Linda Clerihew1, Nicola Austin2, William McGuire3
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Tayside Institute of Child Health, Ninewells Hospital and Medical School, Dundee, UK
2NICU, Christchurch Womens Hospital, Christchurch, New Zealand
3Centre for Reviews and Dissemination, Hull York Medical School, York, UK
Centre for Reviews and Dissemination
Hull York Medical School
University of York
York
Y010 5DD
UK
E-mail: William.McGuire@hyms.ac.uk
| Assessed as Up-to-date: | 29 January 2009 |
|---|---|
| Date of Search: | 26 January 2009 |
| Next Stage Expected: | 26 January 2011 |
| Protocol First Published: | Issue 4, 2002 |
| Review First Published: | Issue 1, 2003 |
| Last Citation Issue: | Issue 4, 2007 |
| Date / Event | Description |
|---|---|
| 30 January 2009 Updated | 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. |
| Date / Event | Description |
|---|---|
| 11 June 2008 Amended | Converted to new review format. |
| 24 July 2007 Updated | This 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). |
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. The available data are insufficient to conclude that topical/oral prophylaxis prevents invasive fungal infection or mortality in very low birth weight infants. Systemic antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection.
To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very low birth weight infants.
The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2009), MEDLINE (1966 - January 2009), EMBASE (1980 - January 2009), conference proceedings, and previous reviews.
Randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy vs. placebo or no drug or another antifungal agent or dose regimen in very low birth weight infants.
Data were extracted using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by each review author and synthesis of data using relative risk, risk difference, and weighted mean difference. The pre-specified outcomes were death prior to hospital discharge, long-term neurodevelopment, incidence of invasive fungal infection, emergence of antifungal resistance, and adverse drug reactions.
Eight eligible trials enrolling a total of 758 participating infants were identified. Meta-analysis of data from five trials that compared prophylactic fluconazole vs. placebo revealed a statistically significant reduction in the risk of invasive fungal infection in the infants who received prophylaxis [typical relative risk: 0.48 (95% confidence interval 0.31, 0.73); typical risk difference: -0.09 (95% confidence interval -0.14, -0.03); number needed to treat: 11 (95% confidence interval 7, 33)]. There was no statistically significant difference in the risk of death prior to hospital discharge [typical relative risk: 0.74 (95% confidence interval 0.51, 1.09); typical risk difference: -0.04 (95% confidence interval -0.1, 0.01)]. Only one trial reported long-term neurodevelopmental outcomes. There were no statistically significant differences in the incidence of developmental delay or motor or sensory neurological impairment in children assessed at a median age of 16 months. One small trial that compared systemic versus oral/topical prophylaxis did not detect a statistically significant effect on invasive fungal infection or mortality. Two trials compared different dosing regimens of prophylactic intravenous fluconazole. These did not detect any significant differences in infection rates or mortality.
Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. This finding should be interpreted cautiously. The incidence of invasive fungal infection was very high in the control groups of most of the included trials. Furthermore, the trials may have been affected by ascertainment bias since use of prophylactic fluconazole may reduce the sensitivity of microbiological culture for detecting fungi in blood, urine, or cerebrospinal fluid. Meta-analysis does not demonstrate a statistically significant effect on overall mortality rates, but the 95% confidence interval around this estimate of effect is wide. 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.
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 kilograms). 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 that giving infants an antifungal drug (fluconazole) regularly for the first four to six weeks after birth reduces the number of infants who develop severe infection. There is no convincing evidence that death or disability rates were affected. However, the findings were based on only a few trials and further trials are needed.
