25 Fungal Infections

In majority of cases, fungal infection is caused by candida species

and rarely, it is caused by Aspergillus, Zygomycetes, Malassezia
and Trichosporon. Prevention and timely management improves
outcome in neonates.

Invasive candida infection

The incidence of invasive candida infection is inversely
proportional to birth weight. The incidence rate in VLBW is 1 to 4
%, ELBW is 2 to 8 % and in incredibly low birth weight (< 750 gm)
or gestation < 26 wks is 20%1. The rate of systemic fungal infection
as reported by DeNIS study group from India is 3.5% (only
outborn cohort)2. Among candida infection C. albicans is the most
common species (50%) followed by C. parapsilosis (33%), C. glabrata,
C. krusei, C. tropicalis and C. pseudotropicalis.

Risk factors1,3,4
Important risk factors associated with invasive candida infection
are : extreme prematurity, prolonged use of antibiotics > 5 days or 2
or more antibiotic use, complicated gastrointestinal disease, lack of
enteral feedings, intralipid use >7 days, use of central venous
catheter, endo-tracheal intubation and mechanical ventilation,
hyperglycaemia, use of steroids/ H2 blockers.

Clinical presentation
Clinical features range from localised skin infection in term
neonates to disseminated infection in extreme preterm neonates.
Severity depends on factors like gestation, birth weight and
invasive procedures. It commonly presents after 2 weeks of age.
Signs and symptoms are similar to bacteremia. Usually neonates
have a smouldering course. Common features include frequent
apnea, lethargy, GI symptoms (distension of abdomen, bloody
stools, gastric aspirates), respiratory distress, increased oxygen
requirement, thrombocytopenia, hyperglycemia, metabolic
acidosis, hypotension and elevated leukocyte count. Thrombo-

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cytopenia lacks specificity and sensitivity for diagnosis of invasive

candidiasis. Various organ system involvements and their clinical
presentation are enlisted below:
1. Renal - UTI, renal abscess
2. CNS- Meningitis, ventriculitis, abscess
3. Gastrointestinal-Peritonitis, spontaneous intestinal
perforation
4. Respiratory-Pneumonia
5. End organ dissemination
a. Eye-endophthalmitis, chorioretinitis
b. Heart-endocarditis and thrombi
c. Bones and joint-septic arthritis and osteomyelitis

Diagnosis
Culture of fungus from a normally sterile site (blood, urine, CSF,
bone or joint, peritoneum, pleural space) is diagnostic. In case of
suspected catheter related infection, culture should be obtained
from both peripheral venous blood and indwelling catheters.
1. Blood culture: Blood culture remains the gold standard5. 90 %
of cultures grow fungus within 72 hrs. Monitor culture for
10 days to ensure growth of slow growing species. Sensitivity
of blood culture varies from 28 % to 78 % from various studies.
2. Urine: Urine should be collected by either suprapubic
aspiration/ sterile catheterization for culture and microscopy.
In microscopy visualise hyphae (true and pseudo) and
budding yeast cells.
a. Candida UTI defined as ³ 104 CFU of candida species/mL
urine.
3. Obtain culture from other sites depending on clinical
presentations (CSF, peritoneal fluid etc).
4. Identification of species and susceptibility: Most of the
species are susceptible to both fluconazole and amphotericin B
except C. glabrata and C. krusei, which are resistant to
fluconazole and C.lusitaniae, which is resistant to amphotericin
B.
5. The following baseline investigation to be done before starting
of treatment with amphotercin B

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a. Hemoglobin, TLC, ANC

b. Urea and creatinine
c. Serum electrolytes
d. Bilirubin and liver enzymes
6. End organ dissemination (EOD) screen to be done in all
confirmed blood stream infection which includes-eye
examination for fungal ophthalmitis or retinitis, renal
ultrasound for fungal balls, echocardiography and cranial
ultrasound/ CT/ MRI.
7. Newer methods of diagnosis are molecular diagnostic assay
using b -1, 3-d-Glucan, PCR, PNA FISH (peptide nucleic acid)
yeast traffic light assay. All these newer methods are costly,
not readily available and still needs further studies.

Treatment
Table 25.1: Drugs used in the treatment of systemic candidiasis- dose,
toxicity and monitoring
Drug Dose Toxicity Monitoring
Amphotericin For doses, refere to Renal, Urine output,
B deoxycholate Annexture A1 hematologic, creatinine, potassium,
hepatic magnesium, liver
enzymes
Lipid Similar to Similar to
formulation amphotercin B; amphotercin B
amphotercin B (decreased renal
toxicities)
Fluconazole Hepatic, Liver enzymes
gastrointestinal
Micafungin Renal, hepatic Creatinine, urine
(Echinocandin) (minimal) output, liver enzymes
1. Infusion related toxicity of Amphotercin B is not seen in neonates. “Lower test” dosage not
required.
2. No enough evidence to support the use of liposomal or lipid formulation Amphotercin B over
deoxycholate form. One study showed increased mortality with lipid formulations.
3. Primary concern for use of fluconazole is emergence of resistance. C krusei and C glabrata are
resistant to fluconazole.

