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

Antifungal therapy in infants and children with proven,

probable or suspected invasive fungal infections (Review)

Blyth CC, Hale K, Palasanthiran P, O’Brien T, Bennett MH

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 4

http://www.thecochranelibrary.com

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

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

20DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional

amphotericin B, Outcome 1 Mortality (all cause). . . . . . . . . . . . . . . . . . . . . . 43


amphotericin B, Outcome 2 Mortality (related to fungal infection). . . . . . . . . . . . . . . . 44


amphotericin B, Outcome 3 Complete resolution of fungal infection. . . . . . . . . . . . . . . 44


amphotericin B, Outcome 5 Resolution of fever in suspected fungal infection. . . . . . . . . . . . 45


amphotericin B, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent. 45


amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total). 46


amphotericin B, Outcome 10 Nephrotoxicity. . . . . . . . . . . . . . . . . . . . . . . . 46


amphotericin B, Outcome 11 Hypokalaemia. . . . . . . . . . . . . . . . . . . . . . . . 47


amphotericin B, Outcome 12 Hepatotoxicity. . . . . . . . . . . . . . . . . . . . . . . . 47


amphotericin B, Outcome 13 Infusion-related reactions. . . . . . . . . . . . . . . . . . . . 48

Analysis 2.1. Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg),

Outcome 1 Mortality (all cause). . . . . . . . . . . . . . . . . . . . . . . . . . . . 49


Outcome 2 Mortality (related to fungal infection). . . . . . . . . . . . . . . . . . . . . . 49


Outcome 5 Resolution of fever in suspected fungal infection. . . . . . . . . . . . . . . . . . 50


Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent. . . . . . . 50


Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation,

dose reduction or change in therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . 51


Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total). . . . . . 51

Analysis 3.1. Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin

B, Outcome 1 Mortality (all cause). . . . . . . . . . . . . . . . . . . . . . . . . . . 52


B, Outcome 2 Mortality (related to fungal infection). . . . . . . . . . . . . . . . . . . . . 52

iAntifungal therapy in infants and children with proven, probable or suspected invasive fungal infections (Review)



B, Outcome 3 Complete resolution of fungal infection. . . . . . . . . . . . . . . . . . . . 53


B, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent. . . . . . 54


B, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation,

dose reduction or change in therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . 54


B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent (total). . . . . 55


B, Outcome 10 Nephrotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . 55


B, Outcome 11 Hypokalaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56


B, Outcome 12 Hepatotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56


B, Outcome 13 Infusion-related reactions. . . . . . . . . . . . . . . . . . . . . . . . . 57


B, Outcome 14 Gastrointestinal toxicity. . . . . . . . . . . . . . . . . . . . . . . . . 57


B, Outcome 15 Neurological disturbances. . . . . . . . . . . . . . . . . . . . . . . . . 58


B, Outcome 16 Haematological disturbances. . . . . . . . . . . . . . . . . . . . . . . . 59

Analysis 4.1. Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole, Outcome 1

Mortality (all cause). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59


Mortality (related to fungal infection). . . . . . . . . . . . . . . . . . . . . . . . . . 60


Complete resolution of fungal infection. . . . . . . . . . . . . . . . . . . . . . . . . 60


Breakthrough fungal infection requiring change / addition of an antifungal agent. . . . . . . . . . . 61

Analysis 4.8. 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61


10 Nephrotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62


11 Hypokalaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62


12 Hepatotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63


13 Infusion-related reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 5.1. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 1 Mortality

(all cause). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 5.8. 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 5.9. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 9 Any

clinically significant adverse reactions attributed to the antifungal agent (total). . . . . . . . . . . . 65

Analysis 5.10. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 10

Nephrotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65


Hypokalaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

iiAntifungal therapy in infants and children with proven, probable or suspected invasive fungal infections (Review)



Hepatotoxicity (>2.5 X ULN). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Analysis 5.13. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome 13 Infusion-

related reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67


Neurological disturbances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67


Haematological disturbances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Analysis 6.1. Comparison 6 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional

amphotericin B (best case for lipid), Outcome 1 Nephrotoxicity. . . . . . . . . . . . . . . . . 68

Analysis 7.1. Comparison 7 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional

amphotericin B (worst case for lipid), Outcome 1 Nephrotoxicity. . . . . . . . . . . . . . . . . 69

69APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

79INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiiAntifungal therapy in infants and children with proven, probable or suspected invasive fungal infections (Review)


[Intervention Review]

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

Christopher C Blyth1, Katherine Hale2, Pamela Palasanthiran3 , Tracey O’Brien4, Michael H Bennett5

1School of Paediatrics and Child Health, University of Western Australia, Subiaco, Australia. 2Department of Allergy, Immunology

& Infectious Diseases, Children’s Hospital at Westmead, Westmead, Australia. 3Department of Immunology and Infectious Diseases,

Sydney Children’s Hospital, Randwick, Australia. 4Centre for Children’s Cancer & Blood Disorders, Sydney Children’s Hospital,

Randwick, Australia. 5Department of Anaesthesia, Prince of Wales Hospital, Randwick, Australia

Contact address: Christopher C Blyth, School of Paediatrics and Child Health, University of Western Australia, Princess Margaret

Hospital, Roberts Road, Subiaco, WA, 6008, Australia. [email protected].

Editorial group: Cochrane Gynaecological Cancer Group.

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2011.

Review content assessed as up-to-date: 17 January 2010.

Citation: Blyth CC, Hale K, Palasanthiran P, O’Brien T, Bennett MH. Antifungal therapy in infants and children with proven,

probable or suspected invasive fungal infections. Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD006343. DOI:

10.1002/14651858.CD006343.pub2.


A B S T R A C T

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).

1Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections (Review)


mailto:[email protected]

Main results

We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candi-

daemia 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 partici-

pants). 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, nephro-

toxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial hetero-

geneity 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.

P L A I N L A N G U A G E S U M M A R Y

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.

B A C K G R O U N D

Invasive fungal infections (IFI) cause significant morbidity and

mortality. The incidence of IFI is increasing (Groll 1996; Marr

2002; Martin 2003). Most children who develop fungal infections

have received chemotherapy for a malignancy or have undergone a

haematopoietic stem cell or solid organ transplant. The incidence

of IFI in these groups is between 5% and 25% (Groll 1999; Rosen

2005). A minority of children developing IFI have a congenital or

acquired immunodeficiency such as chronic granulomatous dis-



ease or HIV/AIDS (Dvorak 2005; Steinbach 2005a). Mortality is

high in those who develop IFI and is influenced by the type of

fungus, site of disease and presence of ongoing immunosuppres-

sion (Dvorak 2005; Lin 2001).

Definitive diagnosis by tissue microscopy and culture is difficult

in the early stages of infection. Using host factor and microbio-

logical and clinical criteria, current definitions exist for proven,

probable and possible invasive fungal infection (Ascioglu 2002;

de Pauw 2008). In practice, IFI is often suspected in those with

persistent fever and neutropenia who fail to respond to broad-

spectrum antibacterial agents, within three to five days, and in

whom a reasonable attempt has been made to exclude bacterial

and viral infections. As mortality is high, early and aggressive treat-

ment of suspected infections with empiric antifungal therapy is

common (Hughes 2002). Empirical antifungal therapy is associ-

ated with a lower incidence of IFI yet no demonstrable survival

benefit (Goldberg 2008). As many of the patients with persistent

fever and neutropenia who receive empiric therapy do not have a

fungal infection, there is increasing interest in biological markers

and radiological imaging to identify those at highest risk of IFI

(Cordonnier 2009; Maertens 2005). There are currently insuffi-

cient data to support this approach in children.

Conventional amphotericin B deoxycholate is a broad spectrum

antifungal agent that has previously been the treatment of choice

for most IFI. Its use is complicated by nephrotoxicity and infu-

sion-related reactions (Gallis 1990). More recently, lipid formu-

lations of amphotericin B have become available and have less

toxicity. Triazole derivatives (fluconazole, itraconazole, voricona-

zole, posaconazole and ravuconazole) and echinocandins (caspo-

fungin, micafungin and anidulafungin) have increased the number

of available agents. The role of biological agents (for example an-

tiHSP90 monoclonal antibodies, Mycograb®) is being explored

(Pachl 2006). The increasing use of combination antifungal ther-

apy adds further complexity to decision making about treatment

(Marr 2004; Mukherjee 2005).

Numerous meta-analyses and randomised controlled trials (RCTs)

have compared different antifungal agents in immunocompro-

mised adults, as empirical treatment in patients with persistent

fever and neutropenia (Johansen 2000; Johansen 2002; Prentice

1997; Walsh 1999; Walsh 2002; Walsh 2004a; Winston 2000),

treatment of invasive aspergillosis (Cornely 2007; Herbrecht

2002) and invasive candidal infections (Kuse 2007; Mora-Duarte

2002; Reboli 2007; Rex 1994). Many differences, particularly with

respect to antifungal toxicity and cost, have been demonstrated. As

significant variation exists between adult and paediatric antifungal

pharmacokinetics (Benson 1989; Brammer 1994; Martin 2003;

Walsh 2004b; Walsh 2005) cautious interpretation of the efficacy,

toxicity and economic endpoints from these trials is required when

managing children with IFI. It remains unclear which is the most

appropriate antifungal agent to treat children with proven, prob-

able or suspected IFI.

O B J E C T I V E S

To assess different antifungal agents or combinations of agents

in children with proven, probable or suspected invasive fungal

infections (including empiric antifungal therapy in children with

persistent fever and neutropenia) with respect to comparative:

• effectiveness;

• toxicity;

• cost.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We considered all randomised and quasi-randomised (using a

method of allocating participants to a treatment that is not strictly

random, for example by date of birth or hospital record number)

clinical trials.

Types of participants

Infants and children (age older than 28 days and up to 16 years)

with proven, probable or suspected invasive fungal infection were

included. Neonates were excluded given the numerous epidemi-

ological differences (Blyth 2009) and the publication of a previ-

ous meta-analysis assessing systemic antifungal drugs for invasive

fungal infection in this population (Clerihew 2004). Proven or

probable invasive fungal infection was defined as a clinical illness

consistent with infection plus either radiological, histopathologi-

cal or microbiological evidence of invasive fungal disease (Ascioglu

2002; de Pauw 2008). Suspected invasive fungal infection was de-

fined pragmatically as an individual clinician’s choice to prescribe

a systemic antifungal agent based on the clinical suspicion of inva-

sive fungal infection in the absence of a confirmed diagnosis. This

definition was inclusive of empiric, systemic antifungal therapy in

patients with persistent fever and neutropenia despite appropriate

antibacterial agents.

Where insufficient information was available to classify infections,

we contacted the study authors.

