Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants

  • Review
  • Intervention

Authors


Abstract

Background

Invasive fungal infection is an important cause of mortality and morbidity in very low birth weight infants. Early diagnosis is difficult and treatment is often delayed. Systemic antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection.

Objectives

To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very low birth weight infants.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to August 2012), conference proceedings, and previous reviews.

Selection criteria

Randomised controlled trials or quasi-randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very low birth weight infants.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors.

Main results

We identified 11 eligible trials enrolling a total of 1136 infants. Seven trials (involving 880 infants) compared systemic antifungal prophylaxis versus placebo or no drug. These trials were generally small but of good methodological quality. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection in infants who received systemic antifungal prophylaxis (typical risk ratio (RR) 0.41, 95% confidence interval (CI) 0.27 to 0.61; risk difference (RD) -0.09, 95% CI -0.14 to -0.05). The average incidence of invasive fungal infection in the control groups of the trials (16%) was much higher than that generally reported from large cohort studies (< 5%). Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge (typical RR 0.74, 95% CI 0.52 to 1.05; RD -0.04, 95% CI -0.08 to 0.01). Very limited data on long-term neurodevelopmental outcomes were available. Two trials that compared systemic versus oral or topical non-absorbed antifungal prophylaxis did not detect any statistically significant effects on invasive fungal infection or mortality. Two trials that compared different dose regimens of prophylactic intravenous fluconazole did not detect any significant differences in infection rates or mortality.

Authors' conclusions

Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. This finding should be interpreted and applied cautiously since the incidence of invasive fungal infection was very high in the control groups of most of the included trials. Meta-analysis does not demonstrate a statistically significant effect on mortality. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance.

Résumé scientifique

Agents antifongiques systémiques prophylactiques dans la prévention de la mortalité et de la morbidité chez le nouveau-né de très faible poids de naissance

Contexte

Une infection fongique invasive est une cause importante de mortalité et de morbidité chez les nouveau-nés de très faible poids de naissance. Son diagnostic précoce est difficile et son traitement est souvent différé. Les agents antifongiques systémiques (généralement des azoles) sont de plus en plus utilisés comme prophylaxie contre les infections fongiques invasives.

Objectifs

Évaluer les effets d'un traitement antifongique systémique prophylactique sur la mortalité et la morbidité chez les nouveau-nés de très faible poids de naissance.

Stratégie de recherche documentaire

Nous avons utilisé la stratégie de recherche standard du groupe thématique Cochrane sur la néonatologie. Elle consistait à effectuer des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library, 2012, numéro 3), MEDLINE, EMBASE et CINAHL (jusqu'à août 2012), les actes de conférence et des revues antérieures.

Critères de sélection

Des essais contrôlés randomisés ou quasi randomisés comparant les effets d'un traitement antifongique systémique prophylactique à un placebo ou à l'absence de médicament ou à un autre agent antifongique ou à un schéma posologique chez des nouveau-nés de très faible poids de naissance.

Recueil et analyse des données

Nous avons extrait les données en utilisant les méthodes standard du groupe thématique Cochrane sur la néonatologie, avec une évaluation de la qualité des essais et une extraction des données séparées par deux auteurs de la revue.

Résultats principaux

Nous avons identifié 11 essais éligibles composés d'un total de 1 136 nouveau-nés. Sept essais (impliquant 880 nouveau-nés) comparaient la prophylaxie antifongique systémique à un placebo ou à l'absence de médicament. Ces essais étaient généralement de petite taille, mais de qualité méthodologique correcte. Une méta-analyse a trouvé une diminution statistiquement significative de l'incidence des infections fongiques invasives chez les nouveau-nés ayant bénéficié d'une prophylaxie antifongique systémique (risque relatif (RR) typique 0,41, intervalle de confiance (IC) à 95 % 0,27 à 0,61 ; différence de risques (DR) - 0,09, IC à 95 % - 0,14 à - 0,05). L'incidence moyenne des infections fongiques invasives dans les groupes témoins des essais (16 %) était beaucoup plus élevée que celle généralement rapportée par des études de cohorte de grande taille (< 5 %). La méta-analyse n'a trouvé aucune différence statistiquement significative des risques de décès avant la sortie d'hôpital (RR typique 0,74, IC à 95 % 0,52 à 1,05 ; DR - 0,04, IC à 95 % - 0,08 à 0,01). Des données très limitées concernant les résultats neurodéveloppementaux à long terme étaient disponibles. Deux essais comparant une prophylaxie antifongique systémique à une prophylaxie antifongique non absorbée par voie orale ou topique n'ont détecté aucun effet statistiquement significatif sur les infections fongiques invasives ou la mortalité. Deux essais comparant différents schémas posologiques de fluconazole prophylactique administré par intraveineuse n'ont détecté aucune différence significative au niveau des taux d'infection ou de la mortalité.

Conclusions des auteurs

Un traitement antifongique systémique prophylactique diminue l'incidence des infections fongiques invasives chez les nouveau-nés de très bas poids de naissance. Ce résultat doit être interprété et appliqué avec prudence étant donné que l'incidence des infections fongiques invasives était très élevée dans les groupes témoins de la majorité des essais inclus. La méta-analyse effectuée ne démontre aucun effet statistiquement significatif sur la mortalité. Il n'existe actuellement que des données limitées sur les conséquences neurodéveloppementales à long terme chez les nouveau-nés exposés à cette intervention. Des données supplémentaires seront également nécessaires afin d'évaluer les effets de cette intervention sur l'émergence des organismes résistants aux antifongiques.

Plain language summary

Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants

Fungi such as candida (the organism that causes thrush) can cause severe infections in very low birth weight infants (birth weight less than 1.5 kg). These infections are often difficult to diagnose. It may be appropriate to attempt to prevent such infections by giving all very low birth weight infants antifungal drugs as a routine part of their care. This review assessed whether evidence exists that such a practice prevents severe fungal infection, death, and disability in very low birth weight infants. There is evidence from some good quality trials that giving infants an antifungal drug regularly for the first four to six weeks after birth reduces the number of infants who develop severe infection. There is not yet any convincing evidence that death or disability rates are affected.

