Original Article
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Efficacy of Prophylactic Fluconazole Therapy in Decreasing the Incidence of Candida Infections in Extremely Low Birth Weight Preterm Infants Merih Cetinkaya, MD, PhD1 Tugba Erener Ercan, MD1 Ozge Kurum Saglam, MD2 Gokhan Buyukkale, MD1 Sultan Kavuncuoglu, MD2 Fatih Mete, MD2 1 Division of Neonatology, Department of Pediatrics, Kanuni Sultan
Suleyman Training and Research Hospital, Istanbul, Turkey 2 Department of Pediatrics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
Address for correspondence Merih Çetinkaya, MD, PhD, Kanuni Sultan Suleyman Eğitim ve Araştırma Hastanesi, Turgut Özal Bulvarı No:1, Halkalı/İstanbul, Turkey (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
Candida fluconazole infection preterm prophylaxis
Objective Systemic fungal infections are major causes of morbidity and mortality, and are associated with significant neurodevelopmental impairment in premature infants. Our objective was to evaluate the efficacy of fluconazole prophylaxis in prevention of systemic fungal infections among preterm infants. Study Design This observational pre-post cohort study was performed in preterm infants with a birth weight of < 1,000 g who were given prophylactic fluconazole starting on the first postnatal day at a dose of 3 mg/kg twice a week. These infants were compared with preterm infants who were not given prophylaxis. Results Prophylaxis group consisted of 90 infants and control group consisted of 107 infants. Systemic fungal infection was observed in five patients (4.7%) in the control group while no fungal infection was detected in the prophylaxis group (p ¼ 0.03). There were no significant differences between two groups in terms of demographic features, maternal and neonatal risk factors, and all-cause mortality rates. No adverse reactions were seen during the prophylaxis period. Conclusions We suggest that intravenous fluconazole prophylaxis at a dose of 3 mg/kg twice a week is a safe and effective strategy for decreasing systemic fungal infections even in neonatal intensive care units with low rates of invasive Candida infection.
Late-onset sepsis is an important cause of mortality among very low birth weight (VLBW) infants ( 1,500 g) admitted to neonatal intensive care units (NICUs). Systemic fungal infections (SFIs), mainly by Candida species, are the third most frequent cause of late-onset sepsis in these VLBW preterm infants with an estimated incidence ranging from 1 to 9%.1–3 The highest incidence of SFI occurs in the extremely low birth weight preterm infants (ELBW, < 1,000 g) which is reported as high as 20% in centers resuscitating infants < 24 weeks’ gestation.4 SFIs are significant causes of morbidity and mortality (20–55%) and are associated with significant neuro-
developmental impairment (57%) especially in infected ELBW infants, even in the absence of documented fungal meningitis.5,6 The susceptibility of preterm infants to SFIs is due to immaturity of their innate and adaptive immunity, their need for invasive therapies (central venous and arterial catheters, endotracheal tubes), the use of broad-spectrum antibiotics, parenteral nutrition, H2-blockers, and steroids.2 In preterm infants, SFI is often due to previous Candida colonization, which probably represents the most important risk factor for invasive candidiasis in this population.2,7 It has been shown that prophylactic fluconazole therapy decreases
received August 26, 2013 accepted after revision January 6, 2014 published online February 28, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1371358. ISSN 0735-1631.
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Am J Perinatol 2014;31:1043–1048.
Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants fungal colonization and subsequent invasive fungal infection in preterm infants.8 Without antifungal prophylaxis, about 60% of ELBW infants become colonized in the first 2 to 3 weeks after birth as horizontal transmission is the main mechanism of colonization in the NICUs.8,9 There is an A-I evidence (data confirmed by randomized controlled trials and these can be directly applicable to the target population) for the recommendation for fluconazole prophylaxis since several studies examining fluconazole prophylaxis in more than 5,000 infants have demonstrated efficacy with an overall reduction of > 80% in invasive Candida infections (ICIs) and a 90% decrease in Candidarelated mortality. Efficacy is reported to be highest for the smallest (< 750 or < 1,000 g) and youngest infants ( 27 weeks).8,10–14 A dosage of 3 mg/kg intravenous (IV) fluconazole twice a-week starting in the first 2 days of life and continued until IV access is no longer required in preterm infants with < 1,000 g birth weight and/or 27 weeks gestation is the recommended schedule with the greatest efficacy and safety without emergence of resistance for preventing ICIs in ELBW infants.8,12 The objective of our study was to evaluate the efficacy of fluconazole prophylaxis starting in the first postnatal day of life in prevention of SFIs among preterm infants weighing < 1,000 g and who are taken care of in a tertiary NICU in Istanbul, Turkey. Although our unit had a lower incidence of SFI, antifungal prophylaxis was started with the aim of decreasing the mortality and neurodevelopmental impairment due to ICIs in ELBW infants.
