Healy et al. 2008 [14]

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**

Rolnitsky et al. 2012 [9]

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 (3^RD 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 [11]

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)**