Invasive fungal infection is an increasingly common cause of morbidity and mortality in very low birth weight infants (Kossoff 1998; Benjamin 2006). The incidence is between about 1% and 5% (Saiman 2000; Makhoul 2002; Clerihew 2006). In extremely low birth weight infants, the incidence has been reported to be as high as 10% (Karlowicz 2002). Additional specific risk factors include fungal colonisation, severe illness at birth, the use of multiple courses of antibiotics, the use of parenteral nutrition, the presence of a central venous catheter, and the use of histamine receptor subtype 2 antagonists (Huang 1998; Saiman 2000). Interunit variation in the incidence of invasive fungal infection is likely to be due to all or some of these population characteristics and clinical practices. The reported mortality rates of greater than 25% are higher than those attributed to nosocomial invasive bacterial infection in very low birth weight 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).
The clinical presentation of invasive fungal and bacterial infection is similar. The diagnosis may be delayed due to an inability to consistently recover the organism 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).
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 low birth weight infants. Prophylactic topical or oral non-absorbed antifungal agents (commonly, nystatin and/or miconazole) can prevent fungal colonisation. However, the currently available data are insufficient to conclude that topical/oral prophylaxis reduces the incidence of invasive fungal infection or mortality (Austin 2003). Over the past few years, the prophylactic use of systemic antifungal agents, principally the azole agent fluconazole, has been adopted as routine practice in some neonatal centres (Burwell 2006; Clerihew 2008a). This review sought to determine whether evidence exists that this practice prevents invasive fungal infection and reduces mortality and morbidity in very low birth weight infants. A further major consideration is the potential for antimicrobial prophylaxis to drive the emergence of drug resistance (Brion 2007).
To assess the effect of prophylactic systemic antifungal therapy on mortality and adverse neurodevelopmental outcomes in very low birth weight infants.
The effects of the following interventions were examined:
The following subgroup analyses were pre-specified:
Very low birth weight (birth weight less than 1500 grams) infants with or without evidence of fungal colonisation but without evidence of invasive fungal infection at study entry cared for in a hospital setting.
Trials comparing systemic antifungal prophylaxis with placebo or no drug or oral/topical antifungal prophylaxis, or another systemic antifungal agent or dose regimen. The drug may have been given by the intravenous or enteral route.
Primary outcomes:
1. Death prior to hospital discharge
2. Neurodevelopmental outcomes during infancy and beyond using validated assessment tools: neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability
3. Confirmed invasive fungal infection as determined by
a. culture of fungus from a normally sterile site: cerebrospinal fluid, blood, urine, bone or joint, peritoneum, pleural space
b. findings on autopsy examination consistent with invasive fungal infection
c. findings on ophthalmological examination consistent with fungal ophthalmitis or retinitis
d. pathognomonic findings on renal ultrasound examination: "renal fungal balls"
Secondary outcomes:
The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2009), MEDLINE (1966 - January 2009) and EMBASE (1980 - January 2009). The search strategy used the following text words and MeSH subject headings: Infant-Newborn, Infant-Low Birth Weight, Infant-Premature, infan$, neonat$, newborn, premature, low birth weight, LBW, fungi, fungemia, fungaemia, candidiasis, Candida albicans, anti fungal agents, fluconazole, azoles, amphotericin B, flucytosine. The searches were limited with the relevant filter for clinical trials. No language restriction was applied.
The references in studies identified as potentially relevant were examined. The abstracts from the Society for Pediatric Research and the European Society for Pediatric Research from 1980 until 2008 were searched. In 2003, all of the manufacturers of antifungal agents that are listed in the 2002 edition of the British National Formulary (BNF 2002): Bristol-Myers Squibb Pharmaceuticals Limited, Cambridge Laboratories, Elan Pharma Limited, Gilead Sciences Limited, ICN Pharmaceuticals Limited, Pfizer Limited were contacted. None provided any data that were unavailable from other sources.
The metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/search.html) website was searched on 2nd Feb 2009 for completed or ongoing trials.
Eight eligible trials were identified (Cabrera 2002; Kaufman 2001; Kaufman 2005; Kicklighter 2001; Manzoni 2007a; Manzoni 2007b; Parikh 2007; Violaris 1998; see Table, Characteristics of Included Studies). Two of the studies have been reported as an abstracts only (Cabrera 2002; Violaris 1998).
