Invasive fungal infection in

neonates
Incidence
IFI was defined as occurring 4 days
after birth and included clinical signs
and symptoms consistent with sepsis
together with isolation of a fungal
causative organism from blood (drawn
from peripheral sites), urine (collected
by suprapubic puncture or bladder
catheterization, with growth of 10. 000
fungi/mL),or cerebrospinal or
peritoneal fluid.
 Fungal colonization was defined as
the detection of at least 1 culture
positive for fungi during the stay in
the NICU.
Do the data of neonatal IFI acturately reflect the
real burden
 Cont.

Stull, Jama.
2004
Cont.

IFI occur in7% of all preterm, VLBW.

74% OF all IFI occurs in infants<1000g.
95% of IFI are due to candida spp.
Risk factors

Gestational age < 32 weeks

Previous fungal colonization (especially of the
gastrointestinal tract), delayed entral feeding
Presence of central venous catheters
Prior use of parenteral nutrition and lipid emulsions
Apgar < 5 at five minutes
Intubation time > 7 days
Shock or coagulopathy.
Candida spp distribution in preterm neonates

C. albicans 58%
C. parapsilosis 34%
C. tropicalis 4%
C. glabrata 2%
C. lusitaniae 2%
C. krusei 0.2%
The clinical signs of systemic candidiasis

Nonspecific and undistinguishable from bacterial sepsis

such as hypothermia,
gastric residue,
hypoactivity,
apnea, worsened respiratory function,
hyperglycemia, hypotension,
bradycardia, and abdominal distension.
A rapid clinical worsening without an apparent cause,
associated with the presence of risk factors, while using
broad-spectrum antibiotics is suggestive of fungal infection .
Cont.

. Involvement of multiple organs is common among

infants. Structures such as kidneys, meninges, eyes, bones
and joints are variably involved in patients with candidemia
and must, therefore, be systematically investigated.
Abdominal and cranial ultrasound, echocardiogram, and
dilated fundus exam by an ophthalmologist should be
requested whenever there is a suspicion of fungal
infection.
Localized signs of candidal infection

-Central nervous system: Meningitis is present in up to 64% of fatal

cases
survivors may have severe sequelae including hydrocephalus,
psychomotor and mental retardation, and aqueductal stenosis.

-Kidneys: Candida is the most frequent cause of urinary tract infection

in intensive care nurseries. Up to 50% of these babies have
candidemia and are predisposed to renal candidiasis, with
development of renal fungus balls or abscesses and unilateral
or bilateral renal obstruction. Renal insufficiency may be the
first clinical manifestation of invasive candidiasis.
Cont.
nd
Heart: Candida endocarditis is the 2 most common
form of endocarditis in VLBW.
Clinical findings may include cardiac murmurs,
petechiae, skin abscesses, arthritis, hepatomegaly and
splenomegaly. Right-sided intracardiac fungal masses
can manifest with heart failure or even with pulmonary
fungal embolism.

-Bones and Joints: Warmth and swelling of the

extremities in combination with radiographic evidence
of osteolysis or arthritis.
Cont.

-Skin and mucous membranes (thrush, diaper

rash or other areas)

-Eyes: Fundoscopic examination is essential for

early diagnosis of invasive disease, as the
incidence of Candida endophthalmitis is as high
as 50%
Congenital Candidiasis:

intrauterine infection is evident at birth. Two forms have

been described:
1) Congenital cutaneous candidiasis in which an extensive
skin rash presents within 12
hours of birth. A macular erythema that may evolve from
a pustular, papular or
vesicular phase finally results in extensive desquamation.
2) Congenital systemic candidiasis: An invasive infection
with a high mortality rate,
especially in VLBW infants. At least 50% do not have a
cutaneous rash. Presenting signs are pneumonia (most
common), meningitis, candiduria and/or candidemia.
 DIAGNOSIS

Consider Candidal infection

In the differential diagnosis of neonatal sepsis,
particularly late-onset.
When blood culture is positive for Candida
One of the factors that reduce sensitivity is the volume of
blood collected, since the chance of detecting a
microorganism with 1 ml of blood is 65% or less.A
decreased concentration and a low rate of replication can
reduce growth rates in culture media and increase the
time needed to establish a positive diagnosis. Negative
blood cultures, however, do not rule out the diagnosis of
candidiasis and samples should, therefore, be serially
collected.
Cont.