Résumé simplifié

Agents antifongiques systémiques prophylactiques dans la prévention de la mortalité et de la morbidité chez le nouveau-né de très faible poids de naissance

Des champignons, comme le candida (l'organisme responsable des mycoses), peuvent provoquer de graves infections chez les nouveau-nés de très faible poids de naissance (poids de naissance inférieur à 1,5 kg). Ces infections sont généralement difficiles à diagnostiquer. Il peut être judicieux d'essayer de les prévenir en administrant à tous les nouveau-nés de très faible poids de naissance des médicaments antifongiques dans le cadre de soins de routine. La présente revue cherchait à identifier des preuves selon lesquelles cette pratique préviendrait d'une infection fongique grave, d'un décès et d'une invalidité chez des nouveau-nés de très faible poids de naissance. Il existe des preuves provenant d'essais de très bonne qualité selon lesquelles l'administration régulière d'un médicament antifongique à des nouveau-nés, pendant les premières quatre à six semaines après leur naissance, réduirait le nombre d'infections graves chez cette population. Il n'existe pas encore de preuves probantes montrant une modification des taux de mortalité ou d'invalidité.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Invasive fungal infection is an important cause of morbidity and mortality in very preterm (< 32 weeks) and very low birth weight (VLBW < 1500 g) infants (Kossoff 1998; Benjamin 2006; Robinson 2009; Wynn 2012). The reported incidence in very preterm or VLBW infants is about 1% to 5%, but the risk of infection is inversely related to gestational age and birth weight. In extremely preterm (< 28 weeks) or extremely low birth weight (ELBW < 1000 g) infants, incidences from 2% to 10% are reported. Much higher incidences, up to 20%, have been reported for infants with birth weight < 750 g or gestational age at birth < 26 weeks (Saiman 2000; Karlowicz 2002; Makhoul 2002; Stoll 2002; Clerihew 2006; Vergnano 2011).

Additional specific risk factors for invasive fungal infection in VLBW infants include fungal colonisation, severe illness at birth, exposure to multiple courses of antibiotics, receipt of parenteral nutrition, the presence of a central venous catheter, and exposure to histamine receptor subtype 2 antagonists (Huang 1998; Saiman 2000). Between centre differences in the incidence of invasive fungal infection may be due to all or some of these population characteristics and clinical practices.

The diagnosis of invasive fungal infection in VLBW infants is often delayed because the clinical presentation can be very similar to bacterial infections and because of difficulties in consistently recovering the infecting organisms from blood, cerebrospinal fluid, or urine. A high index of suspicion and the use of additional laboratory and clinical tests, including retinal examination, echocardiography, and renal ultrasonography, may be needed to confirm the suspected diagnosis (Benjamin 2003).

Mortality attributed to invasive fungal infection is more than 25%, which is higher than mortality attributed to late-onset invasive bacterial infection in VLBW infants (Stoll 1996; Saiman 2000; Makhoul 2002; Stoll 2002). Invasive fungal infection is also associated with short and long-term morbidity, including adverse neurodevelopmental outcomes (Friedman 2000; Saiman 2000; Benjamin 2006; Wynn 2012).

Description of the intervention

In addition to generic infection control practices and avoidance of modifiable risk factors, two broad chemo-prophylactic strategies are employed in current clinical practice:

  • prophylaxis using systemically-absorbed antifungal drugs that achieve fungicidal concentrations in tissue, blood, cerebrospinal fluid, and urine. Over the past 10 years, the prophylactic use of systemic antifungal agents, commonly the azole agent fluconazole or amphotericin B, has been adopted as routine practice in some neonatal centres (Burwell 2006; Clerihew 2008; O'Grady 2008; Kaufman 2010; Kaguelidou 2012). This intervention is the subject of this Cochrane review;

  • prophylaxis using oral or topical non-absorbed agents such as nystatin or miconazole. This intervention is assessed in another Cochrane Review (Austin 2009).

Why it is important to do this review

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 very preterm or VLBW infants (Brecht 2009). This review aimed to evaluate the evidence from randomised controlled trials to determine that systemic antifungal prophylaxis prevents invasive fungal infection and reduces mortality and morbidity in very preterm or VLBW infants. A further major consideration is the potential for antimicrobial prophylaxis to drive the emergence of drug resistance (Brion 2007).

Objectives

To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very preterm or VLBW infants.

The effects of the following interventions were examined:

  1. systemic antifungal prophylaxis versus placebo or no drug;

  2. systemic versus oral or topical non-absorbed antifungal prophylaxis;

  3. one systemic antifungal agent versus another agent or dose regimen.

Methods

Criteria for considering studies for this review

Types of studies

  1. Controlled trials using random or quasi-random patient allocation

  2. Cluster randomised trials where the unit of randomisation was the neonatal nursery

Types of participants

Very preterm or VLBW infants with or without evidence of fungal colonisation but without evidence of invasive fungal infection at study entry.

Types of interventions

Trials comparing systemic antifungal prophylaxis with placebo or no drug, oral or topical antifungal prophylaxis, or another systemic antifungal agent or dose regimen. The drug may have been given by the intravenous or enteral route.

Types of outcome measures

Primary outcomes
  1. Death prior to hospital discharge.

  2. Development: (i) neurodevelopmental outcomes assessed using validated tools at > 12 months corrected age, and classifications of disability including non-ambulant cerebral palsy, developmental delay, auditory and visual impairment; (ii) cognitive and educational outcomes at > 5 years e.g. Intelligence Quotient or indices of educational achievement measured using a validated tool (including school examination results).

  3. Confirmed invasive fungal infection as determined by:

    1. culture of fungus from a normally sterile site e.g. cerebrospinal fluid, blood, urine, bone or joint, peritoneum, pleural space;

    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'.

Secondary outcomes
  1. Emergence of organisms resistant to antifungal agents, as detected in individual infants enrolled in the study or, in the case of cluster randomised studies, on surveillance of other infants in the same unit in the study centre (including infants who were admitted to the unit following completion of the study).

  2. Adverse drug reactions attributed to the antifungal agent, such as rash (including Stevens-Johnson reactions), gastrointestinal disturbance, abnormal hepatic or renal function, cardiac arrhythmias, thrombophlebitis, seizures, and anaphylaxis.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/).

