Challenging issues in neonatal candidiasis

Figures & data

Table 1.  Should empiric antifungal therapy be administered with sepsis evaluations?.

Empiric Antifungal Therapy Approaches	Comments
Not needed	• Treat infections promptly when positive growth from cultures and remove CVC with bloodstream infections (Pickering, 2009)12
	• No randomized controlled studies comparing prompt treatment, including CVC removal to empiric therapy
	• Antifungal prophylaxis use nearly eliminates infection-related mortality (Kaufman, 2008; Healy, 2008)10,39
	• Fungal cultures have positive growth by 48 hours (Schlenoka, 2003)9
All infants <1500 g	• One epidemiologic study suggesting this approach (Makhoul, 2001)7
<1500 g (or >1500 g and critically ill) + risk factors	• Small prospective study with historic controls showing benefit in mortality (Procianoy, 2006)8
	• Candida-related mortality rates in other studies range from 0% to 66%
After 48 hours of empiric antibacterials, with continued signs and symptoms of sepsis and new cultures resent	• Needs further study (Schelonka, 2003)9
New-onset thrombocytopenia	• Needs further study (Benjamin, 2003)6
	• Many organisms are associated with thrombocytopenia (Guida, 2003; Manzoni, 2009; Bhat, 2009)3^–5
	• Fungal infections are associated with the greatest decrease (50%) in platelet counts, similar to gram-negative infections (Guida, 2003)3

CVC = central venous catheter.

Empiric therapy: starting antifungal therapy when cultures performed with signs and symptoms of sepsis.

Table 2.  Site of action of antifungal prevention strategies.

	Fluconazole (IV)	Fluconazole (PO)	Nystatin	Central Venous Catheter ‘Bundles’
Skin	√	√
Respiratory Tract	√	√
Gastrointestinal Tract	√	√	√
Central Venous Catheter	√			√

Table 3.  Comparison of antifungal prophylaxis agents.

	Fluconazole	Nystatin
Effect on Colonization	Decreases CVC, skin, gastrointestinal and respiratory colonization	Only decreases gastrointestinal colonization
Route of Administration	Given IV, so can be given in infants not receiving enteral feeds, and those with NEC, FBP, ileus or GI disease	Given enterally Cannot be given if NEC, FBP, GI disease or ileus
Level of Evidence	Multiple RCTs with significant efficacy even in the most extremely preterm infants (A-I) Efficacy and safety data in over 3100 infants in 14 studies	Only one RCT with no effect on BSIs, only significant decrease in UTIs in <1250 g intubated infants Retrospective and epidemiologic data from three other studies (B-II)
Efficacy	∼90% decrease in ELBWs	Retrospective studies with ∼55% decrease in ELBWs
Extreme Preterm Infants Data	Efficacy ↓95% in <750 g ↓88% in <27 weeks ↓85% in <1000 g	Few infants <750 g or <25 wks Retrospective studies lack data on safety and susceptibility patterns
Combined Outcome (ICI and/or Mortality)	10% (FP) vs. 25% (placebo) patients from RCTs	N/A
Effect on Mortality	Candida-related mortality decreased by 96%	N/A
Osmolarity	300 mOsm/L	3002 mOsm/L
Resistance	No Candida albicans resistance Rare non-albicans resistance	No data. Not examined critically
Dosing Frequency	Twice-a-week dosing	Dosing 3–4 times per day
Cost	Costs less 4-wk prophylaxis: $144	Costs more 4-wk prophylaxis: $314
Cost Benefit	Reduced healthcare cost of ICI by >$500,000 over 18 months	–

BSIs = bloodstream infections; CVC = central venous catheter; ELBW = extremely low birth weight ( < 1000 g); FBP = focal bowel perforation; FP = fluconazole prophylaxis; GI = gastrointestinal tract; ICI = invasive Candida infections (blood, urine, cerebrospinal fluid, or peritonitis); IV = intravenous; N/A = not available from published data; NEC = necrotizing enterocolitis; RCT = randomized controlled trial; UTIs = urinary tract infections.

Table 4.  Preventative strategies and levels of evidence.

Preventative Strategies in the NICU	Guideline	Level of Evidence
Antifungal Prophylaxis	Fluconazole prophylaxis in infants <1000 g while intravenous access (central or peripheral)	A-I
Antifungal Prophylaxis	Nystatin prophylaxis in infants <1500 g	B-II
Antibiotic Stewardship	Restrict third- and fourth-generation cephalosporins and carbapenems to treatment of proven gram-negative infections	B-II
Medication Stewardship	1. Postnatal steroids restriction for severe BPD 2. H2 blockers and proton pump inhibitors for infants with proven gastritis, and use for 3 days or until symptoms resolve	B-II

NICU = neonatal intensive care unit; BPD = bronchopulmonary dysplasia.

Table 5.  Top 10 ways to ‘get to zero’ invasive Candida infections and infection-related mortality.

1. Antifungal prophylaxis (for infants <1000 g and/or ≤27 weeks)

2. Treat proven infections with appropriate antifungal dosing

3. Promptly remove central venous catheters with candidemia

4. Decrease broad-spectrum antibiotic use

5. Decrease H2 blocker and proton pump inhibitor use

6. Decrease postnatal steroid use

7. Feed early with breast milk

8. Use central venous catheter ‘bundles’

9. Consider fungal infection when performing sepsis evaluations

10. Perform speciation and susceptibility testing on all clinical fungal  infections

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