Participants:
The trials have been undertaken in tertiary perinatal centres in North America, Europe, or India within the past 10 years. In total, 758 infants participated. The participants were very low birth weight infants (Kicklighter 2001; Cabrera 2002; Manzoni 2007a; Manzoni 2007b; Parikh 2007; Violaris 1998), or extremely low birth weight infants (Kaufman 2001; Kaufman 2005). Documented fungal colonisation was an entry criterion for Cabrera 2002, but was not an entry criteria for the other trials.
Interventions:
1. Five trials compared intravenous antifungal prophylaxis (fluconazole in all cases) with placebo. 656 infants participated in total. Infants were enrolled within the first few days after birth. Kicklighter 2001 and Parikh 2007 assigned treatment for 28 days. The drug or placebo was given intravenously until the infants tolerated enteral intake and then administered enterally. Kaufman 2001 assigned the treatment for six weeks but discontinued administration when intravenous access was no longer available. Cabrera 2002 administered the drug intravenously initially then enterally when intravenous access was no longer in place. Manzoni 2007a assigned infants to the fluconazole or placebo from birth until 30 days after birth, or 45 days after birth for extremely low birth weight infants.
2. One small trial (N = 21) compared systemic antifungal prophylaxis (fluconazole) with oral/topical antifungal prophylaxis (nystatin) (Violaris 1998).
3. Two trials compared different dose regimens. Kaufman 2005 compared two regimes 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 bodyweight twice weekly for six weeks). Infants were assigned to intervention for six weeks or until intravenous access discontinued. Manzoni 2007a 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 45 days for extremely low birth weight infants).
Outcomes:
The primary outcomes of the trials were fungal colonisation and invasive fungal infection. Data on deaths prior to hospital discharge were provided for seven of the trials (Kaufman 2001; Kicklighter 2001; Kaufman 2005; Manzoni 2007a; Manzoni 2007b; Parikh 2007; Violaris 1998). Three of the studies monitored hepatic function with weekly assessments of the plasma levels of aspartate aminotransferase, alanine aminotransferase, total bilirubin, or alkaline phosphatase (Kaufman 2001; Kicklighter 2001; Kaufman 2005). These studies also monitored the fluconazole minimal inhibitory concentrations of fungal isolates (from both surface colonisation and from invasive infection) during the surveillance period. In Kaufman 2001 and Kaufman 2005, weekly surveillance cultures were collected during the period of prophylaxis. In Kicklighter 2001, surveillance began with the start of prophylaxis and continued for four weeks after completing the prophylaxis. 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 assessed developmental outcomes (Kaufman 2001). These data have been published in abstract form only.
Excluded studies:
Six studies were excluded (see Table, Characteristics of Excluded Studies). These were single centre retrospective observational studies that compared outcomes for cohorts of very low birth weight or extremely low birth weight infants cared for in an epoch immediately prior to the introduction of intravenous antifungal prophylaxis (fluconazole in all studies) vs. infants cared for in the epoch after this intervention was adopted (Aghai 2006; Bertini 2005; Dutta 2005; Healy 2005; Manzoni 2006; Uko 2006). All of these studies reported statistically significant reductions in the incidence of invasive fungal infection associated with the use of fluconazole prophylaxis. Only one study found a statistically significant difference in mortality rates (Aghai 2006). Although Aghai 2006 reported a lower rate of all cause mortality in infants treated with fluconazole prophylaxis, these infants also had statistically higher rates of exposure to antenatal corticosteroids and exogenous surfactant therapy.
Quality assessments are included 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 appears to be complete for the outcomes reported.
