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Candidemia in the Neonatal Intensive Care Unit: A Retrospective, Observational Survey and Analysis of Literature Data.

1. Introduction

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 [1]. Newborns who survive frequently have long-term neurological impairment, including cerebral palsy, blindness, hearing impairment, cognitive deficits, and periventricular leukomalacia [2]. 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 [4]. 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 [7]. 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. Results

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.) [52].

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.

4. Discussion

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 [12]. 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 [20]. 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 [54]. 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 [55].

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 [56]. 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].

5. Conclusions

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.

Ethical Approval

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).

Consent

Written informed consent was obtained from patient parents or their legal guardians.

https://doi.org/10.1155/2017/7901763

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; giuseppina.caggiano@uniba.it

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 [10]                2006

Lagrou et          Belgium/January     Retrospective, data       9
al., 2007          2001 to December     from the hospital
[11]                     2005          information system/
                                         single hospital

Sarvikivi          Finland/January     Retrospective, data      25
et al.,            2000 to December     were laboratory-
2005 [12]           2002 (original        based/single
                  period: 1991-2002)        hospital

Spiliopoulou        Greece/January       Retrospective/         40
et al., 2012       2005 to December      single hospital
[13]                     2009

Lovero et al.,      Italy/January      Retrospective, data      57
2016 [14]          2000 to December     were laboratory-
                         2014             based/single
                                            hospital

Montagna et         Italy/February         Prospective          21
al., 2010 [15]      2007 to August     (Aurora), data were
                         2008          web database-based/
                                        6 neonatal units

Tortorano et        Italy/January       Prospective, data       17
al., 2013 [16]     2009 to December     were laboratory-
                         2009          based/34 hospitals

Rodriguez et        Spain/January       Prospective, data       24
al., 2006 [17]     2002 to December     were laboratory-
                         2003           based/5 hospitals

Peman et al.,       Spain/January          Prospective          27
2011 [18]              2009 to           (FUNGEMYCA)/30
                    February 2010           hospitals

Yalaz et al.,       Turkey/January       Retrospective,         14
2006 [19]          2000 to December     review of medical
                         2002            records/single
                                            hospital

Celebi et al.,      Turkey/January     Prospective/single       28
2012 [20]          2000 to December         hospital
                         2007

Ozkan et al.,       Turkey/January     Prospective/single       24
2014 [21]              2003 to              hospital
                    December 2010

Clerihew et        United Kingdom/         Prospective          67
al., 2006 [22]     February 2003 to    (British Paediatric
                    February 2004      Surveillance Unit)/
                                        56 neonatal units

Vergnano et        United Kingdom/         Prospective          37
al., 2011 [23]       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 [24]          to December 2006     review of medical
                                         records/single
                                            hospital

Feja et al.,        USA/March 2001        Prospective/2         45
2005 [25]          to January 2003       neonatal units

Horn et al.,       USA/July 2004 to     Prospective (PATH       26
2009 [26]             March 2008         Alliance), data
                                            were web
                                        database-based/23
                                            hospitals

Pfaller et         USA-Canada/July      Prospective (PATH       62
al., 2012 [27]         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 [28]     to December 2013     review of medical
                                         records/single
                                            hospital

Natarajan et       USA/January 2006      Retrospective,         29
al., 2009 [29]     to December 2007     review of medical
                                         records/single
                                            hospital

Robinson et        USA/January 2000    Retrospective, data      37
al., 2012 [30]     to December 2010     from the hospital
                                           information
                                          system/single
                                            hospital

Batista et          Brazil/October     Prospective/single       10
al., 2014 [31]         2006 to              hospital
                      March 2007

Hoffmann-           Brazil/January     Retrospective, data      45
Santos et al.,     2006 to December     were laboratory-
2013 [32]                2011           based/2 hospitals

Cortes et al.,     Colombia/January     Prospective, data       143
2011 [33]          2001 to December     were laboratory-
                         2007          based/27 hospitals

Cortes et           Colombia/March        Prospective/7         15
al., 2014 [34]    2008 to March 2009        hospitals

                         Asia

Hua et al.,         China/February       Retrospective,         34
2012 [35]          2008 to February     review of medical
                         2010            records/single
                                            hospital

Wu et al.,          China/January        Retrospective,         37
2014 [36]              2009 to          review of medical
                    December 2011        records/single
                                            hospital

Chen et al.,        China/January      Retrospective, data      43
2015 [37]              2010 to          from the hospital
                    December 2013      information system/
                                         single hospital

Rani et al.,        India/January      Prospective/single       50
2002 [38]         2000 to June 2000         hospital

Agarwal et        India/August 2002    Prospective/single       90
al., 2004 [39]      to April 2003           hospital

Femitha et          India/October      Prospective/single       36
al., 2013 [40]         2009 and             hospital
                      July 2011

Mehara et al.,      India/January        Retrospective,          9
2013 [41]              2012 to          review of medical
                    September 2012       records/single
                                            hospital