Types of interventions

Trials including any of the following agents were reviewed: con-

ventional amphotericin B deoxycholate; lipid preparations of

amphotericin (for example liposomal amphotericin B, ampho-

tericin B colloidal dispersion (ABCD), amphotericin B lipid



complex (ABLC)); 5-fluorocytosine; azoles (for example flucona-

zole, itraconazole, voriconazole, posaconazole and ravuconazole);

echinocandins (for example caspofungin, micafungin and anidula-

fungin) or monoclonal antibodies (for example antiHSP90 mon-

oclonal antibody (Mycograb®). We considered any dose designed

to produce a therapeutic effect. We accepted trials that compared

different systemic antifungal agents or combination of agents, no

treatment or an inactive placebo.

We specifically excluded trials assessing the use of antifungal ther-

apy to prevent invasive fungal infection (that is antifungal pro-

phylaxis).

Types of outcome measures

Studies were eligible for inclusion if they reported any of the fol-

lowing outcome measures.

Primary outcome

1. All-cause mortality (defined as the death of any randomised

patient regardless of cause).

2. Invasive fungal infection-related mortality (defined as death of a

patient diagnosed with invasive fungal infection (IFI) whose death

is attributable to IFI).

3. Complete resolution of invasive fungal infection (defined as

complete resolution of clinical symptoms, with or without radi-

ological or microbiological findings that led to diagnosis of IFI,

enabling cessation of anti-fungal medication).

Secondary outcomes

4. Partial resolution of invasive fungal infection (defined as any

improvement in clinical symptoms with or without radiological

findings that led to diagnosis of IFI yet not fulfilling criteria for

complete resolution).

5. Resolution of fever in suspected fungal infection (defined as

absence of temperature > 38 °C for more than 72 hours or another

closely-related definition of resolution of fever).

6. Progression of disease requiring change or addition of an anti-

fungal agent (defined as progression of existing symptoms with or

without radiological or microbiological findings that are of enough

concern for a clinician to change the antifungal dose or add a new

antifungal agent).

7. Breakthrough fungal infection requiring change or addition of

an antifungal agent (defined as new clinical symptoms or signs

with or without radiological or microbiological findings that are

of enough concern for clinicians to change antifungal dose or add

a new antifungal agent).

8. Any clinically significant adverse reactions attributed to the

antifungal agent resulting in discontinuation, dose reduction or

change in the therapy.

9. Any adverse reactions attributed to the antifungal agent includ-

ing:

a. abnormal renal function (a number of definitions were accepted

including a raised creatinine, a reduced glomerular filtration rate

or creatinine clearance as compared with normal values or baseline

values);

b. electrolyte imbalance such as hypokalaemia;

c. abnormal hepatic function (a number of definitions were ac-

cepted including raised transaminases or bilirubin greater than

normal or baseline values for age);

d. infusion-related reactions such as chills, rigors or anaphylaxis;

e. gastrointestinal disturbances such as nausea, vomiting or diar-

rhoea;

f. neurological disturbances such as blurred vision or dizziness;

g. haematological disturbances such as anaemia, granulocytopenia

or thrombocytopenia.

10. Length of stay (days).

11. Quality of life (QOL).

12. Cost.

Search methods for identification of studies

Electronic searches

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).

A sensitive subject search strategy was combined with the opti-

mum trial search strategy for use in MEDLINE (Appendix 1),

CENTRAL (Appendix 2), EMBASE (Appendix 3) and CINAHL

(Appendix 4). All languages were considered. The search strategies

were devised and executed by the author team.

Searching other resources

We considered letters, abstracts and unpublished trials in an at-

tempt to minimise the impact of publication bias. In addition, we

made a systematic search for relevant controlled trials in this area

by:

• searching citation lists of articles identified in primary

searches;

• contacting experts in the field and leading authors (as

identified by personal communication and searching both the

articles found and the Internet) to ask for additional relevant

data in terms of published or unpublished RCTs;

• handsearching relevant textbooks (Feigin RD, Cherry J,

Demmler GJ, Kaplan S. Textbook of Pediatric Infectious

Diseases, 5th edition; Mandell GL, Bennett JE, Dolin R.

Principles and Practice of Infectious Diseases, 6th edition);

• handsearching conference proceedings, where available:

Interscience Conference of Antimicrobial Agents and

Chemotherapy (ICAAC) (1995 to 2008); General Meeting of



the America Society of Microbiology (ASM) (1999 to 2008);

Annual Meeting of the Infectious Diseases Society of America

(IDSA) (1995 to1997, 2001 to 2008); European Congress of

Clinical Microbiology and Infectious Diseases (ECCMID)

(2001 to 2008); General Meeting of the American Society of

Hematology (ASH) (1990 to 2007); European Society of

Paediatric Infectious Diseases Conference (ESPID) (2001 to

2008).

• contacting relevant drug manufacturers: Astellas/Gilead

(contacted 15th December 2008; reply received 16th April

2009); Merck Sharp & Dohme (contacted 15th December 2008,

reply received 7th January 2009); Pfizer (contacted 20th January

2009, reply received 22nd January 2009); and Schering-Plough

(contacted 15th December 2008, reply received 5th May 2009).

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by electronic and hand searching

were downloaded to a reference management database and dupli-

cates removed. Two review authors (CCB, KH) were responsible

for handsearching, examination of electronic search results and

identification of potentially eligible studies. Full reports of these

studies were retrieved and reviewed independently for inclusion

by the same two review authors. Any differences were resolved

by discussion with and referral to two further review authors (PP,

TO). We contacted authors for clarification of trial methods and

to request individual patient data when required. The reasons for

exclusion of studies that were reviewed as full texts were recorded.

Data extraction and management

Data were independently extracted from included trials by two

review authors (CCB, KH). A standardised data extraction sheet

was used (Appendix 5; Appendix 6) that covered all outcomes

specified above.

Paediatric data from trials inclusive of children and adults were

extracted, when available. Where paediatric data were not ex-

tractable, authors were contacted for paediatric subgroup analysis.

If paediatric analyses were not available, data were excluded from

our analysis.

Actual numbers were extracted, where possible. When required, we

calculated the actual numbers of patients with specified outcomes

from percentages given in the report of a trial.

Assessment of risk of bias in included studies

Two review authors (CCB, KH) graded the selected studies inde-

pendently. Every study was assessed following the criterion grad-

ing system described in the Cochrane Handbook for Systematic

Reviews of Interventions version 5.0.0 (updated September 2009)

(Higgins 2009). The results were summarised in the risk of bias

tables for each included study. The grading was compared and any

inconsistencies between the review authors in the interpretation

of inclusion criteria and their significance to the selected studies

were discussed and resolved.

The methodological quality of included studies was assessed using

the following six questions.

(1) Was the allocation sequence adequately generated?

Each study was graded as yes (that is allocation sequence was ade-

quately generated with a subsequent low risk of bias), no (that is al-

location sequence was not adequately generated with a subsequent

high risk of bias) or unclear. Adequate allocation sequence genera-

tion included: random number tables, computer random number

generators, coin tossing, shuffling cards or envelopes, throwing

dice or drawing of lots.

(2) Was allocation adequately concealed?

Each study was graded as yes (that is allocation sequence was ad-

equately concealed with a subsequent low risk of bias), no (that

is allocation sequence was not adequately concealed with a subse-

quent high risk of bias) or unclear. Adequate allocation conceal-

ment included: central allocation methods (for example telephone,

web-based and pharmacy-controlled randomisation), sequential

numbered drug containers of identical appearance or sequentially

numbered, opaque or sealed envelopes.

(3) Was knowledge of the allocation interventions adequately pre-

vented during the study?

Each study was graded as yes (that is knowledge of the allocation

interventions was adequately prevented with a subsequent low risk

of bias), no (that is knowledge of the allocation interventions was

not adequately prevented with a subsequent high risk of bias) or

unclear. Knowledge of the allocation interventions was adequately

prevented when blinding of participants and outcome assessors

were maintained for objective outcomes, and both of these groups

plus the healthcare workers involved were blinded for subjective

outcomes.

(4) Were incomplete outcome data adequately addressed?

Each study was graded as yes (that is incomplete outcome data

were adequately address with a subsequent low risk of bias), no

(that is incomplete outcome data were not adequately address with

a subsequent high risk of bias) or unclear. Incomplete outcome

data were adequate addressed if: outcome data were not missing,

the reasons for missing outcome data were unlikely to be related to

true outcomes, missing outcome data were balanced in numbers

across the intervention groups with similar reasons for missing data

across groups, the proportion of missing outcomes compared with

the observed event risk was not enough to have a clinically relevant

impact on the intervention effect estimate (dichotomous outcome

data), the plausible effect size among missing outcomes was not

enough to have a clinically relevant impact on the observed effect

sizes (continuous outcome data) or missing data were imputed



using appropriate methods.

(5) Were reports of the study free of suggestion of selective outcome

reporting?

Each study was graded as yes (that is the reports of the study were

free of suggestion of selective outcome reporting with a subsequent

low risk of bias), no (that is the reports of the study were not free

of suggestion of selective outcome reporting with a subsequent

high risk of bias) or unclear. The reports of the study were free

of suggestion of selective outcome reporting if: the study protocol

was available and all of the study’s pre-specified outcomes that were

of interest in the review had been reported in the pre-specified

way; or if the study protocol was not available, it was clear that the

published reports included all expected outcomes including those

that were pre-specified.

(6) Was the study apparently free of other problems that could put

it at a risk of bias?

We recorded any such problems. Specifically we looked for poten-

tial sources of bias related to the study design, early trial cessation

due to some data-dependent process (for example formal-stopping

rule), extreme baseline imbalance between comparator groups and

financial considerations (for example withdrawal of participants

because they could not pay for drugs). Each study was graded as

yes (that is the study was apparently free of other problems that

could put it at a risk of bias with a subsequent low risk of bias), no

(that is the study was not apparently free of other problems that

could put it at a risk of bias with a subsequent high risk of bias)

or unclear.

Data synthesis

All analyses were performed using the RevMan 5.0 software. As

an estimate of the statistical significance of a difference in propor-

tional outcomes between experimental and control interventions,

we calculated the relative risk (RR) for benefit using antifungal

therapy with 95% confidence intervals (CI). We assumed a sta-

tistically significant difference between the experimental interven-

tion and control intervention if the 95% CI of the RR did not

include the value 1.0. As an estimate of the clinical relevance of

any difference between experimental and control interventions,

we calculated the number needed to treat to benefit (NNTB) and

number needed to treat to harm (NNTH) with 95% CI, as appro-

priate. For continuous variables, we converted data to the mean

difference (MD) using the inverse variance method and calculated

an overall MD. We used a fixed-effect model where there was no

evidence of significant heterogeneity between studies (see below),

and employed a random-effects model when such heterogeneity

was likely.

