Candidemia in the Neonatal Intensive Care Unit: A Retrospective, Observational Survey and Analysis of Literature Data.
Although blood stream infection (BSI) due to Candida species (spp.) in the neonatal intensive care unit (NICU) is less frequent than that due to Gram-positive or Gram-negative bacteria, it has higher morbidity and mortality rates. In particular, among newborns with a birth weight < 1000 g, 4-8% will develop candidemia, which has a 30% mortality in this group of patients . Newborns who survive frequently have long-term neurological impairment, including cerebral palsy, blindness, hearing impairment, cognitive deficits, and periventricular leukomalacia . Risk factors for neonatal candidemia include prematurity, use of central venous lines, endotracheal tubes, parenteral nutrition, broad-spectrum antibiotic administration (especially third-generation cephalosporins), prolonged hospitalization, abdominal surgery, exposure to H2 blockers, and Candida colonization. Although Candida albicans is the most prevalent yeast pathogen, BSIs caused by Candida non-albicans, particularly Candida parapsilosis complex and Candida glabrata complex, have increased in recent years [2, 3].
This study aimed (i) to determine the epidemiology of Candida BSIs in the NICU of an Italian university hospital during 9 years of observation; (ii) to analyze the trend in species distribution; and (iii) to examine in vitro susceptibility to common antifungal drugs. Furthermore, for comparative purposes, a systematic review of studies concerning the distribution of Candida spp. causing candidemia in NICU patients is presented.
2. Materials and Methods
2.1. Study Design. A retrospective, observational survey of all consecutive cases of candidemia was conducted at the NICU (capacity of 8 beds; level III) of a university hospital in Southern Italy, from January 1,2007, to December 31,2015. The number of annual admissions ranged from 135 to 169, with no significant variation during the period of study. All of the neonates who had at least one positive blood culture for Candida spp. and signs or symptoms of infection were considered in this study. Only the first episode of candidemia was reported for patients with recurrent or subsequent episodes. Clinical data were searched for in the microbiological laboratory database and included sex, gestational age, birth weight, and predisposing risk factors for Candida BSI (i.e., intravascular devices, prolonged antibiotics, administration of total parental nutrition, and prolonged hospitalization).
2.2. Definitions. Extremely low birth weight (ELBW) infants were defined as those with a birth weight [less than or equal to] 1000 g, very low birth weight (VLBW) infants were those with a birth weight <1500 g, and low birth weight infants were those with a birth weight < 2500 g. Prolonged antibiotic use was defined as >14 days of continuous administration. Late-onset sepsis (LOS) was defined as infection occurring for >48 h of life. Candidemia was considered as probably catheter-related when semiquantitative culture of the catheter tip yielded >15 colony-forming units of Candida.
2.3. Laboratory Procedures. Blood cultures were performed using a lysis-centrifugation system (Isolator; DuPont Co., Wilmington, DE, USA). The samples were cultured on two plates of Sabouraud dextrose agar with 0.05% chloramphenicol (BioRad, Marnes-la-Coquette, France) and then incubated at 36[degrees]C ([+ or -] 1) and 28[degrees]C ([+ or -] 1). The samples were examined daily for 10 days. The isolates were identified using standard procedures (morphology on cornmeal agar plates, germ-tube production in serum, and ability to grow at 37[degrees]C and 42[degrees]C) and biochemical analysis using two methods, the Vitek2 system and ID 32C panels (Bio-Merieux, Rome, Italy), to obtain accurate results. All strains were frozen at -70[degrees] C until further investigations . Candida parapsilosis complex genotyping was performed by PCR amplification as reported previously [5, 6].
Antifungal susceptibility tests to five antifungal drugs (anidulafungin, fluconazole, caspofungin, micafungin, and amphotericin B) were performed for all Candida spp., using the Sensititre YeastOne technique (SYO-09 panel; Trek Diagnostic Systems, Ltd., East Grinstead, England).
The susceptibility values were interpreted taking into account the species-specific clinical breakpoints (CBPs) suggested by the Clinical Laboratory Standards Institute (CLSI) subcommittee for the most common species of Candida . The epidemiological cut-off values were used to define wildtype and non-wild-type isolates if no CBPs were available from the CLSI [8, 9]. Minimum inhibitory concentration (MIC) data are presented as [MIC.sub.50] (MIC causing inhibition of 50% of isolates) and [MIC.sub.90] (MIC causing inhibition of 90% of isolates).
