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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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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Invasive fungal infection accounts for 10% of all cases of late-onset invasive infection in very preterm or very low birth weight (VLBW) infants (Stoll 2002). The reported mortality rates of greater than 25% are higher than those attributed to nosocomial bacterial infection in VLBW infants (Saiman 2000; Makhoul 2002; Stoll 2002; Benjamin 2003). Invasive fungal infection is also associated with short- and long-term morbidity, including adverse neurodevelopmental outcomes (Lee 1998; Friedman 2000; Saiman 2000; Benjamin 2006).

The overall incidence of invasive fungal infection in VLBW infants is between about 1% and 4%, but the risk of infection is inversely related to gestational age and birth weight. In extremely preterm or extremely low birth weight (ELBW) infants, reported incidences are between about 2% and 8%. Much higher incidences, up to 20%, have been reported for infants of birth weight less than 750 grams or gestational age at birth less than 26 weeks (Saiman 2000; Makhoul 2002; Horbar 2002; Karlowicz 2002; Clerihew 2006).

Observational studies suggest that mucocutaneous or tracheal fungal colonisation is a risk factor for invasive infection (Faix 1989; Pappu-Katikaneni 1990; Rowen 1994; Huang 1998). However, multivariate analyses that account for potential confounding variables, particularly ELBW, have not confirmed this association (Saiman 2000). Other putative risk factors for invasive fungal infection in VLBW infants include severity of illness at birth, the use of multiple courses of antibiotics (particularly third-generation cephalosporins), the use of parenteral nutrition, the presence of a central venous catheter, and exposure to histamine receptor subtype 2 antagonists (Rowen 1994; Benjamin 2006; Cotten 2006; Manzoni 2006).

The clinical presentation of invasive fungal infection in VLBW infants is similar to that of bacterial infection and this may cause delays in diagnosis and treatment. The diagnosis may be further delayed due to an inability to recover the organism from microbiological culture of blood, cerebrospinal fluid, or urine. A high index of suspicion and the use of additional laboratory and clinical tests may be needed to confirm the suspected diagnosis (Benjamin 2003).

 

Description of the intervention

Given the difficulty in establishing an early diagnosis and the high level of associated morbidity and mortality, there is a need to assess the effect of strategies to prevent invasive fungal infection in VLBW infants (Brecht 2009). In addition to generic infection control practices and avoidance of modifiable risk factors, two broad chemoprophylactic strategies are employed in current clinical practice (Burwell 2006; Clerihew 2008; Ganesan 2008; O'Grady 2008; Howell 2009; Kaguelidou 2012):

  • Prophylaxis using systemically-absorbed antifungal drugs that achieve fungicidal concentrations in tissue, blood, cerebrospinal fluid, and urine. Evidence exists that systemic antifungal prophylaxis using fluconazole reduces the incidence of invasive fungal infection, but there is concern about toxicity (Frattarelli 2004) as well as the effect that its widespread use may have on the emergence of antifungal resistance (Brion 2007; Austin 2012)

  • Prophylaxis using oral/topical non-absorbed agents such as nystatin or miconazole. Observational studies have suggested that oral/topical non-absorbed antifungal prophylaxis reduces mucocutaneous fungal colonisation and the risk of invasive infection in VLBW infants (Ganesan 2008; Howell 2009). However, the specific effect of antifungal prophylaxis independently of other confounding interventions and variables is unable to be determined from these studies. Another concern is that hyper-osmolar nystatin preparations may increase the risk of adverse gastrointestinal events in VLBW infants (Ernst 1983;Radmacher 2012).

 

Why it is important to do this review

This review focuses on randomised comparisons of oral/topical non-absorbed antifungal prophylaxis compared with no antifungal prophylaxis or compared with systemic antifungal prophylaxis. The effect of systemic antifungal prophylaxis compared with no prophylaxis is addressed in another Cochrane review (Austin 2012).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and adverse neurodevelopmental outcomes in very preterm or VLBW infants.

We examined the following interventions:

  1. oral/topical antifungal prophylaxis versus placebo or no drug;
  2. oral/topical antifungal prophylaxis versus systemic antifungal prophylaxis;
  3. one oral/topical antifungal regimen versus another oral/topical antifungal regimen.