We pooled data for individual agents as applied to specific fungal

infections or described clinical syndromes (that is candidaemia or

invasive candidiasis, prolonged fever and neutropenia). We con-

sidered the appropriateness of groups of both agents and fungal

types for pooled analysis based on the clinical interpretation of the

comparisons made. Below are details of each outcome considered,

with any specific variation to this approach.

Primary outcomes

1. All-cause mortality (defined as death of any randomised patient

regardless of cause): we intended to extract the hazard ratio (HR)

and variance from trial reports, however only absolute numbers of

case fatalities were reported in the included studies. We therefore

compared the case fatality rates at specific times (end of therapy,

12 weeks and six months) to estimate the RR between groups.

2. IFI-related mortality (defined as death of a patient diagnosed

with IFI whose death was attributable to IFI). IFI-related mortality

was analysed in the same way as for all-cause mortality.

3. Complete resolution of invasive fungal infection (defined as

complete resolution of clinical symptoms, with or without radi-

ological or microbiological findings that led to diagnosis of IFI,

enabling cessation of antifungal medication). We dichotomised

participants into complete resolution and not resolved.

Secondary outcomes

4. Partial resolution of invasive fungal infection (defined as any

improvement in clinical symptoms with or without radiological

findings that led to diagnosis of IFI yet not fulfilling criteria for

complete resolution).

5. Resolution of fever in suspected fungal infection (defined as

absence of temperature > 38 °C for more than 72 hours or another

closely-related definition of resolution of fever).

6. Progression of disease requiring change or addition of an anti-

fungal agent (defined as progression of existing symptoms, with

or without radiological or microbiological findings, that were of

enough concern for a clinician to change antifungal dose or add a

new antifungal agent).

7. Breakthrough fungal infection requiring change or addition of

an antifungal agent (defined as new clinical symptoms or signs,

with or without radiological or microbiological findings, that were

of enough concern for clinicians to change antifungal dose or add

a new antifungal agent).

8. Any clinically significant adverse reactions attributed to the

antifungal agent resulting in discontinuation, dose reduction or

change in the therapy.

9. Any adverse reactions attributed to the antifungal agent includ-

ing:

a. abnormal renal function (a number of definitions were accepted

including a raised creatinine, a reduced glomerular filtration rate or

creatinine clearance as compared with normal or baseline values);

b. electrolyte imbalance such as hypokalaemia;

c. abnormal hepatic function (a number of definitions were ac-

cepted including raised transaminases or bilirubin greater than

normal or baseline values for age);

d. infusion-related reactions such as chills, rigors or anaphylaxis;



e. gastrointestinal disturbances such as nausea, vomiting or diar-

rhoea;

f. neurological disturbances such as blurred vision or dizziness;

g. haematological disturbances such as anaemia, granulocytopenia

or thrombocytopenia.

10. Length of stay (days). We intended to compare mean length

of stay between the groups.

11. Quality of life (QOL). We intended to compare mean QOL

scores between the groups.

12. Cost. If available, we intended to discuss the results and impli-

cations of any cost analyses reported in any of the included trials.

Subgroup analysis and investigation of heterogeneity

We examined the data for statistical heterogeneity using the I2

statistic. We considered an I2 greater than 30% as an indication

that an important proportion of the variability between studies

could be due to heterogeneity between studies. In that case, or

when we suspected significant clinical heterogeneity, we consid-

ered the appropriateness of meta-analysis and employed a random-

effects model. In the absence of any such indication, we used a

fixed-effect model. In the presence of important statistical or clin-

ical heterogeneity we also considered the appropriateness of sub-

group analysis for the following factors.

1. Age (infant versus older child).

2. Underlying immunosuppressive condition (e.g. hematopoietic

stem cell transplant, neutropenia, HIV/AIDS, congenital immun-

odeficiency, immunosuppressive medication).

3. Concomitant or pre-existing organ dysfunctions (e.g. renal and

hepatic impairment).

4. Purpose of therapy (antifungal therapy for proven or probable

infection or empiric therapy for suspected infection).

5. Site of infection.

6. Dose of medication.

7. Single agent versus combination therapy.

Sensitivity analysis

We planned to perform sensitivity analyses investigating the effects

of study quality and missing data.

Study quality

If appropriate, we intended to conduct a sensitivity analysis by

study quality based on our estimate of the risk of bias in the ’Risk

of bias’ tables and an assessment of adequate sample size to detect

the clinically important difference in outcome for which the study

was designed.

Missing data

We employed sensitivity analyses using different approaches to

imputing missing data. The best-case scenario assumed that none

of the originally enrolled patients missing from the primary anal-

ysis in the treatment group had the negative outcome of interest

whilst all those missing from the control group did. The worst-

case scenario was the reverse.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

See: Characteristics of included studies; Characteristics of excluded

studies

Results of the search

Trials were selected for inclusion by two review authors (CCB

and KH). There were no disagreements regarding trial inclusion.

A total of 3305 potentially relevant references were reviewed (

Figure 1). A total of 30 trials were retrieved for full text review of

which seven were performed in children or had sufficient paediatric

subgroup analysis, published or available from authors, to satisfy

our inclusion criteria.



Figure 1.

Included studies

Four RCTs enrolling 395 children compared a lipid prepara-

tion of amphotericin B (liposomal amphotericin B or ABCD)

with conventional amphotericin B in the setting of neutropenic

fever persisting for > 72 to 120 hours (that is suspected fun-

gal infection) (Sandler 2000; Prentice 1997; Walsh 1999; White

1998). Three of these trials included both adults and children

(Prentice 1997; Walsh 1999; White 1998). A further trial pub-

lished in abstract form only and enrolling 82 children compared

an echinocandin (caspofungin) and a lipid preparation of ampho-

tericin B (liposomal amphotericin B) in children with neutropenic

fever persistent for > 96 hours (that is suspected fungal infection)

(Maertens 2007). A single trial enrolling 109 neonates and chil-

dren compared an echinocandin (micafungin) with a lipid prepa-

ration of amphotericin B (liposomal amphotericin B) in children

with invasive candidiasis (that is proven invasive fungal infection)

(Queiroz-Telles 2008). Lastly, a trial enrolling 43 children com-

pared two azole agents (enteral itraconazole and enteral flucona-

zole) in children with candidaemia (that is proven invasive fungal

infection) (Mondal 2004).

Excluded studies

Studies were excluded if they were not randomised (n = 4) (Ellis

1995; Khayat 2005; Wheat 2001; Yao 2000) and enrolled only

neonates or adults (n = 2) (Driessen 1996; Rex 1994). Two stud-

ies were excluded as they were duplicate publications of Queiroz-

Telles (Arrietta 2006; Arrietta 2007). Studies which enrolled both

children and adults were further excluded if specific paediatric in-

formation was not available from the text, authors or drug com-

panies (n = 15) (Bodhe 2002; Bowden 2002; Cornely 2007; Ellis

1998; Galgiani 2000; Herbrecht 2002; Kim 2007; Kullberg 2005;

Pizzo 1982; Shikanai-Yasuda 2002; Viscoli 1996; Walsh 2002;

Wang 2007; Wingard 2000; Winston 2000).

Risk of bias in included studies

There was substantial variation in the risk of bias of studies in-

cluded. The risk of bias was low in RCTs performed by Walsh

1999, White 1998, Queiroz-Telles 2008 and Mondal 2004.



Prentice 1997, the largest of the paediatric trials published, con-

ducted an open-label RCT. The outcome data were difficult to

extract from the published paper as whole numbers were not in-

cluded in the text and were not available from authors. Further-

more, it was not stated in the report why all patients were not

included in the analysis of all safety endpoints. Sandler 2000

conducted a double-blind RCT, however insufficient data on the

methods of sequence generation and allocation concealment could

be extracted from the report. Maertens 2007 has only been pub-

lished in abstract form and, as a result, details about the trial meth-

ods and results (including absolute numbers) were limited.

Effects of interventions

Primary outcomes

1. Mortality (all cause)

Lipid preparations of amphotericin B compared with

conventional amphotericin B in children with prolonged

fever and neutropenia (suspected fungal infection;

Comparison 1, Outcome 1)

See Analysis 1.1; Table 1

Table 1. Effects of interventions

Indication Prolonged fever and neutropenia

(suspected IFI)

Candidaemia / Invasive Candidiasis

(proven IFI)

Comparisons 1. Lipid preparations of

amphotericin B com-

pared with conventional

amphotericin B

2. Echinocandin com-

pared with lipid prepara-

tions of amphotericin B

3. Echinocandin com-

pared with lipid prepara-

tions of amphotericin B

4. Fluconazole com-

pared with itraconazole

1. Mortality (all cause) RR = 0.73 (95% CI 0.17

to 3.11), P = 0.67 (

Analysis 1.1)

- RR = 1.05 (95% CI 0.53

to 2.02), P = 0.91 (

Analysis 3.1)

RR = 0.52 (95% CI 0.11

to 2.56), P = 0.42 (

Analysis 4.1)

2. Mortality (related to

fungal infection)

RR = 0.20 (95% CI 0.01

to 3.98), P = 0.29 (

Analysis 1.2)

- RR = 1.38 (95% CI 0.33

to 5.89), P = 0.66 (

Analysis 3.2)

RR = 1.05 (95% CI 0.07

to 15.69), P = 0.97). (

Analysis 4.2)

3. Complete resolution

of fungal infection

RR = 1.50 (95% CI 0.18

to 12.46), P = 0.71 (

Analysis 1.3)

- RR = 0.88 (95% CI 0.68

to 1.13), P = 0.49 (

Analysis 3.3)

RR = 0.99 (95% CI 0.74

to 1.32), P = 0.94 (

Analysis 4.3)

4. Partial resolution of

fungal infection

- - - -

5. Resolution of fever in

suspected fungal infec-

tion

RR = 1.23 (95% CI 1.00

to 1.52), P = 0.05, I 2=

0% (Analysis 1.5)

RR = 1.34 (95% CI 0.70

to 2.56), P = 0.38. (

Analysis 2.5)

- -

6. Progression of disease

requiring change or ad-

dition of an antifungal

agent

- - - -



Table 1. Effects of interventions (Continued)

7. Breakthrough fun-

gal infection requiring

change or addition of an

antifungal agent

RR = 0.67 (95% CI 0.24

to 1.84), P = 0.43, I2 =

0% (Analysis 1.7)

RR = 0.15 (95% CI 0.01

to 3.61), P = 0.24 (

Analysis 2.7)

- -

8. Any clinically signif-

icant adverse reactions

attributed to the anti-

fungal agent resulting in

discontinuation, dose re-

duction or change in the

therapy

- - RR = 0.35 (95% CI 0.04

to 3.22), P = 0.35 (

Analysis 3.8)