2.4. Statistical Analysis. The Shapiro-Wilk test was used to test the normal distribution of data. Non-normally distributed data are expressed as median and interquartile range (IQR) and were compared using the Mann-Whitney U test. Categorical data are expressed as number and percentage and were compared using [chi square] or Fisher's exact test. All p values are two-tailed, and statistical significance was defined as p < 0.05 (Social Sciences (SPSS) software 10 for Mac OS X; SPSS Inc., Chicago, IL, USA).
2.5. Literature Review. A review of full-text articles that were published in English from January 2000 to February 2015 was performed. The MEDLINE database was used for the bibliographic research, using the following key words: "neonatal candidemia", "candidemia neonatal intensive care unit", "Candida neonatal intensive care unit, and "NICU candidemia". Additionally, the bibliographies of the selected articles were reviewed for relevant publications.
The exclusion criteria were as follows: articles that reported a period of study prior to 2000; letters, randomized, controlled trials; and studies that reported a total number of Candida BSIs less than five. The following data were collected from each selected study: geographic location, year of publication, study period, type of study, incidence, influencing factors candidemia, total number of isolated Candida spp., and relative proportion of each of the Candida spp.
3.1. Analysis of Cases in the NICU. A total of 41 infants with Candida infection were reviewed. The overall incidence of candidemia was 3.0 per 100 NICU admissions (range, 2.2-3.0). The male: female ratio was 1.6: 1. The cohort had a median gestational age of 30 weeks (29-31 weeks) and a median birth weight of 1110 g (900-1345 g). The majority of candidemia episodes occurred in VLBW infants (56.1%). The median duration of the total hospital stay was 11 days (8-14 days). Candidemia was catheter-related in 23 cases (56.1%). All Candida infections were classified as LOS. At the moment of candidemia, only ELBW infants were receiving antifungal prophylaxis with fluconazole (3mg/kg/day).
Candida parapsilosis sensu stricto was isolated with the highest frequency (58.5%), followed by C. albicans (34.1%), C. glabrata complex, C. guilliermondii, and C. orthopsilosis (2.4% for each). Therefore, 65.9% of candidemia episodes were caused by Candida non-albicans. With regard to the temporal trend of C. albicans and Candida non-albicans, a variable drift from 2007-2015 was observed, with a considerable percentage (75%) increase in non-albicans species in 2015 (Figure 1). Predisposing factors associated with C. albicans and non-albicans are listed in Table 1. The duration of NICU hospitalization of patients with C. non-albicans was significantly longer than that in those with C. albicans (median days, 10 [7.5-12] versus 12 [10-15], p = 0.045). Patients with C. non-albicans were more likely to have parenteral nutrition than those with C. albicans (96.3% versus 71.4%, p = 0.039).
Results of antifungal susceptibility are shown in Table 2. All of the strains were sensitive to tested drugs. Overall, the [MIC.sub.50]/[MIC.sub.90] values (mg/L) were as follows: amphotericin B, 0.25/0.5; anidulafungin, 1/2; caspofungin, 0.25/0.5; fluconazole, 0.5/2; and micafungin, 1/1.
3.2. Literature Review. A total of 45 articles were selected (Tables 3 and 4). Thirty-two studies reported data from a single hospital and 27 were retrospective studies. Seventeen studies were conducted in Asia, 13 in Europe, 11 in North and South America, and 2 in South Africa. Finally, one cohort was carried out in Australia.
The distribution of Candida spp. varied according to the different geographical areas. Candida albicans was the dominant species in Europe with proportions ranging from 47 to 100% [10, 11, 13, 14, 16, 18, 19, 22, 23, 53] and in North and South America with proportions ranging from 40 to 69.2% [24-31, 33, 34]. Candida non-albicans species were predominant in Asia [36-40, 42, 43, 45, 47, 48], with proportions ranging from 25 to 92%, with a median of 75% (Figure 2). In Australia, C. albicans and C. non-albicans were equally distributed (42% and 43%, resp.) .
