The use of prophylactic

fluconazole in very low birth

weight infants

Martin Skidmore
University of Toronto
 Incidence and burden of fungal
infections in the NICU
• Candida spp 1/3 most common cause of late
onset sepsis (>72 h) in VLBW (<1500g)
• 75% of infected VLBW infants will die or survive
with handicap
• Overall mortality rates estimated at 10-15%
• Case mortality rates as high as 44%
• In Canada (2003-2005): incidence 6.7% infants
<28 weeks
» CNN unpublished
Rationale for antifungal prophylaxis
• Associated with:
– Endocarditis 15.3%
– Meningitis 8.4%
– Intra-abdominal involvement 8%
– Eye involvement 6%

• 50% continue to have positive cultures in

spite of therapy
– 10% culture positive > 14 days
 Risk factors for candidiasis
• ELBW
• Low gestational age
• Therapies
– Intubation
– Ventilation
– Central line placement
– TPN
– Medications
• Steroids
• H2 blockers
• antibiotics
 Strategies
• Optimal infection control practices
• Avoid broad spectrum antibiotic coverage
• Prompt removal of infected devices
• Prevention of colonization
30% of NICUs use some form of antifungal prophylaxis*
– Fluconazole
– Topical nystatin
– Amphoteracin B

*AAP/Neo-Peri Section questionnaire

 Why fluconazonle?
• Has a long half-life
• Well concentrated in tissues and body fluids
• Low lipophilicity
• Low protein binding
• 80% excreted unchanged in the urine
• Persistence of high skin and mucosal concentrations
• 70-90% penetration into CSF
• Concentrated in urine and CSF
However:
• Elevations in liver enzymes (reversible)
• Elevations in serum bilirubin (reversible)
 RCTs of oral antifungal agents *

Study Enrolme N Dosing Protocol Treatm Contr P-

nt Schedule ent ol val
Criteria Group Grou ue
p
Sims et <1250 67 Nystatin po Single- 2/33(6% 11/33 <0.05
al every 8 centre ) (32%)
(1988) hours placebo
Violaris <1500 g 21 Fluconazol Single- 0/8 (0%) 4/9 <0.05
et al e vs. centre (44%)
(1998) nystatin
Wainer <1750 g 60 Miconazole Single- 8/302(3 6/298 NS
et al 0 po every 8 centre %) (2%)
(1992) hours placebo
Ozturk All 39 Nystatin po Single- 36/1996 215/ 0.004
et al infants 91 every 8 centre (1.8%) 1516
(2006) hours, (1.8%
variable )
*from Healy,M: NeoReviews, 2008
 RCTs of fluconazole prophylaxis in
neonates
Study Enrolment N Protocol Dosing Schedule Treatment Control P-value
Criteria Group (IC) Group (IC)

Kaufman et <1000 g 100 Single-centre 3mg/kg x 6 wks or 0/50 (0%) 10/50 (20%) 0.008
al ETT or CVC placebo less if no IV needed (4 Candida-
(2001) ≤ 5 days of q72h (0-14d) related
life q48h (15-28d) deaths)
q24h (29-42d)
Kicklighter <1500 g 103 Single-centre 6 mg/kg IV/PO 1/53 (1.8%) 0/50 (0%) NS
et al ≤ 3 days of placebo For 28 days (1 Candida-
(2001) life related
death)
Cabrera et <1500 g 11 Single-centre, 6 mg/kg IV then PO 0/6 1/5 NS
al (2002) placebo
Parikh et al <1500 g 120 Single-centre, 6 mg/kg IV then po 16/60 15/60 (25%) NS
(2007) placebo for 28 days (26.7%)

Manzoni <1500 g 322 Multi-centre, 6 mg/kg or 3 mg/kg 7/216 (3.2%) 14/106 0.001
et al (2007) ≤ 3 days of placebo qod x 30d (100- (0 Candida- (13.2%)
life 1500g) or 45d related (4 Candida-
(<1000g) or less if no deaths) related
IV needed deaths)
 Safety of fluconazole
• Has minimal toxicity (LFTs)
• No increase in late onset bacterial infection
• No increase in NEC
• Development of antifungal agent resistance
• Increase in frequency of C.glabrata and
C.parapsilosis
• In P/Ts: decrease dose, duration of exposure,
longer dosaging intervals
• No longterm N/D outcome data to date
 Optimal dosing and schedule
• Trials:
– 3-6 mg/kg
– 24-72 h intervals
– 7 different schedules
• Kaufman:
– 3mg/kg PO starting on Day 1 or 2
– Twice per week
– For up to 6 weeks
 Who should receive fluconazole
prophylaxis?

• BW ≤ 750 gm
• GA ≤27 weeks
• IF BASELINE FUNGAL INFECTION
RATES ARE HIGH (eg: >5%)

• Why not ≤ 1500 gm BWs?