epiq review
Developed and established in Canadian neonatal intensive care units, EPIQ (Evidence-based Practice for Improving Quality) is a scientific method
for continuous quality improvement that is evidence based; targeted on key outcomes; collaborative, involving interprofessional teams of experts; and
continuous, promoting a culture of change. Based on the International Liaison Committee on Resuscitation literature review template, the EPIQ
review process addresses important clinical questions by summarizing relevant studies. They are intended as guides to best practices and do not represent unique or mandatory protocols. Full versions of these reviews are available at www.epiq.ca.
Khalid Aziz Md, Assistant editor, Paediatrics & Child Health
Does the use of oral nonabsorbable antifungal
prophylaxis reduce the incidence of fungal colonization
and/or systemic infection in preterm infants?
Russell A Lam MD, Kimberly E Dow MD; Evidence-based Practice for Improving Quality (EPIQ) Review Group
RA Lam, Ke dow; evidence-based Practice for Improving
Quality (ePIQ) Review Group. does the use of oral
nonabsorbable antifungal prophylaxis reduce the incidence of
fungal colonization and/or systemic infection in preterm infants?
Paediatr Child health 2013;18(3):134-136.
BACKGRound: Invasive fungal infection is a significant cause of
mortality and morbidity in preterm infants. Oral nonabsorbable agents
are used prophylactically, but the literature regarding their effectiveness has not been systematically reviewed.
oBjeCtIve: To determine if oral nonabsorbable antifungal prophylaxis reduces the incidence of fungal colonization and/or systemic
infection in preterm infants.
Methods: The literature was reviewed using the methodology for
systematic reviews for the Consensus on Resuscitation Science
adapted from the American Heart Association’s International Liaison
Committee on Resuscitation.
ResuLts: Five studies were reviewed. Three level of evidence 1 studies and two level of evidence 3/4 studies provided evidence that the
prophylactic use of oral nonabsorbable antifungal agents can reduce
the incidence of fungal colonization and/or systemic fungal infection
in preterm infants.
ConCLusIon: Prophylactic oral nonabsorbable antifungal medications are an acceptable approach to reduce colonization and invasive
fungal infection in preterm infants in units with high baseline colonization rates.
Key Words: Antifungal agents; Fungal colonization; Fungal infection;
L’utilisation d’une prophylaxie antifongique orale
non absorbable réduit-elle l’incidence de
colonisation fongique ou d’infection systémique
chez les nourrissons prématurés?
hIstoRIQue : L’infection fongique envahissante est une cause
importante de mortalité et de morbidité chez les nourrissons prématurés.
Des agents oraux non absorbables sont utilisés en prophylaxie, mais les
publications portant sur leur efficacité n’ont fait l’objet d’aucune
analyse systématique.
oBjeCtIF : Déterminer si une prophylaxie antifongique orale non
absorbable réduit l’incidence de colonisation fongique ou d’infection
systémique chez les nourrissons prématurés.
MÉthodoLoGIe : Les chercheurs ont analysé les publications au
moyen de la méthodologie d’analyse systématique du consensus sur la
science de la réanimation adaptée du comité de liaison international
sur la réanimation de l’American Heart Association.
RÉsuLtAts : Les chercheurs ont analysé cinq études. Trois études
dont la qualité de preuve était de catégorie 1 et deux études dont la
qualité de preuve était de catégorie 3 ou 4 ont démontré que
l’utilisation prophylactique d’antifongiques oraux non absorbables
peut réduire l’incidence de colonisation fongique ou d’infection
fongique systémique chez les nourrissons prématurés.
ConCLusIon : Une prophylaxie antifongique orale non absorbable
est une démarche acceptable pour réduire la colonisation et l’infection
fongique envahissante chez les nourrissons prématurés hospitalisés
dans une unité où le taux de colonisation de base est élevé.
Prophylaxis
I
nvasive fungal infection is a significant cause of mortality and
morbidity in preterm infants (1). Because early diagnosis is difficult, which can often result in delayed treatment, there is a need
to evaluate the effectiveness of strategies to prevent fungal colonization and infection (2). We reviewed the literature to determine if
oral nonabsorbable antifungal prophylaxis reduces the incidence of
fungal colonization and/or systemic infection in preterm infants.