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 3), 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 infan* OR neonat*] AND [Mycoses/ OR fung* OR candid* OR Candida albicans OR Antifungal Agents/ OR Triazoles/ OR fluconazole OR azole OR Amphotericin B/]. The search outputs were limited with the use of relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions. 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 reports, 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 titles and abstracts 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 consensus was achieved.

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 consensus was achieved. 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. Additional information was requested 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 non-random 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 reincluded 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 was 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 to describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial heterogeneity (I² > 50%) was detected, we explored the possible causes (for example differences in study design, participants, interventions, or completeness of outcome assessments).

Assessment of reporting biases

We examined a funnel plot for asymmetry.

Data synthesis

We used the fixed-effect model in RevMan 5.1 for meta-analysis.

Subgroup analysis and investigation of heterogeneity

We pre-specified the following subgroup analyses:

  1. ELBW infants (< 1000 g);

  2. infants with fungal colonisation at trial entry.

Results

Description of studies

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

We identified 11 eligible trials: Kaufman 2001; Kicklighter 2001; Cabrera 2002; Kaufman 2005; Manzoni 2007a; Manzoni 2007b; Parikh 2007; Arrieta 2010; Violaris 2010; Aydemir 2011a; Aydemir 2011b.

Participants

The trials were undertaken in tertiary perinatal centres in North America, Europe, or India within the past 12 years. In total, 1136 infants participated. The participants were VLBW infants (Kicklighter 2001; Cabrera 2002; Manzoni 2007a; Manzoni 2007b; Parikh 2007; Arrieta 2010; Violaris 2010; Aydemir 2011a) or ELBW infants (Kaufman 2001; Kaufman 2005). Documented fungal colonisation was an eligibility criterion for Cabrera 2002 but not for any of the other trials.

Interventions

1. Seven trials compared systemic antifungal prophylaxis versus placebo or no drug. Six trials used fluconazole (Kaufman 2001; Kicklighter 2001; Cabrera 2002; Manzoni 2007a; Parikh 2007; Aydemir 2011a) and one trial used amphotericin B (Arrieta 2010). Participating infants were enrolled within the first few days after birth and assigned to receive the intervention or placebo for four weeks (for VLBW infants) to six weeks (for ELBW infants). The study drug was given intravenously until the infants tolerated enteral intake and then either administered enterally (Cabrera 2002; Manzoni 2007a; Parikh 2007; Violaris 2010; Aydemir 2011a) or discontinued when intravenous access was no longer available (Kaufman 2001; Kaufman 2005; Arrieta 2010).

2. Two trials compared systemic antifungal prophylaxis (fluconazole) with oral or topical antifungal prophylaxis (nystatin) (Violaris 2010; Aydemir 2011b).

3. Two trials compared different dose regimens.

Kaufman 2005 compared two regimens of prophylaxis with fluconazole (regimen A: 3 mg/kg body weight every third day for the first two weeks, then every second day during the third and fourth weeks, then daily during the fifth and sixth weeks; regimen B: 3 mg/kg twice weekly for six weeks). Infants were assigned to intervention for six weeks or until intravenous access was discontinued.

Manzoni 2007b randomly allocated infants in the fluconazole group to either 3 mg/kg per 48 hours (regimen A) or 6 mg/kg per 48 hours (regimen B) for 30 days after birth (or for 45 days in ELBW infants).

Outcomes

The primary outcomes of the trials were fungal colonisation or invasive fungal infection. Data on deaths prior to hospital discharge were provided for 10 of the trials. Seven trials monitored plasma levels of aspartate aminotransferase, alanine aminotransferase, total bilirubin, or alkaline phosphatase.

Investigators monitored the fluconazole minimal inhibitory concentrations of fungal isolates (from both surface colonisation and from invasive infection) during the surveillance period in five trials (Kaufman 2001; Kicklighter 2001; Kaufman 2005; Aydemir 2011a; Aydemir 2011b). Cabrera 2002 collected surveillance cultures from day seven, at weekly intervals until six weeks, and began prophylaxis once surveillance cultures were positive.

Only one trial has reported long-term neurodevelopmental outcomes (Kaufman 2001).

Excluded studies

We excluded 15 studies (see table 'Characteristics of excluded studies'). These were all single centre retrospective observational studies that compared outcomes for cohorts of VLBW or ELBW infants cared for in an epoch immediately prior to the introduction of intravenous antifungal prophylaxis (fluconazole in all studies) compared with infants cared for in the epoch after this intervention was adopted (Bertini 2005; Dutta 2005; Healy 2005; Aghai 2006; Manzoni 2006; Uko 2006; McCrossan 2007; Wadhawan 2007; Al Qurashi 2008; Healy 2008; Kim 2008; Manzoni 2008; Weitkamp 2008; Aziz 2010; Rueda 2010). All of these studies reported statistically significant reductions in the incidence of invasive fungal infection associated with the use of fluconazole prophylaxis.

Ongoing trials

We identified one ongoing trial in 20 neonatal care centres in North America (Duke 2012) (see http://clinicaltrials.gov/show/NCT00734539). The investigators aim to randomly allocate 360 preterm infants with a birthweight < 750 g to receive twice weekly fluconazole (6 mg/kg) or placebo for six weeks after birth. The composite primary outcome is death or invasive candidiasis prior to study day 49.

Risk of bias in included studies

Quality assessments are described in the table 'Characteristics of included studies'.

The included trials were generally of good methodological quality. In most studies, allocation was concealed by separating the randomisation process from recruitment and enrolment. Caregivers, investigators, and assessors were all blind to the intervention. Follow-up appeared to be complete for the outcomes reported in all of the included trials.

Effects of interventions

Systemic antifungal agent versus placebo or no drug (Comparison 1)

Seven trials compared systemic antifungal prophylaxis versus placebo or no drug. Six trials used fluconazole (Kaufman 2001; Kicklighter 2001; Cabrera 2002; Manzoni 2007a; Parikh 2007; Aydemir 2011a) and one trial used amphotericin B (Arrieta 2010).

