We evaluated the epidemiology of
Although blood stream infection (BSI) due to
This study aimed (i) to determine the epidemiology of
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
Extremely low birth weight (ELBW) infants were defined as those with a birth weight ≤ 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
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°C (±1) and 28°C (±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°C and 42°C) and biochemical analysis using two methods, the Vitek 2 system and ID 32C panels (Bio-Merieux, Rome, Italy), to obtain accurate results. All strains were frozen at −70°C until further investigations [
Antifungal susceptibility tests to five antifungal drugs (anidulafungin, fluconazole, caspofungin, micafungin, and amphotericin B) were performed for all
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
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
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”, “
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
A total of 41 infants with
Clinical characteristics of the patients with candidemia by species.
Characteristics |
|
|
|
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Low gestational age ≤ 32 wk, |
11 (78.6) | 25 (92.6) | 0.317 |
Gestational age‡ | 31 (29.5–31.5) | 30 (29–31) | 0.193 |
Birth weight ≤ 1500 g, |
11 (78.6) | 25 (92.6) | 0.317 |
Birth weight (g)‡ | 1200 (1013–1625) | 1200 (900–1380) | 0.573 |
Stay in NICU ≤ 7 days, |
12 (85.7) | 27 (100) | 0.111 |
Length of stay before candidemia (days)‡ | 10 (7.5–12) | 12 (10–15) |
|
Presence of CVC, |
13 (92.8) | 27 (100) | 0.342 |
TPN, |
10 (71.4) | 26 (96.3) |
|
Mechanical ventilation, |
11 (78.6) | 26 (96.3) | 0.107 |
Prolonged antibiotic therapy, |
12 (85.7) | 24 (92.3) | 1.000 |
Temporal trend of
Results of antifungal susceptibility are shown in Table
Cumulative distribution of the MICs of 41 clinical
Isolates (number) | Antifungal drugs | Cumulative % of strains inhibited at the indicated concentrations (mg/L) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
0.008 | 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | ||
|
Fluconazole | 4 | 38 | 77 | 92 | 100 | ||||||
Amphotericin B | 4 | 58 | 100 | |||||||||
Anidulafungin | 12 | 65 | 100 | |||||||||
Caspofungin | 12 | 58 | 100 | |||||||||
Micafungin | 19 | 92 | 100 | |||||||||
|
Fluconazole | 17 | 75 | 83 | 100 | |||||||
Amphotericin B | 8 | 17 | 75 | 100 | ||||||||
Anidulafungin | 33 | 67 | 100 | |||||||||
Caspofungin | 12 | 33 | 83 | 100 | ||||||||
Micafungin | 42 | 100 | ||||||||||
All species (41) | Fluconazole | 5 | 25 | 50 | 83 | 93 | 98 | 100 | ||||
Amphotericin B | 5 | 8 | 65 | 100 | ||||||||
Anidulafungin | 10 | 20 | 33 | 40 | 75 | 100 | ||||||
Caspofungin | 5 | 10 | 25 | 33 | 70 | 98 | 100 | |||||
Micafungin | 13 | 30 | 33 | 45 | 93 | 100 |
A total of 45 articles were selected (Tables
Distribution of
Reference | Country/observation time | Study design | Number of |
Distribution of | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CA | CP | CG | CT | CGU | CF | CK | CL | CD | CLI | CST | CKE |
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Presterl et al., 2007 [ |
Austria/January 2001 to December 2006 | Retrospective/single hospital | 16 | 93.8 | 6.2 | |||||||||||
Lagrou et al., 2007 [ |
Belgium/January 2001 to December 2005 | Retrospective, data from the hospital information system/single hospital | 9 | 88.9 | 11.1 | |||||||||||
Sarvikivi et al., 2005 [ |