Materials and Method The study group consisted of all preterm infants with a birth weight of < 1,000 g who were admitted to the NICU of Kanuni Sultan Suleyman Teaching and Research Hospital, Istanbul, Turkey from September 2011 to January 2013, after the introduction of prophylactic antifungal therapy. Prophylactic IV fluconazole therapy was started on the first postnatal day for all of the enrolled study patients at a dose of 3 mg/kg twice a week and continued until IV access was no longer required. Preterm infants with a birth weight of < 1,000 g who were admitted to NICU between April 2010 and August 2011 constituted the control group since antifungal prophylaxis was not a routine practice in our NICU during that time period. However, it is also worthwhile to state that no other significant change in neonatal care practice was made during or between these two periods (September 2011– January 2013 and April 2010–August 2011) with regard to skin care, central line care, total parenteral nutrition, and initial antibiotic choice that could have been a confounder. The rate of Candida infections before and after introduction of IV fluconazole prophylaxis was compared to evaluate the effectiveness of fluconazole in the prevention of fungal infection in our NICU. The study was approved by the local ethics committee. Demographic features, perinatal and clinical characteristics, and outcomes at discharge of the study and control groups were obtained from both maternal and infant patient files. The duration of intubation, hospitalization, and central American Journal of Perinatology
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line usage were recorded. Also, the duration of total parenteral nutrition, outcomes of enteral feeding and antibiotic/ cephalosporin exposure were noted. Neonatal morbidities including bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) were also recorded. Invasive candidiasis was defined as isolation of the organism from normally sterile body fluids (primarily blood and cerebrospinal fluid [CSF]). Isolation of Candida in the urine was not considered as documented infection to avoid any misinterpretation concerning either colonization or contamination. Upon diagnosis of invasive candidiasis, lumbar punctures, eye examinations, liver, spleen, and renal ultrasounds, echocardiography, and bone radiographs were routinely done in all cases. All patients with a suspected or confirmed Candidal infection were given lipid complex amphotericin B (5–7.5 mg/kg/d) as a first-line therapy and fluconazole (10 mg/kg/d) was sequentially added if cultures remained positive after 48 to 72 hour of therapy or if patient had no clinical improvement. Following diagnosis of bloodstream Candida infection, immediate removal of central venous catheters was performed. Weekly monitoring of blood biochemistry including liver (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma glutamyl transpeptidase [GGT], and total and direct bilirubin), kidney function tests (blood urea nitrogen, creatinine), and complete blood counts are routinely practiced in our NICU. Therefore, weekly laboratory data concerning these values were abstracted from patient files of all cases on fluconazole prophylaxis. SPSS software version 16.0 (SPSS Inc., Chicago, IL) was used for statistical analyses. Descriptive statistics were given as mean and percentage. The Shapiro-Wilk test was used to test the normal distribution of data. The categorical data were analyzed using a chi-square test. Mann-Whitney and student’s t-test were used for comparisons between groups as appropriate. Values of p < 0.05 were considered to be significant. The number of patients needed for each group was estimated as 105 infants for fungal infection on the basis of a two-sided type I error rate of 0.05 and a power of 90% to detect a difference of at least 75% (a decrease from 15 to 3%) in the cumulative incidence of fungal infection.
Results Our whole cohort consisted of a total of 267 ELBW infants admitted to the NICU between April 2010 and January 2013, of whom 70 were not included due to death by noninfectious causes in the first week of life leaving a total of 197 infants; 90 in the prophylaxis group and 107 in the control group that had not received antifungal prophylaxis. Demographic features, perinatal characteristics, and maternal risk factors of both groups were summarized in ►Table 1 and clinical characteristics were summarized in ►Table 2. Sex, gestational age, birth weight, Apgar scores, and maternal risk factors for neonatal infection were similar in both groups. Durations of tracheal intubation, vascular line, parenteral nutrition,
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Table 1 Demographic and perinatal characteristics of two groups Characteristic
p-Value
Prophylaxis
Control
N ¼ 90
N ¼ 107
50 (56)
52 (49)
NS
Mean SD
27.2 2.2
27.6 2.1
NS
Median (range)
(24–32)
(24–33)
Mean SD
902 146
930 86.4
NS
Median (range)
910 (520–1000)
900 (500–1000)
NS
Sex Male, n (%) Gestational age (wks)
Birth weight (g)
< 27, n (%)
35 (39)
37 (35)
NS
27–30, n (%)
50 (56)
62 (58)
NS
31–33, n (%)
5 (5)
8 (7)
NS
< 750 g, n (%)
32 (35)
24 (22)
NS
750–1,000 g, n (%)
58 (65)
83 (78)
NS
67 (74)
76 (71)
NS
1st min, mean SD
4.3 2.1
4.5 1.7
NS
5th min, mean SD
6.2 1.8
6.5 1.4
NS
Pre-eclampsia, n (%)
5 (5)
7 (6)
NS
PROM > 18 h, n (%)
5 (5)
6 (6)
NS
Birth weight
Cesarean section delivery, n (%) Apgar score
Maternal risk factors
Abbreviations: h, hours; min, minute; NS, nonsignificant; PROM, premature rupture of membranes; SD, standard deviation.
