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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» CNN unpublished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) q24h (29-42d)

deaths)

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?