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Meta-Analysis
. 2010 Feb 17;2010(2):CD006343.
doi: 10.1002/14651858.CD006343.pub2.

Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections

Christopher C Blyth  1 , Katherine Hale, Pamela Palasanthiran, Tracey O'Brien, Michael H Bennett
Affiliations
Meta-Analysis

Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections

Christopher C Blyth et al. Cochrane Database Syst Rev. .

Abstract

Background: Invasive fungal infections are associated with significant morbidity and mortality in children. Optimal treatment strategies are yet to be defined.

Objectives: This review aims to systematically identify and summarise the effects of different antifungal therapies in children with proven, probable or suspected invasive fungal infections.

Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1966 to September 2008), EMBASE (1980 to September 2008) and CINAHL (1988 to September 2008) without language restrictions. We also handsearched reference lists and abstracts of conference proceedings and scientific meetings, and contacted authors of included studies and pharmaceutical manufacturers.

Selection criteria: We included randomised clinical trials (RCTs) comparing a systemic antifungal agent with a comparator (including placebo) in children (one month to 16 years) with proven, probable or suspected invasive fungal infection.

Data collection and analysis: Two review authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We synthesised data using the random-effects model and expressed results as relative risks (RR) with 95% confidence intervals (CIs).

Main results: We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candidaemia or invasive candidiasis (proven fungal infection). Four trials compared a lipid preparation of amphotericin B with conventional amphotericin B (395 participants), one trial compared an echinocandin with a lipid preparation of amphotericin B (82 participants) in suspected infection; one trial compared an echinocandin with a lipid preparation of amphotericin B in children with candidaemia or invasive candidiasis (109 participants) and one trial compared different azole antifungals in children with candidaemia (43 participants). No difference in all-cause mortality and other primary endpoints (mortality related to fungal infection or complete resolution of fungal infections) were observed. No difference in breakthrough fungal infection was observed in children with prolonged fever and neutropenia.When lipid preparations and conventional amphotericin B were compared in children with prolonged fever and neutropenia, nephrotoxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial heterogeneity was observed (I(2) = 59%, P = 0.06). Children receiving liposomal amphotericin B were less likely to develop infusion-related reactions compared with conventional amphotericin B (chills: RR 0.37, 95% CI 0.21 to 0.64, P = 0.0005). Children receiving a colloidal dispersion were more likely to develop such reactions than with liposomal amphotericin B (chills: RR 1.76, 95% CI 1.09 to 2.85, P = 0.02). The rate of other clinically significant adverse reactions attributed to the antifungal agent (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy; hypokalaemia and hepatotoxicity) were not significantly different. When echinocandins and lipid preparations were compared, the rate of clinically significant adverse reactions (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy) were not significantly different.

Authors' conclusions: Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections.

PubMed Disclaimer

Conflict of interest statement

Dr Christopher Blyth and Dr Katherine Hale are members of the Australian and New Zealand Mycology Interest Group, which is sponsored by Gilead Science, Pfizer, Merck Sharp & Dohme and Schering‐Plough.

Dr Katherine Hale has received investigator initiated research funding from Gilead Sciences and Pfizer for other research projects.

Figures

1
1
1.1
1.1. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 1 Mortality (all cause).
1.2
1.2. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 2 Mortality (related to fungal infection).
1.3
1.3. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 3 Complete resolution of fungal infection.
1.5
1.5. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 5 Resolution of fever in suspected fungal infection.
1.7
1.7. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.
1.9
1.9. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total).
1.10
1.10. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 10 Nephrotoxicity.
1.11
1.11. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 11 Hypokalaemia.
1.12
1.12. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 12 Hepatotoxicity.
1.13
1.13. Analysis
Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B, Outcome 13 Infusion‐related reactions.
2.1
2.1. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 1 Mortality (all cause).
2.2
2.2. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 2 Mortality (related to fungal infection).
2.5
2.5. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 5 Resolution of fever in suspected fungal infection.
2.7
2.7. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.
2.8
2.8. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation, dose reduction or change in therapy.
2.9
2.9. Analysis
Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg), Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total).
3.1
3.1. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 1 Mortality (all cause).
3.2
3.2. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 2 Mortality (related to fungal infection).
3.3
3.3. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 3 Complete resolution of fungal infection.
3.7
3.7. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.
3.8
3.8. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation, dose reduction or change in therapy.
3.9
3.9. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total).
3.10
3.10. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 10 Nephrotoxicity.
3.11
3.11. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 11 Hypokalaemia.
3.12
3.12. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 12 Hepatotoxicity.
3.13
3.13. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 13 Infusion‐related reactions.
3.14
3.14. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 14 Gastrointestinal toxicity.
3.15
3.15. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 15 Neurological disturbances.
3.16
3.16. Analysis
Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B, Outcome 16 Haematological disturbances.
4.1
4.1. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 1 Mortality (all cause).
4.2
4.2. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 2 Mortality (related to fungal infection).
4.3
4.3. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 3 Complete resolution of fungal infection.
4.7
4.7. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.
4.8
4.8. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation, dose reduction or change in therapy.
4.10
4.10. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 10 Nephrotoxicity.
4.11
4.11. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 11 Hypokalaemia.
4.12
4.12. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 12 Hepatotoxicity.
4.13
4.13. Analysis
Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 13 Infusion‐related reactions.
5.1
5.1. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 1 Mortality (all cause).
5.8
5.8. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation, dose reduction or change in therapy.
5.9
5.9. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total).
5.10
5.10. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 10 Nephrotoxicity.
5.11
5.11. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 11 Hypokalaemia.
5.12
5.12. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 12 Hepatotoxicity (>2.5 X ULN).
5.13
5.13. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 13 Infusion‐related reactions.
5.15
5.15. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 15 Neurological disturbances.
5.16
5.16. Analysis
Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 16 Haematological disturbances.
6.1
6.1. Analysis
Comparison 6 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B (best case for lipid), Outcome 1 Nephrotoxicity.
7.1
7.1. Analysis
Comparison 7 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B (worst case for lipid), Outcome 1 Nephrotoxicity.
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Update of

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