For C. non-albicans, the three most prevalent species were C. parapsilosis complex, C. glabrata complex, and C. tropicalis. Generally, C. parapsilosis complex was the second most common pathogen (range, 6.2-77.8%). C. parapsilosis complex was the predominant species in some studies from Europe [12, 15, 17, 20, 21] and Asia [37, 40, 42, 45, 48]. The highest proportions of C. glabrata complex were reported in studies that were conducted in the central part of India (range, 22.2-44.4%), while the lowest proportions were observed in European countries (range, 2.5-5.9%). No cases due to C. glabrata complex were reported in South America. The highest frequency of C. tropicalis was found in South India (36.7-92%), followed by studies from South America (11.2-13.3%) and South Africa (8.8%). The lowest frequencies were observed in Europe (3.7-5%) and Australia (2%). There were no reports of C. tropicalis in North America.
This study aimed to describe the epidemiology and drug susceptibility of Candida isolates causing candidemia in a NICU of an Italian university hospital over 9 years. Our survey showed that candidemia is a common problem among critically ill neonates, with an overall incidence of 3%. This finding is higher than data reported in a literature review from Europe (1.1-1.3%) [15, 17] and the North and South America (0.5-1.6%) [25, 30], but lower than that reported in Asia (4-7.7%) [39,45]. This variability may reflect differences in health care practices among countries, as well as the study design adopted, including differences in the examined population.
VLBW infants are known to be at a high risk of candidemia because of more aggressive and invasive therapies, such as indwelling central lines, mechanical ventilation, parenteral hyperalimentation, and longer hospital stay [1-3]. The majority of infected neonates have a gestational age at birth of 30 weeks or earlier and birth weight is [less than or equal to] 1500 g (87.8%, each one). Intravenous catheters are risk factors for Candida BSI in critically ill infants. We found that all patients had intravenous catheter placement and that candidemia was catheter-related in 56.1% of cases. This finding is not surprising because Candida spp. can adhere to platelets and fibrinogen on the surface of catheters and form biofilms that may become a reservoir for systemic spread [1-3].
In our systematic review, we found that only four species (C. albicans, C. parapsilosis complex, C. tropicalis, and C. glabrata complex) accounted for 95.4% of cases of candidemia. However, the ranking of these four species was variable. Generally, C. albicans was the predominant isolated spp. in Europe[10, 11, 13, 14, 16, 18, 19, 22, 23, 53] and North and South America [24-31,33,34]. However, non-albicans species were predominant in Asia [36-40, 42, 43, 45, 47, 48].
Moreover, data regarding changes in the relative frequencies of isolated Candida spp. showed a shift toward Candida non-albicans, with a frequency higher than 50% in some NICUs. This, in part, is attributed to the increased use of azole prophylaxis and therapy . However, in a recent study, where fluconazole was rarely used for prophylaxis and therapy, a high incidence of non-albicans (60.8% of all candidemia episodes) was found . Similarly, our study showed a higher percentage of C. non-albicans (66%) than C. albicans and a variable drift through 9 years. In 2015, 75% of the cases were caused by non-albicans species.
In our study, appearance of C. parapsilosis complex as the predominant fungal pathogen (61% of all isolates) was consistent with the pattern seen in some hospitals in Europe, Asia, and Africa [12, 15, 17, 20, 37, 42, 45, 48, 51].
Main risk factors for C. parapsilosis complex infection were the presence of indwelling vascular catheters and parenteral nutrition, both of which predispose to formation of biofilms. Morphogenesis from yeast cells to pseudohyphae is essential for biofilm formation and virulence in C. parapsilosis complex. Amino acids mediate cell differentiation, and this could explain the high incidence of this yeast in catheterized neonates who receive amino acid-rich parenteral nutrition solutions . Our data highlights an association between parenteral nutrition and non-albicans spp. The high proportion of C. parapsilosis complex may explain this finding. Notably, we observed that NICU patients were more likely to develop C. parapsilosis sensu stricto (58.5%) than C. orthopsilosis (2.4%) candidemia. This finding may be explained by the greater capacity of C. parapsilosis sensu stricto to adhere to central lines compared with closely related species .