A thorough evaluation to rule out dissiminated

infection should include cultures of urine and CSF,
ophthalmological examination, echocardiogram,
renal ultrasound and, if clinical signs of arthritis or
osteomyelitis are present, radiographic skeletal
survey and consider diagnostic aspiration of
affected area
 Unresolved issues in invasive fungal infections
Blood culture may often be negative need for empiric treatment
Frequent end-organ localisations and high risk of CNS involvement poor
NeuroDevelopmental outcomes better to treat with the most potent and wide-
spectrum antifungal available (to avoid/limit poor outcomes) : Hit fast, Hit hard
strategy
Causative fungal agents 99% Candida spp. , but 510% are inherently
resistant to fluconazole avoid Fluco for treatment
Neonates have a prolonged need for CVC high risk of hub colonisation
+ biofilms choose a drug active on biofilms (not Fluco !!)
Fluconazole is widely used for prophylaxis

Micafungin is authorized, but effective dosages are likely different than those
in the label
Cont.

Hence, ideal antifungal drugs for neonates must have:

Significant activity against biofilms
Significant activity against C. glabrata, C. tropicalis and
C. krusei
(because they may survive prophylactic fluconazole)
Ability to be used in mono-therapy, good tolerability, No
interactions
Management
Breast feeding fresh human milk
Hygiene measures
Cautious CVC management
enhancing enteric microbiota composition
with use of probiotics
H2 blockers, steroids, 3rd generation
cephalosporin restrictions
Pharmacological management

Bioactive substance(Bovine
lactoferrin)
Probiotics
Non absorbable anti fungal agents
preventing gut colonisation:Nystatin
Bovine lactoferrin

Lactoferrin (LF) is a glycoprotein of mammalian milk that

is involved in innate immunity mechanisms with several
documented anti-infective properties, including
antifungal activity. This mechanism is related to both
fungistatic effects, and the activity of the N-terminal
aminoacidic peptide of LF called lactoferricin [hLF(1-11)].
Lactoferricins potent candidacidal activity occurs
through stimulation of an increase in the mitochondrial
membranes potential and permeability, resulting in the
synthesis and secretion of adenosine triphosphate and
the production of reactive oxygen species, thereby
leading to Candida albicans cell death. Noteworthy,
bovine and human LF shares a high structural homology,
as well as the same antimicrobial properties.
Which Probiotics to be used?

Bifidobacteria and lactobacilli are the species of choice in

probiotics, given the evolution of the gut flora in preterm
neonates.
lactobacilli are a minor component of the intestinal
microbiota.
Bifidobacteria are the dominant strains in infancy, and the
combination of lactobacilli and bifidobacteria is known to
promote the growth of indigenous lactic-acid bacteria
(bifidogenic effect) by formation of short-chain fatty acids
as a product of the fermentation process
It have been suggested to modify the enteric microflora,
suppress the overgrowth and translocation of pathogens
in the gut, and therefore prevent life-threatening
Good practices to reduce fungal infection in neonates

Hand hygiene
as Candida transmission, particulary Candida
parapsilosis, occur through the hands
Closed vascular systems
will avoid frequent changes and multiple connections.
Use of appropriate antiseptic agents
with transparent dressing around the place of catheters
insertion is recommended.
Catheters
should be removed as soon as there is suspicion of
severe fungal infection
Cont.

Rational use of antibiotics

Avoid petrolatum use
Care with extreme premature infants skin, avoiding abrasions
resultant from dressings adhesion and venous punctures,
Early onset of enteral diet
Breast milk intake must be encouraged, as it contains candida
antibodies
The administration of fluconazole
for 6 weeks in prematures with < 1,000 Kg birth weight
(3mg/kg/day) in places of high fungal sepsis can decrease the
incidence of invasive diseases.

Avoid H2 blockers Gastric pH changes favors fungal colonization

Fluconazole prophylaxis prevents invasive
fungal infection in preterm infants

Fluconazole prophylaxis reduces

The chance of developing IFI in high risk infants
<1000gm by 91% and in <1500gm by 85%.
The overall mortality rate by 26%
The candida related mortality by 96%
No effect on developmental long term outcome
No shift towards fluconazole resistant spp, No
selection of resistant strains
Amphotericin B

Amphotericin B deoxycholate remains as the first-line

drug of choice in the treatment of systemic candidiasis
in infants. Amphotericin B is a macrocyclic polyene
which acts by binding to ergosterol in the fungal cell
membrane, increasing its permeability and leading to
cell lysis and death. Amphotericin is not absorbed orally;
therefore, it is only administered by the parenteral
route, combined with deoxycholate, which improves its
solubility in water. In the bloodstream, it dissociates
from deoxycholate and binds to plasma proteins, being
later distributed to tissues.
Amphotericin B administration