-

9. Any adverse reactions

attributed to the antifun-

gal agent (total)

RR = 0.49 (95% CI 0.21

to 1.17), P = 0.11, I2 =

86% (Analysis 1.9)

- RR = 0.86 (95% CI 0.53

to 1.38), P = 0.53 (

Analysis 3.9)

-

9a. Abnormal renal func-

tion

RR = 0.43 (95% CI 0.21

to 0.90), P = 0.02, I2 =

59% (Analysis 1.10)

- - RR = 0.71 (95% CI 0.13

to 3.72), P = 0.68 (

Analysis 4.10)

9b. Elec-

trolyte imbalance such as

hypokalaemia

RR = 0.71 (95% CI 0.45

to 1.14), P = 0.16, I2 =

54% (Analysis 1.11)

- RR = 0.47 (95% CI 0.18

to 1.27), P = 0.14 (

Analysis 3.11)

RR = 1.06 [95% CI 0.25

to 4.54], P = 0.94 (

Analysis 4.11)

9c. Abnormal hepatic

function

RR = 1.12 (95% CI 0.74

to 1.71), P = 0.59, I2=

0% (Analysis 1.12)

- RR = 1.93 (95% CI 0.19

to 20.12), P = 0.58 (

Analysis 3.12)

RR = 1.06 (95% CI 0.07

to 15.62), P = 0.97 (

Analysis 4.12)

9d. Infusion-related re-

actions such as chills, rig-

ors or anaphylaxis

see text; Effects of

interventions

- RR = 0.73 (95% CI 0.30

to 1.77), P = 0.48 (

Analysis 3.13)

-

9e. Gastrointestinal dis-

turbances such as nausea,

vomiting or diarrhoea

- - Vomiting: RR = 1.19

(95% CI 0.46 to 3.04),

P = 0.72 (Analysis 3.14)

Diarrhoea: RR = 0.83

(95% CI 0.24 to 2.92),

P = 0.77 (Analysis 3.14)

-

9f. Neurological distur-

bances such as blurred vi-

sion or dizziness

- - - -

9g. Haematological dis-

turbances

such as anaemia, gran-

ulocytopaenia or throm-

- - RR = 1.56 (95% CI 0.60

to 4.07), P = 0.37 (

Analysis 3.16)

-



Table 1. Effects of interventions (Continued)

bocytopaenia

10. Length of stay - - - -

11. Quality of life - - - -

12. Cost - - - -

Four trials compared a lipid preparation of amphotericin B

with conventional amphotericin B in febrile neutropenic children

(Prentice 1997; Sandler 2000; Walsh 1999; White 1998). At-

tempts were made to obtain these data from all authors, only data

from Walsh 1999 were available for analysis of all-cause mortality.

This trial reported that seven children died during the course of

the study; 3 of 48 children (6.3%) in the liposomal amphotericin

group (3 mg/kg/day) and 4 of 47 children (8.5%) in the conven-

tional amphotericin group (0.6 mg/kg/day). This difference was

not statistically significant (RR of dying with a lipid preparation

was 0.73, 95% CI 0.17 to 3.11, P = 0.67).

Prentice 1997 reported that three children died during the trial but

gave no details regarding which antifungal each patient received.

White 1998 and Sandler 2000 did not report mortality endpoints.

Echinocandin compared with lipid preparations of

amphotericin B in children with prolonged fever and

neutropenia (suspected fungal infection; Comparison 2,

Outcome 1)

See Analysis 2.1

One trial, reported in abstract form, compared an echinocandin

(caspofungin 70 mg/m2 on day one followed by 50 mg/m2/day)

with a lipid preparation of amphotericin B (liposomal ampho-

tericin B 3 mg/kg/day) in febrile neutropenic children (Maertens

2007). No deaths were reported in children receiving either drug

therapy up to seven days post-treatment.


amphotericin B in children with candidaemia or invasive

candidiasis (proven fungal infection; Comparison 3,

Outcome 1)


One trial compared an echinocandin (micafungin 2 mg/kg/day)

with a lipid preparation of amphotericin B (liposomal ampho-

tericin B 3 mg/kg/day) in neonates, infants and children with in-

vasive candidiasis (Queiroz-Telles 2008). Queiroz-Telles reported

that whilst receiving treatment, all-cause mortality was 1 of 52

(1.9%) in neonates and children receiving micafungin and 6 of

54 (11.1%) in neonates and children receiving liposomal ampho-

tericin B. During the entire study period, including the 12-week

follow up, all-cause mortality was 13 of 52 (25%) in neonates and

children receiving micafungin and 13 of 54 (24.1%) in those re-

ceiving liposomal amphotericin. This difference was not statisti-

cally significant (RR of dying with micafungin was 1.05, 95% CI

0.53 to 2.02, P = 0.91). Outcome data in neonates could not be

separated from outcome data in infants and children and thus are

included in the analysis.

Fluconazole compared with itraconazole in children with

candidaemia or invasive candidiasis (proven fungal infection;



One trial compared enteral itraconazole (approximately 10 mg/kg/

day) and fluconazole (approximately 10 mg/kg/day) in children

aged one month to 12 years who were admitted to an intensive

care unit with candidaemia (Mondal 2004). Two of 21 children

(9.5%) who received itraconazole and 4 of 22 children (18.2%)

who received fluconazole died during treatment and follow up.

This difference was not statistically significant (RR of dying with

itraconazole was 0.52, 95% CI 0.11 to 2.56, P = 0.42).

2. Mortality (related to fungal infection)






Two trials reported this outcome (Prentice 1997; Walsh 1999),

however only Walsh 1999 reported IFI-related mortality in all

groups. In this trial, 2 of 48 children (4.2%) died with IFI (the

leading cause of death in the conventional amphotericin B group).

No IFI-related deaths were observed in children receiving liposo-

mal amphotericin B. This difference was not statistically signifi-



cant (RR of dying with a lipid preparation was 0.20, 95% CI 0.01

to 3.98, P = 0.29).

Prentice 1997 reported that 1 of 71 children (1.4%) receiving

liposomal amphotericin B died with Candidemia that developed

one day following enrolment. An autopsy revealed Pneumocystiscarinii lung infection. IFI-related mortality was not reported for

the other groups.

Echinocandin compared with lipid preparations of ampho-

tericin B in children with prolonged fever and neutropenia

(suspected fungal infection; Comparison 2, Outcome 2)

No deaths were reported in children receiving either caspofungin

or liposomal amphotericin B up to seven days post-treatment (

Maertens 2007).




Outcome 2)


Queiroz-Telles 2008 reported that fungal infection was considered

by the investigators to have contributed to death in 4 of 52 children

(7.7%) receiving micafungin and 3 of 54 children (5.6%) receiving

liposomal amphotericin B. This difference was not statistically

significant (RR of dying with micafungin was 1.38, 95% CI 0.33

to 5.89, P = 0.66).





Mondal 2004 reported that IFI-related mortality was observed in

1 of 21 children (4.8%) receiving itraconazole and 1 of 22 children

(4.5%) receiving fluconazole. This different was not statistically

significant (RR of dying with itraconazole was 1.05, 95% CI 0.07

to 15.69, P = 0.97).

3. Complete resolution of fungal infection






Resolution of a baseline IFI in febrile neutropenic children was

considered relevant to this outcome. Resolution of fever in neu-

tropenic children was included in outcome 5. Resolution of base-

line IFI was reported in two trials (Prentice 1997; Walsh 1999).

Baseline fungal infection was reported in 2 of 48 children (4.2%)

receiving liposomal amphotericin B compared with 3 of 47 chil-

dren (6.4%) receiving conventional amphotericin B (Walsh 1999).

Resolution of baseline fungal infection was observed in one child

in each treatment group (2.0% and 2.1% respectively). This dif-

ference was not statistically significant (RR of resolution of a base-

line IFI with a lipid preparation was 1.50, 95% CI 0.18 to 12.46,

P = 0.71).

No children in Prentice 1997 had a baseline IFI.




The number of children with baseline IFI was not reported in

Maertens 2007.




Outcome 3)


The primary endpoint of the study performed by Queiroz-Telles

2008 was treatment success (defined by both clinical and myco-

logical responses). Clinical response was defined as a complete or

partial resolution of signs and symptoms. Mycologic response was

defined as eradication or presumed eradication of positive cultures.

Data on the number of children with complete resolution of signs

and symptoms were not available. Treatment success in infants and

children was similar in both groups (micafungin: 28/41 children,

68.3%; liposomal amphotericin B: 34/43 children, 79.1%). This

difference was not statistically significant (RR of treatment success

with micafungin was 0.88, 95% CI 0.68 to 1.13, P = 0.49).

Fluconazole compared with itraconazole in children with can-

didaemia or invasive candidiasis (proven fungal infection;



The primary endpoint of the study performed by Mondal 2004

was treatment success (defined by both clinical and mycological re-

sponses). Treatment success in children was similar in both groups

(itraconazole: 17/21, 81%; fluconazole: 18/22, 82%). This differ-

ence was not statistically significant (RR of treatment success with

itraconazole was 0.99, 95% CI 0.74 to 1.32, P = 0.94).

Secondary outcomes

4. Partial resolution of invasive fungal infection







Partial resolution of a baseline IFI in febrile neutropenia studies

was considered relevant to this outcome.

No children in Prentice 1997 had a baseline IFI. Walsh 1999,

White 1998 and Sandler 2000 did not report this outcome.




The number of children with baseline IFI was not reported by

Maertens 2007.


tericin B in children with candidaemia or invasive candidiasis

(proven fungal infection; Comparison 3, Outcome 4)

Queiroz-Telles 2008 did not separately report this outcome. They

combined complete and partial clinical response with mycologic

response into treatment success (see Analysis 3.3).

Fluconazole compared with itraconazole in children with can-

didaemia or invasive candidiasis (proven fungal infection;


Mondal 2004 did not report on this outcome.

5. Resolution of fever in suspected fungal infection






Two studies reported resolution of fever in children with prolonged

fever and neutropenia (Prentice 1997; Walsh 1999). Prentice 1997

considered treatment response as at least three consecutive days

without fever (at 38 °C). Forty-five of 70 children (64.3%) who re-

ceived liposomal amphotericin B (1 mg/kg/day) and 45 of 71 chil-

dren (63.4%) who received liposomal amphotericin B (3 mg/kg/

day) responded to treatment. Thirty-one of 61 children (50.8%)

randomised to conventional amphotericin B (1 mg/kg/day) re-

sponded to treatment. Walsh 1999 included fever resolution in

the composite endpoint used to define treatment success. Thirty-

two of 48 children (66.7%) who received liposomal amphotericin

B and 26 of 47 children (55.3%) who received conventional am-

photericin B had resolution of their fever during neutropenia.