In agreement with other studies [13-15, 17, 18], none of the isolated strains showed resistance to fluconazole and amphotericin B. These are the antifungal drugs of choice that are used in prophylaxis and treatment of Candida BSI in neonates . No fluconazole resistance may be related to the treatment policy in use at our hospital, where systemic antifungal prophylaxis with fluconazole was used only in ELBW infants. In neonates, fluconazole prophylaxis has been linked to the emergence of azole resistance [12, 57].
Limitations of the present study are mainly related to its retrospective nature with limited follow-up data. Although all of the data were prospectively collected, some variables could not be examined because of missing data. Furthermore, we did not have data on specific characteristics of noninfected patients in our NICU. Therefore, we were not able to risk-adjust our rates to compare with incidences from other reports.
Nevertheless, this study shows that C. non-albicans candidemia is increasing, despite limited use of fluconazole for prophylaxis/empiric therapy in our unit. Our results also confirm that candidemia plays an important pathogenic role in NICU patients. There is a significant variation in cases of candidemia in different geographic regions, even within the same continent. Therefore, monitoring epidemiological data to facilitate the choice of treatment is important.
The study protocol was approved by the Ethics Committee of the Azienda Ospedaliero-Universitaria Policlinico of Bari, Italy (Application no. 1321, 2007). Registered data were managed in accordance with the Italian data protection laws (privacy law).
Written informed consent was obtained from patient parents or their legal guardians.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
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Giuseppina Caggiano, (1) Grazia Lovero, (1) Osvalda De Giglio, (1) Giovanna Barbuti, (2) Osvaldo Montagna, (3) Nicola Laforgia, (4) and Maria Teresa Montagna (1)
(1) Department of Biomedical Science and Human Oncology, Hygiene Section, University of Bari "Aldo Moro", Bari, Italy
(2) Department of Biomedical Science and Human Oncology, General Pathology Section, University of Bari "Aldo Moro", Bari, Italy
(3) Neonatology and NICU Section, Azienda Ospedaliero-Universitaria Policlinico of Bari, Bari, Italy
(4) Department of Biomedical Science and Human Oncology, Neonatology and NICU Section, University of Bari "Aldo Moro", Bari, Italy
Correspondence should be addressed to Giuseppina Caggiano; firstname.lastname@example.org
Received 16 March 2017; Accepted 18 June 2017; Published 13 August 2017
Academic Editor: Stanley Brul
Caption: FIGURE 1: Temporal trend of Candida albicans and Candida nonalbicans during a 9-year period.
Caption: FIGURE 2: Distribution of Candida spp. according to the different geographical areas.
TABLE 1: Clinical characteristics of the patients with candidemia by species. Characteristics Candida albicans Candida p value (n = 14) non-albicans (n = 27) Low gestational age 11 (78.6) 25 (92.6) 0.317 [less than or equal to] 32 wk, n (%) Gestational age 31 (29.5-31.5) 30 (29-31) 0.193 ([dagger]) Birth weight [less 11 (78.6) 25 (92.6) 0.317 than or equal to] 1500 g, n (%) Birth weight (g) 1200 (1013-1625) 1200 (900-1380) 0.573 ([dagger]) Stay in NICU [less 12 (85.7) 27 (100) 0.111 than or equal to] 7 days, n (%) Length of stay 10 (7.5-12) 12 (10-15) 0.045# before candidemia (days) ([dagger]) Presence of CVC, 13 (92.8) 27 (100) 0.342 n (%) TPN, n (%) 10 (71.4) 26 (96.3) 0.039# Mechanical 11 (78.6) 26 (96.3) 0.107 ventilation, n (%) Prolonged antibiotic 12 (85.7) 24 (92.3) 1.000 therapy, n (%) ([dagger]) Median (interquartile range). CVC: central venous catheter; TPN: total parenteral nutrition. Bold values are significant. Note: # values are significant. TABLE 2: Cumulative distribution of the MICs of 