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Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants

  1. Nicola Austin1,*,
  2. Brian A Darlow2,
  3. William McGuire3

Editorial Group: Cochrane Neonatal Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 31 DEC 2012

DOI: 10.1002/14651858.CD003478.pub4

How to Cite

Austin N, Darlow BA, McGuire W. Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD003478. DOI: 10.1002/14651858.CD003478.pub4.

Author Information

  1. 1

    Christchurch Womens Hospital, NICU, Christchurch, New Zealand

  2. 2

    Christchurch School of Medicine, Department of Paediatrics, CHRISTCHURCH, New Zealand

  3. 3

    Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK

*Nicola Austin, NICU, Christchurch Womens Hospital, Christchurch, New Zealand. nicola.austin@cdhb.govt.nz.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Aydemir 2011a

MethodsRandomised controlled trial


Participants185 VLBW infants


InterventionsOral nystatin 100,000 U/ml 8 hourly (N = 94) versus normal saline placebo* (N= 91) every third day versus until the 30th day after birth (or 45th day in ELBW infants)


OutcomesFungal colonisation and invasive infection

Death prior to hospital discharge

Emergence of fungi with native azole resistance
Adverse drug reactions


NotesSetting: Zekai Tahir Burak Maternity Hospital, Ankara, Turkey; 2008-9

*Report states placebo controlled but unclear how this was achieved

The same infants form the oral nystatin group in both Aydemir 2011a and Aydemir 2011b


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskComputer-generated allocation

Blinding (performance bias and detection bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Aydemir 2011b

MethodsRandomised controlled trial


Participants187 VLBW infants.


InterventionsOral nystatin 100,000 U/ml 8 hourly (N = 94) versus fluconazole 3 mg/kg (N = 93) every third day versus until the 30th day after birth (or 45th day in ELBW infants)


OutcomesFungal colonisation and invasive infection

Death prior to hospital discharge

Emergence of fungi with native azole resistance
Adverse drug reactions


NotesSetting: Zekai Tahir Burak Maternity Hospital, Ankara, Turkey; 2008-9

The same infants form the oral nystatin group in both Aydemir 2011a and Aydemir 2011b


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskComputer-generated allocation

Blinding (performance bias and detection bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskReport states placebo controlled but unclear how this was achieved

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Ozturk 2006

MethodsRandomised controlled trial


Participants938 VLBW infants with subgroup report for ELBW infants (N = 349)


InterventionsNystatin 100000 IU orally, 8 hourly (N = 475) versus no drug (N = 463)


OutcomesFungal colonisation and invasive fungal infection


NotesSetting: Division of Neonatology, Erciyes University Hospital, Turkey, 2002-2005

25% of control VLBW infants received nystatin (100000 IU orally, 8 hourly) to treat oral fungal colonisation detected at trial entry or during the trial period


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskRandomly assigned by "someone not directly involved in the study" using random number tables

Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Sims 1988

MethodsQuasi-randomised controlled trial; odd or even hospital number allocation


Participants67 infants of birth weight < 1250 grams


InterventionsNystatin 1ml orally, 8 hourly (N = 33) versus no drug (N = 34)

Treatment from inclusion until one week after endotracheal extubation


OutcomesFungal colonisation and invasive fungal infection

Duration of mechanical ventilation and duration of intensive care admission


NotesSetting: Los Angeles County-University of Southern California Medical Centre, 1985 to 1986

The study took place during a period of overcrowding in the intensive care unit; 222 infants with a birthweight < 1250 grams were born during a 12 month period; 55 died within 48 hours, 88 relatively healthy infants were transferred elsewhere and 67 of the remaining 88 infants were recruited to the study.