Juyal et al.,       India/January       Prospective, data       132
2013 [42]              2012 to          were laboratory-
                    December 2012         based/single
                                            hospital

Chaurasia et        India/January        Retrospective,         30
al., 2015 [43]    2013 to June 2013     review of medical
                                         records/single
                                            hospital

Wadile and          India/January        Retrospective,         20
Bhate, 2015        2014 to December     review of medical
[44]                     2014            records/single
                                            hospital

Al-Sweih et         Kuwait/January       Retrospective,         108
al., 2009 [45]     2000 to December     review of medical
                    2006 (original       records/single
                  period: 1995-2006)        hospital

Hammoud et          Kuwait/January       Retrospective,         89
al., 2013 [46]     2007 to December     review of medical
                         2010            records/single
                                            hospital

Khan et al.,       Pakistan/January      Retrospective,         41
2015 [47]          2009 to January          data were
                         2014           laboratory-based/
                                         single hospital

Wu et al.,          Taiwan/January       Retrospective,         13
2009 [48]          2001 to December     review of medical
                         2006            records/single
                                            hospital

Tsai et al.,        Taiwan/January       Retrospective,         52
2014 [49]          2004 to December     review of medical
                         2011              records and
                                         administrative
                                        databases/single
                                            hospital

Lim et al.,         Taiwan/January       Retrospective,          6
2012 [50]          2005 to December     review of medical
                         2009              records and
                                         administrative
                                         database/single
                                            hospital

Chen et al.,        Taiwan/January       Retrospective,          9
2015 [37]          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 [51]     January 2007 to       single hospital
                    December 2011

                       Oceania

Chen et al.,       Australia/August    Retrospective, data      35
2006 [52]         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 [10]

Lagrou et         88.9
al., 2007
[11]

Sarvikivi          32     68
et al.,
2005 [12]

Spiliopoulou      67.5    25    2.5     5
et al., 2012
[13]

Lovero et al.,     47     44     4             5
2016 [14]

Montagna et        35     60     5
al., 2010 [15]

Tortorano et      58.8   35.3   5.9
al., 2013 [16]

Rodriguez et      29.2   66.7   4.1
al., 2006 [17]

Peman et al.,     51.9   33.3   3.7    3.7    3.7    3.7
2011 [18]

Yalaz et al.,     100
2006 [19]

Celebi et al.,    42.9   57.1
2012 [20]

Ozkan et al.,     33.3   66.7
2014 [21]

Clerihew et       55.2   32.8
al., 2006 [22]

Vergnano et        73
al., 2011 [23]

Aziz et al.,       40     40     10
2010 [24]

Feja et al.,       62     31     2
2005 [25]

Horn et al.,      69.2   26.9
2009 [26]

Pfaller et        54.8   30.6   1.6
al., 2012 [27]

Bizzarro et        50     35     5
al., 2015 [28]

Natarajan et      58.6   27.6   6.9           3.4           3.4
al., 2009 [29]

Robinson et       59.5   24.3          8.1
al., 2012 [30]

Batista et         60     40
al., 2014 [31]

Hoffmann-         33.3   48.9          11.2
Santos et al.,
2013 [32]

Cortes et al.,     61     15                          5
2011 [33]

Cortes et          60    13.3          13.3
al., 2014 [34]

Hua et al.,       38.2   32.4   2.9    5.9    5.9    11.8   2.9
2012 [35]

Wu et al.,        16.2                        54.1
2014 [36]

Chen et al.,       14    39.5                 32.6    14
2015 [37]

Rani et al.,       4                    92
2002 [38]

Agarwal et        15.6
al., 2004 [39]

Femitha et         25           44.4
al., 2013 [40]

Mehara et al.,    44.4          22.2   33.3
2013 [41]

Juyal et al.,     19.7    25    14.4    24                  10.6
2013 [42]

Chaurasia et       20    23.3    10    36.7                  10
al., 2015 [43]

Wadile and         65     15     10     5                    5
Bhate, 2015
[44]

Al-Sweih et       41.7   45.4
al., 2009 [45]

Hammoud et        47.2   38.2   6.7           1.1    4.5
al., 2013 [46]

Khan et al.,       26
2015 [47]

Wu et al.,        23.1   69.2
2009 [48]

Tsai et al.,      61.5   30.8   7.7
2014 [49]

Lim et al.,       66.7   33.3
2012 [50]

Chen et al.,      22.2   77.8
2015 [37]

Motara et al.,     80     20
2005

Ballot et         28.1   56.1   3.5    8.8
al., 2013 [51]

Chen et al.,       42     43     9      2
2006 [52]

                     Distribution of Candida spp. (%)

Reference         CL    CD    CLI   CST   CKE   Candida
                                                spp. (b)

Presterl
et al.,
2007 [10]

Lagrou et                                         11.1
al., 2007
[11]

Sarvikivi
et al.,
2005 [12]