Finland/January 2000 to December 2002 (original period: 1991–2002) | Retrospective, data were laboratory-based/single hospital | 25 | 32 | 68 | |||||||||||
Spiliopoulou et al., 2012 [ |
Greece/January 2005 to December 2009 | Retrospective/single hospital | 40 | 67.5 | 25 | 2.5 | 5 | |||||||||
Lovero et al., 2016 [ |
Italy/January 2000 to December 2014 | Retrospective, data were laboratory-based/single hospital | 57 | 47 | 44 | 4 | 5 | |||||||||
Montagna et al., 2010 [ |
Italy/February 2007 to August 2008 | Prospective (Aurora), data were web database-based/6 neonatal units | 21 | 35 | 60 | 5 | ||||||||||
Tortorano et al., 2013 [ |
Italy/January 2009 to December 2009 | Prospective, data were laboratory-based/34 hospitals | 17 | 58.8 | 35.3 | 5.9 | ||||||||||
Rodriguez et al., 2006 [ |
Spain/January 2002 to December 2003 | Prospective, data were laboratory-based/5 hospitals | 24 | 29.2 | 66.7 | 4.1 | ||||||||||
Pemán et al., 2011 [ |
Spain/January 2009 to February 2010 | Prospective (FUNGEMYCA)/30 hospitals | 27 | 51.9 | 33.3 | 3.7 | 3.7 | 3.7 | 3.7 | |||||||
Yalaz et al., 2006 [ |
Turkey/January 2000 to December 2002 | Retrospective, review of medical records/single hospital | 14 | 100 | ||||||||||||
Celebi et al., 2012 [ |
Turkey/January 2000 to December 2007 | Prospective/single hospital | 28 | 42.9 | 57.1 | |||||||||||
Ozkan et al., 2014 [ |
Turkey/January 2003 to December 2010 | Prospective/single hospital | 24 | 33.3 | 66.7 | |||||||||||
Clerihew et al., 2006 [ |
United Kingdom/February 2003 to February 2004 | Prospective (British Paediatric Surveillance Unit)/56 neonatal units | 67 | 55.2 | 32.8 | 12 | ||||||||||
Vergnano et al., 2011 [ |
United Kingdom/January 2006 to December 2008 | Prospective (NeonIN), data were web database-based/12 neonatal units | 37 | 73 | 27 | |||||||||||
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Aziz et al., 2010 [ |
USA/January 2000 to December 2006 | Retrospective, review of medical records/single hospital | 10 | 40 | 40 | 10 | 10 | |||||||||
Feja et al., 2005 [ |
USA/March 2001 to January 2003 | Prospective/2 neonatal units | 45 | 62 | 31 | 2 | 2 | 2 | ||||||||
Horn et al., 2009 [ |
USA/July 2004 to March 2008 | Prospective (PATH Alliance), data were web database-based/23 hospitals | 26 | 69.2 | 26.9 | 3.8 | ||||||||||
Pfaller et al., 2012 [ |
USA-Canada/July 2004 to December 2008 | Prospective (PATH Alliance), data were web database-based/23 medical centers in the USA and two in Canada | 62 | 54.8 | 30.6 | 1.6 | 6.5 | 6.5 | ||||||||
Bizzarro et al., 2015 [ |
USA/January 2004 to December 2013 | Retrospective, review of medical records/single hospital | 20 | 50 | 35 | 5 | 5 | 5 | ||||||||
Natarajan et al., 2009 [ |
USA/January 2006 to December 2007 | Retrospective, review of medical records/single hospital | 29 | 58.6 | 27.6 | 6.9 | 3.4 | 3.4 | ||||||||
Robinson et al., 2012 [ |
USA/January 2000 to December 2010 | Retrospective, data from the hospital information system/single hospital | 37 | 59.5 | 24.3 | 8.1 | 5.4 | 2.7 | ||||||||
Batista et al., 2014 [ |
Brazil/October 2006 to March 2007 | Prospective/single hospital | 10 | 60 | 40 | |||||||||||
Hoffmann-Santos et al., 2013 [ |
Brazil/January 2006 to December 2011 | Retrospective, data were laboratory-based/2 hospitals | 45 | 33.3 | 48.9 | 11.2 | 6.7 | |||||||||
Cortés et al., 2011 [ |
Colombia/January 2001 to December 2007 | Prospective, data were laboratory-based/27 hospitals | 143 | 61 | 15 | 5 | 19 | |||||||||
Cortés et al., 2014 [ |