Methods
Key words selected with synonyms were “antifungal” OR “antifungal agent”; “oral drug administration” OR “topical drug
administration”; and “preterm” OR “premature infant” OR “neonate” OR “newborn”. These concepts were combined with the
Boolean operator “AND”. Exclusion criteria were non-English
language, abstract only, review articles, editorials or commentaries. Databases searched were Ovid MEDLINE 1950 to 2010,
Scopus 1967 to 2010, Web of Science 1990 to 2010, EMBASE
1980 to 2010, CINAHL 1996 to 2010 and the Cochrane Database
of Systematic Reviews 4th Quarter 2010. The abstracts of all
the articles and the bibliographies of all selected articles were
reviewed, and several review articles were manually searched for
additional studies. From an initial review of 534 citations, five
studies were eligible for inclusion in the present review. They were
scored using the Evidence Evaluation Worksheet adapted from the
American Heart Association’s International Liaison Committee
on Resuscitation (3). Two reviewers independently assigned level
of evidence (LOE), direction of support and quality for each study
(4). Inconsistencies were resolved by consensus.
Queen’s University, Kingston, Ontario
Correspondence: Dr Kimberly E Dow, Room 6-303, Doran 3, Kingston General Hospital, Kingston, Ontario K7L 2V7.
Telephone 613-548-6046, fax 613-548-1369, e-mail [email protected]
Accepted for publication October 1, 2012
134
©2013 Pulsus Group Inc. All rights reserved
Paediatr Child Health Vol 18 No 3 March 2013
EPIQ Review
TablE 1
Characteristics of included studies
author
Study
(ref), year population
Study
Outcomes
Comment
Observational study over two time Reduction in the rate of fungal colonization (18% Historical controls were used
periods. Historical controls (n=714) versus 35.5%), invasive infection (1.8% versus Controls received nystatin if
4.1%) and mortality (11.8% versus 17.8%) in
from January 1998 to October
they became colonized
prophylaxis group
2000 were compared with infants
born between November 2000 and
December 2003 (n=735) who
received nystatin prophylaxis
(100,000 units every 6 h)
Ganesan
et al (7),
2009
Single centre
n=1459
infants,
<33 weeks’
gestation
Howell
et al (8),
2009
Multicentre
Prospective surveillance study of
invasive fungal infection from
n=12,607,
<1500 g birth 1993 to 2006 in Australia and
New Zealand
weight
Reduction in the rate of invasive infection in units Mortality or colonization rate
using selective or universal nystatin prophylaxis not indicated
(0.54%) compared with units using no
prophylaxis (1.23%)
Ozturk
et al (6),
(2006)
Single centre Randomly assigned blindly into
three groups – no nystatin
n=3991, term
and preterm, (n=1516), 100,000 units of
nystatin three times daily if
<37 weeks’
infant was colonized (n=479),
gestation
nystatin given to all infants
(n= 1596)
(n=1996)
Reduction in the rate of invasive candidiasis in
prophylactic (1.8%) and selective treatment
group (5.6%) versus control (14.2%)
Reduction in the rate of rectal colonization in
prophylactic (6%) and selective treatment
(13.8%) groups versus control (24.7%)
lOE*
3 (S)
Quality: fair
4 (S)
Quality: fair
In a subset analysis of infants 1 (S)
<1500 g (n=197), invasive
Quality: good
candidiasis was reduced in the
prophylaxis (5.5%) and
selected treatment (18.3%)
groups versus control (41.9%).
