title: Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections.
abstract: BACKGROUND
  Invasive fungal infections are associated with significant morbidity and mortality in children. Optimal treatment strategies are yet to be defined.
  
  
  OBJECTIVE
  This review aims to systematically identify and summarise the effects of different antifungal therapies in children with proven, probable or suspected invasive fungal infections.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  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.
  
  
  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.
authors.affiliation: Centre for Infectious Disease and Microbiology, ICPMR, Westmead Hospital, Darcy Road, Westmead, New South Wales, Australia, 2145.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Blyth
authors.forename: Katherine
authors.initials: K
authors.lastname: Hale
authors.forename: Pamela
authors.initials: P
authors.lastname: Palasanthiran
authors.forename: Tracey
authors.initials: T
authors.lastname: O'Brien
authors.forename: Michael H
authors.initials: MH
authors.lastname: Bennett
mesh_terms: D000293:Adolescent; D000666:Amphotericin B / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D002177:Candidiasis / Q000188:drug therapy; D002648:Child; D002675:Child, Preschool; D054714:Echinocandins / Q000627:therapeutic use; D005334:Fever / Q000188:drug therapy; D006801:Humans; D007223:Infant; D009181:Mycoses / Q000188:drug therapy* / Q000401:mortality; D009503:Neutropenia / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; C068538:liposomal amphotericin B; D000666:Amphotericin B