Primary outcomes

Death prior to hospital discharge (Outcome 1.1)

Data were reported by six trials (Kaufman 2001; Kicklighter 2001; Manzoni 2007a; Parikh 2007; Arrieta 2010; Aydemir 2011a). There were not any statistically significant differences in any of the individual trials or in a meta-analysis of all data (typical RR 0.74, 95% CI 0.52 to 1.05; typical RD -0.04, 95% CI -0.08 to 0.01; 6 studies, 869 infants). There was no evidence of statistical heterogeneity or funnel plot asymmetry (Analysis 1.1; Figure 1).

Figure 1.

Funnel plot of comparison: 1 Systemic antifungal agent versus placebo or no drug, outcome: 1.1 Death prior to hospital discharge.

Neurodevelopment (Outcome 1.2, 1.3)

Neurodevelopmental outcomes were reported by only one trial. Kaufman 2001 reported no significant difference in the incidence of developmental delay (modified Gesell test) or motor or sensory neurological impairment in infants assessed at a median age of 16 months. These findings were reported in abstract form only. Long-term follow-up assessments (at 8 to 10 years) conducted on 45% of surviving children did not find any statistically significant differences in Vineland Adaptive Behavior Scales-II (VABS-II) or the Child Health Questionnaire Parent-Completed Form 28 (CHQ-PF28).

  • VABS-II Domain Scores for the fluconazole group (N = 21) compared with the placebo group (N = 17) were not statistically different for communication, daily living skills , socialisation, motor skills (Analysis 1.2). Internalising and externalising behaviours and the maladaptive behaviour index were also reported to be similar.

  • The CHQ-PF28 found no statistically significant differences in self esteem scores (Analysis 1.3). Survivors were happy or satisfied with school (90% versus 100%), friendships (90% versus 88%), and life (95% versus 100%). There were not any statistically significant differences in reported emotional difficulties or behaviour problems.

Confirmed invasive fungal infection (Outcome 1.4)

Seven trials were included in this analysis (Kaufman 2001; Kicklighter 2001; Cabrera 2002; Manzoni 2007a; Parikh 2007; Arrieta 2010; Aydemir 2011a). Kaufman 2001, Manzoni 2007a and Aydemir 2011a reported statistically significantly lower incidences in the intervention group. The other trials did not find any statistically significant differences. Meta-analysis of data from all of the trials found a statistically significant lower incidence of invasive fungal infection in the intervention group (typical RR 0.41, 95% CI 0.27 to 0.61; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; 7 studies, 880 infants) (Analysis 1.4).

There was evidence of statistical heterogeneity in this meta-analysis (I² = 62%) but no evidence of funnel plot asymmetry (Figure 2). Exclusion of Parikh 2007 (but not any of the other trials) removed this heterogeneity (revised RR 0.22, 95% CI 0.12 to 0.40; revised I² = 0%).

Figure 2.

Funnel plot of comparison: 1 Systemic antifungal agent versus placebo or no drug, outcome: 1.4 Invasive fungal infection.

Secondary outcomes

Emergence of organisms resistant to antifungal agents

Four reports commented on this outcome but presented limited data.

  • Kaufman 2001 did not find any statistically significant changes in the minimal inhibitory concentration of fluconazole for fungal isolates during the 30 months study period.

  • Kicklighter 2001 did not find any statistically significant differences in the minimal inhibitory concentration of fluconazole for Candida albicans isolates between the study groups during the treatment period or for four weeks after discontinuation of the study drug.

  • Manzoni 2007a stated that "patterns of sensitivity to fluconazole remained the same".

  • Aydemir 2011a stated that "sensitivity to fluconazole did not vary during the study period" (no other data presented).

Adverse drug reactions attributed to the antifungal agent

There were no clinically significant adverse reactions attributed to antifungal agents in the included studies. No infants were withdrawn from the trials because of adverse effects.

Subgroup analyses

ELBW infants

Kaufman 2001 enrolled only ELBW infants. Manzoni 2007a stated that there was a statistically significant lower incidence of invasive fungal infection in the subgroup of ELBW infants but numerical data were not presented. The report did not comment on mortality rates in ELBW infants. When these data become available they will be included in an update of this review. Kicklighter 2001, Arrieta 2010 and Aydemir 2011a enrolled VLBW infants and ELBW subgroup data were not available.

Infants with fungal colonisation at entry to study

Only the smallest trial restricted participation to infants with fungal colonisation (Cabrera 2002). Subgroup analysis of infants with fungal colonisation was not possible with the available data from the other trials.

Systemic antifungal agent versus oral or topical antifungal therapy (Comparison 2)

Two trials compared systemic antifungal prophylaxis (fluconazole) with oral or topical antifungal prophylaxis (nystatin) (Violaris 2010; Aydemir 2011b).

Primary outcomes

Death prior to hospital discharge (Outcome 2.1)

Meta-analysis of data from two trials (Violaris 2010; Aydemir 2011b) did not find a statistically significant difference (typical RR 0.61, 95% CI 0.27 to 1.38; typical RD -0.04, 95% CI -0.11 to 0.02) (Analysis 2.1).

Confirmed invasive fungal infection (Outcome 2.2)

Meta-analysis of data from two trials (Violaris 2010; Aydemir 2011b) did not find a statistically significant difference (typical RR 0.53, 95% CI 0.19 to 1.51; typical RD -0.03, 95% CI -0.09 to 0.02) (Analysis 2.2).

Secondary outcomes

Emergence of organisms resistant to antifungal agents

Violaris 2010 did not report this outcome. Aydemir 2011b stated that "sensitivity to fluconazole did not vary during the study period" (no other data presented).

Adverse drug reactions attributed to the antifungal agent

There were no clinically significant adverse reactions attributed to antifungal agents in the included studies. No infants were withdrawn from the trials because of adverse effects.

Subgroup analyses

ELBW infants

Violaris 2010 and Aydemir 2011b enrolled VLBW infants and ELBW subgroup data were not available.

Infants with fungal colonisation at entry to study

Neither trial restricted participation to infants with fungal colonisation.