No significant difference in the
rate of mortality was found in
this subset or the entire group
Sims et al Single centre Randomly assigned to control or
(5), 1988 n=67, <1250 g 100,000 units of nystatin every
8h
birth weight
Reduction in the rate of fungal colonization (12%) High baseline fungal
1 (S)
and systemic infection (6%) in treatment group
colonization rate (44%), likely Quality: good
compared with control (44% colonization, 32%
due to selection bias as
systemic infection)
suggested by authors
Wainer
et al (9),
1992
Reduction in the rate of fungal colonization in
No infants <1000 g were
treatment group (23%) compared with control (38%) intubated
No significant differences in the rate of systemic
infection or mortality
No significant difference in rate of mortality
Single centre Randomly assigned to control or
miconazole 15 mg twice daily
n=600,
<1750 g birth
weight
1 (S)
colonization
1 (N) systemic
Quality: good
*Level of evidence (LOE) supporting intervention (S: Support; N: Neutral)
ResuLts
Study characteristics and the LOE are presented in Table 1. Sims et
al (5) performed a randomized controlled trial (RCT) (LOE 1) in
which 67 infants with birth weights between 500 g and 1250 g were
randomly assigned either to group A (33 patients) and received
100,000 units of nystatin every 8 h for one week postextubation or
group B (34 patients) and received no therapy. There was no mention of whether the study was blinded. Nystatin prophylaxis decreased
the rate of fungal colonization (12% versus 44%; P<0.01) and systemic fungal infection (6% versus 32%; P<0.001) compared with the
control group. There was no significant difference in the mortality
rate between the two groups (12% versus 20%; P>0.05). It is important to note that the overall colonization rate was quite high in this
study (44%), which the authors postulated was due to their institutional practice of transferring stable infants to other centres within
the first 24 h. This practice created a selection bias because only
unstable patients, who may have been at higher risk of developing
fungal colonization or infection, remained in their centre.
Ozturk et al (6) performed a RCT (LOE 1) in which
3911 infants, 1596 of whom were premature (<37 weeks’ gestation), were randomly assigned to one of three groups. Neonates in
group A1 did not receive nystatin. Neonates in group A2 that were
known yeast carriers, determined by the presence of oral moniliasis, received 100,000 units of nystatin three times a day. Neonates
in group B received nystatin prophylaxis starting on day 1 of
admission. Urine and rectal cultures were taken on admission and
weekly thereafter. Cerebrospinal fluid (CSF) cultures were ordered
if meningitis was suspected, and blood and endotracheal cultures
were ordered if septicemia was suspected. The authors found that
prophylaxis (group B) or directed treatment of yeast carriage
Paediatr Child Health Vol 18 No 3 March 2013
(group A2) significantly reduced the rate of rectal colonization
(24.7% versus 13.8% versus 6 % for groups A1, A2 and B, respectively; P=0.001) and invasive candidiasis (14.2% versus 5.6%
versus 1.8%, for groups A1, A2 and B, respectively; P=0.004). The
significant difference between groups A2 and B suggested that
directed treatment after the discovery of yeast carriage remained
effective in reducing the incidence of rectal colonization and invasive candidiasis. There was a significant difference in the invasive
candidiasis rate in the very low birth weight patient subset among
the three groups (41.9% versus 18.3% versus 5.5%, for groups A1,
A2 and B, respectively; P<0.001) but no difference in the mortality rate was found (7.5% versus 7.0% versus 7.2%, for groups A1,
A2 and B, respectively; P=0.96).
In an observational study (LOE 3) of preterm infants <33 weeks’
gestation, Ganesan et al (7) compared an intervention group
(n=735), treated with 100,000 units of nystatin every 6 h until the
termination of intensive care, with a group of historical controls
(n=714). The infants in the control group received nystatin only
if they were found to be colonized as per the clinical practice for
that hospital. A reduction in the rate of fungal colonization (18%
versus 35.5%; P<0.0001), invasive fungal infection (1.8% versus
4.1%; P<0.008) and mortality (11.8% versus 17.8%; P<0.0001)
was found in the prophylaxis group. This was the only study that
found a reduction in the rate of mortality between the prophylaxis
and control groups. The authors postulated that this may have
been a result of an overall decrease in invasive fungal infections
over the six-year study period or local changes in practice related
to antibiotic or surfactant usage.
Howell et al (8) reported a multicentre surveillance study (LOE 4)
from 15 neonatal intensive care units in Australia and New Zealand
135
EPIQ Review
over a 14-year period. Invasive fungal infection rates were studied,
but fungal colonization rates were not. Of the 15 units studied,
10 had data available for infants <1500 g; a total of 12,607 infants.
Five of the units used oral nystatin prophylaxis variably, with the
variations attributed to local practice change within the hospital
over time, and five of the units did not use prophylaxis. The authors
found that units using nystatin prophylaxis had significantly lower
rates of invasive fungal infection (0.54% versus 1.23%; P<0.001).
Differences in colonization rates or mortality rates between the prophylaxis and nonprophylaxis units were not mentioned.