Pooled analysis using paediatric data from Prentice 1997 and

Walsh 1999 was performed. The probability of fever resolution

with a lipid preparation compared with conventional ampho-

tericin B was of borderline significance (RR of fever resolution

with a lipid preparation was 1.23, 95% CI 1.00 to 1.52, P = 0.05)

(Analysis 1.5). No significant heterogeneity was observed (I 2=

0%).




Outcome 5)


Resolution of fever in suspected fungal infection (defined as a tem-

perature below 38 °C for at least 48 hours) was observed in 24

of 56 children (43%) receiving caspofungin and 8 of 25 children

(32%) receiving liposomal amphotericin B (Maertens 2007). This

difference was not statistically significant. The RR of fever resolu-

tion with caspofungin was 1.34 (95% CI 0.70 to 2.56, P = 0.38).




Outcome 5)

Queiroz-Telles 2008 did not report on resolution of fever.




Mondal 2004 reported time to clinical cure (defined as com-

plete resolution of fever and improvement in signs and symptoms

present at time of enrolment). Mean time to clinical cure was not

significantly different: 7.9 ± 1.3 days (itraconazole) compared with

7.0 ± 2.6 days (fluconazole).

6. Progression of disease requiring change or addition of an

antifungal agent





This outcome was not reported in sufficient detail in any paper

(Prentice 1997; Sandler 2000; Walsh 1999; White 1998).




Outcome 6)

This outcome was not reported in Maertens 2007.






Outcome 6)

Mycologic persistence at the end of therapy was observed in 7 of

45 (15.6%) of neonates, infants and children receiving both mica-

fungin and liposomal amphotericin B (Queiroz-Telles 2008). In-

sufficient published data were available to exclude neonates from

these analyses. Antifungal drugs administered following trial ther-

apy were not reported on.




No children had progression of disease requiring change or addi-

tion of an antifungal agents (Mondal 2004).

7. Breakthrough fungal infection requiring change or

addition of an antifungal agent






Three trials reported breakthrough fungal infection in febrile neu-

tropenic children (Prentice 1997; Sandler 2000; Walsh 1999). One

of 61 children (1.6%) who received conventional amphotericin

B, 3 of 71 children (4.2%) who received liposomal amphotericin

B (1 mg/kg/day) and 2 of 71 children (2.8%) who received lipo-

somal amphotericin B (3 mg/kg/day) developed a breakthrough

fungal infection (Prentice 1997). Six of 47 (12.8%) children in

the conventional amphotericin B arm and 3 of 48 (6.3%) who

received liposomal amphotericin B developed a breakthrough IFI

(Walsh 1999). One of 26 (3.8%) children who received ABCD

(4 mg/kg/day) developed IFI compared with 2 of 22 (9.1%) who

received conventional amphotericin B (0.8 mg/kg/day) (Sandler

2000).

Pooled analyses of data from Prentice 1997, Walsh 1999 and

Sandler 2000 were performed. No significant differences in break-

through fungal infection requiring change or addition of an anti-

fungal agent were observed when lipid preparations and conven-

tional amphotericin B were compared in febrile neutropenic chil-

dren (RR 0.67, 95% CI 0.24 to 1.84, P = 0.43) (Analysis 1.7).

No heterogeneity was observed (I2 = 0%, P = 0.46).




Outcome 7)


Breakthrough fungal infection was not observed in children re-

ceiving caspofungin. One of 25 children (4%) receiving liposo-

mal amphotericin had a breakthrough fungal infection (Maertens

2007). This difference was not statistically significant (RR of

breakthrough fungal infection caspofungin was 0.15, 95% CI 0.01

to 3.61, P = 0.24).




Outcome 7)

No breakthrough fungal infection was observed whilst on therapy

in infants and children receiving either treatment (Queiroz-Telles

2008).




No breakthrough fungal infection was observed whilst on therapy

in infants and children receiving either treatment (Mondal 2004).

8. Any clinically significant adverse reactions attributed to

the antifungal agent resulting in discontinuation, dose

reduction or change in the therapy





Eight of 48 children (16.7%) receiving liposomal amphotericin B

and 7 of 47 children (14.9%) receiving conventional amphotericin

B discontinued therapy for reasons of toxicity or lack of efficacy

(Walsh 1999). This difference was not statistically significant (RR

of therapy discontinuation was 1.12, 95% CI 0.44 to 2.84, P

= 0.81). The proportion of children who discontinued therapy

or had a dose reduction or change in therapy due to clinically

significant adverse reactions was not reported. This outcome was

not reported by Prentice 1997, White 1998 or Sandler 2000.




Outcome 8)



Discontinuation due to drug-related adverse events was noted in

4% of children receiving caspofungin compared with 12% receiv-

ing liposomal amphotericin B (Maertens 2007). Absolute num-

bers were not published.




Outcome 8)


One of 52 neonates, infants and children (1.9%) receiving mica-

fungin and 3 of 54 (5.6%) neonates, infants and children receiving

liposomal amphotericin B had a treatment-related adverse event

that led to treatment discontinuation (Queiroz-Telles 2008). This

difference was not statistically significant. The RR of a treatment-

related adverse event that led to treatment discontinuation with

micafungin was 0.35 (95% CI 0.04 to 3.22, P = 0.35). Treatment

discontinuation (regardless of causality) occurred less frequently

with micafungin (2/52, 3.8%) compared with liposomal ampho-

tericin B (9/54, 16.7%, P = 0.05 as reported).




No drug discontinuation was observed secondary to adverse reac-

tions in children receiving either therapy (Mondal 2004).


amphotericin B in children (any indication; Comparison 5,

Outcome 8)

See Analysis 5.8

Clinically significant adverse reactions attributed to the antifungal

agent resulting in discontinuation, dose reduction or change in

therapy were assessed using data from children with fever and neu-

tropenia (Maertens 2007) and candidaemia or invasive candidiasis

(Queiroz-Telles 2008) and receiving either echinocandins or lipid

preparations. Absolute numbers were not published by Maertens

2007 so, for pooled analyses, absolute numbers have been calcu-

lated from percentages. There was no significant heterogeneity (I2= 0%) and no significant differences were observed (RR 0.32,

95% CI 0.08 to 1.27, P = 0.1) (Analysis 5.8).

9. Any adverse reactions attributed to the antifungal agent

(total)






Walsh 1999 and Prentice 1997 reported total adverse reactions

attributed to the antifungal agents. Twenty-four of 48 (50%) chil-

dren who received liposomal amphotericin B and 32 of 47 (68.1%)

children who received conventional amphotericin B experienced

a drug-related adverse event (Walsh 1999). Serious drug-related

adverse events were reported in 12 children in each treatment

group. Six per cent of children receiving liposomal amphotericin

(1 mg/kg/day), 17% of children receiving liposomal amphotericin

(3 mg/kg/day) and 36% receiving conventional amphotericin B

groups had an adverse reaction attributable to the antifungal agent

(Prentice 1997). Severe drug-related adverse events were reported

in 1% of both cohorts receiving liposomal amphotericin B and 8%

receiving conventional amphotericin B. Absolute numbers were

not published by Prentice 1997 so, for pooled analyses, absolute

numbers have been calculated from percentages.

Pooled analysis of Prentice 1997 and Walsh 1999 was performed.

No significant differences in total adverse reactions attributed

to the antifungal agent were observed when lipid preparations

and conventional amphotericin B were compared in febrile neu-

tropenic children (RR 0.49, 95% CI 0.21 to 1.17, P = 0.11)

(Analysis 1.9). Significant heterogeneity was observed (I2 = 86%,

P = 0.008).




Outcome 9)

Drug-related adverse events were noted in 48% of children re-

ceiving caspofungin compared with 46% receiving liposomal am-

photericin B (Maertens 2007). Serious treatment-related adverse

events were reported in 2% of children receiving caspofungin com-

pared with 11% receiving liposomal amphotericin B. Absolute

numbers were not published.




Outcome 9)


Nineteen of 52 (36.5%) children who received micafungin com-

pared with 23 of 54 (42.6%) receiving liposomal amphotericin B

reported a treatment-related adverse event (Queiroz-Telles 2008).

This difference was not statistically significant (RR of any treat-

ment related adverse event with micafungin was 0.86, 95% CI

0.53 to 1.38, P = 0.53). Serious treatment-related adverse events

were reported in 2 of 52 children (3.8%) who receiving micafun-

gin compared with 5 of 54 children (9.3%) who received liposo-

mal amphotericin B.






One patient developed gastrointestinal side effects in the trial

(Mondal 2004). The therapy received by the patient was not re-

ported. The total number of treatment-related adverse events with

either therapy was not reported.


amphotericin B in children (any indication: Comparison 5,

Outcome 9)

See Analysis 5.9

Using data from children with fever and neutropenia (Maertens

2007) and candidaemia or invasive candidiasis (Queiroz-Telles

2008), echinocandins were compared with lipid preparations

with regard to clinically significant adverse reactions attributed to

the antifungal agent. Absolute numbers were not published by

Maertens 2007 so, for pooled analyses, absolute numbers have

been calculated from percentages. No significant differences were

observed (RR of a clinically significant adverse reaction with an

echinocandin was 0.94, 95% CI 0.67 to 1.33, P = 0.73) (Analysis

5.9). There was no significant heterogeneity (I 2= 0%).

a. Abnormal renal function




Comparison 1, Outcomes 10)

See Analysis 1.10; Table 1; Analysis 6.1; Analysis 7.1

All four trials comparing lipid preparations of amphotericin B and

conventional amphotericin B in children with fever and neutrope-

nia reported nephrotoxicity endpoints (Prentice 1997; Sandler

2000; Walsh 1999; White 1998). Nephrotoxicity (defined as ≥

100% rise in serum creatinine) occurred in 10 of 48 children

(20.1%) receiving liposomal amphotericin and 9 of 47 children

(19.1%) receiving conventional amphotericin B (Walsh 1999).

Nephrotoxicity (defined as ≥ 100% rise in serum creatinine) oc-

curred in 8% of children receiving liposomal amphotericin B (1

mg/kg/day), 11% receiving liposomal amphotericin B (3 mg/kg/

day) and 21% of children receiving conventional amphotericin B

(Prentice 1997). Absolute numbers were not published by Prentice

1997 so, for pooled analyses, absolute numbers have been calcu-

lated from percentages. Three of 25 children (12.0%) receiving

ABCD (4 mg/kg/day in both trials) and 11 of 21 (52.4%) receiv-

ing conventional amphotericin B (0.8 mg/kg/day in both trials)

developed nephrotoxicity (Sandler 2000; White 1998). Nephro-

toxicity was defined in both trials as doubling in serum creatinine

level from baseline, an increase of 88 mmol/L (1.0 mg/dL) in the

serum creatinine level from baseline, or a ≥ 50% decrease in the

calculated creatinine clearance from baseline during study drug

administration. It should be noted that rates of nephrotoxicity in

White 1998 and Sandler 2000 were the same. As many children

enrolled in the study were treated at the same institutions during

similar time periods, it is possible that data have been duplicated

in these publications. Clarification from the authors was not forth-

coming.

