patients. Clin Infect Dis 1995;20:115-25. 41. Cheng MF, Yang YL, Yao TJ, Lin CY, Liu JS, Tang RB, et al. Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species. BMC Infect Dis 2005;5:22. 42. Serefhanoglu K, Timurkaynak F, Can F, Cagir U, Arslan H, Ozdemir FN. Risk factors for candidemia with non-albicans Candida spp. in intensive care unit patients with end-stage renal disease on chronic hemodialysis. J Formos Med Assoc 2012;111:325-32. 43. Chi HW, Yang YS, Shang ST, Chen KH, Yeh KM, Chang FY, et al. Candida albicans versus non-albicans bloodstream infections: the comparison of risk factors and outcome. J Microbiol Immunol Infect 2011;44:369-75. 44. Montagna MT, Lovero G, Borghi E, Amato G, Andreoni S, Campion L, et al. Candidemia in intensive care unit: a nationwide prospective observational survey (GISIA-3 study) and review of the European literature from 2000 through 2013 European Review for Medical and Pharmacological Sciences. Eur Rev Med Pharmacol Sci 2014;18:661-74. 45. Blot S, Vandijck D, Vandewoude K. Risk factors for Candida non-albicans candidemia. Diagn Microbiol Infect Dis 2008;61:362-3. 46. Liu W, Tan J, Sun J, Xu Z, Li M, Yang Q, et al. Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study. J Antimicrob Chemother 2014;69:162-7.
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
Original Research Article
Invasive candidiasis in intensive care units in China: Risk factors and prognoses of Candida albicans and non–albicans Candida infections Xiaoying Gong MD a, Ting Luan MD a, Xingmao Wu MD a, Guofu Li MD a, Haibo Qiu MD b, Yan Kang MD c, Bingyu Qin MD d, Qiang Fang MD e, Wei Cui MD f, Yingzhi Qin MD g, Jianguo Li MD h, Bin Zang MD a,* a
Department of Intensive Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China Department of Intensive Care Medicine, Nanjing Zhongda Hospital, Southeast University School of Medicine, Nanjing, China Department of Intensive Care Medicine, West China Hospital, Sichuan University, Chengdu, China d Department of Intensive Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, China e Department of Intensive Care Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China f Department of Intensive Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medcine, Hangzhou, China g Department of Intensive Care Medicine, Tianjin Third Central Hospital, Tianjin, China h Department of Intensive Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China b c
Key Words: Candida albicans non-albicans infection risk factor intensive care unit China
Background: To investigate the risk factors and prognoses of patients with invasive Candida albicans and non–albicans Candida (NAC) infection in intensive care units (ICUs) in China. Methods: Between November 2009 and April 2011, we performed a prospective study of critically ill patients with invasive Candida infection from 67 ICUs across China to compare the risk factors and mortality between patients with C albicans and NAC infection. Results: There were 306 patients with proven invasive Candida; 244 cases (a total 389 Candida isolates) were sent to laboratory for strain identification (C albicans, 40.1%; NAC, 59.9%). More patients admitted for surgery or trauma had NAC infection than C albicans infection. C albicans infection was more common in patients with subclavian vein catheters or peritoneal drainage tubes. Compared with patients with C albicans infection, patients with NAC infection had longer antifungal therapy (P < .001), longer ICU (P = .004) or hospital stay (P = .002), and slightly higher mortality (38.4% vs 29.6%), but the difference was not significant (P = .17). Conclusions: C albicans remains the most common pathogen in candidiasis in critical care patients. However, the number of NAC infections exceeded C albicans infections. Compared with patients with C albicans infection, patients with NAC infection had heavier disease burdens. © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
Invasive Candida infection is very common in intensive care units (ICUs); the mortality rate is high. This is true especially in immunosuppressed patients or patients with severe diseases, in whom the mortality rate is 35%-80%.1-4 Although difficult to diagnose, invasive Candida infection remains the third leading cause of ICU infections,5 causing (responsible for) 17% of all ICU infections.6 The major risk factors in critically ill patients with invasive fungal in-
* Address correspondence to Bin Zang, MD, Department of Intensive Care Medicine, Shengjing Hospital of China Medical University, Sanhao St No 36, Heping District, Shenyang, China 110004. E-mail address: [email protected] (B. Zang). Conflicts of Interest: This work was supported by Merck Sharp & Dohme China, who sponsored the study. Medical writing and editing assistance were supported by Merck & Co., Inc., Whitehouse Station, NJ, USA.