We pre-specified these subgroup analyses:

  1. extremely preterm (< 28 weeks) or ELBW infants (< 1000 grams);
  2. trials in which participants were infants with fungal colonisation.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised or quasi-randomised controlled trials, including cluster randomised trials.

 

Types of participants

VLBW infants (< 1500 grams) or very preterm infants (< 32 weeks at birth).

 

Types of interventions

Antifungal prophylaxis with oral/topical non-absorbed drugs versus placebo or nothing or another antifungal drug regimen.

 

Types of outcome measures

 

Primary outcomes

  1. Confirmed invasive fungal infection as determined by:
    1. culture of fungus from a normally sterile site: cerebrospinal fluid, blood, urine, bone or joint, peritoneum, pleural space. Samples should have been collected using methods to minimise contamination with surface colonising organisms;
    2. findings on autopsy examination consistent with invasive fungal infection;
    3. findings on ophthalmological examination consistent with fungal ophthalmitis or retinitis;
    4. pathognomonic findings on renal ultrasound examination such as 'renal fungal balls'.
  2. Death prior to hospital discharge.
  3. Neurodevelopmental outcomes assessed beyond infancy (neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability, non-ambulant cerebral palsy, developmental delay) and cognitive and educational outcomes at five years or older (intelligence quotient and/or indices of educational achievement measured using a validated tool including school examination results).

 

Secondary outcomes

  1. Incidence of bronchopulmonary dysplasia (oxygen supplementation at 36 weeks postmenstrual age);
  2. Incidence of necrotising enterocolitis (Bell stage 2 or 3);
  3. Incidence of retinopathy of prematurity: a) any stage; b) requiring treatment;
  4. Duration of intensive care unit or hospital admission (days);
  5. Adverse events attributed to drug reactions or toxicity sufficient to cease drug administration.

 

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group.

 

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2012, Issue 1), MEDLINE (1966 to August 2012), EMBASE (1980 to August 2012), and CINAHL (1982 to August 2012), using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR LBW OR infan* OR neonat*] AND [Mycoses/ OR fung* OR candid* OR Candida albicans OR Antifungal Agents/ OR Triazoles/ OR fluconazole OR azole OR amphotericin B OR nystatin OR nystan OR mycostatin OR nilstat OR nystex OR miconazole OR daktarin OR ketoconazole OR clotrimazole]. The search outputs were limited with the relevant search filters for clinical trials as recommended in the Cochrane Handbook. We did not apply any language restriction.

We searched ClinicalTrials.gov and Current Controlled Trials for completed or ongoing trials.

 

Searching other resources

We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2011), the UK Royal College of Paediatrics and Child Health (2000 to 2012), and the Perinatal Society of Australia and New Zealand (2000 to 2012). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

 

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group.

 

Selection of studies

Two review authors screened the title and abstract of all studies identified by the above search strategy. We reassessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until we achieved consensus.

 

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements until we achieved consensus. We asked the investigators for further information if data from the trial reports were insufficient.

 

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. We requested additional information from the trial authors to clarify methodology and results as necessary. We evaluated and reported the following issues in the Risk of Bias tables:

  1. Sequence generation: We categorised the method used to generate the allocation sequence as:
    1. low risk: any random process e.g. random number table; computer random number generator;
    2. high risk: any nonrandom process e.g. odd or even date of birth; patient case-record number;
    3. unclear.
  2. Allocation concealment: We categorised the method used to conceal the allocation sequence as:
    1. low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;
    2. high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;
    3. unclear.
  3. Blinding: We assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:
    1. low risk;
    2. high risk;
    3. unclear.
  4. Incomplete outcome data: We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we reinstated missing data in the analyses. We categorised completeness as:
    1. low risk: < 20% missing data;
    2. high risk: > 20% missing data;
    3. unclear.

 

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI). We determined the number needed to treat for benefit (NNTB) or harm (NNTH) for analyses with a statistically significant difference in the RD.

 

Unit of analysis issues

The unit of analysis is the participating infant in individually randomised trials, and the neonatal unit for cluster randomised trials.

 

Assessment of heterogeneity

We examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each RR analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than to sampling error. If we detected substantial heterogeneity (I² > 50%), we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments).