One systemic antifungal agent versus another agent or dose regimen (Comparison 3)

Kaufman 2005 and Manzoni 2007b compared two regimens of fluconazole prophylaxis.

Primary outcomes

Death prior to hospital discharge (Outcome 3.1)

Neither trial found a statistically significant difference:

  • Kaufman 2005: RR 0.98 (95% CI 0.34 to 2.77); RD 0.00 (95% CI -0.16 to 0.15);

  • Manzoni 2007b: RR 1.08 (95% CI 0.44 to 2.61); RD 0.01 (95% CI -0.07 to 0.08).

Neurodevelopmental outcome

Not reported by either trial.

Confirmed invasive fungal infection (Outcome 3.2)

Neither trial found a statistically significant difference:

  • Kaufman 2005: RR 1.95 (95% CI 0.18 to 20.7); RD 0.02 (95% CI -0.06 to 0.11);

  • Manzoni 2007b: RR 1.44 (95% CI 0.33 to 6.26); RD 0.01 (95% CI -0.04 to 0.11).

Secondary outcomes

Emergence of organisms resistant to antifungal agents

Kaufman 2005 did not find any statistically significant difference in the mean minimal inhibitory concentration of fluconazole for fungi isolated from surveillance cultures from infants during the first 12 months versus the second 12 months of the study. Manzoni 2007b stated that "patterns of sensitivity to fluconazole remained the same".

Adverse drug reactions attributed to the antifungal agent

There were no clinically significant adverse reactions attributed to fluconazole and no infants were withdrawn from either study.

Subgroup analyses

ELBW infants

All participants in Kaufman 2005 were of ELBW. Manzoni 2007b did not provide ELBW subgroup data.

Infants with fungal colonisation at entry to study

Neither trial restricted participation to infants with fungal colonisation.

Discussion

Summary of main results

The available trial data indicate that prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in VLBW infants. The pooled estimate suggests that treating 11 VLBW infants with prophylactic antifungal therapy would prevent one extra case of invasive fungal infection. Meta-analysis did not find a statistically significant effect on all-cause mortality and there were very little data on long-term neurodevelopmental outcomes.

We found limited trial data on outcomes for VLBW infants who received systemic versus oral or topical non-absorbed antifungal prophylaxis. The two trials that looked at this did not find any statistically significant differences, but larger trials would be needed to exclude more modest yet important effect sizes. Similarly, the currently available trial data are insufficient to determine which dose regimens of antifungal prophylaxis are superior.

Overall completeness and applicability of evidence

High incidence of invasive fungal infection in controls

The main factor limiting generalisabilty of the findings of this review is the high incidence of invasive fungal infection in the placebo groups of the included trials. The average incidence of invasive fungal infection was 16% (range 4% to 26%) compared to incidences of < 5% generally reported from other large cohort studies of VLBW infants (Kossoff 1998; Karlowicz 2002; Clerihew 2006; Vergnano 2011). Consequently the effect size estimates from the meta-analyses should be applied cautiously. In neonatal care centres where the incidence of invasive fungal infection is lower, a much larger number of infants than the number derived from the meta-analysis would need to be exposed to prophylaxis to prevent a single extra case of invasive fungal infection. For example, 1% of VLBW infants in a UK prospective national surveillance study developed invasive fungal infection (Clerihew 2006). In neonatal care centres where the incidence of invasive fungal infection matches this UK national estimate, 130 VLBW (or 62 ELBW) infants would need to be exposed to systemic antifungal prophylaxis in order to prevent a single extra case of invasive fungal infection.

Diagnostic sensitivity of microbiological culture affected by systemic antifungal prophylaxis

Another issue that may limit the validity of these trial data is that the diagnostic sensitivity of microbiological culture for invasive fungal infection may be lower in infants receiving systemic antifungal treatment (Schelonka 2003). This may have caused selective under-diagnosis in the treatment group and over-estimation of the effect size. Mortality was included as a primary outcome for this review since ascertaining this outcome is less likely to be affected by bias. Furthermore, as it is often difficult to precisely define the cause of death in VLBW infants, and since invasive fungal infection is not always diagnosed, all-cause mortality rather than death attributed to fungal infection was the pre-specified outcome. The mortality rates in the placebo cohorts were similar to rates in large cohort studies of VLBW infants cared for in similar settings (Horbar 2002). The review did not find a statistically significant effect of prophylactic systemic antifungal therapy on all-cause mortality, with the 95% CI around this estimate of effect consistent with a 26% risk reduction to a 5% risk increase. When data from further trials are available, these may be included in this meta-analysis to provide a more precise estimate of the effect on mortality.

Lack of data on antifungal resistance

There is a possibility that widespread use of systemic antifungal prophylaxis may lead to the emergence of antifungal resistance. A meta-analysis of trials of fluconazole prophylaxis in immunosuppressed adults found evidence of an increased risk for colonisation, but not invasive infection, with fungi partially or completely resistant to fluconazole (Brion 2007). Although the data available from the trials identified in this review are reassuring in terms of the emergence of fluconazole resistance, the follow-up periods (up to 30 months) of the trials are probably insufficient to detect clinically significant changes in the resistance profile of fungal isolates. Antifungal resistance may take many years following the introduction of fluconazole prophylaxis to become established in neonatal intensive care units (Sarvikivi 2008).

In the trial undertaken in an Indian neonatal care centre where fluconazole had been used routinely for treating infants with fungal infection during the preceding six years, the most common fungal isolates causing invasive infection were non-albicans Candida species with relatively reduced azole susceptibility (Parikh 2007). This may partly explain why this trial did not detect a statistically significant effect of fluconazole prophylaxis on the incidence of invasive fungal infection. Continued mycological surveillance in those units where systemic antifungal prophylaxis is used is essential.

Regarding the potential adverse effects of prophylactic systemic antifungal therapy, there were no clinically significant drug-related adverse events reported in these trials, nor was any infant withdrawn from any study because of unacceptable adverse reactions. To date, fluconazole has appeared to be a safe treatment for newborn infants with invasive fungal infection. Only a mild and transient elevation of plasma levels of hepatic enzymes has been described as a common side effect (Huttova 1998). However, there are rare but important side effects such as toxic epidermal necrolysis and Stevens-Johnson syndrome reported in other populations of patients. If fluconazole exposure becomes more widespread through use as prophylaxis then these side effects may be observed in newborn infants. Additionally, widespread use of prophylactic fluconazole may increase the risk of potential drug interactions with medications that are prescribed for very low birth weight infants including theophylline and thiazide diuretics (Neely 2001).