fections include age, underlying diseases,7-12 multisite Candida colonization, invasive procedures,13-16 medication, upper abdominal surgery,13-16 and immunosuppressive diseases.17-20 Candida albicans is one of the most common pathogens of invasive fungal infections, with an incidence of 40%-82%.4,21-23 C albicans infections account for 50%-70% of ICU infections in the United States;2,24 in Asia, South America, and Northern Europe, the incidence of non– albicans Candida (NAC) infection is higher.3 In the last 20 years, C albicans has been the most common strain isolated from hospitalized patients; however, there is currently a growing trend of NAC infection. In many countries, Candida glabrata infections account for 15%-20% of Candida infections.1,25 Fungal resistance has changed, and there is decreased fluconazole susceptibility in some Candida spp. Compared with C albicans, approximately 60% of NAC is less fluconazole-sensitive.26-28 The rate of mortality caused by NAC
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infection is higher than that caused by C albicans.1-4,26-28 Therefore, diagnosing Candida infections early, screening pathogens into C albicans or NAC, and early appropriate empirical therapy are crucial, especially for selecting NAC antifungal drugs. To our knowledge, the risk factors or large-scale surveys and analysis of C albicans and NAC infection prognoses in mainland China have not been reported. This was a prospective multicenter study of critically ill Chinese patients with invasive candidiasis in ICUs. The study has important implications and identifies empirical treatment strategies for clinicians. METHODS Patient identification and data collection We conducted a multicenter, prospective, observational study between November 2009 and April 2011 that involved 67 ICUs across China (China-SCAN). We enrolled patients who were aged ≥18 years, with clinical signs of infection (in the treating physician’s opinion) and at least 1 of the listed diagnostic criteria: (1) confirmation through histopathology, cytopathology, or direct microscopy of yeast cells in a needle aspiration or biopsy specimen from a normally sterile site (other than mucous membranes); (2) at least 1 Candidapositive peripheral blood culture; and (3) a Candida-positive culture from a sample obtained by a sterile technique from a normally sterile site (eg, cerebrospinal, pleural, peritoneal, peritoneal abscess fluid). The attending physicians, who also acted as the investigators for the study, managed the patients at their discretion; patients were followed until discharge or death, whichever occurred first. Demographic information, ICU type, clinical patient characteristics (admission diagnosis, ICU admission diagnosis, Acute Physiology and Chronic Health Evaluation score, sepsis-related organ failure assessment score) (Table 1), and medical interventions (total parenteral nutrition, surgery, mechanical ventilation, arterial and venous catheters, body cavity drainage tubes, catheters, antibiotics and antifungal treatment within 2 weeks before diagnosis) (Table 2) were recorded when the patients were admitted to the ICUs. Investigators evaluated both clinical and microbiologic outcomes for invasive candidiasis. Regarding clinical outcome, we defined complete cure as the disappearance of signs and symptoms caused by Invasive Candida Infections and infectious lesions on radiologic examination, partial cure as partial relief of clinical signs and symptoms and improved radiologic findings, and clinical ineffectiveness as persistent or worsened signs, symptoms, and radiologic lesions. The details have been described previously.29 ICU or hospital stay duration and outcome were recorded. Pathogen