SYSTEMIC ANTIFUNGAL AGENT VS. PLACEBO OR NO DRUG (COMPARISON 01):
Five trials are included in this analysis (Cabrera 2002; Kaufman 2001; Kicklighter 2001;Manzoni 2007a; Parikh 2007):
Primary outcomes:
Death prior to hospital discharge (Outcome 01.01):
Data were reported by the four trials (Kaufman 2001; Kicklighter 2001; Manzoni 2007a; Parikh 2007). There was no statistically significant differences in the incidence of death prior to hospital discharge in any of the individual trials or in a meta-analysis of data [typical relative risk: 0.74 (95% confidence interval 0.51, 1.09); typical risk difference: -0.04 (95% confidence interval -0.1, 0.01)]. There was no statistical heterogeneity in this meta-analysis.
Neurodevelopmental outcome:
Neurodevelopmental outcomes were reported by only one trial. Kaufman 2001 reported no significant differences 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. When further data are available, these will be included in an update of this review.
Confirmed invasive fungal infection (Outcome 01.02):
Kaufman 2001 and Manzoni 2007a reported statistically significantly lower incidences of invasive fungal infection in the fluconazole group. Kicklighter 2001, Cabrera 2002 and Parikh 2007 did not find any statistically significant differences. Meta-analysis of data from the five trials found a statistically significantly lower incidence of invasive fungal infection in the fluconazole group [typical relative risk: 0.48 (95% confidence interval 0.31, 0.73); typical risk difference: -0.09 (95% confidence interval -0.14, -0.03); number needed to treat: 11 (95% confidence interval 7, 33)]. There was evidence of statistical heterogeneity in this meta-analysis.
Secondary outcomes:
Emergence of organisms resistant to antifungal agents:
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. The data were not presented separately for isolates from infants in the fluconazole and placebo groups. Kicklighter 2001 did not find any statistically significant differences in the minimal inhibitory concentration of fluconazole for fungal isolates (Candida albicans isolates only assessed) between the fluconazole and placebo 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". This was reported in abstract form only. If further data become available, these will be included in an update of this review.
Adverse drug reactions attributed to the antifungal agent:
There were no clinically significant adverse reactions attributed to fluconazole in the included studies. No infants were withdrawn from the trials because of adverse effects of fluconazole.
Subgroup analyses:
Infants with birth weight less than 1000 grams:
Kaufman 2001 and Kaufman 2005 enrolled only infants with birth weight less than 1000 grams. Manzoni 2007a stated that there was a statistically significantly lower incidence of invasive fungal infection in the subgroup of infants of birth weight less than 1000 grams. This was reported in abstract form only and no numerical data were presented. The abstract made no comment on mortality rates in extremely low birth weight infants. When these data become available, they will be included in an update of this review. Kicklighter 2001 enrolled infants with birth weight less than 1500 grams. A subgroup analysis of extremely low birth weight infants has not been possible.
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 VS. ORAL OR TOPICAL ANTIFUNGAL THERAPY (COMPARISON 02):
One trial is included in this analysis Violaris 1998)
Primary outcomes:
Death prior to hospital discharge (Outcome 02.01):
Violaris 1998 found no significant difference in death prior to hospital discharge [relative risk: 0.17 (95% confidence interval 0.01, 2.84); risk difference: -0.31 (95% confidence interval -0.62, 0.01)].
Confirmed invasive fungal infection (Outcome 02.02):
Violaris 1998 found no significant difference in confirmed invasive fungal infection [relative risk: 0.17 (95% confidence interval 0.01, 2.84); risk difference: -0.31 (95% confidence interval -0.62, 0.01)].
No other outcomes were reported by Violaris 1998. If further data become available these will be included in an update of this review.
Subgroup analyses:
Infants with birth weight less than 1000 grams: This analysis was not possible.
Infants with fungal colonisation at entry to study: This analysis was not possible.
ONE SYSTEMIC ANTIFUNGAL AGENT VS. ANOTHER AGENT OR DOSE REGIMEN (COMPARISON 03):
Two trials are included in this analysis (Kaufman 2005; Manzoni 2007a):
Primary outcomes:
Death prior to hospital discharge (Outcome 03.01):
Kaufman 2005 found no statistically significant difference between the two dose regimens [relative risk: 0.98 (95% confidence interval 0.34, 2.77); typical risk difference 0.00 (95% confidence interval -0.16, 0.15)].