 

Assessment of reporting biases

If more than five trials were included in a meta-analysis, we examined a funnel plot for asymmetry.

 

Data synthesis

We used the fixed-effect model in Review Manager 5 (RevMan 2011) for meta-analysis.

 

Subgroup analysis and investigation of heterogeneity

We prespecified the following subgroup analyses:

  1. extremely preterm (< 28 weeks) or ELBW infants (< 1000 grams);
  2. infants with fungal colonisation at trial entry.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

We included six eligible trials (reported in five primary publications): Sims 1988; Wainer 1992: Ozturk 2006; Violaris 2010; Aydemir 2011a; Aydemir 2011b; see Characteristics of included studies. We found one ongoing trial: Yekta 2012; see Characteristics of ongoing studies.

 

Included studies

ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL PROPHYLAXIS VERSUS PLACEBO OR NO DRUG (COMPARISON 1):

Four trials compared oral/topical non-absorbed antifungal prophylaxis with placebo or no drug:

Sims 1988 quasi-randomly allocated 67 infants of birth weight < 1250 grams to receive either oral nystatin or no treatment until one week after endotracheal extubation (average five weeks).

Wainer 1992 recruited 600 infants of birth weight < 1750 grams. We made a consensus decision to include the trial because most participating infants were < 1500 grams. Participants were randomised to receive either oral miconazole or placebo until discharge. The study was undertaken in the late 1980s in South Africa. Due to limited resources mechanical ventilation was not offered to ELBW infants (12% of the participants).

Ozturk 2006 randomly allocated 938 VLBW infants to receive either prophylactic oral nystatin (100000 IU three times daily) or no treatment. Infants in the control group who had oral fungal colonisation detected at trial entry or on surveillance cultures were treated with nystatin (100,000 IU three times daily).

Aydemir 2011a randomly allocated 185 VLBW infants to receive either oral nystatin 100000 IU three times daily or "equal volumes of intravenous or oral normal saline" placebo every third day until the 30th day after birth (or 45th day in ELBW infants).

The primary outcomes of all studies were fungal colonisation and invasive fungal infection. All provided data on in-hospital mortality but none assessed any postdischarge outcomes.

ORAL/TOPICAL NON-ABSORBED VERSUS SYSTEMIC ANTIFUNGAL PROPHYLAXIS (COMPARISON 2):

Two trials compared oral/topical antifungal prophylaxis with systemic antifungal prophylaxis:

Violaris 2010 randomised 80 VLBW infants to receive either oral nystatin or fluconazole beginning between days five to seven after birth. Outcome data on invasive fungal infection and mortality were reported.

Aydemir 2011b randomly allocated 187 VLBW infants to receive either oral nystatin 100,000 U/ml eight hourly or intravenous fluconazole 3 mg/kg every third day versus until 30 days after birth (or 45 days after birth in ELBW infants).

ONE ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL REGIMEN VERSUS ANOTHER ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL REGIMEN (COMPARISON 3):

We did not find any trials that compared different dose regimens of oral/topical non-absorbed antifungal prophylaxis.

 

Excluded studies

We excluded three studies (Harris 1960; Damjanovic 1993; Herruzo-Cabrera 1994; see Characteristics of excluded studies).

 

Risk of bias in included studies

Quality assessments are described in the table Characteristics of included studies and displayed in Figure 1. Only one small trial was quasi-randomised and lacked allocation concealment (Sims 1988). The most common methodological weakness was lack of blinding of caregivers and investigators and assessors to the nature of the intervention. Only one trial is likely to have been truly placebo-controlled (Wainer 1992). All of the trials reported complete or near-complete assessment for primary outcomes.

 FigureFigure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

 

Effects of interventions

ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL PROPHYLAXIS VERSUS PLACEBO OR NO DRUG (COMPARISON 1):

Primary outcomes:

Incidence of invasive fungal infection (Outcome 1.1): Meta-analysis of data from four trials found a statistically significant reduction in the intervention group but with significant and substantial statistical heterogeneity (Figure 2): typical RR 0.20 (95% CI 0.14 to 0.27), I² = 80%; typical RD -0.18 (95% CI -0.21 to -0.16); NNTB five infants.