One infant in the control group had Candida albicans pneumonia supported by postmortem evidence. All the other affected infants had positive urine and blood cultures


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskQuasi-randomised

Blinding (performance bias and detection bias)
All outcomes
High riskUnblinded

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnblinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Violaris 2010

MethodsRandomised controlled trial


Participants80 VLBW infants

Haemodynamically unstable infants and infants with severe congenital anomalies or abnormal liver function tests were not eligible to participate


InterventionsNystatin (100,000 units/kg/day) in each side of the mouth (N = 42) versus fluconazole (4 mg/kg) orally (N = 38) beginning on day five after birth

Medications were continued until full oral feedings were attained or systemic fungal infection was diagnosed


OutcomesInvasive fungal infection, invasive bacterial infection, biochemical indices related to liver function, mortality


NotesSetting: Brooklyn Hospital Center, New York; 1997- 1998


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskComputerised randomisation and allocation

Blinding (performance bias and detection bias)
All outcomes
High riskUnable to blind interventions

Blinding of participants and personnel (performance bias)
All outcomes
High riskUnable to blind interventions

Blinding of outcome assessment (detection bias)
All outcomes
High riskUnable to blind interventions

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow up

Wainer 1992

MethodsRandomised controlled trial


Participants600 infants of birth weight < 1750 grams.


InterventionsMiconazole 0.75ml orally 3 times daily (N = 302) vs. placebo (N = 298)


OutcomesFungal colonisation and invasive fungal infection. Duration of mechanical ventilation and duration of intensive care admission


NotesSetting: Baragwanath Hospital, South Africa from October 1989 to July 1990

Due to limited resources, mechanical ventilation was not offered to infants with birth weight < 1000 gm. This group made up 12% (73/600) of the infants and had a high mortality rate (67%)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo-controlled

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo-controlled

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo-controlled

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Damjanovic 1993Not a randomised controlled trial

Harris 1960The gestational age or birth weight of participants was not reported - assumed to include term and preterm infants

Herruzo-Cabrera 1994A prospective cohort study but not a randomised controlled trial

 
Characteristics of ongoing studies [ordered by study ID]
Yekta 2012

Trial name or titleComparison of Lactobacillus reuteri and nystatin prophylaxis on Candida colonization and infection in very low birth weight Infants

MethodsRandomised controlled trial

ParticipantsVery preterm or VLBW infants

Interventions
  • Probiotic: Lactobacillus reuteri 100 million CFU/day
  • Nystatin 50000 unit/3 times a day, both for orally and by orogastric route

OutcomesRectal and skin swabs for Candida colonization taken weekly. Blood culture for Candida infection taken weekly

Starting dateFebruary 2012

Contact informationMehmet Yekta, Zekai Tahir Burak Maternity and Teaching Hospital, Turkey

NotesClinicalTrials.gov Identifier: NCT01531192

 
Comparison 1. Oral/topical non-absorbed antifungal prophylaxis vs placebo or nothing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of invasive fungal infection4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 All VLBW infants
41800Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.14, 0.27]

    1.2 Only ELBW infants
1349Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.06, 0.26]

 2 Mortality4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 All VLBW infants
41800Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.05]

    2.2 Only ELBW infants
1349Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.51, 2.25]

 3 Bronchopulmonary dysplasia1171Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.67, 2.49]

 4 Necrotising enterocolitis1185Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.40, 2.33]

 5 Retinopathy of prematurity1177Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.30, 1.28]

 6 Length of stay in NICU (days)3833Mean Difference (IV, Fixed, 95% CI)-0.52 [-4.34, 3.29]

 
Comparison 2. Oral/topical non-absorbed prophylaxis vs. systemic antifungal prophylaxis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of invasive fungal infection2267Risk Ratio (M-H, Fixed, 95% CI)1.89 [0.66, 5.39]

 2 Mortality2267Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.72, 3.77]

 3 Bronchopulmonary dysplasia1171Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.67, 2.49]

 4 Necrotising enterocolitis2267Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.58, 2.60]

 5 Retinopathy of prematurity1171Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.51, 2.98]

 6 Length of stay in NICU (days)1171Mean Difference (IV, Fixed, 95% CI)-1.0 [-7.63, 5.63]