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Keywords:

  • Adolescent;
  • Amphotericin B [therapeutic use];
  • Antifungal Agents [*therapeutic use];
  • Candidiasis [drug therapy];
  • Echinocandins [therapeutic use];
  • Fever [drug therapy];
  • Mycoses [*drug therapy; mortality];
  • Neutropenia [drug therapy];
  • Randomized Controlled Trials as Topic;
  • Child;
  • Child, Preschool;
  • Humans;
  • Infant

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 (I2 = 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.

Plain Language Summary

Antifungal agents for infants and children with invasive fungal infections

Invasive fungal infections are a significant problem for children whose immune system is not functioning properly. The majority of the children have cancer. Antifungal medications can be given when these children develop a fever (for example a fever occurring when the white cells or neutrophils are low during chemotherapy) or when an infection has been formally identified (as in candidaemia, candidiasis and invasive aspergillosis). The antifungal agents that were compared appear equally efficacious. Pooling the data from the few studies that were available suggest kidney damage was less likely with a lipid preparation of amphotericin B compared with conventional amphotericin B. It is reasonable to recommend a lipid preparation of amphotericin B, if cost permits. No significant differences have been observed in children when other antifungal agents have been compared. More studies in children evaluating available antifungal are required to further clarify any benefits with regard to the risk of dying, prospects of complete recovery and drug toxicities.