identification Specimens were sent to the China-SCAN Central Laboratory (Peking University First Hospital) for pathogen detection. We used chromogenic medium (CHROMagar, Paris, France) and API 20C AUX yeast identification kit (bioMérieux, Marcy l’Etoile, France) for species identification. We used the large subunit (26S) ribosomal DNA gene D1/D2 sequences when necessary.30,31 Statistical analysis We performed statistical analysis using SAS 9.1 software (SAS Institute, Cary, NC). Categorical variables were described using frequencies and 95% confidence intervals. Skewed distribution was described using medians, interquartile ranges, and maximums and minimums. The significance threshold was 0.05. Based on the pathogen detection results, the fungal isolates were classified as C albicans alone or NAC (non-albicans infection, mixed non-albicans
Table 1 Characterization of patients with Candida albicans and NAC infection Risk factor Age (y) Sex Female Male Weight (kg) ICU type Medical Surgical Integrated Others Diagnosis for hospitalization Infection Organ failure Single organ Multiple organ Surgery and trauma Surgery Trauma Diagnosis for ICU admission Infection Organ failure Single organ Multiple organ Surgery and trauma Surgery Trauma APACHE II score SOFA score Underlying disease Solid tumor Hematologic malignancy Diabetes COPD Chronic liver dysfunction Chronic renal insufficiency Chronic heart failure Neutropenia within 2 wk (<500/mm3) Digestive dysfunction
C albicans
NAC
P value
62.2 ± 17.26
61.4 ± 21.36
.7644
37 (37.8) 61 (62.2) 61.8 ± 10.27
40 (27.4) 106 (72.6) 64.0 ± 11.78
.0937
1 (1.0) 13 (13.3) 77 (78.6) 7 (7.1)
6 (4.1) 16 (11.0) 122 (83.6) 2 (1.4)
.0570
44 (44.9)
56 (38.4)
.3531
13 (8.9) 4 (2.7)
.3700
4 (4.1) 3 (3.1)
.2086
.0283 3 (3.1) 11 (11.2)
18 (12.3) 19 (13.0)
60 (61.2)
76 (52.1)
.1888
14 (14.3) 6 (6.1)
35 (24.0) 9 (6.2)
.1777
20 (20.4) 10 (10.2) 27.2 ± 7.1 10.4 ± 3.4
31 (21.2) 21 (14.4) 26.7 ± 7.1 11.2 ± 3.3
.6239 .0738
17 (17.3) 1 (1.0) 20 (20.4) 14 (14.3) 4 (4.1) 9 (9.1) 19 (19.4) 3 (3.1) 55 (56.1)
29 (19.9) 2 (1.4) 33 (22.6) 19 (13.0) 9 (6.2) 14 (9.6) 30 (20.5) 2 (1.4) 86 (58.9)
.5669 >.9999 .9243 .8492 .5706 .4571 .8189 .3934 .6930
.6158
NOTE. Values are mean ± SD, n (%), or as otherwise indicated. Count data between groups were compared using Fisher exact test. Quantitative data between groups were compared using analysis of variance. Data between groups of chronic heart failure (New York Heart Association classification) were compared using the KruskalWallis rank-sum test. Other indicators were compared by Fisher exact test. APACHE II, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; NAC, non–albicans Candida; SOFA, sepsis-related organ failure assessment.
Table 2 Comparison of medical intervention and treatment in Candida albicans and NAC groups Risk factor
C albicans
NAC
P value
Total parenteral nutrition in recent 2 wk Surgery Mechanical ventilation Noninvasive Invasive Both Intravascular catheter Internal jugular vein Subclavian vein Femoral vein Ductus arteriosus Nonintravascular catheter Chest tube Peritoneal drainage tube Subdural, intradural, or ventricular drainage tube Urine catheter Antibiotic treatment before diagnosis Antifungal treatment before diagnosis
43 (43.9) 40 (40.8)
60 (41.1) 54 (37.0)
.6930 .5923 .3448
2 (2.0) 76 (77.6) 2 (2.0)
6 (4.1) 113 (77.4) —
17 (17.3) 23 (23.5) 12 (12.2) 7 (7.1)
17 (11.6) 18 (12.3) 19 (13.0) 7 (4.8)
.2580 .0351 1.0000 .5759
4 (4.1) 9 (9.2) 1 (1.0)
5 (3.4) 3 (2.1) 3 (2.1)
1.0000 .0154 .6508
15 (15.3) 76 (77.6) 22 (22.4)
19 (13.0) 121 (82.9) 49 (33.6)
.7067 .3234 .0637
NOTE. Values are n (%) or as otherwise indicated. Count data between groups were compared using Fisher exact test. NAC, non–albicans Candida.