Spiliopoulou
et al., 2012
[13]

Lovero et al.,
2016 [14]

Montagna et
al., 2010 [15]

Tortorano et
al., 2013 [16]

Rodriguez et
al., 2006 [17]

Peman et al.,
2011 [18]

Yalaz et al.,
2006 [19]

Celebi et al.,
2012 [20]

Ozkan et al.,
2014 [21]

Clerihew et                                        12
al., 2006 [22]

Vergnano et                                        27
al., 2011 [23]

Aziz et al.,                  10
2010 [24]

Feja et al.,       2                 2
2005 [25]

Horn et al.,                                      3.8
2009 [26]

Pfaller et        6.5                             6.5
al., 2012 [27]

Bizzarro et        5     5
al., 2015 [28]

Natarajan et
al., 2009 [29]

Robinson et       5.4                             2.7
al., 2012 [30]

Batista et
al., 2014 [31]

Hoffmann-                                         6.7
Santos et al.,
2013 [32]

Cortes et al.,                                     19
2011 [33]

Cortes et                                         13.3
al., 2014 [34]

Hua et al.,
2012 [35]

Wu et al.,                                        29.7
2014 [36]

Chen et al.,
2015 [37]

Rani et al.,                               4
2002 [38]

Agarwal et                                        84.4
al., 2004 [39]

Femitha et                                        30.6
al., 2013 [40]

Mehara et al.,
2013 [41]

Juyal et al.,                                     8.3
2013 [42]

Chaurasia et
al., 2015 [43]

Wadile and
Bhate, 2015
[44]

Al-Sweih et                                       12.9
al., 2009 [45]

Hammoud et        2.2
al., 2013 [46]

Khan et al.,                                       74
2015 [47]

Wu et al.,                                        7.7
2009 [48]

Tsai et al.,
2014 [49]

Lim et al.,
2012 [50]

Chen et al.,
2015 [37]

Motara et al.,
2005

Ballot et         1.8   1.8
al., 2013 [51]

Chen et al.,             2                         2
2006 [52]

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 [11]    patient-days.

Sarvikivi et      Fluconazole prophylaxis contributed to the
al., 2005 [12]    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.
[13]              Mortality (35.7%) was associated with low
                  gestational age and low birth weight.

Lovero et al.,    Incidence rate of Candida non-albicans increased
2016 [14]         from 46% in 2000-2004 to 71% in 2010-2014.

Montagna et       Overall incidence: 1.3 per 100 NICU discharges.
al., 2010 [15]    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 [17]    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 [18]         than in the pediatric ICU.

Yalaz et al.,     Candidemia markedly increased in 2002 compared with
2006 [19]         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 [20]         The mortality rate was 42.8%.

Ozkan et al.,     Gram-positive sepsis (67.6%) was more common than
2014 [21]         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 [22]    seated infections than C. albicans, but mortality
                  was similar.

Vergnano et       A decrease in candidemia was observed: 1.8% in
al., 2011 [23]    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 [24]         infants was associated with a decreased rate
                  of candidemia.

Feja et al.,      Overall incidence: 1.6 per 100 NICU discharges.
2005 [25]         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 [28]    EOS sepsis.

Natarajan et      Candidemia refractory to conventional antifungals
al., 2009 [29]    was associated with prolonged antibiotic use and
                  Candida non-albicans infection.

Robinson et       Overall incidence: 0.45 per 100 NICU discharges.
al., 2012 [30]    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 [31]    factor for candidemia.

Hua et al.,       Patients with C. parapsilosis had a significantly
2012 [35]         longer hospital stay than those with C. albicans
                  sepsis.

Wu et al.,        C. guilliermondii was associated with preterm
2014 [36]         infants and with low birth weight.

Chen et al.,      Fluconazole prophylaxis alone was not efficacious;
2015 [37]         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 [38]         the cases of neonatal candidemia.

Agarwal et        Overall incidence: 77 per 1000 NICU discharges.
al., 2004 [39]    Candida non-albicans is gaining importance as a
                  cause of neonatal septicemia.

Femitha et        Overall incidence: 0.82 cases per 100 NICU
al., 2013 [40]    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 [41]         sepsis.

Juyal et al.,     Candida non-albicans accounted for 80.30% of the
2013 [42]         cases of neonatal candidemia. The crude mortality
                  was 34.85%.

Chaurasia et      Clinical features in neonates with candida sepsis
al., 2015 [43]    were nonspecific. A common laboratory feature was
                  thrombocytopenia.

Al-Sweih et       Overall incidence: 4 per 100 NICU discharges.
al., 2009 [45]

Hammoud et        C. albicans was the most prevalent species in
al., 2013 [46]    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 [48]         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 [49]         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 [50]         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 [37]         study period.

Ballot et         Increased incidence of Candida non-albicans during
al., 2013 [51]    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
Article Type:Report
Date:Jan 1, 2017
Words:7514
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