41 clinical Candida isolates. Cumulative % of strains inhibited at the indicated concentrations (mg/L) Isolates Antifungal 0.008 0.015 0.03 0.06 (number) drugs Fluconazole Candida Amphotericin B 4 parapsilosis Anidulafungin complex (25) Caspofungin Micafungin Fluconazole Candida Amphotericin B 8 albicans (14) Anidulafungin 33 67 100 Caspofungin 12 33 83 Micafungin 42 100 All species Fluconazole (41) Amphotericin B 5 Anidulafungin 10 20 33 Caspofungin 5 10 25 Micafungin 13 30 33 Cumulative % of strains inhibited at the indicated concentrations (mg/L) Isolates Antifungal 0.12 0.25 0.5 1 (number) drugs Fluconazole 4 38 77 Candida Amphotericin B 58 100 parapsilosis Anidulafungin 12 65 complex (25) Caspofungin 12 58 100 Micafungin 19 92 Fluconazole 17 75 83 100 Candida Amphotericin B 17 75 100 albicans (14) Anidulafungin Caspofungin 100 Micafungin All species Fluconazole 5 25 50 83 (41) Amphotericin B 8 65 100 Anidulafungin 40 75 Caspofungin 33 70 98 Micafungin 45 93 Cumulative % of strains inhibited at the indicated concentrations (mg/L) Isolates Antifungal 2 4 8 (number) drugs Fluconazole 92 100 Candida Amphotericin B parapsilosis Anidulafungin 100 complex (25) Caspofungin Micafungin 100 Fluconazole Candida Amphotericin B albicans (14) Anidulafungin Caspofungin Micafungin All species Fluconazole 93 98 100 (41) Amphotericin B Anidulafungin 100 Caspofungin 100 Micafungin 100 TABLE 3: Distribution of Candida spp. from bloodstream infections in NICU patients from 2000-2015 in various studies. Reference Country/ Study design Number of observation time isolates (a) Europe Presterl Austria/January Retrospective/ 16 et al., 2001 to December single hospital 2007  2006 Lagrou et Belgium/January Retrospective, data 9 al., 2007 2001 to December from the hospital  2005 information system/ single hospital Sarvikivi Finland/January Retrospective, data 25 et al., 2000 to December were laboratory- 2005  2002 (original based/single period: 1991-2002) hospital Spiliopoulou Greece/January Retrospective/ 40 et al., 2012 2005 to December single hospital  2009 Lovero et al., Italy/January Retrospective, data 57 2016  2000 to December were laboratory- 2014 based/single hospital Montagna et Italy/February Prospective 21 al., 2010  2007 to August (Aurora), data were 2008 web database-based/ 6 neonatal units Tortorano et Italy/January Prospective, data 17 al., 2013  2009 to December were laboratory- 2009 based/34 hospitals Rodriguez et Spain/January Prospective, data 24 al., 2006  2002 to December were laboratory- 2003 based/5 hospitals Peman et al., Spain/January Prospective 27 2011  2009 to (FUNGEMYCA)/30 February 2010 hospitals Yalaz et al., Turkey/January Retrospective, 14 2006  2000 to December review of medical 2002 records/single hospital Celebi et al., Turkey/January Prospective/single 28 2012  2000 to December hospital 2007 Ozkan et al., Turkey/January Prospective/single 24 2014  2003 to hospital December 2010 Clerihew et United Kingdom/ Prospective 67 al., 2006  February 2003 to (British Paediatric February 2004 Surveillance Unit)/ 56 neonatal units Vergnano et United Kingdom/ Prospective 37 al., 2011  January 2006 (NeonIN), data were to December 2008 web database- based/12 neonatal units North and South America Aziz et al., USA/January 2000 Retrospective, 10 2010  to December 2006 review of medical records/single hospital Feja et al., USA/March 2001 Prospective/2 45 2005  to January 2003 neonatal units Horn et al., USA/July 2004 to Prospective (PATH 26 2009  March 2008 Alliance), data were web database-based/23 hospitals Pfaller et USA-Canada/July Prospective (PATH 62 al., 2012  2004 to Alliance), data December 2008 were web database- based/23 medical centers in the USA and two in Canada Bizzarro et USA/January 2004 Retrospective, 20 al., 2015  to December 2013 review of medical records/single hospital Natarajan et USA/January 2006 Retrospective, 29 