Wainer et al (9) performed a blinded RCT (LOE 5) in which
298 infants <1750 g were allocated to a control group and 302 were
allocated to a group that received 15 mg of miconazole gel orally three
times a day. Importantly, no infants <1000 g were intubated at birth in
this neonatal intensive care unit. The authors found that there was a
high mortality rate (52% of all infants) within the first week, but
there was no significant difference in the mortality rate between the
miconazole and control groups (38.9% versus 33.8%; P>0.05). In the
<1000 g birth weight subset who were not intubated, there was also
no difference in the mortality rate (62.2% versus 72.2%; P>0.05). In
week 1, there was a significant reduction in the rate of rectal fungal
colonization in the treatment group (16.8% versus 35.2%; P<0.001)
but no significant difference in the following week. After week 3,
when all results were summated, there was still a significant reduction
in the rate of rectal fungal colonization in the treatment and placebo
groups (23% versus 38%; P<0.05). During the entire period, there was
no difference in the rate of systemic infection in the treatment versus
placebo groups (2.6% versus 2%; P>0.05).
dIsCussIon
A recent Cochrane review on this topic (10), which included
three of the articles described here (5,6,9), concluded that the data
were insufficient to guide clinical practice. The present systematic
review used the two databases searched in the Cochrane review
(MEDLINE and EMBASE) but further extended the search to
include Scopus, Web of Science and CINAHL. Five articles were
identified that were directly relevant to the clinical question.
Overall, these five studies, although heterogenous in methodology, suggested that oral nonabsorbable antifungal prophylaxis
was effective in reducing colonization and invasive fungal infection rates. There did not appear to be a significant change in
mortality rate and none of these studies mentioned long-term
neurodevelopmental outcomes. No adverse effects were reported
with the use of oral nonabsorbable antifungal prophylaxis in
these studies.
Interestingly, there was a considerable amount of variation in
the definitions used for both colonization and systemic infection,
as well as in the observed colonization rates among these studies
(Sims et al [5] 44%, Ozturk et al [6] 24.7%, Ganesan et al [7]
35.5%, Wainer et al [9] 35.2% [Howell et al (8) did not study colonization rates]). These studies were also conducted at different
times periods and in different countries (United States, Turkey,
United Kingdom, Australia and South Africa).
It is the opinion of the authors that there is insufficient evidence to support routine use of oral nonabsorbable antifungal
prophylaxis in all neonatal intensive care nurseries. However,
depending on the baseline fungal colonization rate, guided prophylaxis could be an option to reduce invasive fungal infection.
Additional studies could be directed toward a three-arm placebo
controlled trial comparing oral nonabsorbable antifungal prophylaxis, systemic antifungal prophylaxis and placebo.
Consensus on sCIenCe
Three LOE 1 and two LOE 3/4 studies provide evidence that prophylactic use of oral nonabsorbable antifungal medications can
reduce the incidence of fungal colonization and/or systemic fungal
infection in preterm infants.
ReCoMMendAtIon
Prophylactic oral nonabsorbable antifungal medications are an
acceptable approach to reduce colonization and invasive fungal
infection in preterm infants in units with high baseline colonization rates.
ACKnoWLedGeMent: The authors thank Paola Durando, for
her assistance with the literature review and Chris Dow for his help
with access to Scopus.
ePIQ evIdenCe RevIeW GRouP
Principal investigator: Dr Shoo K Lee, Mount Sinai Hospital, Toronto, Ontario
Committee Chair: Dr Nalini Singhal, Foothills Medical Centre, Calgary, Alberta
Committee Members: Dr Kimberly Dow, Kingston General Hospital, Kingston; Dr Andrew James, The Hospital for Sick Children,
Toronto, Ontario; Dr Ibrahim Mohamed, Hôpital Sainte-Justine, Montreal, Quebec; Dr Nicole Rouvinez-Bouali, Children’s Hospital of
Eastern Ontario, Ottawa, Ontario; Dr Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Dr Vibhuti Shah,
Mount Sinai Hospital, Toronto, Ontario; Dr Anne Synnes, BC Children’s Hospital, Vancouver, British Columbia, Dr Wendy Yee, Foothills
Medical Centre, Calgary, Alberta
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Paediatr Child Health Vol 18 No 3 March 2013