Manzoni 2007a found no statistically significant difference between the two dose regimens [relative risk: 1.08 (95% confidence interval 0.44, 2.61); typical risk difference 0.01 (95% confidence interval -0.07, 0.08)].
Neurodevelopmental outcome: Not reported by either trial.
Confirmed invasive fungal infection (Outcome 03.02):
Kaufman 2005 found no statistically significant difference in confirmed invasive fungal infection [relative risk 1.95 (95% confidence interval 0.18, 20.68); risk difference 0.02 (95% confidence interval -0.06, 0.11)].
Manzoni 2007a: found no statistically significant difference [relative risk 1.44 (95% confidence interval 0.33, 6.26); risk difference 0.01 (95% confidence interval -0.04, 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 of infants during the first 12 months vs. the second 12 months of the study.
Manzoni 2007a stated that "patterns of sensitivity to fluconazole remained the same". This was reported in abstract form only. If further data become available, these will be included in an update of this review.
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:
Infants with birth weight less than 1000 grams:
All participants in Kaufman 2005 were of birth weight less than 1000 grams.
Manzoni 2007a: Subgroup analyses for extremely low birth weight infants are not possible with the currently reported data. When further data are available, these will be included in an update of this review.
Infants with fungal colonisation at entry to study: This analysis was not possible.
The available data suggest that prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. The pooled effect size estimates that treating 11 infants with prophylactic fluconazole would prevent one extra case on invasive fungal infection. The included trials were generally of good methodological quality. However, the existence of statistical heterogeneity in the meta-analysis raises concern that the estimate is not robust. This finding should be interpreted and applied with caution for several additional reasons.
In the trials that contributed most weight to the pooled estimate of effect size (Kaufman 2001; Manzoni 2007a; Parikh 2007), the reported incidences of invasive fungal infection in the placebo groups were much higher than in other large cohort studies (Karlowicz 2002; Kossoff 1998; Clerihew 2006). Applying this finding to units with lower incidences of invasive fungal infection would require treatment of a much larger number of infants to prevent a single extra case of invasive fungal infection.
The diagnostic sensitivity of microbiological culture for invasive fungal infection is lower in infants receiving systemic antifungal treatment (Schelonka 2003). This may cause selective under-diagnosis in the treatment group and over-estimation of the effect size. For that reason, mortality was included as a primary outcome for this review, since ascertaining this outcome is not likely to be affected by bias. Furthermore, as it is often difficult to define precisely the cause of death in very low birth weight infants, and since invasive fungal infection is not always diagnosed, all-cause mortality rather than death attributed to fungal infection was a pre-specified outcome. The review did not find a statistically significant effect of prophylactic systemic antifungal therapy on all-cause mortality. The mortality rates in the placebo cohorts were similar to rates in large cohort studies of very low birth weight infants cared for in similar settings (Horbar 2002). However, the 95% confidence interval around this estimate of effect is wide (49% risk reduction to 9% 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.
Regarding the potential adverse effects of prophylactic fluconazole, 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 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).
There is concern 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 colonization 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 most recently published trial, undertaken in a neonatal intensive care unit where fluconazole had been used routinely for 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 if invasive fungal infection. Continued mycological surveillance in those units where systemic antifungal prophylaxis is used is essential.
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 extremely low birth weight than very low birth weight infants, targeting prophylaxis to this population reduces the number of infants who need to be exposed to fluconazole. A subgroup analysis of extremely low birth weight infants was planned but the data are not available from the published reports of the two largest trials (Kicklighter 2001; Manzoni 2006). If these data become available, they will be included in a future update of the review. Even within the extremely low birth weight population, the burden of invasive fungal infection is confined to the smallest and least mature infants (Clerihew 2006). Invasive fungal infection is three time more common in infants born before 26 weeks' gestation or with birth weight less than 750 grams than in infants of birth weight 750 grams to less than 1000 grams. Evidence exists that clinicians who use systemic antifungal prophylaxis already target the smallest and least mature infants with additional risk factors for invasive fungal infection (Burwell 2006; Clerihew 2008a). It may be appropriate to focus future research efforts on this risk high population. A multi-centre study to determine the effect of fluconazole prophylaxis on mortality and neuro-morbidity for infants of birth weight less than
750 grams is currently being developed in North America (http://clinicaltrials.gov/ct2/show/NCT00734539).
