Background: Nosocomial infection remains an important contributing factor for morbidity and mortality in neonates. Coagulase-negative staphylococci have emerged as the predominant pathogens of late onset sepsis. This is followed by staphylococcus aurous, gram negative bacilli, and fungi. Old studies noted that mortality due to candidemia was higher in infants weigh less than 2000 g after being exposed to risk factors. The prophylactic use of fluconazole for the prevention of IC in extremely low birth weight was first reported in 2001. Methods: Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016. Conclusion: Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms. Risk-based approach towards fluconazole prophylaxis seems to be safe and effective.
Nosocomial infection remains an important contributing factor for morbidity and mortality. Neonatal sepsis is divided into two classifications: early onset and late onset sepsis. Early onset sepsis occurs within the first 72 hours of life, while late onset sepsis occurs after 72 hours of birth. The incidence of late onset sepsis is inversely related to birth weight and gestational age [
Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016, that reported on fluconazole prophylaxis in neonates restricted to English language. The following searching strings were used [Fluconazole AND prophylaxis AND preterm AND neonates AND invasive candidiasis AND central venous catheters]. Only clinical trials and meta-analysis reported on fluconazole prophylaxis in neonates were reviewed for analysis (
Kaufman et al. conducted the first prospective study to evaluate the efficacy of fluconazole prophylaxis in preterm neonates. The birth weight at baseline was 717 +/− 150 in the fluconazole group and 744 +/− 157 in the placebo group. All neonates were preterm with mean gestational age of 25.5 +/− 1.6 in fluconazole group and 25.7 +/− 2 in placebo group. They were randomized to receive Intravenous fluconazole 3 mg/kg every
third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week vs. placebo. They limited their study for the first 6 weeks of life of preterm neonates with extreme low birth weight and fluconazole was discontinued once central venous catheters are removed and neonates are extubated. Unfortunately, the incidence of IC at their facility was not stated in this study and was not specified if fluconazole will continue if other risk factors were still existed (
Rolnitsky et al. conducted a retrospective study to evaluate the efficacy of fluconazole prophylaxis in VLBW neonates. The incidence of candidiasis in their institution is low so they developed a risk based approach to initiate fluconazole in high risk neonates. They considered neonates with ELBW, gestational age of less than 28 weeks, and broad-spectrum antibiotics as major criteria and fluconazole will be discontinued once the risk factor is no longer available. Central venous catheters, endotracheal intubation, Total parenteral nutrition were considered minor criteria and a VLBW neonate will not receive fluconazole prophylaxis if he had only one risk factor (
Manzoni et al. conducted a randomized controlled trial to evaluate the prophylactic use of fluconazole in VLBW and ELBW preterm infants. The mean weight was 1065 +/− 280 in the 6 mg/kg group, 1060 +/− 245 in the 3 mg/kg group, and 1120 +/− 270 in the placebo group. The mean gestational age was 28.9 +/− 2.3. The primary outcome in this study was the incidence of colonization, and the incidence of IC. Colonization occurred less frequently in the 6-mg group (9.8%) and the 3-mg group (7.7%) than in the placebo group (29.2%); P < 0.001 for both comparisons. Lastly, invasive fungal infection occurred in 2.7% in the 6-mg group and in 3.8% in the 3-mg group, as compared with 13.2% in the placebo group; P 0.005 and P 0.02, respectively (
VLBW | Less than 1500 g |
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ELBW | Less than 1000 g |
IC | Invasive candidiasis |
NICU | Neonatal ICU |
TNA | Total parenteral nutrition |
placebo, however, it didn’t reach statistical significance 2.6% versus 18.9% > P 0.05 (
Ericson et al. conducted a meta-analysis for four clinical trials conducted in United States that looked at the efficacy of fluconazole in preventing IC. 72% of the enrolled neonates had a birth weight of less than 750 g in the placebo group and 75.58% had a birth weight of less than 1000 g in the fluconazole group. The primary outcome of this meta-analysis was the composite endpoint of IC and death. The OR for the composite end point was 0.48, P < 0.003, and the OR for IC was 0.2, P < 0.001. The incidence of death was not significantly different between placebo group and fluconazole group OR.68, P 0.14 [
1) Very low birth weight and extremely low birth weight (
2) Central venous catheter/Umbilical catheter.
3) Third generations cephalosporins and broad spectrum antibiotics.
4) Corticosteroids therapy.
5) Candida colonization.
6) Mechanical ventilation.
7) TNA.