 FigureFigure 2. Forest plot of comparison: 1 Oral/topical non-absorbed antifungal prophylaxis vs placebo or nothing, outcome: 1.1 Incidence of invasive fungal infection.

Forest plot inspection suggested that the direction of the effect size estimate from Wainer 1992 was inconsistent with those of the other three trials. Meta-analysis omitting data from Wainer 1992 removed heterogeneity, but did not change the pooled effect size estimate [revised typical RR 0.16 (95% CI 0.11 to 0.23), I² = 0%].

Death prior to hospital discharge (Outcome 1.2): None of the individual trials or a meta-analysis of data from all four trials found a statistically significant effect. We found no evidence of statistical heterogeneity (Figure 3): typical RR 0.87 (95% CI 0.72 to 1.05), I² = 0%; typical RD -0.03 (95% CI -0.06 to 0.01).

 FigureFigure 3. Forest plot of comparison: 1 Oral/topical non-absorbed antifungal prophylaxis vs placebo or nothing, outcome: 1.2 Mortality.

Neurodevelopmental outcomes: Not reported by any trials.

Secondary outcomes:

Incidence of bronchopulmonary dysplasia (Outcome 1.3): Aydemir 2011a did not find a statistically significant difference: RR 1.29 (95% CI 0.67 to 2.49). Outcome not reported in the other trials.

Incidence of necrotising enterocolitis (Outcome 1.4): Aydemir 2011a did not find a statistically significant difference: RR 0.97 (95% CI 0.40 to 2.33). Outcome not reported in the other trials.

Incidence of retinopathy of prematurity (Outcome 1.5): Aydemir 2011a did not find a statistically significant difference in the incidence of retinopathy requiring surgery: RR 0.62 (95% CI 0.30 to 1.28). Outcome not reported in the other trials.

Duration of intensive care unit stay (Outcome 1.6): Three trials reported length of stay in intensive care (Sims 1988; Wainer 1992; Aydemir 2011a). None of the trials individually, or a meta-analysis of data from all trials, found a statistically significant difference: WMD -0.52 (95% CI -4.34 to 3.29) days (I² = 0%) (Figure 4).

 FigureFigure 4. Forest plot of comparison: 1 Oral/topical non-absorbed antifungal prophylaxis vs placebo or nothing, outcome: 1.6 Length of stay in NICU (days).

Adverse events attributed to drug reactions or toxicity sufficient to cease drug administration: Not reported by any trials.

Subgroup analyses

  1. Extremely preterm or ELBW infants: Data were available from one trial (Ozturk 2006).
    1. invasive fungal infection: Ozturk 2006 found a statistically significant reduction RR 0.12 (95% CI 0.06 to 0.26); RD -0.27 (95% CI -0.35 to -0.20).
    2. mortality: Ozturk 2006 did not find a statistically significant effect: RR 1.07 (95% CI 0.51 to 2.25); RD 0.01 (95% CI -0.05 to 0.06).
  2. Trials in which participants were infants with fungal colonisation: None of the trials restricted participation to infants with fungal colonisation at trial entry.

ORAL/TOPICAL NON-ABSORBED VERSUS SYSTEMIC ANTIFUNGAL PROPHYLAXIS (COMPARISON 2)

Primary outcomes:

Incidence of invasive fungal infection (Outcome 2.1): Meta-analysis of data from two trials did not detect a statistically significant difference (Figure 5): typical RR 1.89 (95% CI 0.66 to 5.39), I² = 0%; typical RD 0.03 (95% CI -0.02 to 0.09).

 FigureFigure 5. Forest plot of comparison: 2 Oral/topical non-absorbed prophylaxis vs. systemic antifungal prophylaxis, outcome: 2.1 Incidence of invasive fungal infection.

Death prior to hospital discharge (Outcome 2.2): Meta-analysis of data from two trials did not detect a statistically significant difference (Figure 6): typical RR 0.04 (95% CI -0.02 to 0.11), I² = 66%; typical RD 0.03 (95% CI -0.02 to 0.09).

 FigureFigure 6. Forest plot of comparison: 2 Oral/topical non-absorbed prophylaxis vs. systemic antifungal prophylaxis, outcome: 2.2 Mortality.