enteral nutrition, antibiotic therapy, and hospital stay were similar between prophylaxis and control group (►Table 2). In the year before prophylaxis, five patients (4.7%) in the control group developed Candida infection with positive blood cultures. Of these five Candida infections, three were due to Candida albicans, one each was due to Candida parapsilosis and Candida glabrata, respectively. Cultures of other sterile sites including CSF and urine remained negative in those five patients. ►Table 3 shows the clinical characteristics of these five patients. Case fatality rate was zero since no deaths associated with Candida infection were observed. In the year following the introduction of prophylaxis, none of the patients (prophylaxis group) developed Candida infection indicating a significant decline in the rate of Candida infection (p ¼ 0.03). All-cause mortality between groups was similar. Rates of associated morbidities, such as IVH, NEC, BPD, ROP, and sepsis, were found to be similar between the prophylaxis and control groups. Clinical characteristics of the groups were summarized in ►Table 2. Although two infants in both groups had bowel perforation complicating NEC, no Candida peritonitis was detected. Although we excluded infants with Candida urinary tract infections, C. albicans was isolated from urine culture in one infant in the control group.
No serious adverse effects were observed in patients on fluconazole prophylaxis. Specifically, there was no appreciable adverse effect of fluconazole therapy on the levels of AST, ALT, ALP, GGT, total bilirubin or direct bilirubin.
Discussion Fungal-related morbidity and mortality is a major concern for most NICUs worldwide. The incidence of fungal infection varies between different NICUs and is primarily determined by the number of extremely preterm infants, namely, those infants < 26 weeks taken care of in a specific NICU. Gestational age is reported to be more closely correlated with infection.2 Incidence is reported to be approximately 20% for infants < 25 weeks; 10 to 20% for 25 to 26 weeks; 5 to 10% for 27 to 28 weeks; and < 5% for > 28 weeks.4–6,12 However, incidence rates might be higher than reported due to the challenges associated with the diagnosis of fungal infections.2 The sensitivity of the blood culture for invasive candidiasis was found to be only 29% based on multiple large volume blood samples in an adult autopsy study.15 Due to small blood culture volumes ranging between 0.5 to 1 mL, sensitivity of blood cultures may even be lower in premature infants.16 In American Journal of Perinatology
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Gestational age (wks)
Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants
Cetinkaya et al.
Table 2 Systemic fungal infection rate and clinical characteristics of the study groups Characteristic
p-Value
Prophylaxis
Control
N ¼ 90
N ¼ 107
0
5 (4.7)
Candida albicans
0
3
Candida parapsilosis
0
1
Candida glabrata
0
1
Days of intubation
14.1 4.4
13.2 4.1
NS
Days of TPN
32.0 5.5
30.5 5.2
NS
Start of enteral feeding
5.3 1.2
5.7 1.4
NS
Day of full feeding
20.5 3.4
21.1 2.9
NS
62 (69)
73 (68)
NS
SFI, n (%)
0.03
Candida species
Neonatal risk factors
Type of feeding, n (%) Human milk
28 (31)
34 (32)
NS
Days of central line
Formula
10.9 4.7
9.8 4.6
NS
Total antibiotic days during hospital stay
24.0
22.6
NS
Cephalosporin days
14.6
13.9
NS
H2 blocker use days
6.2
6.5
NS
Length of stay for survivors
58.2
56.4
NS
Focal bowel perforation
2 (2.2)
2 (1.8)
NS
IVH
23 (26)
30 (28)
NS
PDA
33 (37)
34 (32)
NS
Associated diseases, n (%)
BPD
24 (27)
28 (26)
NS
ROP
24 (27)
26 (24)
NS
Sepsis
42 (46)
48 (45)
NS
NEC (stage 2), n (%)
24 (27)
27 (23)
NS
All cause, n (%)
11 (12)
14 (13)
NS
Candida-associated
0
0
Mortality
Abbreviations: BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NS, nonsignificant; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; SFI; systemic fungal infection; TPN, total parenteral nutrition. Note: The p value in bold (0.03) represents the significance between two groups.
our cohort, the rate of SFI was found as 4.7% in the control group who were not on prophylaxis. In a 2013 Cochrane review17 assessing the effect of prophylactic systemic antifungal therapy on mortality and morbidity in VLBW infants, the average incidence of invasive fungal infection in the control groups of the trials was much higher (16%). Relatively lower incidence in our control group compared with the average incidence mentioned in the Cochrane review might be due to lower number of preterm infants with a gestational age < 26 weeks (18/107; 16.8%) in our control group that consisted of preterms with a mean gestational week of 27.6 2.1. However, although Candida infections occurred in infants’ 1,000 g, four infants were born at a gestational age of 27 weeks. These data show that the incidence of American Journal of Perinatology
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Candida infections were higher in premature infants with older gestational age and it may be reasonable to suggest that targeting prophylaxis is actually necessary despite their gestational age in infants < 1,000 g. Both prematurity and immature immunity put the preterm infants at a greater risk for the development of fungal colonization and systemic infections.7 Invasive candidiasis is associated with a high mortality (30–40%) as well as poor neurodevelopmental outcomes among survivors with higher rates of cerebral palsy, blindness, or deafness than uninfected infants.5,16 In a recent study, risk of death and neurodevelopmental impairment were reported to be highest among infants with Candida infection and/or meningitis.18 Therefore, increased frequency of end-organ localizations and
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Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants
Cetinkaya et al.