Amphotercin B deoxycholate, 1 mg/kg daily, is first line drug

recommended for systemic candidiasis including meningitis.

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Fluconazole, 12 mg/kg intravenous or oral daily, is an

alternative in neonates who have not been on fluconazole
prophylaxis. Lipid formulation amphotercin B, 3–5 mg/kg
daily, is an alternative, but should be used with caution, it may
not be effective in urinary tract infection. The addition of
flucytosine, 25 mg/kg 4 times daily, may be considered as
salvage therapy in meningitis in conditions with inadequate
clinical response amphotercin B therapy. Echinocandins are
used in treatment of fungal infections unresponsive or resistant
to amphotercin B and fluconazole. The recommended duration
is 2 weeks (3 weeks for meningitis) after documented clearance
of candida species from the bloodstream6. There is no evidence
to recommend empiric therapy in extreme preterm neonates.

Central venous catheter care in neonates with blood stream

infection
• Administer a dose of antifungal through the ‘old’ CVC (for
diagnostic purposes- perform a blood culture from CVC)
• Place a peripheral line
• Remove the CVC and send tip for culture
• Place a new CVC in a site other than the previous at least
36–48 h after CVC removal (ideally wait for 3 sterile blood
culture)

Prophylaxis
In NICUs with high (>10%) and moderate rate (5- 10%) of
invasive candidiasis, intravenous or oral fluconazole
prophylaxis, 3–6mg/kg twice weekly for 6 weeks is
recommended in ELBW neonates. Oral nystatin, 100,000 units
3 times daily for 6 weeks, is an alternative to fluconazole but
there is not enough evidence.6

Evidence for prophylactic antifungal therapy7,8

Prophylactic systemic antifungal therapy compared to placebo/no
therapy in VLBW neonates reduced incidence of invasive fungal
infection (RR- 0.43, 95% CI 0.31 to 0.59). (Studies done in NICUs with
high incidence of invasive infection (Cochrane 2015)).

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Prophylactic oral/topical non-absorbed antifungal prophylaxis vs.

placebo/no therapy resulted in decreased incidence of invasive fungal
infection (RR- 0.20, 95% CI 0.14 to 0.27). However, oral/topical non -
absorbed antifungal prophylaxis is not recommended due to
methodological weakness in studies (Cochrane 2015).

References
1. Saiman L, Ludington E, Pfaller M, Rangel-Frausto S, Wiblin RT,
Dawson J, et al. Risk factors forcandidemia in Neonatal Intensive
Care Unit patients. The National Epidemiology of Mycosis Survey
study group. Pediatr Infect Dis J. 2000 Apr;19(4):319–24.
2. Characterisation and antimicrobial resistance of sepsis pathogens in
neonates born in tertiary care centres in Delhi, India: a cohort
study.Investigators of the Delhi Neonatal Infection Study (DeNIS)
collaboration.Lancet Glob Health. 2016 Oct;4(10):e752-60.
3. Barton M, O’Brien K, Robinson JL, Davies DH, Simpson K, Asztalos E,
et al. Invasive candidiasis in low birth weight preterm infants: risk
factors, clinical course and outcome in a prospective multicenter
study of cases and their matched controls. BMC Infect Dis.
2014;14:327.
4. Benjamin DK, Stoll BJ, Gantz MG, Walsh MC, Sanchez PJ, Das A, et al.
Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical
Judgment. Pediatrics. 2010 Oct;126(4):e865–73.
5. Tezer H, Canpolat FE, Dilmen U. Invasive fungal infections during
the neonatal period: diagnosis, treatment and prophylaxis. Expert
Opin Pharmacother. 2012;13:193-205.
6. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-
Zeichner L, et al. Clinical Practice Guideline for the Management of
Candidiasis: 2016 Update by the Infectious Diseases Society of
America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50.
7. Cleminson J, Austin N, McGuire W. Prophylactic systemic antifungal
agents to prevent mortality and morbidity in very low birth weight
infants. Cochrane Database Syst Rev. 2015 Oct 24;(10):CD003850.
8. Austin N, Cleminson J, Darlow BA, McGuire W. Prophylactic
oral/topical non-absorbed antifungal agents to prevent invasive
fungal infection in very low birth weight infants. Cochrane Database
Syst Rev. 2015 Oct 24;(10):CD003478.

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