al., 2009  to December 2007 review of medical records/single hospital Robinson et USA/January 2000 Retrospective, data 37 al., 2012  to December 2010 from the hospital information system/single hospital Batista et Brazil/October Prospective/single 10 al., 2014  2006 to hospital March 2007 Hoffmann- Brazil/January Retrospective, data 45 Santos et al., 2006 to December were laboratory- 2013  2011 based/2 hospitals Cortes et al., Colombia/January Prospective, data 143 2011  2001 to December were laboratory- 2007 based/27 hospitals Cortes et Colombia/March Prospective/7 15 al., 2014  2008 to March 2009 hospitals Asia Hua et al., China/February Retrospective, 34 2012  2008 to February review of medical 2010 records/single hospital Wu et al., China/January Retrospective, 37 2014  2009 to review of medical December 2011 records/single hospital Chen et al., China/January Retrospective, data 43 2015  2010 to from the hospital December 2013 information system/ single hospital Rani et al., India/January Prospective/single 50 2002  2000 to June 2000 hospital Agarwal et India/August 2002 Prospective/single 90 al., 2004  to April 2003 hospital Femitha et India/October Prospective/single 36 al., 2013  2009 and hospital July 2011 Mehara et al., India/January Retrospective, 9 2013  2012 to review of medical September 2012 records/single hospital Juyal et al., India/January Prospective, data 132 2013  2012 to were laboratory- December 2012 based/single hospital Chaurasia et India/January Retrospective, 30 al., 2015  2013 to June 2013 review of medical records/single hospital Wadile and India/January Retrospective, 20 Bhate, 2015 2014 to December review of medical  2014 records/single hospital Al-Sweih et Kuwait/January Retrospective, 108 al., 2009  2000 to December review of medical 2006 (original records/single period: 1995-2006) hospital Hammoud et Kuwait/January Retrospective, 89 al., 2013  2007 to December review of medical 2010 records/single hospital Khan et al., Pakistan/January Retrospective, 41 2015  2009 to January data were 2014 laboratory-based/ single hospital Wu et al., Taiwan/January Retrospective, 13 2009  2001 to December review of medical 2006 records/single hospital Tsai et al., Taiwan/January Retrospective, 52 2014  2004 to December review of medical 2011 records and administrative databases/single hospital Lim et al., Taiwan/January Retrospective, 6 2012  2005 to December review of medical 2009 records and administrative database/single hospital Chen et al., Taiwan/January Retrospective, 9 2015  2008 to December review of medical 2013 Africa records/single hospital Motara et al., South Africa/July Retrospective, data 10 2005 2002 to July 2003 were laboratory- based/single hospital Ballot et South Africa/ Retrospective/ 57 al., 2013  January 2007 to single hospital December 2011 Oceania Chen et al., Australia/August Retrospective, data 35 2006  2001 to July 2004 were laboratory- based/50 microbiology laboratories Distribution of Candida spp. (%) Reference CA CP CG CT CGU CF CK Presterl 93.8 6.2 et al., 2007  Lagrou et 88.9 al., 2007  Sarvikivi 32 68 et al., 2005  Spiliopoulou 67.5 25 2.5 5 et al., 2012  Lovero et al., 47 44 4 5 2016  Montagna et 35 60 5 al., 2010  Tortorano et 58.8 35.3 5.9 al., 2013  Rodriguez et 29.2 66.7 4.1 al., 2006  Peman et al., 51.9 33.3 3.7 3.7 3.7 3.7 2011  Yalaz et al., 100 2006  Celebi et al., 42.9 57.1 2012  Ozkan et al., 33.3 66.7 2014  Clerihew et 55.2 32.8 al., 2006  Vergnano et 73 al., 2011  Aziz et al., 40 40 10 2010  Feja et al., 62 31 2 2005  Horn et al., 69.2 26.9 2009  Pfaller et 54.8 30.6 1.6 al., 2012  Bizzarro et 50 35 5 al., 2015  Natarajan et 58.6 27.6 6.9 3.4 3.4 al., 2009  Robinson et 59.5 24.3 8.1 al., 2012  Batista et 60 40 al., 2014  Hoffmann- 33.3 48.9 11.2 Santos et al., 2013  Cortes et al., 61 15 5 2011  Cortes et 60 13.3 13.3 al., 2014  Hua et al., 38.2 32.4 2.9 5.9 5.9 11.8 