Pooled analysis of Prentice 1997, Walsh 1999, White 1998 and

Sandler 2000 was performed. Treatment with a lipid preparation

decreased the risk of nephrotoxicity by 57% compared with con-

ventional amphotericin B (RR 0.43, 95% CI 0.21 to 0.90, P =

0.02) (Analysis 1.10). Substantial heterogeneity was observed (I2 = 59%, P = 0.06). The number of children needing to receive

a lipid preparation of amphotericin B to avoid one child devel-

oping nephrotoxicity was 6 (95% CI 3.9 to 11.8). A sensitivity

analysis was performed to investigate the effects of missing data.

Lipid preparations were significantly less toxic in both best-case

(RR 0.42, 95% CI 0.20 to 0.89, P = 0.02) (Analysis 6.1) and

worst-case scenarios (RR 0.50, 95% CI 0.28 to 0.90, P = 0.02)

(Analysis 7.1). If White 1998 or Sandler 2000 were excluded from

the analysis (allowing for the possibility of duplicated reporting)

the treatment effect was not preserved (RR 0.51, 95% CI 0.22 to

1.18, P = 0.12).




Outcome 10)

Maertens 2007 did not report on abnormal renal function.




Outcome 10)

No children receiving micafungin or liposomal amphotericin B

developed nephrotoxicity (defined as ≥ 100% rise in serum crea-

tinine) (Queiroz-Telles 2008).



Comparion 4, Outcome 10)


Two of 17 children (11.8%) receiving itraconazole group and 3 of

18 (16.7%) receiving fluconazole experienced a serum creatinine >

1 mg/dL on therapy. This difference was not statistically significant

(RR of nephrotoxicity with itraconazole was 0.71, 95% CI 0.13

to 3.72, P = 0.68). Doubling of serum creatinine was not reported

(Mondal 2004).



b. Electrolyte imbalance such as hypokalaemia





See Analysis 1.11; Table 1;

Three trials comparing a lipid preparation to conventional am-

photericin B in children with fever and neutropenia reported elec-

trolyte disturbances (Prentice 1997; Walsh 1999; White 1998).

Eighteen of 48 children (37.5%) in the liposomal amphotericin

group and 22 of 47 children (46.8%) receiving conventional

amphotericin B developed hypokalaemia < 3.0 mmol/L (Walsh

1999). Thirteen of 25 children (52.0%) receiving ABCD and 11

of 21 children (52.4%) receiving conventional amphotericin B

developed hypokalemia (Sandler 2000). Hypokalemia was not de-

fined in this paper. Ten pe rcent of children in the liposomal am-

photericin B (1 mg/kg/day) group, 11% in the 3 mg/kg/d liposo-

mal amphotericin B group and 26% in the conventional ampho-

tericin B group developed hypokalemia < 2.5 mmol/L (Prentice

1997). Absolute numbers were not published so, for pooled anal-

yses, absolute numbers have been calculated from percentages.

Pooled analysis of Prentice 1997, Walsh 1999 and Sandler 2000

were performed. No differences in the rate of hypokalaemia were

observed with lipid preparations compared with conventional am-

photericin B (RR 0.71, 95% CI 0.45 to 1.14, P = 0.16) (Analysis

1.11). Substantial heterogeneity was observed (I2 = 54%, P = 0.11).

These pooled data need to be interpreted with caution given the

variable case definition used in different trials.




Outcome 11)

Maertens 2007 did not report on electrolyte imbalance.


amphotericin B in children with candidemia or invasive


Outcome 11)


FIve of 52 neonates, infants and children (9.6%) receiving mica-

fungin developed hypokalaemia (not defined) compared with 11

of 54 (20.4%) receiving liposomal amphotericin B (Queiroz-Telles

2008). This difference was not statistically significant (RR of hy-

pokalaemia with micafungin was 0.47, 95% CI 0.18 to 1.27, P =

0.14).


candidemia or invasive candidiasis (proven fungal infection;



Three of 17 (17.6%) children receiving itraconazole developed

hypokalaemia (< 3.5 mmol/L) compared with 3 of 18 (16.7%)

receiving fluconazole (Mondal 2004). This difference was not sta-

tistically significant (RR of hypokalaemia with itraconazole was

1.06, 95% CI 0.25 to 4.54, P = 0.94).

c. Abnormal hepatic function







photericin B in children with fever and neutropenia reported dis-

turbances in hepatic function (Prentice 1997; Walsh 1999; White

1998). Seventeen of 48 (16.7%) in the liposomal amphotericin

group and 15 of 47 (14.9%) in the conventional amphotericin B

group developed hepatotoxicity, defined as transaminases twice the

normal values for age (Walsh 1999). No children receiving either

ABCD or conventional amphotericin B developed hepatotoxicity

(not defined) (Sandler 2000). Seventeen per cent of children re-

ceiving liposomal amphotericin B (1 mg/kg/day), 22% receiving

liposomal amphotericin B and 17% receiving conventional am-

photericin B group developed transaminitis (≥ 110 U/L) (Prentice

1997). Eleven per cent of children receiving liposomal ampho-

tericin B (1 mg/kg/day), 12% receiving liposomal amphotericin B

and 10% receiving conventional amphotericin B group developed

hyperbilirubinaemia (≥ 35 µmol/L). Absolute numbers were not

published by Prentice 1997 so, for pooled analyses, absolute num-

bers have been calculated from percentages.

Pooled analysis of Prentice 1997, Walsh 1999 and Sandler 2000

was performed. No significant differences in the rate of hepatotox-

icity were observed with lipid preparations when compared with

conventional amphotericin B (RR 1.12, 95% CI 0.74 to 1.71, P

= 0.59) (Analysis 1.12). There was no significant heterogeneity (I2 = 0%). These pooled data need to be interpreted with caution

given the variable case definition used in the different trials.

Echinocandin compared with Lipid preparations of

Amphotericin B in children with prolonged fever and


Outcome 12)

Maertens 2007 did not report on abnormal hepatic function.






Outcome 12)


Two of 29 (6.9%) neonates, infants and children receiving mica-

fungin developed a raised alanine aminotransferase (ALT) (> 2.5

times upper limit of normal) compared with 1 of 28 (3.6%) re-

ceiving liposomal amphotericin B. This difference was not sta-

tistically significant (RR of developing hepatotoxicity with mica-

fungin was 1.93, 95% CI 0.19 to 20.12, P = 0.58). Two of 30

(6.7%) neonates, infants and children receiving micafungin de-

veloped a raised aspartate aminotransferase (AST) (> 2.5 times

upper limit of normal) compared with 1 of 25 (4.0%) receiving

liposomal amphotericin B. No children receiving either therapy

developed hyperbilirubinaemia (> 2.5 times upper limit of nor-

mal) (Queiroz-Telles 2008).





One of 17 (5.9%) children receiving itraconazole had a serum

bilirubin < 2mg/dL following therapy compared with none receiv-

ing fluconazole. One of 18 (5.6%) children receiving fluconazole

had a serum glutamic-oxaloacetic transaminase (SGOT) > 40 IU/

L following fluconazole compared with none receiving itracona-

zole (Mondal 2004). This difference was not statistically signifi-

cant (RR of developing hepatotoxicity with itraconazole was 1.06,

95% CI 0.07 to 15.62, P = 0.97).

d. Infusion-related reactions such as chills, rigors or

anaphylaxis







photericin B in children with fever and neutropenia reported infu-

sion-related reactions (Prentice 1997; Walsh 1999; White 1998).

Forty-six of 48 children (95.8%) receiving liposomal amphotericin

and 45 of 47 children (95.7%) receiving conventional ampho-

tericin B had an infusion-related reaction (Walsh 1999). Eleven

of 48 children (22.9%) receiving liposomal amphotericin B and

30 of 47 children (63.8%) receiving conventional amphotericin

B developed infusion-related chills (Walsh 1999). Forty-three of

48 children (89.6%) receiving liposomal amphotericin and 44

of 47 children (93.6%) receiving conventional amphotericin B

developed infusion-related fevers (Walsh 1999). Two of 25 chil-

dren (8.0%) receiving ABCD and 0 of 21 children (0%) receiving

conventional amphotericin B developed chills and rigors (Sandler

2000). Nineteen of 25 children (76.0%) receiving ABCD and 10

of 21 children (47.6%) children receiving conventional ampho-

tericin B developed chills (Sandler 2000). Nineteen of 25 children

(76.0%) receiving ABCD and 17 of 21 children (80.1%) receiv-

ing conventional amphotericin B developed fevers (Sandler 2000).

One per cent of children receiving liposomal amphotericin B (1

mg/kg/day), 1% of children receiving liposomal amphotericin B

(3 mg/kg/day) and 2% of children receiving conventional ampho-

tericin B developed an allergic reaction following drug administra-

tion (Prentice 1997). “Allergic reaction” was not further defined

by the authors.

Given the variation in endpoints reported, definitions used and the

previously demonstrated differences in infusion-related reactions

between liposomal amphotericin B and ABCD, these data have

not been pooled. Analysis of individual studies (Sandler 2000)

identified an increased risk of chills with ABCD compared with

conventional amphotericin (RR 1.76, 95% CI 1.09 to 2.85, P =

0.02). Liposomal amphotericin B was associated with a decreased

risk of chills compared with conventional amphotericin B (RR

0.37, 95% CI 0.21 to 0.64, P = 0.0005) (Walsh 1999). No other

significant differences were identified.




Outcome 13)

Maertens 2007 did not report on infusion-related reactions.




Outcome 13)


An infusion-related reaction was reported in 7 of 52 (13.5%)

neonates, infants and children receiving micafungin compared

with 10 of 54 (18.5%) receiving liposomal amphotericin B

(Queiroz-Telles 2008). This difference was not statistically signif-

icant (RR of an infusional-related reaction with micafungin was

0.73, 95% CI 0.30 to 1.77, P = 0.48).




Chills, fever and dyspnoea did not complicate therapy in any chil-

dren receiving itraconazole or fluconazole (Mondal 2004).



e. Gastrointestinal disturbances such as nausea, vomiting or

diarrhoea





Only one trial comparing a lipid preparation to conventional am-

photericin B in children with fever and neutropenia reported gas-

trointestinal disturbances (Sandler 2000). Vomiting was reported

in 14.8% of children who received ABCD compared with 18.2%

who received conventional amphotericin B. Nausea was reported

in 11.1% of children who received ABCD and 9.1% who re-

ceived conventional amphotericin B. Absolute numbers were not

reported.