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 as a risk factor for invasive infection by some (PappuKatikaneni 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 (Kaufman 2005; Kicklighter 2001; 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 will provide clinically useful findings.
Finally, 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 incidence of invasive fungal infection. However, the 95% confidence intervals were wide and further trials are need to identify the most appropriate dosing regimen for this intervention.
There is some evidence that prophylactic systemic antifungal agents reduce invasive fungal infection in very low birth weight infants but the currently available data do not find 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, but the 95% confidence intervals for these estimates are wide.
Further randomised controlled trials of systemic antifungal prophylaxis are needed to provide more precise estimates of effect size. Because most neonatologists who currently use systemic antifungal prophylaxis target infants thought to be at greatest risk, mainly extremely low birth weight or extremely preterm infants with additional risk factors, a trial restricted in this population of infants, or perhaps even smaller or lower gestation infants, may be appropriate and acceptable (Burwell 2006; Parikh 2007). Systemic antifungal prophylaxis may be compared with placebo or with topical/oral prophylaxis. Any trial should aim to assess long-term outcomes, particularly disability-free survival, as well as the effect on invasive fungal infection. 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.
We thank Dr David Kaufman and Dr Stephen 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.
Nicola Austin (NA) and William McGuire (WM) screened the title and abstract of all studies identified by the search strategy. Linda Clerihew (LC) and WM screened the full text of the report of each study identified as of potential relevance. LC and WM extracted the data separately, compared data, and resolved differences by consensus, and with discussion with NA. LC, NA, and WM completed the final review.
| Methods | Blinding of randomisation: Can't tell Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 11 infants of birthweight less than 1500 g with fungal colonisation demonstrated on rectal, oro-pharyngeal, or tracheal weekly surveillance cultures. |
| Interventions | Fluconazole (N=6) 6 mg / kg body weight, 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. |
| Outcomes | Invasive fungal infection. |
| Notes | Published in abstract form only (additional data obtained from authors). |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Unclear | D - Not used |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 100 infants less than five days old, and of birthweight less than 1000 g. Infants with evidence of liver failure were not eligible for inclusion. |
| Interventions | Fluconazole (N=50) 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 versus normal saline placebo (N=50). Assigned to intervention for six weeks, or until intra-venous access discontinued. |
| Outcomes | Fungal colonisation and invasive infection. Emergence of fluconazole resistance. |
| 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. |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | A - Adequate |
| Methods | Blinding of randomisation: Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 81 infants of birthweight less than 1000 grams, less than 5 days old, and with either an endotracheal tube or central venous catheter in situ. |
| Interventions | Regimen A (N=41): Fluconazole 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 |
| Outcomes | Fungal colonisation and invasive infection. Mortality (all cause) was reported as a secondary outcome. |
| Notes |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | A - Adequate |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 103 infants less than three days old, and of birthweight less than 1500 g. Infants with evidence of liver failure, congenital heart disease, or congenital defects needing surgery were not eligible for inclusion. |
| Interventions | Fluconazole 6 mg / kg body weight (N=112), or fluconazole 3 mg/kg (N=104), or placebo (N=106) every second day from birth until the 30th day after birth (or 45th day in infants of birth weight less than 1000 grams). Administered intravenously and then oro-gastrically when tolerated. |
| Outcomes | Fungal colonisation and invasive infection. Emergence of fluconazole resistance. |