Colombia/March 2008 to March 2009 | Prospective/7 hospitals | 15 | 60 | 13.3 | 13.3 | 13.3 | |||||||||
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Hua et al., 2012 [ |
China/February 2008 to February 2010 | Retrospective, review of medical records/single hospital | 34 | 38.2 | 32.4 | 2.9 | 5.9 | 5.9 | 11.8 | 2.9 | ||||||
Wu et al., 2014 [ |
China/January 2009 to December 2011 | Retrospective, review of medical records/single hospital | 37 | 16.2 | 54.1 | 29.7 | ||||||||||
Chen et al., 2015 [ |
China/January 2010 to December 2013 | Retrospective, data from the hospital information system/single hospital | 43 | 14 | 39.5 | 32.6 | 14 | |||||||||
Rani et al., 2002 [ |
India/January 2000 to June 2000 | Prospective/single hospital | 50 | 4 | 92 | 4 | ||||||||||
Agarwal et al., 2004 [ |
India/August 2002 to April 2003 | Prospective/single hospital | 90 | 15.6 | 84.4 | |||||||||||
Femitha et al., 2013 [ |
India/October 2009 and July 2011 | Prospective/single hospital | 36 | 25 | 44.4 | 30.6 | ||||||||||
Mehara et al., 2013 [ |
India/January 2012 to September 2012 | Retrospective, review of medical records/single hospital | 9 | 44.4 | 22.2 | 33.3 | ||||||||||
Juyal et al., 2013 [ |
India/January 2012 to December 2012 | Prospective, data were laboratory-based/single hospital | 132 | 19.7 | 25 | 14.4 | 24 | 10.6 | 8.3 | |||||||
Chaurasia et al., 2015 [ |
India/January 2013 to June 2013 | Retrospective, review of medical records/single hospital | 30 | 20 | 23.3 | 10 | 36.7 | 10 | ||||||||
Wadile and Bhate, 2015 [ |
India/January 2014 to December 2014 | Retrospective, review of medical records/single hospital | 20 | 65 | 15 | 10 | 5 | 5 | ||||||||
Al-Sweih et al., 2009 [ |
Kuwait/January 2000 to December 2006 (original period: 1995–2006) | Retrospective, review of medical records/single hospital | 108 | 41.7 | 45.4 | 12.9 | ||||||||||
Hammoud et al., 2013 [ |
Kuwait/January 2007 to December 2010 | Retrospective, review of medical records/single hospital | 89 | 47.2 | 38.2 | 6.7 | 1.1 | 4.5 | 2.2 | |||||||
Khan et al., 2015 [ |
Pakistan/January 2009 to January 2014 | Retrospective, data were laboratory-based/single hospital | 41 | 26 | 74 | |||||||||||
Wu et al., 2009 [ |
Taiwan/January 2001 to December 2006 | Retrospective, review of medical records/single hospital | 13 | 23.1 | 69.2 | 7.7 | ||||||||||
Tsai et al., 2014 [ |
Taiwan/January 2004 to December 2011 | Retrospective, review of medical records and administrative databases/single hospital | 52 | 61.5 | 30.8 | 7.7 | ||||||||||
Lim et al., 2012 [ |
Taiwan/January 2005 to December 2009 | Retrospective, review of medical records and administrative database/single hospital | 6 | 66.7 | 33.3 | |||||||||||
Chen et al., 2015 [ |
Taiwan/January 2008 to December 2013 | Retrospective, review of medical records/single hospital | 9 | 22.2 | 77.8 | |||||||||||
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Motara et al., 2005 | South Africa/July 2002 to July 2003 | Retrospective, data were laboratory-based/single hospital | 10 | 80 | 20 | |||||||||||
Ballot et al., 2013 [ |
South Africa/January 2007 to December 2011 | Retrospective/single hospital | 57 | 28.1 | 56.1 | 3.5 | 8.8 | 1.8 | 1.8 | |||||||
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Chen et al., 2006 [ |
Australia/August 2001 to July 2004 | Retrospective, data were laboratory-based/50 microbiology laboratories | 35 | 42 | 43 | 9 | 2 | 2 | 2 |
CA:
Main candidemia finding in the NICU as reported in various studies.