Neurodevelopmental outcomes: Neither of the trials reported any neurodevelopmental outcomes.

Secondary outcomes:

Incidence of bronchopulmonary dysplasia in surviving infants: Aydemir 2011b did not find a statistically significant difference: RR 1.29 [95% CI 0.67 to 2.49] RD 0.04 [95% CI -0.07 to 0.16]. Not reported by Violaris 2010.

Incidence of necrotising enterocolitis: Meta-analysis of data from both trials did not detect a statistically significant difference (Figure 7): typical RR 1.22 (95% CI 0.58 to 2.60), I² = 0%; RD 0.02 (95% CI -0.05 to 0.09).

 FigureFigure 7. Forest plot of comparison: 2 Oral/topical non-absorbed prophylaxis vs. systemic antifungal prophylaxis, outcome: 2.4 Necrotising enterocolitis.

Incidence of retinopathy of prematurity: Aydemir 2011b did not find a statistically significant difference in the incidence of retinopathy requiring surgery in surviving infants: RR 1.24 [95% CI 0.51 to 2.98], RD 0.02 [95% CI -0.07 to 0.11]. Not reported by Violaris 2010.

Duration of intensive care unit stay: Aydemir 2011b did not find a statistically significant difference: MD -1.00 (95% CI -7.63 to 5.63) days. Not reported by Violaris 2010.

Adverse events attributed to drug reactions or toxicity sufficient to cease drug administration: Not reported by either of the trials.

Subgroup analyses

  1. Extremely preterm or ELBW infants: Neither of the trials provided subgroup data.
  2. Trials in which participants were infants with fungal colonisation: Neither of the trials restricted participation to infants with fungal colonisation at trial entry.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

Meta-analysis of data from four trials suggests that oral/topical non-absorbed prophylaxis reduces the risk of invasive fungal infection in VLBW infants significantly and substantially. None of the trials or a meta-analysis of their data found a statistically significant effect on mortality. Meta-analysis of data from three trials did not detect an effect on the duration of intensive care. The trials reported only limited data on other neonatal morbidities that may be affected by invasive fungal infection. None of the trials assessed long-term neurodevelopmental outcomes.

Two trials assessed the effect of oral/topical non-absorbed antifungal prophylaxis (nystatin) versus systemic antifungal (fluconazole) prophylaxis. Meta-analyses did not find any statistically significant effects on the incidence of invasive fungal infection or all-cause mortality but much larger studies would be needed to exclude more modest but important effect sizes. Meta-analysis did not detect an effect on the incidence of necrotising enterocolitis but only limited data on other neonatal morbidities were reported.

 

Overall completeness and applicability of evidence

The finding that oral/topical non-absorbed antifungal prophylaxis reduces the risk of invasive fungal infection in VLBW infants should be interpreted and applied with caution. The existence of substantial statistical heterogeneity in the meta-analysis raises concern that the estimate of effect is not robust. The applicability of the finding is also limited by the very high incidence of invasive fungal infection in the control populations in the three trials that found a statistically significant effect on the incidence of invasive fungal infection (Sims 1988; Ozturk 2006; Aydemir 2011a). About one-sixth to one-third of infants in the control groups developed invasive fungal infection, much higher than the < 5% incidence estimated in large cohort studies (Saiman 2000; Makhoul 2002; Horbar 2002; Karlowicz 2002; Clerihew 2006; Howell 2009). This limits the applicability of the NNTB estimate (five infants), since in clinical settings with lower incidences of invasive fungal infection a much larger number of infants would need treatment to prevent a single extra case of invasive fungal infection.

 

Quality of the evidence

The largest trial (N = 948) contributed 84% of the weighted estimate of risk ratio effect on invasive fungal infection (Ozturk 2006). This trial of nystatin prophylaxis was undertaken in Turkey within the past decade. More than one-third of participants were ELBW infants receiving intensive care interventions. The criteria for diagnosing invasive fungal infection appear to be have been robust. Efforts to limit contamination of microbiological cultures by surface colonising organisms were made, for example, fungal urinary tract infection was based on culture of organisms from two separate supra-pubic bladder aspirates. However, caregivers or assessors were not blinded to the intervention and this may have caused surveillance and ascertainment bias if thresholds for investigation and diagnosis of suspected invasive fungal infection were adjusted according to treatment status. Although 25% of control VLBW infants received nystatin to treat oral fungal colonisation detected at trial entry or during the trial period, this is likely to have reduced the effect size of the primary intervention.