Quality of the evidence

The included trials, although small, were generally of good methodological quality with satisfactory allocation concealment and blinding using placebo in most cases. Assessment of in hospital outcomes was complete in all of the trials (Figure 3). Only very limited data on long-term outcomes and on the emergence of antifungal resistance are available.

Figure 3.

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

Potential biases in the review process

The existence of substantial statistical heterogeneity in the meta-analysis of the effect of antifungal prophylaxis on the incidence of invasive fungal infection raises concern that the estimate is not robust. The source of heterogeneity does not appear to be due to differences in either the participants or the intervention, or related to trial design or quality. One exception is the trial undertaken in India in which the most common fungal isolates causing invasive infection were non-albicans Candida species with relatively reduced azole susceptibility (Parikh 2007). Removal of this trial from the meta-analysis removed the statistical heterogeneity of the RR estimate and did not change the direction or size of the estimate.

Concern exists that widespread use of antifungal prophylaxis may drive the emergence of antifungal resistant species in the neonatal care centre. Limiting prophylaxis to infants at highest risk may help delay the emergence of antifungal resistance. Since invasive fungal infection is about twice as common in ELBW than VLBW infants, targeting prophylaxis to this population reduces the number of infants who need to be exposed to prophylaxis. Insufficient subgroup data were available to undertake the planned subgroup analysis of ELBW infants. If these data become available, they will be included in a future update of the review.

Similarly, a planned subgroup analysis of outcomes for infants who were colonised with fungi at trial entry was not possible. Colonisation, especially heavy gastrointestinal colonisation, has been suggested by some as a risk factor for invasive infection (Pappu-Katikaneni 1990) but not other (Huang 1998; Saiman 2000) observational studies. The subgroup data for only those infants colonised at trial entry were not available in the published reports of the largest studies (Kicklighter 2001; Kaufman 2005; Manzoni 2007a). As only about 10% of all of the participating infants were colonised at trial entry, it is unlikely that the analysis of these small numbers would provide clinically useful findings.

It is plausible that limiting the exposure of infants to systemic antifungal prophylaxis by using less intensive dose regimens may help in limiting the emergence of antifungal resistance. Two trials compared 'standard' dosing regimens to less intensive, lower dose regimens (Kaufman 2005; Manzoni 2007b). Neither found statistically significant differences on mortality before hospital discharge or the incidence of invasive fungal infection. However, the 95% confidence intervals were wide and further trials are needed to identify the most appropriate dosing regimen for this intervention.

Authors' conclusions

Implications for practice

Systemic antifungal prophylaxis reduces the incidence of invasive fungal infection in VLBW infants. The available trial data do not indicate a statistically significant effect on mortality and there are only limited data on long-term neurodevelopmental outcomes. Lower dose regimens appear to be as effective at preventing invasive fungal infection as more frequently administered prophylaxis doses, but the 95% confidence intervals for these estimates are wide.

Implications for research

Further randomised controlled trials of systemic antifungal prophylaxis are needed to provide more precise estimates of effect size. Systemic antifungal prophylaxis may be compared with placebo or with topical or oral prophylaxis. Any trial should aim to assess long-term outcomes, particularly disability-free survival, as well as the effect on invasive fungal infection.

Because the burden of invasive fungal infection is confined mainly to the smallest and least mature infants and neonatologists who currently use systemic antifungal prophylaxis target infants thought to be at greatest risk, which are mainly ELBW or extremely preterm infants with additional risk factors, a trial restricted to this population of infants or perhaps even smaller or lower gestation infants may be appropriate and acceptable (Burwell 2006; Parikh 2007; Clerihew 2008; Kaguelidou 2012). Invasive fungal infection is three time more common in infants born before 26 weeks gestation or with birth weight less than 750 g than in infants with birth weight between 750 g and 1000 g. A multicentre study to determine the effect of fluconazole prophylaxis on mortality and neuro-morbidity for infants of birth weight less than 750 g is currently being developed in North America (ClinicalTrials.gov Identifier: NCT00734539).

Finally, although randomised controlled trials may attempt to measure the effect of prophylaxis on antifungal resistance, there is also a need for on-going local and national surveillance to detect the emergence of resistant organisms, particularly if prophylactic use of fluconazole becomes more widespread.

Acknowledgements

We thank Drs Kaufman and Kicklighter for providing clarification on some aspects of their studies. We are grateful to Bristol-Myers Squibb Pharmaceuticals Limited, Cambridge Laboratories, Elan Pharma Limited, Gilead Sciences Limited, ICN Pharmaceuticals Limited, and Pfizer Limited for searching their respective databases for unpublished data.

Data and analyses

Download statistical data

Comparison 1. Systemic antifungal agent versus placebo or no drug
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death prior to hospital discharge6869Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.52, 1.05]
2 VABS-II Domain Scores1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Communication138Mean Difference (IV, Fixed, 95% CI)2.0 [-6.71, 10.71]
2.2 Daily living skills138Mean Difference (IV, Fixed, 95% CI)0.5 [-5.83, 6.83]
2.3 Socialisation138Mean Difference (IV, Fixed, 95% CI)2.80 [-2.64, 8.24]
2.4 Motor skills138Mean Difference (IV, Fixed, 95% CI)-3.0 [-13.30, 7.30]
3 Self esteem scores138Mean Difference (IV, Fixed, 95% CI)-2.40 [-10.74, 5.94]
4 Invasive fungal infection7880Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.27, 0.61]
Analysis 1.1.

Comparison 1 Systemic antifungal agent versus placebo or no drug, Outcome 1 Death prior to hospital discharge.

Analysis 1.2.

Comparison 1 Systemic antifungal agent versus placebo or no drug, Outcome 2 VABS-II Domain Scores.

Analysis 1.3.

Comparison 1 Systemic antifungal agent versus placebo or no drug, Outcome 3 Self esteem scores.