In order to quickly achieve therapeutic levels, an immediate

administration of 0.5 to 1 mg/kg/day of amphotericin B is
currently recommended, since no response to the test dose
has been observed in infants, who apparently tolerate the
drug well. Amphotericin B should be diluted in a 5% glucose
solution, with a concentration of 0.5 mg/ml for infusion via
central catheter, or 0.1 mg/ml for infusion via peripheral
veins. There are no advantages associated with a prolonged
time of infusion. Short-term infusion increases drug
availability by establishing a higher blood-tissue partition
coefficient, without contributing to the frequency of adverse
reactions. Amphotericin B does not need to be protected
from fluorescent light.
The main side effects of amphotericin B

Include nephrotoxicity, hepatotoxicity, myelotoxicity and,

less frequently, cardiotoxicity.
Nephrotoxicity is cumulative, induces systemic electrolytic
alterations, and is characterized by renal tubular acidosis,
hypokalemia and renal failure. Hypokalemia and
hypomagnesemia are frequently observed in infants,
requiring adequate supplementation.
Anemia and thrombocytopenia may also accompany the use
of amphotericin.
Monitoring of urea, creatinine, magnesium, serum
potassium, hematocrit and platelets is necessary during
treatment.
Flucytosine

Flucytosine, also known as 5-FC, is a fluorinated cytosine analogue

converted to fluorouracil by the body.
Fluorouracil inhibits thymidylate synthetase
affecting fungal DNA and protein synthesis.
The drug is well absorbed from the gastrointestinal tract,
binds minimally to plasma proteins.
Due to its synergism and high penetration in the central nervous system, flucytosine is
used in association with amphotericin B
Flucytosine is available only for oral administration, which restricts its use in extremely
preterm infants, who frequently do not tolerate oral drugs.
Azoles
Voriconazole is a new azole, a synthetic derivative of
fluconazole
It affects membrane integrity by inhibiting
cytochrome p-450 dependent enzymes needed for
converting lanosterol to ergosterol.
Voriconazole can work as a fungicide against some
filamentous microorganisms and presents a wide
spectrum of action against fluconazole- resistant
species: Candida krusei and Candida glabrata.
Voriconazole appears to be a promising drug for the
treatment of candidiasis, but no reports of its use in
infants have been published yet.
Guidelines for treatment of fungal infections in newborns
(IDSA)

Candidemia
Therapy should be continued for 2 weeks after the last positive blood culture
result. Amphotericin B may be switched to fluconazole (intravenous or oral)
for completion of therapy, the choice depends on the patients sensibility.
Removal of existing intravascular catheters is desirable.

Congenital candidiasis
Prematurely born neonates and neonates with low birth weight should be
considered for systemic therapy: amphotericin B (10- 25 mg/kg) or
fluconazole. In healthy full term infants with no evidence of candidemia,
treatment with topical agents is generally appropriate.
Cont.
Urinary candidiasis
Candiduria must be taken into account in neonates with very low birth
weight.
The infection can be treated with amphotericin B for 7 - 14 days;
removal of urinary catheters is often helpful. Fluconazole is recommended as
well.
Bladder irrigation with amphotericin B is rarely indicated.
Candidal meningitis
Because of the tendency for this disease to relapse, therapy should
be administered for a minimum of 4 weeks after resolution of all
signs and symptoms associated with the infection. Amphotericin B
(0.7 mg/kg per day) plus flucytosine is appropriate as initial therapy.
Prosthetic devices must be removed
Candidal endocarditis
amphotericin B at maximal tolerated doses for 6 weeks.
A propensity for relapse and requires careful follow-up for at least 1 year.
Long-term therapy with fluconazole has been used after initial treatment.
Clinical treatment, with no surgery, was shown to be effective in neonates
with low birth weight.
Candidal endophtalmitis
Use of the maximal doses of amphotericin B appropriate for other forms of
invasive candidiasis would be appropriate for endophtalmitis treatment.
Therapy should be continued until complete resolution of disease or
stabilization. Courses of 6 - 12 weeks of therapy are typically required.
Fluconazole can be used to complete treatment if sensibility allows.
Cont.

Candidal osteomyelitis and arthritis

Surgical debridement and an initial course of amphotericin B
for 2 - 3 weeks followed by fluconazole, for a total duration of
therapy of 6 - 12 months, appear to be appropriate. Drainage
and prolonged courses of therapy are required for arthritis
management. The use of intra-articular therapy is
discouraged.
Take home message
Consider any premature infant with microbiological or
clinical evidence of invasive candidiasis as having
disseminated disease.
Information on fungal ecology is mandatory and pivotal
to guide initial therapeutic choices
Consider colonisation status
Consider CVC status and the possibility that biofilms
have formed
Switch to a different antifungal class if there is
previous antifungal prophylaxis
Rule out possible end organ localisation
Consider anti fungal targeting CNS and biofilms.
Thank you