The second largest trial (N = 600) did not detect a statistically significant effect of miconazole prophylaxis on the incidence of invasive fungal infection (Wainer 1992). This trial was placebo-controlled and therefore less prone to surveillance bias. The trial was undertaken in South Africa 25 years ago in a settling with few intensive care resources. Twelve per cent of participants were ELBW and the overall incidence of invasive fungal infection was 2% in the control group. This lower incidence may be related to the fact that because of resource limitations ELBW infants did not receive intensive care interventions. Two-thirds of ELBW infants died. The applicability of the trial's findings to modern neonatal intensive care settings in high-income countries is therefore likely to be limited.

A subgroup analysis of outcomes for infants colonised with fungi at trial entry was not possible. None of the trials prespecified fungal colonisation as an entry criterion. Between 25% and 45% of participating infants had fungal colonisation, but subgroup data for these infants were not available in the published reports of the included trials. Even if these data become available for analysis, those from the largest trial would be of limited value since infants in the control group received antifungal treatment if oral fungal colonisation was detected (Ozturk 2006).

 

Potential biases in the review process

The existence of substantial statistical heterogeneity in the meta-analysis of the effect of oral/topical non-absorbed antifungal prophylaxis versus placebo or no drug on the incidence of invasive fungal infection raises concern that the estimate is not robust (Figure 2). The heterogeneity may be due to differences between the trials including population characteristics (proportion of ELBW infants), nature of the intervention (miconazole in one trial, nystatin in the others), methodological quality issues (particularly unblinded allocation and intervention) and the effect of other co-interventions (availability of intensive care for ELBW infants). Forest plot inspection suggested that the direction of the effect size estimate from Wainer 1992 was inconsistent with those of the other three trials. In a post hoc sensitivity analysis, removal of this trial from the meta-analysis removed statistical heterogeneity from the RR estimate and but did not change the direction or size of the estimate.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

The available trial data remain insufficient to guide clinical practice. Although meta-analysis suggests that oral/topical non-absorbed antifungal agents (nystatin or miconazole) reduce the risk of invasive fungal infection, methodological weaknesses limit the validity and applicability of this finding.

 
Implications for research

Further randomised controlled trials of oral/topical non-absorbed antifungal prophylaxis are needed to provide more valid and precise estimates of effect size. Because most neonatologists who currently use antifungal prophylaxis target infants thought to be at greatest risk, mainly ELBW or extremely preterm infants with additional risk factors, a trial restricted to this population of infants or even smaller or lower gestation infants may be appropriate and acceptable (Burwell 2006; Clerihew 2008; Howell 2009). Oral/topical non-absorbed antifungal prophylaxis may be compared with placebo or with systemic prophylaxis (Isaacs 2008; Austin 2012). Any trial should aim to assess long-term outcomes, particularly disability-free survival, as well as the effect on invasive fungal infection.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

David Henderson-Smart for his guidance.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
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]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 31 December 2012.


DateEventDescription

27 January 2013New search has been performedThis updates the review 'Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants' (Austin 2009).

27 January 2013New citation required but conclusions have not changedUpdated search identified new trials for inclusion (Violaris 2010; Aydemir 2011a; Aydemir 2011b).

Conclusions unchanged.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Protocol first published: Issue 1, 2002
Review first published: Issue 1, 2004


DateEventDescription

4 June 2009New citation required and conclusions have changedSubstantive update.

14 October 2007New citation required and conclusions have changedSubstantive amendment.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

William McGuire (WM) screened the title and abstract of all studies identified by the search strategy. Nicola Austin (NA) and WM screened the full text of the report of each study identified as of potential relevance. NA and WM extracted the data separately, compared data, and resolved differences by consensus, and with discussion with Brian Darlow (BD). NA, BD and WM completed the final review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

None.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Christchurch Women's Hospital, Christchurch, New Zealand.
  • Centre for Reviews and Dissemination, University of York, UK.