2.9 2012  Wu et al., 16.2 54.1 2014  Chen et al., 14 39.5 32.6 14 2015  Rani et al., 4 92 2002  Agarwal et 15.6 al., 2004  Femitha et 25 44.4 al., 2013  Mehara et al., 44.4 22.2 33.3 2013  Juyal et al., 19.7 25 14.4 24 10.6 2013  Chaurasia et 20 23.3 10 36.7 10 al., 2015  Wadile and 65 15 10 5 5 Bhate, 2015  Al-Sweih et 41.7 45.4 al., 2009  Hammoud et 47.2 38.2 6.7 1.1 4.5 al., 2013  Khan et al., 26 2015  Wu et al., 23.1 69.2 2009  Tsai et al., 61.5 30.8 7.7 2014  Lim et al., 66.7 33.3 2012  Chen et al., 22.2 77.8 2015  Motara et al., 80 20 2005 Ballot et 28.1 56.1 3.5 8.8 al., 2013  Chen et al., 42 43 9 2 2006  Distribution of Candida spp. (%) Reference CL CD CLI CST CKE Candida spp. (b) Presterl et al., 2007  Lagrou et 11.1 al., 2007  Sarvikivi et al., 2005  Spiliopoulou et al., 2012  Lovero et al., 2016  Montagna et al., 2010  Tortorano et al., 2013  Rodriguez et al., 2006  Peman et al., 2011  Yalaz et al., 2006  Celebi et al., 2012  Ozkan et al., 2014  Clerihew et 12 al., 2006  Vergnano et 27 al., 2011  Aziz et al., 10 2010  Feja et al., 2 2 2005  Horn et al., 3.8 2009  Pfaller et 6.5 6.5 al., 2012  Bizzarro et 5 5 al., 2015  Natarajan et al., 2009  Robinson et 5.4 2.7 al., 2012  Batista et al., 2014  Hoffmann- 6.7 Santos et al., 2013  Cortes et al., 19 2011  Cortes et 13.3 al., 2014  Hua et al., 2012  Wu et al., 29.7 2014  Chen et al., 2015  Rani et al., 4 2002  Agarwal et 84.4 al., 2004  Femitha et 30.6 al., 2013  Mehara et al., 2013  Juyal et al., 8.3 2013  Chaurasia et al., 2015  Wadile and Bhate, 2015  Al-Sweih et 12.9 al., 2009  Hammoud et 2.2 al., 2013  Khan et al., 74 2015  Wu et al., 7.7 2009  Tsai et al., 2014  Lim et al., 2012  Chen et al., 2015  Motara et al., 2005 Ballot et 1.8 1.8 al., 2013  Chen et al., 2 2 2006  CA: Candida albicans; CP: C. parapsihsis; CG: C. glabrata; CT: C. tropicalis; CGU: C. guilliermondii; CF: C. famata; CK: C. krusei; CL: C. lusitaniae; CD: C. dubliniensis; CLI: C. lipolytica; CST: C. stelloidea; CKE: C. kefyr. (a) Total number of Candida isolates from blood (or the total number of candidemia episodes when the number of isolates was not available from the original study). (b) Including Candida spp. not depicted in the table and Candida spp. not identified at the species level. TABLE 4: Main candidemia finding in the NICU as reported in various studies. Reference Main candidemia finding in the NICU Lagrou et Annual incidence: 0.30 episodes per 10,000 al., 2007  patient-days. Sarvikivi et Fluconazole prophylaxis contributed to the al., 2005  emergence of C. parapsilosis with decreased susceptibility to fluconazole. Spiliopoulou Candidemia incidence decreased. C. albicans was et al., 2012 most frequently isolated from ELBW infants.  Mortality (35.7%) was associated with low gestational age and low birth weight. Lovero et al., Incidence rate of Candida non-albicans increased 2016  from 46% in 2000-2004 to 71% in 2010-2014. Montagna et Overall incidence: 1.3 per 100 NICU discharges. al., 2010  The incidence in ELBW infants was 4.3% versus 0.2% in LBW infants. Rodriguez et Annual incidence: 1.1 per 100 NICU discharges and al., 2006  1.08 per 1000 patient-days. Low mortality (21%) rate may have been caused by a high prevalence of C. parapsilosis fungemia. Peman et al., C. albicans was more common in the NICU setting 2011  than in the pediatric ICU. Yalaz et al., Candidemia markedly increased in 2002 compared with 2006  previous years. A significant association was found between Candida infection and the duration of antibiotic therapy. Celebi et al., Overall incidence: 11.5 per 1000 NICU admissions. 