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Cases
Gestational age (wks)
Birth weight (g)
Gender
Cause
Predisposing factors
Clinical features
Case 1
26
880
Female
Candida albicans
Low Apgar score at minute 1, mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, prolonged TPN
RDS, ROP
Case 2
30
990
Female
C. albicans
Low Apgar score at minute 1, mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, neutropenia
RDS
Case 3
31
1,000
Male
Candida parapsilosis
Mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, prolonged TPN
RDS, NEC, ROP, BPD
Case 4
28
800
Female
Candida glabrata
Low Apgar score at minute 1, broad-spectrum antibiotic
RDS, NEC, ROP
Case 5
29
930
Male
C. albicans
Broad-spectrum antibiotic, prolonged TPN
RDS, ROP, BPD
Abbreviations: BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; TPN, total parenteral nutrition; wks, weeks.
mortality, an unacceptably high risk for neurodevelopmental sequelae in survivors with SFIs, even if treatment is adequate justify the implementation of antifungal prophylaxis in preterm infants.2 Starting in September 2011, routine prophylaxis of IV fluconazole at a dose of 3 mg/kg twice a week for ELBW preterms was also implemented in our NICU after reviewing the literature demonstrating that the fluconazole prophylaxis significantly reduces the risk of invasive fungal infection.9–12 After adoption of antifungal prophylaxis, our SFI rate decreased from 4.7 to 0% (p ¼ 0.03). This finding was in accordance with the existing literature.8–12,17,19–25 No adverse effect was observed during the prophylaxis period in any of the patients. An important finding of this study was to favor the use of fluconazole prophylaxis in a unit with a low incidence of SFI. Recently, it was reported that antifungal prophylaxis might be warranted in units with a lower incidence of systemic Candida infections as mortality and neurodevelopmental impairment might occur in majority of ELBW infants.8,26 It was also suggested that antifungal prophylaxis should be considered to reduce the incidence of SFIs even in NICUs with low rates of ICI.12 Howell et al27 in a study involving 15,000 infants < 1,500 g at birth from New Zealand and Australia demonstrated the benefit of antifungal prophylaxis even in NICUs with a baseline ICI rate of less than 2%. Therefore, our results were also in accordance with these data and we suggest that antifungal prophylaxis could be considered for prevention of SFIs in all NICUs even in units with low incidence of SFIs. We relied on blood cultures and cultures from other sterile sites for the diagnosis of SFI. Since blood cultures are said to have low sensitivity,15,16 this might have led to the underes-
timation of Candida infections in our cohort both in the control and study groups. Nevertheless, present study gives further support to the growing body of literature supporting the efficacy and safety of fluconazole prophylaxis in ELBW infants. A limitation of this study was that only blood culture– proven Candida infections were included. However, fungal urinary tract infections were reported to account for an additional 3 to 4% of ICIs.8,9,26 Two recent multicenter studies also reported that ELBW infants with candiduria have the same high associated mortality as infants with bloodstream infections.26,28 Therefore, future studies that include cultureproven Candida infections of the blood, urine, CSF, peritoneal, and other sterile body fluids may provide additional data about the effect of antifungal prophylaxis on these types of Candida infections. In conclusion, we suggest that IV fluconazole prophylaxis at a dose of 3 mg/kg twice a week is a safe and effective therapeutic strategy to decrease the rate of SFIs even in NICUs with low rates of ICI. Both birth weight and gestational age should be used to determine candidate infants for prophylaxis.