 

External sources

  • The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C., USA.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

None.

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Aydemir 2011a {published data only}
  • Aydemir C, Oguz SS, Dizdar EA, Akar M, Sarikabadayi YU, Saygan S, et al. Randomised controlled trial of prophylactic fluconazole versus nystatin for the prevention of fungal colonisation and invasive fungal infection in very low birth weight infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2011;96(3):F164-8. [PUBMED: 20659937]
Aydemir 2011b {published data only}
  • Aydemir C, Oguz SS, Dizdar EA, Akar M, Sarikabadayi YU, Saygan S, et al. Randomised controlled trial of prophylactic fluconazole versus nystatin for the prevention of fungal colonisation and invasive fungal infection in very low birth weight infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2011;96(3):F164-8. [PUBMED: 20659937]
Ozturk 2006 {published data only}
Sims 1988 {published data only}
Violaris 2010 {published data only}
  • Violaris K, Carbone T, Bateman D, Olawepo O, Doraiswamy B, LaCorte M. Comparison of fluconazole and nystatin oral suspensions for prophylaxis of systemic fungal infection in very low birthweight infants. American Journal of Perinatology 2010;27(1):73-8. [PUBMED: 19504425]
  • Violaris K, Doraiswamy B, Olawepo O, Gulrajani-LaCorte M. Fluconazole versus nystatin prophylaxis for fungal infection in very low birth weight (VLBW) infants. Pediatric Research. 1998; Vol. 44:254A.
Wainer 1992 {published data only}
  • Wainer S, Cooper PA, Funk E, Bental RY, Sandler DA, Patel J. Prophylactic miconazole oral gel for the prevention of neonatal fungal rectal colonization and systemic infection. Pediatric Infectious Disease Journal 1992;11(9):713-6.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Damjanovic 1993 {published data only}
  • Damjanovic V, Connolly CM, van Saene HK, Cooke RW, Corkill JE, van Belkum A, van Velzen D. Selective decontamination with nystatin for control of a candida outbreak in a neonatal intensive care unit. Journal of Hospital Infection 1993;24(4):245-59.
Harris 1960 {published data only}
  • Harris LJ. Further observations on a simple procedure to eliminate thrush from hospital nurseries. American Journal of Obstetrics and Gynecology 1960;80:30-1.
Herruzo-Cabrera 1994 {published data only}
  • Herruzo-Cabrera R, Garcia Gonzalez JI, Garcia-Magan P, del Rey-Calero J. Nosocomial infection in a neonatal intensive care unit and its prevention with selective intestinal decolonization. A multivariant evaluation of infection reduction. European Journal of Epidemiology 1994;10(5):573-80.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Austin 2012
Benjamin 2003
  • Benjamin DK Jr, Poole C, Steibach WJ, Rowen JL, Walsh TJ. Neonatal candidemia and end-organ damage: a critical appraisal of the literature using meta-analytic techniques. Pediatrics 2003;112(3 Pt 1):634-40.
Benjamin 2006
  • Benjamin DK Jr, Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins RD, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics 2006;117(1):84-92.
Brecht 2009
  • Brecht, M, Clerihew, L, McGuire, W. Prevention and treatment of invasive fungal infection in very low birthweight infants. Archives of Disease in Childhood. Fetal & Neonatal Edition 2009;94(1):F65-9.
Brion 2007
Burwell 2006
  • Burwell LA, Kaufman D, Blakely J, Stoll BJ, Fridkin SK. Antifungal prophylaxis to prevent neonatal candidiasis: a survey of perinatal physician practices. Pediatrics 2006;118(4):e1019-26.
Clerihew 2006
  • Clerihew L, Lamagni TL, Brocklehurst P, McGuire W. Invasive fungal infection in very low birthweight infants: national prospective surveillance study. Archives of Disease in Childhood. Fetal and Neonatal Edition 2006;91(3):F188-92.
Clerihew 2008
Cotten 2006
  • Cotten CM, McDonald S, Stoll B, Goldberg RN, Poole K, Benjamin DK Jr: National Institute for Child Health and Human Development Neonatal Research Network. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006;118(2):717-22.