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infection, C albicans, and NAC mixed infection). We compared the 2 groups with the Student t test or Mann-Whitney U test according to their distribution. RESULTS Candida spp Of 96,060 ICU patients from 67 centers throughout China, 306 were diagnosed with invasive candidiasis and were included in this study. The incidence rate of invasive Candida infection was 0.32%; the rate of mortality was 36.6%. Of the 244 cases (389 strains) sent for strain identification, C albicans was present in 40.1%, Candida parapsilosis was present in 21.3%, Candida tropicalis was present in 17.2%, C glabrata was present in 12.9%, and other Candida was present in 8.6%. Among these were 98 cases of C albicans infection, 139 cases of NAC infection, 3 cases of NAC mixed infections, and 4 cases of C albicans and NAC mixed infection. Patient characteristics There was no significant difference in age, sex, weight, ICU type, and disease severity score between the C albicans and NAC groups. More surgery or trauma patients were diagnosed with NAC than with C albicans (25.3% vs 14.3%, respectively; P = .028). There was no significant difference between patients with infection, organ failure, or other underlying conditions at hospital admission. On a consolidated basis of diseases, such as solid tumors, blood disorders, diabetes, chronic obstructive pulmonary disease, chronic liver failure, chronic heart failure, chronic renal insufficiency, neutropenia (within 2 weeks, <500/mm3), and digestive dysfunction, there was no significant difference between the C albicans and NAC groups (Table 1). Intervention factors between patients infected with C albicans or NAC More patients with subclavian vein catheter (23.5% vs 12.3%, respectively; P = .035) or peritoneal drainage tube (9.2% vs 2.1%, respectively; P = .009) had NAC infection than C albicans infection 2 weeks before diagnosis. There was no significant difference between other types of central venous catheter or drainage. There was also no difference between other risk factors, such as total parenteral nutrition (>2 weeks), mechanical ventilation, and surgery in the 2 groups (Table 2). Compared with C albicans and 3 common NACs (C glabrata, C parapsilosis, and C tropicalis), the proportion of patients who received total parenteral nutrition within 2 weeks before invasive candidiasis diagnosis was lowest in patients infected with C parapsilosis (C albicans, C glabrata, C parapsilosis, and C tropicalis were 43.9%, 51.9%, 25.5%, and 48.8% of such patients, respectively). A slightly higher proportion of patients receiving antibiotic therapy before diagnosis had NAC infection than C albicans infection (82.9% vs 77.6%, respectively; P = .32). However, among patients who received antibiotics before diagnosis, there were significantly more with C parapsilosis infection than patients with other Candida infection (there was C albicans, C glabrata, C parapsilosis, and C tropicalis infection in 77.6%, 74.6%, 98.2%, and 65.9% of such patients, respectively). The proportion of C parapsilosis infection diagnosed before antifungal treatment was received was the highest among the NAC infections (38.2%) and was significantly higher than that of C albicans (P = .041). Most patients received triazole drug monotherapy as C albicans and NAC antifungal therapy. The most commonly used drugs were triazole, echinocandin, and polyenes, which were used to treat 64.7%,
3
31.8%, and 0% of patients with C albicans infection and 62.8%, 34.1%, and 2.3% of NAC patients, respectively (P = .38). On treatment timing, more patients with NAC infection received empirical therapy (30.2% vs 24.7%), whereas more patients with C albicans infection received targeted therapy (68.2% vs 56.6%), which may be associated with the more serious condition of the former, but the difference was not significant (P = .19). Treating patients with NAC infection was more difficult, reflected by longer treatment durations (20.4 vs 12.85 days, P < .001), and more patients with NAC infection required treatment adjustment (52.7% vs 30.6%, P = .002), which included alterations to dosage (33.3% vs 16.3%), administration route (6.1% vs 5.0%), drug replacement (36.4% vs 66.3%), single to multiple drugs (15.2% vs 3.8%), and multiple to single drug (0% vs 1.3%). Evaluation of treatment and prognostic factors At the end of the treatment, the clinical and microbiologic evaluations yielded similar results for both groups. In the C albicans group, there was complete cure in 28.6%, partial cure in 40.5%, and clinical ineffectiveness in 31%; in the NAC group, there was complete cure, partial cure, and clinical ineffectiveness in 35.9%, 38.3%, and 25.8%, respectively (P = .50). There was 41.2% and 54.3% clearance in the C albicans and NAC group, respectively; 10.6% and 7.8% of patients in the C albicans and NAC group, respectively, had persistent infection (P = .17). The mortality rate in the NAC and C albicans groups was 38.4% and 29.6%, respectively, which was not statistically significant (P = .17). The analysis of the 244 patients showed that they had single Candida infections and that C parapsilosis and