2012  The mortality rate was 42.8%. Ozkan et al., Gram-positive sepsis (67.6%) was more common than 2014  Gram-negative bacteremia (16.6%) and candidemia (15.8%). Candida spp. caused LOS (58.3%), VLOS (41,7%), and no EOS sepsis. Clerihew et C. parapsilosis was associated with fewer deep- al., 2006  seated infections than C. albicans, but mortality was similar. Vergnano et A decrease in candidemia was observed: 1.8% in al., 2011  2006,1.2% in 2007, and 1.3% in 2008. Candida spp. were more common in LOS (97%) than in EOS (3%) sepsis. Aziz et al., Fluconazole prophylactic administration to ELBW 2010  infants was associated with a decreased rate of candidemia. Feja et al., Overall incidence: 1.6 per 100 NICU discharges. 2005  Catheter use, previous bacterial sepsis, and GI pathology were significantly associated with candidemia. Bizzarro et Candida spp. were more common in LOS than in al., 2015  EOS sepsis. Natarajan et Candidemia refractory to conventional antifungals al., 2009  was associated with prolonged antibiotic use and Candida non-albicans infection. Robinson et Overall incidence: 0.45 per 100 NICU discharges. al., 2012  An increased time between blood culture draw and initial antifungal therapy was associated with an increased incidence of persistent candidemia. Batista et Oral colonization should be considered as a risk al., 2014  factor for candidemia. Hua et al., Patients with C. parapsilosis had a significantly 2012  longer hospital stay than those with C. albicans sepsis. Wu et al., C. guilliermondii was associated with preterm 2014  infants and with low birth weight. Chen et al., Fluconazole prophylaxis alone was not efficacious; 2015  it had to be combined with reinforcement of management and supervision of hand hygiene to effectively prevent invasive candidiasis. Rani et al., Candida non-albicans accounted for 96% of 2002  the cases of neonatal candidemia. Agarwal et Overall incidence: 77 per 1000 NICU discharges. al., 2004  Candida non-albicans is gaining importance as a cause of neonatal septicemia. Femitha et Overall incidence: 0.82 cases per 100 NICU al., 2013  discharges. Mortality was 44.4%. Presence of candiduria was a significant riskfactor for death. Mehara et al., Candida spp. were more common in LOS than in EOS 2013  sepsis. Juyal et al., Candida non-albicans accounted for 80.30% of the 2013  cases of neonatal candidemia. The crude mortality was 34.85%. Chaurasia et Clinical features in neonates with candida sepsis al., 2015  were nonspecific. A common laboratory feature was thrombocytopenia. Al-Sweih et Overall incidence: 4 per 100 NICU discharges. al., 2009  Hammoud et C. albicans was the most prevalent species in al., 2013  nonpersistent candidemia. C. parapsilosis was more common among infants with persistent candidemia. Persistent candidemia was associated with an increased risk of mortality. Wu et al., The most common causative microorganisms of LOS 2009  sepsis were CONS and Candida spp. C. parapsilosis was associated with a high mortality rate. Tsai et al., Candidemia had a significantly higher rate of 2014  infectious complications, persistent bloodstream infection, and sepsis-attributable mortality than Gram-negative and Gram-positive bacteremia. Lim et al., Sepsis by Gram-negative bacteria or Candida spp. 2012  presented with more severe clinical symptoms and was associated with a higher mortality rate compared with that by Gram-positive bacteria. Chen et al., Decrease incidence of candidemia during the 2015  study period. Ballot et Increased incidence of Candida non-albicans during al., 2013  the study period. CONS: coagulase-negative staphylococci; ELBW: extremely low birth weight; VLBW: very low birth weight; GI: gastrointestinal; EOS: early-onset sepsis; LOS: late-onset sepsis; VLOS: very late-onset sepsis; NICU: neonatal intensive care unit; ICU: intensive care unit.
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|Title Annotation:||Research Article|
|Author:||Caggiano, Giuseppina; Lovero, Grazia; De Giglio, Osvalda; Barbuti, Giovanna; Montagna, Osvaldo; Lafo|
|Publication:||BioMed Research International|
|Date:||Jan 1, 2017|
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