| Notes |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | A - Adequate |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 322 infants of birthweight less than 1500 grams. |
| Interventions | Fluconazole 3 mg/kg or 6 mg/kg body weight, every second day from birth for 30 days, or 45 days for extremely low birth weight infants (N=216) versus placebo (N=106). |
| Outcomes | Fungal colonisation and invasive infection. Emergence of fluconazole resistance. |
| Notes |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | A - Adequate |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 216 infants of birthweight less than 1500 grams. |
| Interventions | Fluconazole 3 mg/kg (N=104) versus fluconazole 6 mg/kg (N=112), every second day from birth for 30 days, or 45 days for extremely low birth weight infants. |
| Outcomes | Fungal colonisation and invasive infection. Emergence of fluconazole resistance. Death prior to hospital discharge was also reported. |
| Notes | This population forms the intervention cohort in Manzoni 2007a. |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | A - Adequate |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measurement: Yes |
|---|---|
| Participants | 121 infants less than three days old, and of birthweight less than 1500 g. "Critically ill" infants and infants with biochemical evidence of hepatic insufficiency were not eligible for inclusion. |
| Interventions | Fluconazole (N=60) 6 mg / kg body weight, 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. |
| Notes | Most invasive fungal infection was due to non-albicans Candida species (mainly C. glabrata) which were relatively less susceptible to fluconazole. |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Yes | Sealed opaque envelopes. |
| Methods | Blinding of randomisation: Can't tell Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: No |
|---|---|
| Participants | 21 infants of birthweight less than 1500 grams. |
| Interventions | Fluconazole (4mg/kg) orally (N=8) versus nystatin (100,000 units/kg/day) in each side of the mouth (N=13), beginning on day five after birth. Medications were continued until full oral feedings were attained or systemic fungal infection was diagnosed. |
| Outcomes | Invasive fungal infection and mortality. |
| Notes | Published in abstract form only. |
| Item | Judgement | Description |
|---|---|---|
| Allocation concealment? | Unclear | B - Unclear |
| Reason for exclusion | Not a randomised controlled trial. Observational study of extremely low birth weight infants cared for in pre-and post- fluconazole prophylaxis epochs at Cooper University Hospital, New Jersey, USA (1998-2005). |
|---|
| Reason for exclusion | Not a randomised controlled trial. Observational study at Careggi University Hospital, Florence, Italy. Compared outcomes for very low birth infants during a baseline period (1998-2000) with infants cared for during a study period (2001-2003) when infants received fluconazole prophylaxis. |
|---|
| Reason for exclusion | Not a randomised controlled trial. Retrospective observational study in Chandigarh, India. Compared incidences of invasive fungal infection in newborn infants cared for in a level III neonatal unit during pre- and post-fluconazole prophylaxis epochs. |
|---|
| Reason for exclusion | Not a randomised controlled trial. Observational study of extremely low birth weight infants cared for in the Women's Hospital of Texas, USA prior to the introduction of fluconazole prophylaxis (2000-2001) and after the introduction of prophylaxis (2002-2004). |
|---|
| Reason for exclusion | Not a randomised controlled trial. Retrospective cohort study of very low birth weight infants in Santa'Anna, Torino, Italy (2000-2005). Outcomes compared between two epochs pre- and post- fluconazole prophylaxis. |
|---|
| Reason for exclusion | Not a randomised controlled trial. Observational study of very low birth weight infants cared for in pre-and post- fluconazole prophylaxis epochs at the Children's Hospital at Montefiore, New York, USA (2001-2004). |
|---|
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Summary Table of Comparisons and Outcomes
1 Systemic antifungal agent versus placebo or no drug
1.1 Death prior to hospital discharge
1.2 Invasive fungal infection
2 Systemic antifungal agent versus oral/topical antifungal prophylaxis
2.1 Death prior to hospital discharge
2.2 Invasive fungal infection
3 One systemic antifungal agent versus another agent or dose regimen
3.1 Death prior to hospital discharge
3.2 Invasive fungal infection
| This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2009 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review. |