Fluconazole prophylaxis was effective in reducing the incidence of colonization and the incidence of IC in neonates with risk factors. The primary and secondary outcomes were not similar between studies (
Literature of the recent years supports the prophylactic use of fluconazole in ELBW and in VLBW preterm neonates with one or more risk factors (
Author | Study design | Inclusion criteria | Drug/dose | Results | Conclusion/Comments |
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Kaufman et al. 2001 [ | Prospective, randomized, double-blind clinical trial, 100 infants (50:50) (May 5, 1998, and October 10, 2000) | ELBW, Preterm neonates, and/or Central venous catheter, endotracheal intubation | IV fluconazole 3 mg/kg every third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week vs. placebo (Schedule A) | Primary outcome: ColonizationΨ: Fungal colonization at one or more sites occurred in 30 of placebo group vs. 11 in the fluconazole group P 0.002 Infection developed in 10 in placebo group (20%) and none in fluconazole arm. (Risk difference: 0.20% P 0.008) Secondary outcome: No difference in mortality between groups P 0.22 | Due to the concern of azole resistance fluconazole was limited to preterm infants who required central venous catheters and intubation during the six weeks of life Author didn’t specify if additional risk factors are needed to be present in addition to ELBW, preterm and/or central venous catheter, endotracheal intubation **Candiuria was considered IC in this study** **>Number of sites colonized >IC incidence** |
Kaufman et al. 2005 [ | Prospective, randomized, double-blind clinical trial, 82 infants (41:40) | ELBW, Preterm, and/ or central venous catheter, endotracheal intubation | Regimen above (Schedule A) vs. Twice weekly (Schedule B) | Primary outcome: ColonizationΨ: Fungal colonization at one or more sites developed in 5 in group A vs. 4 in group B P 0.83 Infection: Two developed (Schedule A) IC vs. 1 in Schedule B. P value 0.68 Secondary outcome: No significant difference in mortality P 1.00 | Twice weekly fluconazole is as effective as conventional regimen. No adverse effects except reversible elevation in transaminases Serum aminotransferrases were elevated in 2 of group A and in 4 of group B |
Manzoni et al. 2007 [ | Multicentre, prospective randomized, double-blind, placebo controlled trial, 322 infants (112 in 6 mg/kg group, 104 in 3 mg/kg group, 106 in placebo group) | VLBW, ELBW | IV fluconazole 3 mg/kg vs. 6 mg/kg vs. 1 ml NS every third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week | Primary outcome: Colonization occurred less frequently in the 6-mg group 9.8% (11/112) and the 3-mg group 7.7% (8/104) than in the placebo group 29.2% (31/106) P < 0.001 for both comparisons. IC occurred in 2.7% (3/112) of 6 mg/kg, 3.8% (4/104) of 3 mg/kg, and 13.2% (14/106) in placebo group P 0.005 and P value 0.02, respectively | Selection of fluconazole should be directed to high risk patients to minimize the overgrowth of fluconazole resistant candida strains. Elevation in serum aminotransferases was reported in 4 neonates in fluconazole group and no elevation in placebo group P 0.31 **Candiduria was considered IC if >10,000 organisms/milliliter |
Healy et al. 2008 [ | Retrospective, 3012 (2000-2001) and 6393 (2002-2006) (Cohort) **2000-2001 didn’t implement fluconazole prophylaxis protocol** | ELBW, BW close to 1 kg, other risk factors in the opinion of neonatologist | IV fluconazole 3 mg/kg every third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week | Primary outcome: Incidence of IC reduced from 0.6% (19 of 3012) to 0.3% (22 of 6393) P value 0.05 Secondary outcome: IC related mortality was reduced from 0.1% to 0%, P 0.004 | Fluconzole prophylaxis should be strongly recommended in ELBW and others with VLBW additional risk factors to limit total exposure to fluconazole **Urine candida was not considered IC** |
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Rolnitsky et al. 2012 [ | Retrospective cohort study VLBW-ELBW cohort infants received risk-based fluconazole (2007-2008 vs placebo (2002-2004) Treatment group number = 130 Placebo group number = 319 | VLBW + 1 major risk factor or 2 minor risk factors, ELBW Major risk factor: ELBW, Gestational age less than 28 weeks, Broad spectrum antibiotics (3RD generation cephalosporins, Carbapenems etc.) Minor risk factors: CVC, Endotracheal intubation, H2 blockers, Steroid therapy, TNA | IV fluconazole 6 mg/kg every other day until risk factors are removed in VLBW, 6 weeks in ELBW | Primary outcome: Invasive candidiasis in 1 out of 130 in fluconazole group, and 19 out of 319 in control group P 0.016 Incidence of Blood stream fungal infection reduced from 5.96% in control group to. 77% in fluconazole group Secondary outcome: No difference in mortality between the groups P 0.77 | VLBW infants received fluconazole only if one or more risk factors were present e.g. central catheter, preterm, antibiotics etc. Consider in high risk patients with combined risk factors, no adverse effects reported The incidence of Candida infection was low in their institute , and they used risk-based strategy |
Kirpal et al. 2016 [ | Randomized double-blinded randomized controlled trial Total (80) (40:40) | 1-Broad spectrum antibiotics (vancomycin, Azosyn, carbapenems, fluroquinolones) 2-VLBW 3-Preterm neonates | IV fluconazole 6 mg/kg every third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week | Primary outcome: IC 21% (8/38) in fluconazole group vs. 43.2% (16/37) in placebo group (ARR:22.2%, NNT:5) P 0.04 **Incidence of IC in larger infants (>1500 g) was not different** Secondary outcome: Fungal attributed mortality was 2.6% (1/37) in fluconazole group vs 18.9% (7/37) in placebo group) P 0.02 | Fluconazole prophylaxis decreases IC and fungal attributable mortality Elevation of transaminases in 2 of fluconazole arm and 1 of placebo arm P of >0.05 **Central venous catheters, IV lipids, intubation** were not included in baseline characteristics** **Analyzed data from last 3 years: candida rectal colonization in 30%, candida infection in 23% (Retrospective review of hospital data)** |
proach towards fluconazole prophylaxis seems to be safe and effective. Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms [
Two dose regimens were used in the clinical trials and both of them showed similar outcomes:
・ Fluconazole 3 - 6 mg /kg every third day for 2 weeks, then every other day for the third and fourth week, then daily during the fifth and sixth week.
・ Fluconazole 3 - 6 mg/kg twice weekly for 6 weeks.
This literature review has some limitations. First, trials that investigated the safety and efficacy of oral non-absorbable antifungal agents were excluded (
Fluconazole prophylaxis in preterm neonates and/or neonates with ELBW seems to be safe and effective in reducing IC. Important to remember that only IV fluconazole was tested in clinical trials for 6 weeks or as long as risk factors are available.
Author declares that he has no conflict of interest.
Almulhim, A. (2016) Fluconazole Prophylaxis in Neonates (Non-Systematic) Literature Review. Pharmacology & Pharmacy, 7, 473-480. http://dx.doi.org/10.4236/pp.2016.712053