References 1 Shetty SS, Harrison LH, Hajjeh RA, et al. Determining risk factors
for candidemia among newborn infants from population-based surveillance: Baltimore, Maryland, 1998-2000. Pediatr Infect Dis J 2005;24(7):601–604 2 Manzoni P, Jacqz-Aigrain E, Rizzollo S, et al. Antifungal prophylaxis in neonates. Early Hum Dev 2011;87(Suppl 1):S59–S60 3 Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2 Pt 1):285–291 American Journal of Perinatology
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Table 3 The demographic and clinical features of infants with Candida infection
Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants 4 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and
5
6
7
8
9
10
11
12
13
14
15
fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004;17(3):638–680 Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117(1):84–92 Stoll BJ, Hansen NI, Adams-Chapman I, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292(19):2357–2365 Castagnola E, Jacqz-Aigrain E, Kaguelidou F, et al. Fluconazole use and safety in the nursery. Early Hum Dev 2012;88(Suppl 2): S11–S15 Kaufman DA. “Getting to Zero”: preventing invasive Candida infections and eliminating infection-related mortality and morbidity in extremely preterm infants. Early Hum Dev 2012;88 (Suppl 2):S45–S49 Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001;345(23):1660–1666 Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis for prevention of invasive Candida infection in high-risk infants of
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Efficacy of Prophylactic Fluconazole Therapy in Decreasing the Incidence of Candida Infections in Extremely Low Birth Weight Preterm Infants Merih Cetinkaya, MD, PhD1 Tugba Erener Ercan, MD1 Ozge Kurum Saglam, MD2 Gokhan Buyukkale, MD1 Sultan Kavuncuoglu, MD2 Fatih Mete, MD2 1 Division of Neonatology, Department of Pediatrics, Kanuni Sultan
Suleyman Training and Research Hospital, Istanbul, Turkey 2 Department of Pediatrics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
Address for correspondence Merih Çetinkaya, MD, PhD, Kanuni Sultan Suleyman Eğitim ve Araştırma Hastanesi, Turgut Özal Bulvarı No:1, Halkalı/İstanbul, Turkey (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
Candida fluconazole infection preterm prophylaxis
Objective Systemic fungal infections are major causes of morbidity and mortality, and are associated with significant neurodevelopmental impairment in premature infants. Our objective was to evaluate the efficacy of fluconazole prophylaxis in prevention of systemic fungal infections among preterm infants. Study Design This observational pre-post cohort study was performed in preterm infants with a birth weight of < 1,000 g who were given prophylactic fluconazole starting on the first postnatal day at a dose of 3 mg/kg twice a week. These infants were compared with preterm infants who were not given prophylaxis. Results Prophylaxis group consisted of 90 infants and control group consisted of 107 infants. Systemic fungal infection was observed in five patients (4.7%) in the control group while no fungal infection was detected in the prophylaxis group (p ¼ 0.03). There were no significant differences between two groups in terms of demographic features, maternal and neonatal risk factors, and all-cause mortality rates. No adverse reactions were seen during the prophylaxis period. Conclusions We suggest that intravenous fluconazole prophylaxis at a dose of 3 mg/kg twice a week is a safe and effective strategy for decreasing systemic fungal infections even in neonatal intensive care units with low rates of invasive Candida infection.
Late-onset sepsis is an important cause of mortality among very low birth weight (VLBW) infants ( 1,500 g) admitted to neonatal intensive care units (NICUs). Systemic fungal infections (SFIs), mainly by Candida species, are the third most frequent cause of late-onset sepsis in these VLBW preterm infants with an estimated incidence ranging from 1 to 9%.1–3 The highest incidence of SFI occurs in the extremely low birth weight preterm infants (ELBW, < 1,000 g) which is reported as high as 20% in centers resuscitating infants < 24 weeks’ gestation.4 SFIs are significant causes of morbidity and mortality (20–55%) and are associated with significant neuro-
developmental impairment (57%) especially in infected ELBW infants, even in the absence of documented fungal meningitis.5,6 The susceptibility of preterm infants to SFIs is due to immaturity of their innate and adaptive immunity, their need for invasive therapies (central venous and arterial catheters, endotracheal tubes), the use of broad-spectrum antibiotics, parenteral nutrition, H2-blockers, and steroids.2 In preterm infants, SFI is often due to previous Candida colonization, which probably represents the most important risk factor for invasive candidiasis in this population.2,7 It has been shown that prophylactic fluconazole therapy decreases
received August 26, 2013 accepted after revision January 6, 2014 published online February 28, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1371358. ISSN 0735-1631.
Downloaded by: East Carolina University. Copyrighted material.
Am J Perinatol 2014;31:1043–1048.
Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants fungal colonization and subsequent invasive fungal infection in preterm infants.8 Without antifungal prophylaxis, about 60% of ELBW infants become colonized in the first 2 to 3 weeks after birth as horizontal transmission is the main mechanism of colonization in the NICUs.8,9 There is an A-I evidence (data confirmed by randomized controlled trials and these can be directly applicable to the target population) for the recommendation for fluconazole prophylaxis since several studies examining fluconazole prophylaxis in more than 5,000 infants have demonstrated efficacy with an overall reduction of > 80% in invasive Candida infections (ICIs) and a 90% decrease in Candidarelated mortality. Efficacy is reported to be highest for the smallest (< 750 or < 1,000 g) and youngest infants ( 27 weeks).8,10–14 A dosage of 3 mg/kg intravenous (IV) fluconazole twice a-week starting in the first 2 days of life and continued until IV access is no longer required in preterm infants with < 1,000 g birth weight and/or 27 weeks gestation is the recommended schedule with the greatest efficacy and safety without emergence of resistance for preventing ICIs in ELBW infants.8,12 The objective of our study was to evaluate the efficacy of fluconazole prophylaxis starting in the first postnatal day of life in prevention of SFIs among preterm infants weighing < 1,000 g and who are taken care of in a tertiary NICU in Istanbul, Turkey. Although our unit had a lower incidence of SFI, antifungal prophylaxis was started with the aim of decreasing the mortality and neurodevelopmental impairment due to ICIs in ELBW infants.
