Management of systemic fungal infection in newborn
D. K. BHAGWANI
1. premature infants are at risk of invasive fungal infections -their
2. The overall incidence of fungal septicemia on neonatal units is
increasing because of both increased survival of VLBW neonates and
use of broad spectrum antibiotics.
3. Invasive fungal infections are caused by Candida species
4.C albicans is responsible for most neonatal infections (up to 80% ),
whereas C parapsilosis and C tropicalis account for 14% and 6% of
4. Colonisation of healthcare workers with fungus (predominantly C
parapsilosis ) is common and can be as high as 30%. This organism is
usually responsible for NICU outbreaks.
2. 1. fungal colonisation is seen in 10% of VLBW infants by the
first week of life and this can increase more than 50%by the
4th week of life.
2. Intial site of colonisation is usually gastrointestinal tract.
3.Colonisation with fungal organisms is an independent
risk factor for subsequent invasive fungal infection,
particularly in VLBW infants and the rate of progression to
invasive candidiasis can vary from 7 to 24%.
4.. Colonisation is the isolation of candida from high risk
sites ( catheter urine, ETT).
1. Infection/ isolation of candida species in the blood.
2.Invasive candidiasis is an important cause of neonatal sepsis in
VLBW infants accounting for upto 12% of late onset infection and
carries an overall mortality of up to 30%.
2. Candida species is the 3rd mo0st frequent organism isolated (after
CONS and Staph. aureus).
4. Invasive/ Disseminated
1. Isolation of candida from other normally sterile body fluids or a
persistent infection after removal of catheter.
2. Candida is capable of invading all vital organs and following
candidaemia, end organ dissemination is more likely with persistent
candidaemia of more than 7 days.
3. Disseminated candidiasis involving the CNS has a mortality rate of 30%
and survivors have a high incidence (up to 50%) of neurodevelopmental
including cerebral palsy, hearing and visual problems.
4. Usual CNS involment includes Meningitis (15%), and Ventriculitis (4%).
5. Candida also results in other end organ damage such as endopthalmitis
(3%), endocarditis (4%) and renal fungal balls which may calcify (5%)
5. Risk factors and transmission:
Transmission of cabndida may be vertical ( from maternal to vaginal
infection/colonisation) or horizontal.
1. Low birth weight (<1500g) and low gestational age (<28 weeks)
2. use of broad spectrum antibiotics and/or multiple antibiotics
3.central venous catheters
4.parentral nutrition, being NBM
5. H2 receptor blockers
6. fungal colonisation in VLBW infants.
Risk factors for IFI in neonatal age
or birth weight
Treatment with broadspectrum antibiotics
Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205.
Invasive devices &
3rd most common cause of late-onset sepsis in NICU
Bimodal frequency: early-onset (within 3 days of birth)
& late-onset (7 – 60 days & later)
Median gestational age: 27.5 weeks
Mortality in neonatal patients: 25 – 60%
Castagnola E, et al. Drugs 2009; 69 (1): 45 -50.
6. Clinical manifestations:
1. The clinical picture of systemic fungal infection in neonates is
indistinguishable from bacterial sepsis.
2.Often signs and symptoms are generalised such as apnoea,
worsening cardio respiratory function, abnormal renal function and/or
3.. Candidiasis can also present with GIT symptoms similar to NEC,
where there may be paucity of classic radiological signs of NEC.
1. Isoaltion of candida from blood or other sterile body fluids is
. 2. Always consider candida in the differential diagnosis of neonatal
sepsis. Particularly late onset sepsis.
1. When a blood culture is positive for candida.
2.important investigations include: urine MC+S, LP, renal and cranial
USS and ophthalmological examination (as candida may worsen ROP
and causes endopthalmitis).
3. Fungal endocarditis may occur even with only one positive blood
culture, so consider an Echocardiogram if there is clinical suspicion of
4. Consider taking out the long line as prompt removal of central
catheters is associated with improved short and long term outcomes.
4. Commencing antifungal thetrapy has to be a Neonatal consultant
decision often involving the microbiologists.
1. Oral Nystatin suspension 0.5ml OD is given to infants <27 weeks
gestation and/or <750gms from birth until removal of central venous
catheters and whilst on broad spectrum antibiotics.
2.This is shown to reduce both colonisation of gastrointestinal tract
and the rate of invasive candidiasis.
3. Fluconazole prophylaxis is effective in reducing the rate of
colonisation and progression to systemic infection in neonatal units
with a high rate of fungal infection (>10%).
4. Oral nystatin used in unit the incidence of systemic fungal infection
is very low (1%), hence Fluconazole prophylaxis is currently not
indicated (the NNT to prevent one case on the unit is around 200).
Antifungals used in neonatal period & susceptibility of
Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205.
Mechanism of Action of Amphotericin B
• Irreversibly binds
• Damages cell
• Fungal cell
Fungicidal activity is believed to be caused by leakage of essential
nutrients from the fungal cell
Lipid-based deliveries of AmB Colloid
AmB Lipid Complex
Occurred when AmB conc
increased > 3 mol %
Size: 1600-11,000 nm
Complexed with non-PL
1:1 molar ratio of AmB plus
2 molecules of AmB and 2
molecules of CS forming a
tetramer that has hydrophilic
and hydrophobic portion
Aggregates into disc-like
Not a liposome
Size: 120-140 nm
Sterol component and
Hydrogenated soy PC
Size: < 80 nm
Advantages of LAmB over Conventional AmB
Increased daily dosage up to 10-fold
Mean duration of Rx with LAmB is shorter than Amb
but has similar efficacy
High tissue concentrations in lungs, liver & spleen
Higher dose administered with LAmB than AmB, but has
1. infusion related side effects
2. renal toxicity & hepatotoxicity
Jeon GW, et al. Yonsei Med J, 2007; 48 (4): 621-626
Extent of tissue
may be an
Nephrotoxicity with Amphotericin B
ARF rates: 49%-65%
Serum creatinine x 2 in 53% cases
Represents ↓ renal function by 70%
15% patients reqd dialysis
Direct damage to tubular cells
45 min after infusion
How does amphotericin B cause nephrotoxicity?
Constriction of afferent
arterioles leading to
Direct damage of distal
tubular membranes leading to
wasting of Na+, K+ and Mg++
Further constriction of arterioles
1st line in systemic
Mode of action
Start at 1mg and
5mg/kg have been
to ergosterol imn
cause leakage of
cations- cell death
serum K and Mg
– Enzyme inducer
that in plasma.
1st Line in fungal
2nd line in systemic
Alternatives: caspofungin 2mg/kg/d is fungicidal, poor CSF
Flucytosine can be used as adjunct to Amphotercin, only available PO.
DURATION OF ANTIFUNGAL
Duration of treatment
Catheter- related infection
Minimum of 7days after removal of
14-21 days after clinical improvement
and negative blood culture
Minimum of 6 weeks, surgery often
require for cure
6- 12 weeks after vitrectomy
Minimum of 4 weeks after resolution of
signs and sympotms