Outcome 14)

Maertens 2007 did not report on gastrointestinal disturbances.




Outcome 14)


Vomiting was reported in 8/52 (15.4%) of neonates, infants and

children receiving micafungin compared with 7/54 (13%) receiv-

ing liposomal amphotericin B (Queiroz-Telles 2008). This differ-

ent was not statistically significant. The RR of vomiting with mi-

cafungin was 1.19 (95% CI 0.46 to 3.04, P = 0.72). Diarrhoea was

reported in 4/52 (7.7%) of neonates, infants and children receiv-

ing micafungin compared with 5/54 (9.3%) receiving liposomal

amphotericin B. This difference was not statistically significant

(RR of diarrhoea with micafungin was 0.83 (95% CI 0.24 to 2.92,

P = 0.77).




One patient developed gastrointestinal side effects however it was

not reported whether they received itraconazole or fluconazole

(Mondal 2004).

f. Neurological disturbances such as blurred vision or

dizziness





No study reported this outcome (Prentice 1997; Sandler 2000;

Walsh 1999; White 1998).




Outcome 15)

Maertens 2007 did not report on neurological disturbances.




Outcome 15)

No infants or children with neurological disturbances were re-

ported in either treatment arms (Queiroz-Telles 2008).




Mondal 2004 did not report on neurological disturbances.

g. Haematological disturbances such as anaemia,

granulocytopaenia or thrombocytopaenia





No study reported this outcome (Prentice 1997; Sandler 2000;

Walsh 1999; White 1998).




Outcome 16)

Maertens 2007 did not report on haematological disturbances.






Outcome 16)


Anaemia (not defined) was reported in 9/52 (17.3%) of neonates,

infants and children receiving micafungin compared with 6/

54 (11.1%) receiving liposomal amphotericin B (Queiroz-Telles

2008). This difference was not statistically significant (RR of

anaemia with micafungin was 1.56, 95% CI 0.60 to 4.07, P =

0.37).




Mondal 2004 did not report on haematological disturbances.

10. Length of stay (days)

No trials reported on length of stay.

11. Quality of life (QOL)

No trials reported on quality of life.

12. Cost (Outcome 19)

No trials reported on cost of antifungal therapy.

D I S C U S S I O N

Using data from RCTs comparing antifungal agents in adult pop-

ulations is a challenge for paediatricians due to differences in com-

parators, conditions, populations, power and duration of follow

up. The paucity of paediatric studies compounds this. Limited

data are therefore available to guide paediatricians when managing

neonates and children with invasive fungal infection.

Data were available from seven randomised controlled trials en-

rolling children from two distinct populations, children with can-

didaemia and invasive candidiasis (that is proven invasive fun-

gal infection) and children with prolonged fever and neutropenia

(that is suspected invasive fungal infection). Lipid preparations

of amphotericin B (liposomal amphotericin B or amphotericin B

colloidal dispersion (ABCD)) were compared with conventional

amphotericin B in children with prolonged neutropenic fever;

echinocandins (caspofungin and micafungin) were compared with

liposomal amphotericin B in children with prolonged neutropenic

fever and candidaemia or invasive candidiasis respectively; and

itraconazole was compared with fluconazole in children with can-

didaemia and invasive candidiasis. No differences in all-cause mor-

tality and other primary endpoints (invasive fungal infection (IFI)

related mortality or complete resolution of fungal infections) were

observed in indiividual trials or pooled analyses.

The only significant differences in secondary endpoints identified

in children with prolonged fever and neutropenia were i) reduced

nephrotoxicity with lipid preparations of amphotericin B (lipo-

somal amphotericin B or ABCD) compared with conventional

amphotericin B; ii) reduced chills with liposomal amphotericin B

when compared with conventional amphotericin B; and iii) in-

creased chills with ABCD compared with conventional ampho-

tericin B. No significant differences were identified in other analy-

ses. The finding of reduced nephrotoxicity with lipid preparations

of amphotericin B needs to be interpreted with caution as signifi-

cant heterogeneity was observed (I 2 = 59%) and it is possible that

duplicated reporting (Sandler 2000; White 1998) occurred.

This is the first attempt to use a meta-analytical approach to guide

antifungal use in paediatric patients. The comprehensive search

for published trials, rigorous attempts to obtain unpublished pae-

diatric data, use of strict outcome definitions and analysis of both

individual drugs and drug classes strengthen the findings of the

analysis.The studies included were of moderate to high quality

as sequence generation was judged to be adequate in five studies,

allocation concealment was present in five and blinding used in

six of seven included trials.

Numerous limitations exist. In pooling data from the seven trials,

low numbers limited power to detect real differences between com-

parators. Despite attempts to obtain unpublished data, included

in combined adult and paediatric trials, this was not always pos-

sible. Paediatric patients were enrolled in studies comparing con-

ventional amphotericin B with placebo in the setting of prolonged

fever and neutropenia (Pizzo 1982); and numerous studies com-

paring amphotericin B based products with triazoles in the set-

ting of prolonged fever and neutropenia (Kim 2007; Viscoli 1996;

Walsh 2002; Winston 2000), candidaemia or invasive candidia-

sis (Kullberg 2005) and invasive aspergillosis (Herbrecht 2002).

Trials comparing amphotericin B preparations and echinocandins

in prolonged fever and neutropenia (Wang 2007) and different

formulations or dosages of amphotericin B products in prolonged

fever and neutropenia (Wingard 2000) and invasive aspergillosis

(Bowden 2002; Cornely 2007; Ellis 1998) also enrolled children.

As paediatric subgroup analysis was not made available for these

trials, it is possible that only significant results have been reported.

Furthermore, as unpublished data were only obtained from one

study in febrile neutropenic participants (Walsh 1999) and one

study in children with candidaemia (Mondal 2004), selective re-

porting may have influenced results. Attempts to overcome this

by comparing mixed studies with children-only studies (data not

shown) were confounded by the different percentages of children

and age ranges in each study. Requests for further data from the



relevant companies, not available at the time of publication, may

be forthcoming and will be included in any further amendments.

Definitions of treatment success and toxicity varied in different

trials making comparison difficult. Differences in duration of fol-

low up in children with fever and neutropenia (seven days in

Sandler 2000; 30 days in Prentice 1997 and Walsh 1999) and

candidaemia or invasive candidiasis (12 weeks in Queiroz-Telles

2008; median eight weeks in Mondal 2004) are another source

of potential bias. The shorter studies may under-report impor-

tant outcomes such as invasive fungal infection, death or toxic-

ity. In most studies in febrile neutropenic participants (including

Maertens 2007; Prentice 1997; Sandler 2000; Walsh 1999; White

1998) treatment success was measured by a composite endpoint.

Key features of the composite endpoints include survival, resolu-

tion of fever and the absence of breakthrough fungal infection.

Definitions varied however between trials. The relevance of the

composite endpoints is debatable, particularly when resolution of

fever is a main contributor (Bennett 2003; de Pauw 2006). Minor

differences in definition of fever may be relevant, and the resolu-

tion of fever is not specific for fungal infection. The power needed

to detect real differences in individual endpoints remains a prob-

lem as most studies are not of adequate size to do this. Pooling

data goes some way to overcoming this. Using data from three

trials of children with febrile neutropenia (Prentice 1997; Sandler

2000; Walsh 1999) greater treatment success was observed with

lipid preparations of amphotericin compared with conventional

amphotericin B deoxycholate (RR 0.72, 95% CI 0.56 to 0.93, P =

0.01, data not shown). This was not defined a priori in our proto-

col and, therefore, we have not presented it in the results. Cautious

interpretation of this finding is necessary as only three trials were

included in the analysis, treatment success was defined differently

in the different trials, different doses of conventional amphotericin

and liposomal amphotericin B were used and no other difference

in efficacy endpoints including mortality and breakthrough fungal

infection were observed. Moreover, as initial placebo-controlled

trials of conventional amphotericin B in prolonged fever and neu-

tropenia were underpowered (EORTC 1989; Pizzo 1982) and re-

cent meta-analyses have demonstrated no survival benefit when

using empiric antifungal therapy (Goldberg 2008), some authors

question the role of empiric antifungal therapy in the setting of

prolonged fever and neutropenia. A pre-emptive approach to di-

agnosis of IFI using biological marks and radiological imaging has

been studied as an alternative to empiric antifungal therapy in pro-

longed febrile neutropenia in adults (Cordonnier 2009; Maertens

2005). In the absence of any paediatric data, it is likely that empiric

antifungal therapy for suspected antifungal infection will continue

to be used in the future.

The analysis of paediatric data yields very similar results to pre-

vious adult studies and meta-analyses. No difference in mortality

has been demonstrated when lipid preparations of amphotericin

B and conventional amphotericin B (Johansen 2000) or ampho-

tericin B based products and echinocandins (Walsh 2004a) are

compared in the setting of prolonged fever and neutropenia. No

difference in mortality has been demonstrated in the setting of

candidaemia or invasive candidiasis when amphotericin B based

products and echinocandins (Kuse 2007; Mora-Duarte 2002) or

different triazole preparations (Kullberg 2005) have been com-

pared. A reduced rate of nephrotoxicity with lipid preparations in

children is consistent with previous adult studies and meta-analy-

ses (Barrett 2003; Girois 2006; Walsh 1999). Children generally

tolerate the renal effects of amphotericin B better than adults due

to increased nephronal reserve (Steinbach 2005b). The relevance

of a doubling of serum creatinine equating to nephrotoxicity is de-

batable, however it was the most commonly used definition. Less

extreme changes in serum creatinine may also be clinically relevant

in certain populations, particularly high-risk patients with multi-

ple co-morbidities receiving concurrent nephrotoxins (for exam-

ple haematopoietic stem cell recipients).

There are numerous deficiencies in the paediatric literature. Pae-

diatric data are insufficient to determine the role of triazole drugs

particularly in children with prolonged fever and neutropenia and

candidaemia or invasive candidiasis. Despite the increasing use

of mould-active triazoles and echinocandins, particularly in chil-

dren with confirmed or suspected invasive mould infections, little

comparative paediatric data exists to guide therapy. The costs of

antifungal agents are real considerations for many centres when

choosing antifungal therapy. No studies specifically addressed this.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

Few significant differences were observed in paediatric antifungal

trials in children with prolonged fever and neutropenia and can-

didaemia or invasive candidiasis. No differences in mortality and

efficacy were observed. Conventional amphotericin B was more

likely to be associated with nephrotoxicity in children than a lipid

preparation. Given the paucity of data and the findings of previ-

ous meta-analyses, it is reasonable to recommend a lipid prepara-

tion of amphotericin B in this population if cost permits. In stud-

ies comparing children receiving an echinocandin and liposomal

amphotericin B, no significant differences in efficacy and toxic-

ity were observed. Echinocandins may be considered for use in

children with fever with neutropenia and candidaemia or invasive

candidiasis as efficacy and safety compared with amphotericin B

based products have been demonstrated.