Materials and Method The study group consisted of all preterm infants with a birth weight of < 1,000 g who were admitted to the NICU of Kanuni Sultan Suleyman Teaching and Research Hospital, Istanbul, Turkey from September 2011 to January 2013, after the introduction of prophylactic antifungal therapy. Prophylactic IV fluconazole therapy was started on the first postnatal day for all of the enrolled study patients at a dose of 3 mg/kg twice a week and continued until IV access was no longer required. Preterm infants with a birth weight of < 1,000 g who were admitted to NICU between April 2010 and August 2011 constituted the control group since antifungal prophylaxis was not a routine practice in our NICU during that time period. However, it is also worthwhile to state that no other significant change in neonatal care practice was made during or between these two periods (September 2011– January 2013 and April 2010–August 2011) with regard to skin care, central line care, total parenteral nutrition, and initial antibiotic choice that could have been a confounder. The rate of Candida infections before and after introduction of IV fluconazole prophylaxis was compared to evaluate the effectiveness of fluconazole in the prevention of fungal infection in our NICU. The study was approved by the local ethics committee. Demographic features, perinatal and clinical characteristics, and outcomes at discharge of the study and control groups were obtained from both maternal and infant patient files. The duration of intubation, hospitalization, and central American Journal of Perinatology
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No. 12/2014
Cetinkaya et al.
line usage were recorded. Also, the duration of total parenteral nutrition, outcomes of enteral feeding and antibiotic/ cephalosporin exposure were noted. Neonatal morbidities including bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) were also recorded. Invasive candidiasis was defined as isolation of the organism from normally sterile body fluids (primarily blood and cerebrospinal fluid [CSF]). Isolation of Candida in the urine was not considered as documented infection to avoid any misinterpretation concerning either colonization or contamination. Upon diagnosis of invasive candidiasis, lumbar punctures, eye examinations, liver, spleen, and renal ultrasounds, echocardiography, and bone radiographs were routinely done in all cases. All patients with a suspected or confirmed Candidal infection were given lipid complex amphotericin B (5–7.5 mg/kg/d) as a first-line therapy and fluconazole (10 mg/kg/d) was sequentially added if cultures remained positive after 48 to 72 hour of therapy or if patient had no clinical improvement. Following diagnosis of bloodstream Candida infection, immediate removal of central venous catheters was performed. Weekly monitoring of blood biochemistry including liver (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma glutamyl transpeptidase [GGT], and total and direct bilirubin), kidney function tests (blood urea nitrogen, creatinine), and complete blood counts are routinely practiced in our NICU. Therefore, weekly laboratory data concerning these values were abstracted from patient files of all cases on fluconazole prophylaxis. SPSS software version 16.0 (SPSS Inc., Chicago, IL) was used for statistical analyses. Descriptive statistics were given as mean and percentage. The Shapiro-Wilk test was used to test the normal distribution of data. The categorical data were analyzed using a chi-square test. Mann-Whitney and student’s t-test were used for comparisons between groups as appropriate. Values of p < 0.05 were considered to be significant. The number of patients needed for each group was estimated as 105 infants for fungal infection on the basis of a two-sided type I error rate of 0.05 and a power of 90% to detect a difference of at least 75% (a decrease from 15 to 3%) in the cumulative incidence of fungal infection.
Results Our whole cohort consisted of a total of 267 ELBW infants admitted to the NICU between April 2010 and January 2013, of whom 70 were not included due to death by noninfectious causes in the first week of life leaving a total of 197 infants; 90 in the prophylaxis group and 107 in the control group that had not received antifungal prophylaxis. Demographic features, perinatal characteristics, and maternal risk factors of both groups were summarized in ►Table 1 and clinical characteristics were summarized in ►Table 2. Sex, gestational age, birth weight, Apgar scores, and maternal risk factors for neonatal infection were similar in both groups. Durations of tracheal intubation, vascular line, parenteral nutrition,
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Table 1 Demographic and perinatal characteristics of two groups Characteristic
p-Value
Prophylaxis
Control
N ¼ 90
N ¼ 107
50 (56)
52 (49)
NS
Mean SD
27.2 2.2
27.6 2.1
NS
Median (range)
(24–32)
(24–33)
Mean SD
902 146
930 86.4
NS
Median (range)
910 (520–1000)
900 (500–1000)
NS
Sex Male, n (%) Gestational age (wks)
Birth weight (g)
< 27, n (%)
35 (39)
37 (35)
NS
27–30, n (%)
50 (56)
62 (58)
NS
31–33, n (%)
5 (5)
8 (7)
NS
< 750 g, n (%)
32 (35)
24 (22)
NS
750–1,000 g, n (%)
58 (65)
83 (78)
NS
67 (74)
76 (71)
NS
1st min, mean SD
4.3 2.1
4.5 1.7
NS
5th min, mean SD
6.2 1.8
6.5 1.4
NS
Pre-eclampsia, n (%)
5 (5)
7 (6)
NS
PROM > 18 h, n (%)
5 (5)
6 (6)
NS
Birth weight
Cesarean section delivery, n (%) Apgar score
Maternal risk factors
Abbreviations: h, hours; min, minute; NS, nonsignificant; PROM, premature rupture of membranes; SD, standard deviation.