C glabrata infections caused the highest mortality (41.8% and 40.7%, respectively), followed by C tropicalis (36.6%). The mortality rate after C albicans infection was 29.6%, and the mortality rate after other NAC infections was 26.67%. Seven patients had ≥2 Candida infections. Two of the 4 cases with C albicans and NAC mixed infections died, and 1 of the 3 cases with NAC mixed infection died. After 2.1 and 6.3 days, a few patients in the C albicans and NAC groups, respectively, had relapse or reinfection (2.5% vs 1.6%, P = .65). The median ICU stay of the C albicans and NAC groups was 18 and 29 days, respectively; the median duration of hospitalization of the C albicans and NAC groups was 32 and 44 days, respectively. The difference in ICU and hospital stay was statistically significant between the 2 groups (ICU: P = .004; hospitalization: P = .002). DISCUSSION C albicans infection accounts for the largest proportion of candidemia, but an increasing number of studies has shown a growing proportion of NAC infection. The incidence of NAC infection differs greatly between regions, and the reasons for this are unclear.26 Furthermore, the incidence of Candida infection is associated with species, which differ according to the study population.32,33 There remains a lack of large-scale data on Candida infections in critically ill patients in mainland China. This study is the first large-scale, prospective, clinical multicenter study in mainland China. The ICUs involved were comprehensive, medical, and surgical ICUs. C albicans accounted for up to 40.1% infections, followed by C parapsilosis (21.3%), C tropicalis (17.2%), and C glabrata (12.9%). The incidence of C albicans infection was consistent with that of other domestic reports,22,23,34-37 but it was lower than that reported by the ARTEMIS DISK Global Antifungal Surveillance Study (64%-67%).38 The rate of NAC infection was 51.4%, which is higher than that in other reports (eg, 32% in the ARTEMIS DISK study,38 39% in the study by Holley et al23). The age, sex, weight, and ICU type between the populations infected with C albicans and NAC were not significantly different. Holley
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et al reported that women are high risk when infected with NAC,23 which differs from our findings. In terms of diagnosis and underlying diseases, there was a higher incidence of NAC infection in hospitalized patients admitted with surgery or trauma than C albicans infection. Holley et al also considered surgery or trauma risk factors for NAC infection.23 We found no significant differences between C albicans and NAC infection in patients with other infections and organ failure. NAC infection may be associated with malignant hematologic disease, allogeneic hepatocyte transplantation, severe illness, and immune suppression.32,39-42 A study in Taiwan showed that in patients infected with NAC, neutropenia is more common and positive Candida urine culture is less common.43 However, in our study, there was no difference in hematologic malignances and neutropenia (in the recent 2 weeks) between patients with C albicans or NAC infection. This may have been because there were very few cases of blood disorders (n = 3; progressive: n = 2 [0.8%]; nonprogressive: n = 1 [0.4%]) and neutropenia (5/244, 2%): in the C albicans group, there were 3 patients (3.1%), and in the NAC group there were 2 patients (1.4%). However, this study was not limited to non-neutropenic ICU patients. C albicans infection was more common than NAC infection in patients with indwelling peritoneal drainage tubes (9.6% vs 2.1%, respectively). Among the enrolled patients, 38.2% underwent surgical procedures within 2 weeks; abdominal surgery was the most common (25.2%), suggesting that indwelling peritoneal drainage may be a C albicans infection risk factor. Similarly, the Gruppo Italiano per lo Studio In Vitro degli Antifungini (GISIA-1) study found that C albicans infection was more common than NAC infection in surgical patients.44 Previous studies have reported a higher incidence of NAC infection than C albicans infection in patients with longterm indwelling central venous catheters and parenteral nutrition.23,32,40 One study reported that indwelling central venous catheters are the only risk factor for NAC infection.42 In our study, C albicans infection was more common than NAC infection in patients with subclavian vein catheters (P = .035); there was no difference in patients with jugular vein or femoral vein catheters. Second to C albicans, C parapsilosis infection accounted for 21.3% of infections; previous studies have suggested that central venous catheters may be a C parapsilosis infection risk factor.23,32,40 We found no difference between C albicans and NAC infection in patients who received total parenteral nutrition or with mechanical ventilation 2 weeks before diagnosis, even though others have reported that these medical interventions potentially act as NAC infection risk factors. Because all patients enrolled in the study were diagnosed with invasive fungal infections, we did not include risk factor analysis for NAC infection, which could be studied in