Analysis 1.4.

Comparison 1 Systemic antifungal agent versus placebo or no drug, Outcome 4 Invasive fungal infection.

Comparison 2. Systemic antifungal agent versus oral or topical antifungal prophylaxis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death prior to hospital discharge2267Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.27, 1.38]
2 Invasive fungal infection2267Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.19, 1.51]
Analysis 2.1.

Comparison 2 Systemic antifungal agent versus oral or topical antifungal prophylaxis, Outcome 1 Death prior to hospital discharge.

Analysis 2.2.

Comparison 2 Systemic antifungal agent versus oral or topical antifungal prophylaxis, Outcome 2 Invasive fungal infection.

Comparison 3. One systemic antifungal agent versus another agent or dose regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death prior to hospital discharge2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Invasive fungal infection2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 One systemic antifungal agent versus another agent or dose regimen, Outcome 1 Death prior to hospital discharge.

Analysis 3.2.

Comparison 3 One systemic antifungal agent versus another agent or dose regimen, Outcome 2 Invasive fungal infection.

What's new

DateEventDescription
31 August 2012New search has been performedThis updates the review "Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants" (McGuire 2004).
31 August 2012New citation required but conclusions have not changedOur updated search in August 2012 identified 3 new trials for inclusion in this review update (Arrieta 2010; Aydemir 2011a; Violaris 2010).
No change to conclusions.

History

Protocol first published: Issue 4, 2002
Review first published: Issue 1, 2003

DateEventDescription
30 January 2009New search has been performed

This updates the review "Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants" published in The Cochrane Database of Systematic Reviews, Issue 4, 2007 (Clerihew 2007).

Search updated January 2009. One new trial identified (Parikh 2007) and incorporated into review update.

11 June 2008AmendedConverted to new review format.
24 July 2007New search has been performedThis review updates the review "Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants" published in the Cochrane Database of Systematic Reviews, The Cochrane Library, Issue 1, 2004 (McGuire 2004).

For this update, the title was changed to "Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants" since this better reflects the clinical context. Consequently, one small trial in which a systemic antifungal agent was administered enterally is now included (Violaris 1998).

The electronic search was updated in May 2007. Two new trials that fulfilled eligibility criteria were identified. One of these is the largest trial of this intervention yet reported (Manzoni 2007a). Inclusion of this trial more than doubled the total number of participants in the review. Inclusion of the data in the meta-analyses increased the precision of the estimates of effect size. The finding of a reduced incidence of invasive fungal infection in infants who received systemic antifungal prophylaxis was not altered. However, the previous finding of a statistically significantly lower mortality rate no longer holds.

Six observational studies of the intervention were found and we have described these in the excluded studies section.

Contributions of authors

Nicola Austin (NA) and William McGuire (WM) screened the titles and abstracts of all studies identified by the search strategy.

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.

NA and WM completed the final review.

Declarations of interest

None

Sources of support

Internal sources

  • Christchurch Womens Hospital, New Zealand.

  • CRD, University of York, UK.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded 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. HHSN275201100016C.

Differences between protocol and review

None

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arrieta 2010

MethodsRandomised controlled trial
Participants40 VLBW infants with central vascular catheter in situ
InterventionsIntravenous liposomal amphotericin B 5 mg/kg (N = 20) versus dextrose water placebo (N= 20) once weekly until 6 weeks old
Outcomes

Fungal colonisation and invasive infection

Death prior to hospital discharge
Incidence of necrotising enterocolitis and severe intraventricular haemorrhage

NotesSetting: Children's Hospital of Orange County, California, USA; 2004- 6
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskPharmacy allocation from computer-generated random sequence
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as "open-label, placebo-controlled"
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as "open-label, placebo-controlled"
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as "open-label, placebo-controlled"
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up

Aydemir 2011a

MethodsRandomised controlled trial
Participants184 VLBW infants
InterventionsFluconazole 3 mg/kg (N = 93) every third day versus normal saline placebo (N = 91) until the 30th day after birth (or 45th day in ELBW infants)
Outcomes

Fungal 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated
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
InterventionsFluconazole 3 mg/kg (N = 93) every third day versus oral nystatin 100,000 U/ml 8 hourly (N= 94) until the 30th day after birth (or 45th day in ELBW infants)
Outcomes

Fungal 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated
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

Cabrera 2002

MethodsRandomised controlled trial
Participants11 VLBW infants with fungal colonisation detected on rectal, oro-pharyngeal, or tracheal weekly surveillance cultures
Interventions

Fluconazole 6 mg/kg (N = 6) versus placebo (N = 5)

The dosage interval is not known. The study drug was given intravenously until intravenous access was no longer otherwise required, when oral study drug was given. The total duration of treatment with the study drug, or of follow-up is not clear

OutcomesInvasive fungal infection
Notes

Published in abstract form only (some additional data obtained from authors)

Setting: Medical School of Georgia, Augusta, USA; before 2002

Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskAllocation method not stated
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

Kaufman 2001

MethodsRandomised controlled trial
Participants

100 ELBW infants < 5 days old

Infants with evidence of liver failure were not eligible for inclusion

InterventionsFluconazole (N = 50) 3 mg/kg every third day for the first two weeks, then every second day during the third and fourth weeks, then daily during the fifth and sixth weeks versus normal saline placebo (N = 50). Assigned to intervention for six weeks, or until intravenous access discontinued
Outcomes

Fungal colonisation and invasive infection

Emergence of fluconazole resistance
Adverse drug reactions
Incidence of bacterial infections, necrotising enterocolitis, isolated intestinal perforation, ligation of patent ductus arteriosus, retinopathy of prematurity, abnormal findings on cranial ultrasonography
Death prior to hospital discharge

Neurodevelopmental status and quality of life of survivors at 8 to 10 years old assessed using the Vineland Adaptive Behavior Scales-II (VABS-II) and the Child Health Questionnaire Parent-Completed Form 28 (CHQ-PF28) respectively

Notes

Kaufman 2001 reported that 13 of the 50 infants in the placebo group developed invasive fungal infection. Ten episodes were detected during the six weeks period when the intervention was administered, and three episodes occurred following discontinuation of the intervention. There were no episodes of invasive fungal infection in the fluconazole group during the six weeks intervention period. One case occurred following discontinuation of the intervention.
In the report of the outcomes in abstract form (published in Pediatric Research), the investigators state that invasive fungal infection occurred in nine, rather than 10, infants in the placebo group during the six weeks treatment period, and in two, rather than three, infants in the control group. These differences were related to less information being available at the time that the first (abstract) report was prepared (personal communication Dr Kaufman).