enteral nutrition, antibiotic therapy, and hospital stay were similar between prophylaxis and control group (►Table 2). In the year before prophylaxis, five patients (4.7%) in the control group developed Candida infection with positive blood cultures. Of these five Candida infections, three were due to Candida albicans, one each was due to Candida parapsilosis and Candida glabrata, respectively. Cultures of other sterile sites including CSF and urine remained negative in those five patients. ►Table 3 shows the clinical characteristics of these five patients. Case fatality rate was zero since no deaths associated with Candida infection were observed. In the year following the introduction of prophylaxis, none of the patients (prophylaxis group) developed Candida infection indicating a significant decline in the rate of Candida infection (p ¼ 0.03). All-cause mortality between groups was similar. Rates of associated morbidities, such as IVH, NEC, BPD, ROP, and sepsis, were found to be similar between the prophylaxis and control groups. Clinical characteristics of the groups were summarized in ►Table 2. Although two infants in both groups had bowel perforation complicating NEC, no Candida peritonitis was detected. Although we excluded infants with Candida urinary tract infections, C. albicans was isolated from urine culture in one infant in the control group.
No serious adverse effects were observed in patients on fluconazole prophylaxis. Specifically, there was no appreciable adverse effect of fluconazole therapy on the levels of AST, ALT, ALP, GGT, total bilirubin or direct bilirubin.
Discussion Fungal-related morbidity and mortality is a major concern for most NICUs worldwide. The incidence of fungal infection varies between different NICUs and is primarily determined by the number of extremely preterm infants, namely, those infants < 26 weeks taken care of in a specific NICU. Gestational age is reported to be more closely correlated with infection.2 Incidence is reported to be approximately 20% for infants < 25 weeks; 10 to 20% for 25 to 26 weeks; 5 to 10% for 27 to 28 weeks; and < 5% for > 28 weeks.4–6,12 However, incidence rates might be higher than reported due to the challenges associated with the diagnosis of fungal infections.2 The sensitivity of the blood culture for invasive candidiasis was found to be only 29% based on multiple large volume blood samples in an adult autopsy study.15 Due to small blood culture volumes ranging between 0.5 to 1 mL, sensitivity of blood cultures may even be lower in premature infants.16 In American Journal of Perinatology
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Gestational age (wks)
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Table 2 Systemic fungal infection rate and clinical characteristics of the study groups Characteristic
p-Value
Prophylaxis
Control
N ¼ 90
N ¼ 107
0
5 (4.7)
Candida albicans
0
3
Candida parapsilosis
0
1
Candida glabrata
0
1
Days of intubation
14.1 4.4
13.2 4.1
NS
Days of TPN
32.0 5.5
30.5 5.2
NS
Start of enteral feeding
5.3 1.2
5.7 1.4
NS
Day of full feeding
20.5 3.4
21.1 2.9
NS
62 (69)
73 (68)
NS
SFI, n (%)
0.03
Candida species
Neonatal risk factors
Type of feeding, n (%) Human milk
28 (31)
34 (32)
NS
Days of central line
Formula
10.9 4.7
9.8 4.6
NS
Total antibiotic days during hospital stay
24.0
22.6
NS
Cephalosporin days
14.6
13.9
NS
H2 blocker use days
6.2
6.5
NS
Length of stay for survivors
58.2
56.4
NS
Focal bowel perforation
2 (2.2)
2 (1.8)
NS
IVH
23 (26)
30 (28)
NS
PDA
33 (37)
34 (32)
NS
Associated diseases, n (%)
BPD
24 (27)
28 (26)
NS
ROP
24 (27)
26 (24)
NS
Sepsis
42 (46)
48 (45)
NS
NEC (stage 2), n (%)
24 (27)
27 (23)
NS
All cause, n (%)
11 (12)
14 (13)
NS
Candida-associated
0
0
Mortality
Abbreviations: BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NS, nonsignificant; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; SFI; systemic fungal infection; TPN, total parenteral nutrition. Note: The p value in bold (0.03) represents the significance between two groups.
our cohort, the rate of SFI was found as 4.7% in the control group who were not on prophylaxis. In a 2013 Cochrane review17 assessing the effect of prophylactic systemic antifungal therapy on mortality and morbidity in VLBW infants, the average incidence of invasive fungal infection in the control groups of the trials was much higher (16%). Relatively lower incidence in our control group compared with the average incidence mentioned in the Cochrane review might be due to lower number of preterm infants with a gestational age < 26 weeks (18/107; 16.8%) in our control group that consisted of preterms with a mean gestational week of 27.6 2.1. However, although Candida infections occurred in infants’ 1,000 g, four infants were born at a gestational age of 27 weeks. These data show that the incidence of American Journal of Perinatology
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Candida infections were higher in premature infants with older gestational age and it may be reasonable to suggest that targeting prophylaxis is actually necessary despite their gestational age in infants < 1,000 g. Both prematurity and immature immunity put the preterm infants at a greater risk for the development of fungal colonization and systemic infections.7 Invasive candidiasis is associated with a high mortality (30–40%) as well as poor neurodevelopmental outcomes among survivors with higher rates of cerebral palsy, blindness, or deafness than uninfected infants.5,16 In a recent study, risk of death and neurodevelopmental impairment were reported to be highest among infants with Candida infection and/or meningitis.18 Therefore, increased frequency of end-organ localizations and
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Cases
Gestational age (wks)
Birth weight (g)
Gender
Cause
Predisposing factors
Clinical features
Case 1
26
880
Female
Candida albicans
Low Apgar score at minute 1, mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, prolonged TPN
RDS, ROP
Case 2
30
990
Female
C. albicans
Low Apgar score at minute 1, mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, neutropenia
RDS
Case 3
31
1,000
Male
Candida parapsilosis
Mechanical ventilation, broad-spectrum antibiotic, umbilical catheter, prolonged TPN
RDS, NEC, ROP, BPD
Case 4
28
800
Female
Candida glabrata
Low Apgar score at minute 1, broad-spectrum antibiotic
RDS, NEC, ROP
Case 5
29
930
Male
C. albicans
Broad-spectrum antibiotic, prolonged TPN
RDS, ROP, BPD
Abbreviations: BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; TPN, total parenteral nutrition; wks, weeks.