Reference | Main candidemia finding in the NICU |
---|---|
Lagrou et al., 2007 [ |
Annual incidence: 0.30 episodes per 10,000 patient-days. |
Sarvikivi et al., 2005 [ |
Fluconazole prophylaxis contributed to the emergence of |
Spiliopoulou et al., 2012 [ |
Candidemia incidence decreased. |
Lovero et al., 2016 [ |
Incidence rate of |
Montagna et al., 2010 [ |
Overall incidence: 1.3 per 100 NICU discharges. The incidence in ELBW infants was 4.3% versus 0.2% in LBW infants. |
Rodriguez et al., 2006 [ |
Annual incidence: 1.1 per 100 NICU discharges and 1.08 per 1000 patient-days. Low mortality (21%) rate may have been caused by a high prevalence of |
Pemán et al., 2011 [ |
|
Yalaz et al., 2006 [ |
Candidemia markedly increased in 2002 compared with previous years. A significant association was found between |
Celebi et al., 2012 [ |
Overall incidence: 11.5 per 1000 NICU admissions. The mortality rate was 42.8%. |
Ozkan et al., 2014 [ |
Gram-positive sepsis (67.6%) was more common than Gram-negative bacteremia (16.6%) and candidemia (15.8%). |
Clerihew et al., 2006 [ |
|
Vergnano et al., 2011 [ |
A decrease in candidemia was observed: 1.8% in 2006, 1.2% in 2007, and 1.3% in 2008. |
Aziz et al., 2010 [ |
Fluconazole prophylactic administration to ELBW infants was associated with a decreased rate of candidemia. |
Feja et al., 2005 [ |
Overall incidence: 1.6 per 100 NICU discharges. Catheter use, previous bacterial sepsis, and GI pathology were significantly associated with candidemia. |
Bizzarro et al., 2015 [ |
|
Natarajan et al., 2009 [ |
Candidemia refractory to conventional antifungals was associated with prolonged antibiotic use and |
Robinson et al., 2012 [ |
Overall incidence: 0.45 per 100 NICU discharges. An increased time between blood culture draw and initial antifungal therapy was associated with an increased incidence of persistent candidemia. |
Batista et al., 2014 [ |
Oral colonization should be considered as a risk factor for candidemia. |
Hua et al., 2012 [ |
Patients with |
Wu et al., 2014 [ |
|
Chen et al., 2015 [ |
Fluconazole prophylaxis alone was not efficacious; it had to be combined with reinforcement of management and supervision of hand hygiene to effectively prevent invasive candidiasis. |
Rani et al., 2002 [ |
|
Agarwal et al., 2004 [ |
Overall incidence: 77 per 1000 NICU discharges. |
Femitha et al., 2013 [ |
Overall incidence: 0.82 cases per 100 NICU discharges. Mortality was 44.4%. Presence of candiduria was a significant riskfactor for death. |
Mehara et al., 2013 [ |
|
Juyal et al., 2013 [ |
|
Chaurasia et al., 2015 [ |
Clinical features in neonates with candida sepsis were nonspecific. A common laboratory feature was thrombocytopenia. |
Al-Sweih et al., 2009 [ |
Overall incidence: 4 per 100 NICU discharges. |
Hammoud et al., 2013 [ |
|
Wu et al., 2009 [ |
The most common causative microorganisms of LOS sepsis were CONS and |
Tsai et al., 2014 [ |
Candidemia had a significantly higher rate of infectious complications, persistent bloodstream infection, and sepsis-attributable mortality than Gram-negative and Gram-positive bacteremia. |
Lim et al., 2012 [ |
Sepsis by Gram-negative bacteria or |
Chen et al., 2015 [ |
Decrease incidence of candidemia during the study period. |
Ballot et al., 2013 [ |
Increased incidence of |
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.
The distribution of
Distribution of
For
This study aimed to describe the epidemiology and drug susceptibility of
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 [
In our systematic review, we found that only four species (
Moreover, data regarding changes in the relative frequencies of isolated
In our study, appearance of
Main risk factors for
In agreement with other studies [
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
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.
The authors declare that they have no conflicts of interest.