the future. More patients with NAC infection (32.9%) were diagnosed before antifungal therapy than with C albicans (22.4%); however, the difference was not significant. Triazole is one of the most common antifungal drugs. It is generally believed that azole drugs increase NAC infections, which may be associated with improper treatment of asymptomatic bacteriuria and inappropriate prevention of cryptococcal infection in HIV-infected patients. Similar incidences of C albicans and NAC infections have also been reported under appropriate empirical treatment.45 On the timing of treatment, more NAC patients received empirical therapy, whereas more C albicans patients received treatment when the diagnosis was confirmed. These results may suggest that patients with NAC infection are in worse clinical conditions, which make the clinicians prone to starting antifungal therapy earlier. During treatment, more regimens for treating NAC patients were adjusted primarily to replace the antifungal drugs. Using in vitro susceptibility testing, our previously published data demonstrated a significant difference between C albicans and NAC,46 especially fluconazole resistance. NAC fluconazole susceptibility is
much lower than that of C albicans, whereas triazole is the most commonly used antifungal drug for treating both C albicans and NAC infections. Lack of sensitivity to initial treatment may be the main reason for changing strategies in NAC treatment. Slow replication in addition to antifungal therapy resistance result in longer-lasting treatment for NAC infection. In addition, both ICU and hospital stay for patients with NAC infection were significantly longer than that for C albicans–infected patients. Our previous data show that the mortality of patients with isolates sensitive to initial therapy is significantly lower than that of patients with intermediate sensitivity or resistant isolates and that they have higher rates of full clinical recovery and fungal elimination.46 Therefore, antifungal therapy in patients with NAC infection lasts longer, they have longer ICU and hospital stays, and their treatment is more difficult and accompanied by higher mortality compared with patients with C albicans infection, which is all caused by the combined effect of pathogens and the choice of initial antifungal agents. CONCLUSIONS Although C albicans is one of the most common pathogens in ICU patients with invasive fungal infections, NAC infection incidence exceeded that of C albicans. The proportion of NAC infection in patients with surgery or trauma when admitted to hospital is higher than that with C albicans infection. C albicans infection is more common than NAC infection in patients with indwelling subclavian vein catheters and peritoneal drainage tubes. Patients with NAC infection receive longer but less effective antifungal therapy and have longer ICU and hospital stays and higher mortality. References 1. Méan M, Marchetti O, Calandra T. Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care 2008;12:204. 2. Kett D, Azoulay E, Echeverria P, Vincent JL; Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med 2011;39:665-70. 3. Falagas M, Roussos N, Vardakas K. Relative frequency of albicans and non-albicans Candida spp among candidemia isolates from inpatients in various parts of the world: a systematic review. Int J Infect Dis 2010;14:e954-66. 4. Horn DL, Neofytos D, Anaissie EJ, Fishman JA, Steinbach WJ, Olyaei AJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009;48:1695-703. 5. Concia E, Azzini AM, Conti M. Epidemiology, incidence and risk factors for invasive candidiasis in high-risk patients. Drugs 2009;69(Suppl):5-14. 6. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9. 7. Craven DE, Barber TW, Steget KA, Montecalvo MA. Nosocomial pneumonia in the 1990: update of epidemiology and risk factors. Semin Respir Infect 1990;5:157. 8. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infect Dis 2001;33:1824-33. 9. Rees JR, Pinner RW, Hajjeh RA, Brandt ME, Reingold AL. The epidemiological features of invasive mycotic infections in the San Francisco Bay area, 1992-1993: results of population-based laboratory active surveillance. Clin Infect Dis 1998;27:1138-47. 10. Borzotta AP, Beardsley K. Candida infections in critically ill trauma patients: a retrospective case-control study. Arch Surg 1999;134:657-64, discussion 664-5. 11. Hoerauf A, Hammer S, Muller-Myhsok B, Rupprecht H. Intra-abdominal Candida infection during acute necrotizing pancreatitis has a high prevalence and is associated with increased mortality. Crit Care Med 1998;26:2010-5. 12. de Vera F, Martinez JF, Clara Verdu R, López MM, Gómez A. Pancreatic abscess caused by Candida following wide-spectrum antibiotic treatment. Gastroenterol Hepatol 1998;21:188-90. 13. Leon C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J, Alvarez-Lerma F, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006;34:730-7. 14. Kourkoumpetis T, Manolakaki D, Velmahos G, Chang Y, Alam HB, De Moya MM, et al. Candida infection and colonization among non-trauma emergency surgery patients. Virulence 2010;1:359-66.
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