mortality, an unacceptably high risk for neurodevelopmental sequelae in survivors with SFIs, even if treatment is adequate justify the implementation of antifungal prophylaxis in preterm infants.2 Starting in September 2011, routine prophylaxis of IV fluconazole at a dose of 3 mg/kg twice a week for ELBW preterms was also implemented in our NICU after reviewing the literature demonstrating that the fluconazole prophylaxis significantly reduces the risk of invasive fungal infection.9–12 After adoption of antifungal prophylaxis, our SFI rate decreased from 4.7 to 0% (p ¼ 0.03). This finding was in accordance with the existing literature.8–12,17,19–25 No adverse effect was observed during the prophylaxis period in any of the patients. An important finding of this study was to favor the use of fluconazole prophylaxis in a unit with a low incidence of SFI. Recently, it was reported that antifungal prophylaxis might be warranted in units with a lower incidence of systemic Candida infections as mortality and neurodevelopmental impairment might occur in majority of ELBW infants.8,26 It was also suggested that antifungal prophylaxis should be considered to reduce the incidence of SFIs even in NICUs with low rates of ICI.12 Howell et al27 in a study involving 15,000 infants < 1,500 g at birth from New Zealand and Australia demonstrated the benefit of antifungal prophylaxis even in NICUs with a baseline ICI rate of less than 2%. Therefore, our results were also in accordance with these data and we suggest that antifungal prophylaxis could be considered for prevention of SFIs in all NICUs even in units with low incidence of SFIs. We relied on blood cultures and cultures from other sterile sites for the diagnosis of SFI. Since blood cultures are said to have low sensitivity,15,16 this might have led to the underes-
timation of Candida infections in our cohort both in the control and study groups. Nevertheless, present study gives further support to the growing body of literature supporting the efficacy and safety of fluconazole prophylaxis in ELBW infants. A limitation of this study was that only blood culture– proven Candida infections were included. However, fungal urinary tract infections were reported to account for an additional 3 to 4% of ICIs.8,9,26 Two recent multicenter studies also reported that ELBW infants with candiduria have the same high associated mortality as infants with bloodstream infections.26,28 Therefore, future studies that include cultureproven Candida infections of the blood, urine, CSF, peritoneal, and other sterile body fluids may provide additional data about the effect of antifungal prophylaxis on these types of Candida infections. In conclusion, we suggest that IV fluconazole prophylaxis at a dose of 3 mg/kg twice a week is a safe and effective therapeutic strategy to decrease the rate of SFIs even in NICUs with low rates of ICI. Both birth weight and gestational age should be used to determine candidate infants for prophylaxis.
References 1 Shetty SS, Harrison LH, Hajjeh RA, et al. Determining risk factors
for candidemia among newborn infants from population-based surveillance: Baltimore, Maryland, 1998-2000. Pediatr Infect Dis J 2005;24(7):601–604 2 Manzoni P, Jacqz-Aigrain E, Rizzollo S, et al. Antifungal prophylaxis in neonates. Early Hum Dev 2011;87(Suppl 1):S59–S60 3 Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2 Pt 1):285–291 American Journal of Perinatology
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Table 3 The demographic and clinical features of infants with Candida infection
Prophylactic Fluconazole Therapy Efficacy in Candida Infections in ELBW Infants 4 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and
5
6
7
8
9
10
11
12
13
14
15
fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004;17(3):638–680 Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117(1):84–92 Stoll BJ, Hansen NI, Adams-Chapman I, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292(19):2357–2365 Castagnola E, Jacqz-Aigrain E, Kaguelidou F, et al. Fluconazole use and safety in the nursery. Early Hum Dev 2012;88(Suppl 2): S11–S15 Kaufman DA. “Getting to Zero”: preventing invasive Candida infections and eliminating infection-related mortality and morbidity in extremely preterm infants. Early Hum Dev 2012;88 (Suppl 2):S45–S49 Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001;345(23):1660–1666 Kaufman D, Boyle R, Hazen KC, Patrie JT, Robinson M, Grossman LB. Twice weekly fluconazole prophylaxis for prevention of invasive Candida infection in high-risk infants of