Ernst 1983
Faix 1989
  • Faix RG, Kovarik SM, Shaw TR, Johnson RV. Mucocutaneous and invasive candidiasis among very low birth weight (<1,500 grams) infants in intensive care nurseries: a prospective study. Pediatrics 1989;83(1):101-7.
Frattarelli 2004
Friedman 2000
  • Friedman S, Richardson SE, Jacobs SE, O'Brien K. Systemic candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome. Pediatric Infectious Disease Journal 2000;19(6):499-504.
Ganesan 2008
  • Ganesan K, Harigopal S, Neal T, Yoxall CW. Prophylactic oral nystatin for preterm babies under 33 weeks gestation decreases fungal colonisation and invasive fungaemia. Archives of Disease in Childhood Fetal & Neonatal Edition 2009;94(4):F275-8.
Horbar 2002
  • Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, et al. Members of the Vermont Oxford Network. Trends in mortality and morbidity for very low birth weight infants, 1991–1999. Pediatrics 2002;110(1 Pt 1):143-51.
Howell 2009
  • Howell AJ, Isaacs D, Halliday R. Oral nystatin prophylaxis and neonatal fungal infections. Archives of Disease in Childhood. Fetal & Neonatal Edition 2009;94(6):F429-33.
Huang 1998
  • Huang YC, Li CC, Lin TY, Lien RI, Chou YH, Wu JL, et al. Association of fungal colonization and invasive disease in very low birth weight infants. Pediatric Infectious Diseases Journal 1998;17(9):819-22.
Isaacs 2008
Kaguelidou 2012
  • Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E. European survey on the use of prophylactic fluconazole in neonatal intensive care units. European Journal of Pediatrics 2012;171(3):439-45. [PUBMED: 21912893]
Karlowicz 2002
  • Karlowicz MG, Rowen JL, Barnes-Eley ML, Burke BL, Lawson ML, Bendel CM, et al. The role of birth weight and gestational age in distinguishing extremely low birth weight infants at high risk of developing candidemia from infants at low risk: a multicenter study. Pediatric Research 2002;51:301A.
Lee 1998
  • Lee BE, Cheung PY, Robinson JL, Evanochko C, Robertson CM. Comparative study of mortality and morbidity in premature infants (birth weight < 1,250g) with candidemia or candidal meningitis. Clinical Infectious Diseases 1998;27(3):559-65.
Makhoul 2002
  • Makhoul IR, Sujov P, Smolkin T, Lusky A, Reichman B. Epidemiological, clinical, and microbiological characteristics of late-onset sepsis among very low birth weight infants in Israel: a national survey. Pediatrics 2002;109(1):34-9.
Manzoni 2006
  • Manzoni P, Farina D, Leonessa M, d'Oulx EA, Galletto P, Mostert M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics 2006;118(6):2359-64.
O'Grady 2008
Pappu-Katikaneni 1990
  • Pappu-Katikaneni LD, Rao KP, Banister E. Gastrointestinal colonization with yeast species and Candida septicemia in very low birth weight infants. Mycoses 1990;33(1):20-3.
Radmacher 2012
  • Radmacher PG, Adamkin MD, Lewis ST, Adamkin DH. Milk as a vehicle for oral medications: hidden osmoles. Journal of Perinatology 2012;32(3):227-9. [PUBMED: 21701446]
RevMan 2011
  • The Nordic Cochrane Centre. The Cochrane Collabortion. Review Manager (Revman). 5.1. Copenhagan: The Nordic Cochrane Centre. The Cochrane Collabortion, 2011.
Rowen 1994
  • Rowen JL, Rench MA, Kozinetz CA, Adams JM, Baker CJ. Endotracheal colonization with candida enhances risk of systemic candidiasis in very low birth weight neonates. Journal of Pediatrics 1994;124(5 Pt 1):789-94.
Saiman 2000
  • Saiman L, Ludington BA, Pfaller M, Rangel-Frausto S, Wiblin RT, Dawson J, et al. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The national epidemiology of mycosis survey study group. Pediatric Infectious Disease Journal 2000;19(4):319-24.
Stoll 2002
  • Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2 Pt 1):285-91.

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Austin 2004
  • Austin NC, Darlow B. Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD003478.pub2]
Austin 2009