Setting: University of Virginia School of Medicine, Charlottesville; 1998- 2000

Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated, pharmacy randomly assigned
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 risk

In hospital follow-up complete.

Long-term follow-up assessments (at 8 to 10 years) conducted on 46% and 43% of surviving children in the intervention and control groups, respectively

Kaufman 2005

MethodsRandomised controlled trial
Participants81 ELBW infants < 5 days old, and with either an endotracheal tube or central venous catheter in situ
InterventionsRegimen A (N = 41): fluconazole 3 mg/kg every third day for the first two weeks, then every second day during the third and fourth weeks, then daily during the fifth and sixth weeks
Regimen B (N = 40): fluconazole 3mg/kg twice weekly for 6 weeks
Assigned to intervention for six weeks, or until intravenous access discontinued
Outcomes

Fungal colonisation and invasive infection

Mortality (all cause) was reported as a secondary outcome

NotesSetting: University of Virginia School of Medicine, Charlottesville; before 2005
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated, pharmacy randomly assigned
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 assessment

Kicklighter 2001

MethodsRandomised placebo-controlled trial
Participants

103 VLBW infants < 3 days old

Infants with evidence of liver failure, congenital heart disease, or congenital defects needing surgery were not eligible for inclusion

InterventionsFluconazole 6 mg/kg (N = 53) or placebo (N = 50) every third day for one week than daily for three more weeks. Administered intravenously and then oro-gastrically when tolerated
Outcomes

Fungal colonisation and invasive infection

Emergence of fluconazole resistance
Adverse drug reactions
Death prior to hospital discharge

NotesSetting: University of Medical University of South Carolina; 1998-1999
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskRandom assignment by separate trials centre
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

Manzoni 2007a

MethodsRandomised controlled trial
Participants322 VLBW infants
InterventionsFluconazole 3 mg/kg (N = 104) or 6 mg/kg (N = 112) versus placebo (N = 106) given every second day from birth for 30 days (or 45 days for ELBW infants (N = 216))
Outcomes

Fungal colonisation and invasive infection

Death prior to hospital discharge

Emergence of fluconazole resistance

NotesSetting: eight level III neonatal units in Turin, Rome, Milan, or Pavia, Italy (2004-2006)
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated and allocated
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

Manzoni 2007b

MethodsRandomised controlled trial
Participants216 VLBW infants
InterventionsFluconazole 3 mg/kg (N = 104) versus 6 mg/kg (N = 112) given every second day from birth for 30 days (or 45 days for ELBW infants (N = 216))
Outcomes

Fungal colonisation and invasive infection

Death prior to hospital discharge

Emergence of fluconazole resistance

Notes

Setting: eight level III neonatal units in Turin, Rome, Milan, or Pavia, Italy (2004-2006)

Manzoni 2007b is the internal dose comparison of Manzoni 2007a intervention group

Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskComputer-generated and allocated
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

Parikh 2007

MethodsRandomised controlled trial
Participants

121 VLBW infants < 3 days old (one infant was withdrawn on day of randomisation and not included in any analyses)

"Critically ill" infants and infants with biochemical evidence of hepatic insufficiency were not eligible for inclusion

InterventionsFluconazole (N = 60) 6 mg/kg every third day for the first week after birth, then every day until four weeks versus "sugar solution" placebo (N = 60). Administered intravenously and then enterally when tolerated
Outcomes

Fungal colonisation and invasive infection

Emergence of fluconazole resistance
Adverse drug reactions
Death prior to hospital discharge

Notes

Most invasive fungal infection was due to non-albicans Candida species (mainly C. glabrata) which were relatively less susceptible to fluconazole

Setting: KEM Hospital and Seth GS Medical College, Mumbai; 2003-2004

Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskSealed opaque envelopes
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 riskNear-complete follow-up

Violaris 2010

MethodsRandomised controlled trial
Participants

80 VLBW infants

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

InterventionsFluconazole (4 mg/kg) orally (N = 38) versus nystatin (100,000 units/kg/day) in each side of the mouth (N = 42), 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

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Aghai 2006Observational (before-after) study, not a randomised controlled trial
Al Qurashi 2008Observational (before-after) study, not a randomised controlled trial
Aziz 2010Observational (before-after) study, not a randomised controlled trial
Bertini 2005Observational (before-after) study, not a randomised controlled trial
Dutta 2005Observational (before-after) study, not a randomised controlled trial
Healy 2005Observational (before-after) study, not a randomised controlled trial
Healy 2008Observational (before-after) study, not a randomised controlled trial
Kim 2008Observational (before-after) study, not a randomised controlled trial
Manzoni 2006Observational (before-after) study, not a randomised controlled trial
Manzoni 2008Observational (before-after) study, not a randomised controlled trial
McCrossan 2007Observational (before-after) study, not a randomised controlled trial
Rueda 2010Observational (before-after) study, not a randomised controlled trial
Uko 2006Observational (before-after) study, not a randomised controlled trial
Wadhawan 2007Observational (before-after) study, not a randomised controlled trial
Weitkamp 2008Observational (before-after) study, not a randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

Duke 2012

Trial name or titleFluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
MethodsRandomised controlled trial
Participants360 newborn infants with a birthweight <750g cared for in one of 20 neonatal centres in North America
InterventionsTwice weekly fluconazole (6 mg/kg) or placebo for 6 weeks after birth
OutcomesDeath or invasive candidiasis before day 49
Starting date2009
Contact informationPrincipal Investigator: Daniel K Benjamin, Duke Univerisity Medical Center, Duke Clinical Research Institute, USA
NotesSee: http://clinicaltrials.gov/show/NCT00734539

Ancillary