Implications for research

Numerous questions remain unanswered when managing inva-

sive fungal infection. Further epidemiological studies highlighting

differences between neonates, children and adults with invasive

fungal infection are needed to allow accurate interpretation of the

published literature. Further randomised controlled antifungal tri-



als enrolling children are required. The two recent paediatric stud-

ies (Maertens 2007; Queiroz-Telles 2008) have given hope that

more RCTs in paediatric mycology will be undertaken, enabling

evidence-based choice when selecting an antifungal agent.

A C K N O W L E D G E M E N T S

The authors wish to acknowledge Professor Tania Sorrell, Associate

Professor Katrina Williams and Danielle Wheeler for their critical

review of the protocol.

R E F E R E N C E S

References to studies included in this review

Maertens 2007 {published and unpublished data}

Maertens J, Madero L, Reilly A, Lehrnbecher T, Groll A, Jafri H, et

al.A randomized, double blind, multicenter trial of caspofungin

(CAS) versus (vs) liposomal amphotericin B (LAMB) for empirical

antifungal therapy (EAFRx) of pediatric patients (pts) with

persistent fever & neutropenia (PFN). Program and abstracts of the

47th Annual Interscience Conference on Antimicrobial Agents and

Chemotherapy. Chicago, USA [Abstract M-621]. 2007 Sept.

Mondal 2004 {published and unpublished data}

Mondal RK, Singhi SC, Chakrabarti A, Jayashree M. Randomized

comparison between fluconazole and itraconazole for the treatment

of candidemia in a pediatric intensive care unit: a preliminary

study. Pediatric Critical Care Medicine 2004;5(6):561–5.

Prentice 1997 {published data only (unpublished sought but not used)}

Prentice HG, Hann IM, Herbrecht R, Aoun M, Kvaloy S,

Catovsky D, et al.A randomized comparison of liposomal versus

conventional amphotericin B for the treatment of pyrexia of

unknown origin in neutropenic patients. British Journal of

Haematology 1997;98(3):711–8.

Queiroz-Telles 2008 {published data only (unpublished sought but not

used)}

Queiroz-Telles F, Berezin E, Leverger G, Freire A, van der Vyver A,

Chotpitayasunondh T et al for the Micafungin Invasive Candidiasis

Study Group. Micafungin versus liposomal amphotericin B for

pediatric patients with invasive candidiasis: Substudy of a

randomized double-blind trial. Pediatric Infectious Disease Journal

2008;27(9):820-6.

Sandler 2000 {published data only (unpublished sought but not used)}

Sandler ES, Mustafa MM, Tkaczewski I, Graham ML, Morrison

VA, Green M, et al.Use of amphotericin B colloidal dispersion in

children. Journal of Pediatric Hematology/Oncology 2000;22(3):

242–6.

Walsh 1999 {published and unpublished data}

Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C,

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therapy in patients with persistent fever and neutropenia. National

Institute of Allergy and Infectious Diseases Mycoses Study Group.

New England Journal of Medicine 1999;340(10):764–71.

White 1998 {published data only (unpublished sought but not used)}

White MH, Bowden RA, Sandler ES, Graham ML, Noskin GA,

Wingard JR, et al.Randomized, double-blind clinical trial of

amphotericin B colloidal dispersion vs. amphotericin B in the

empirical treatment of fever and neutropenia. Clinical Infectious

Diseases 1998;27(2):296–302.

References to studies excluded from this review

Arrietta 2006 {published data only}

Arrieta AC, Telles Filho F, Berezin E, Freire A, Diekmann-Berndt

H. A randomized, double-blind trial comparing micafungin

(MCFG) and liposomal amphotericin B (L-AMB) in pediatric

patients with invasive candidiasis.. Program and abstracts of the

46th Annual Interscience Conference on Antimicrobial Agents and

Chemotherapy. San Francisco USA [Abstract M-1308b]. 2006

Sept.

Arrietta 2007 {published data only}

Arrieta A, Queiroz-Telles F, Berezin E, Freire A, Diekmann S,

Koblinger S. Micafungin versus liposomal amphotericin B

(AmBisome®) in paediatric patients with invasive candidiasis or

candidaemia. Program and abstracts of the 17th European

Congress of Clinical Microbiology and Infectious Diseases.

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Bodhe 2002 {published data only}

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Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ,

Bouza E, et al.AmBiLoad Trial Study Group. Liposomal

amphotericin B as initial therapy for invasive mold infection: a

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Amphotericin B and itraconazole as empirical antifungal therapy in

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Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM,

Edwards JE, et al.A randomized trial comparing fluconazole with

amphotericin B for the treatment of candidemia in patients without

neutropenia. Candidemia Study Group and the National Institute.


Shikanai-Yasuda 2002 {published data only}

Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GM, Hoo S,

Vaccari EH, et al.Randomized trial with itraconazole, ketoconazole

and sulfadiazine in paracoccidioidomycosis. Medical Mycology

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Viscoli 1996 {published data only}

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Walsh 2002 {published data only}

Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli

J, et al.National Institute of Allergy and Infectious Diseases

Mycoses Study Group. Voriconazole compared with liposomal

amphotericin B for empirical antifungal therapy in patients with

neutropenia and persistent fever. New England Journal of Medicine

2002;346(4):225–34.

Wang 2007 {published data only}

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Wingard 2000 {published data only}

Wingard JR, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta

A, L Amph/ABLC Collaborative Study Group. A randomized,

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amphotericin B versus amphotericin B lipid complex in the

empirical treatment of febrile neutropenia. L Amph/ABLC

Collaborative Study Group. Clinical infectious Diseases 2000;31(5):

1155–63.

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with cancer. American Journal of Medicine 2000;108(4):282–9.



Yao 2000 {published data only}

Yao Z, Liao W, Wen H. Antifungal therapy for treatment of

cryptococcal meningitis. Chinese Medical Journal 2000;113(2):

178–80.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Maertens 2007

Methods Multicentred, international (Belgium, Germany, Spain, US), doubled blind, randomised

trial

Participants Paediatric patients (2 - 17 years) with fever and neutropenia. Neutropenia was defined as

ANC < 0.5x109/L. Pyrexia of unknown origin was defined as 96 hours of fever > 38°C

not responding to broad-spectrum antibacterial therapy

Interventions Caspofungin versus liposomal amphotericin B

Patients were enrolled in a 2:1 fashion comparing caspofungin (70mg/m2 on day 1

followed by 50mg/m2) with liposomal amphotericin B (Ambisome® 3mg/kg/day). An

increase to caspofungin 70 mg/m2 (maximum 70 mg daily) or liposomal amphotericin

B 5 mg/kg was allowed after 5 days. The period of follow up was 7 days following

completion of therapy

Outcomes Primary endpoint: the proportion of patients with more than one drug-related adverse

event during the study period and 14 days post-therapy

Secondary endpoints: drug-related serious adverse events, discontinuation due to drug-

related adverse events and proportion of patients with a favourable overall efficacy out-

come based on a five-part composite endpoint (Walsh 2004a). Treatment was judged

to be successful if all of the following criteria were met: i) successful treatment of any

baseline fungal infection, ii) absence of any breakthrough fungal infection during ther-

apy or within seven days after the completion of therapy, iii) survival for seven days after

the completion of therapy, iv) no premature discontinuation of study therapy because

of drug related toxicity or lack of efficacy, and v) resolution of fever (defined as a tem-

perature below 38°C for at least 48 hours) during neutropenia.

Notes Paediatric population only (range: 2 to 17 years).

Authors contacted for further data (3/12/2008). Data was only available in abstract form.

Some absolute numbers are not yet published so therefore for pooled analyses, some

absolute numbers were calculated from percentages.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Unclear from the abstract although it is

likely to be adequate as the study was mod-

elled on Walsh 2004a.

Allocation concealment? Unclear Unclear from the abstract although it is

likely to be adequate as the study was mod-

elled on Walsh 2004a.



Maertens 2007 (Continued)

Blinding?

All outcomes

Yes Patients and investigators were blinded to

the treatment administered.

Incomplete outcome data addressed?

All outcomes

Unclear Patients enrolled: 82 patients. One patient

had no screening temperature above 38°C.

Modified Intention to treat population: 81

patients. Five patients received < 4 days

of study therapy, 1 patient received con-

comitant antifungal therapy and 14 pa-

tients had other protocol violations. Evalu-

able-patient population: 65 patients.

Free of selective reporting? Unclear All expected outcomes are included in the

abstract however full data was not available.

Free of other bias? Unclear The study appears to be free from other

sources of bias although only published in

an abstract form.

Mondal 2004

Methods Single-centre (India) double-blind randomised trial conducted in a paediatric intensive

care unit

Participants Pediatric patients (1 month - 12 years) with candidaemia

Interventions Itraconazole versus fluconazole. Itraconazole (10mg/kg daily either orally or via gastric

tube) or fluconazole (10mg/kg daily either orally or via gastric tube) were administered.

The therapy was continued ≥1 wk after the blood culture become negative. Minimum

duration of therapy was 2 weeks. Patients were followed for a median of 8 weeks

Outcomes Primary endpoint: cure (treatment success) included both clinical and mycological end-

points. Clinical cure was defined as complete resolution of fever and improvement in

signs and symptoms present at the time of enrolment. Mycological cure was defined as

no growth of yeast in blood culture on two consecutive occasions 48 hrs apart

Secondary endpoints: all-cause mortality, IFI related mortality (candida-attributable

mortality was defined as death of a patient who had documented candidaemia (positive

blood culture for Candida) within the previous 48 hrs), toxicities


Authors contacted for further data (17/11/2008). Further data was received (11/12/

2008).

The study was conducted during an outbreak of C. pelliculosa with 62% of cases caused

by this unusual species.

Risk of bias




Mondal 2004 (Continued)

Adequate sequence generation? Yes Randomisation was achieved by using ran-

dom tables.

Allocation concealment? Yes A person not directly involved in the study

made case allocation as per random num-

ber. The envelopes containing drug were

stored with a member of staff who was re-

sponsible for case allocation.

Blinding?

All outcomes




All outcomes

Yes Patients enrolled: 43 patients. Six patients

received less than 1 week of therapy (3 pa-

tients each receiving itraconazole and flu-

conazole): Itraconazole; 1 patient died, two

discontinued therapy. fluconazole; 2 pa-

tients died, one discontinued therapy.

Free of selective reporting? Yes All expected outcomes are included in the

report.

Free of other bias? No One potential bias given the small num-

bers in the study is the discontinuation of

treatment due to social and financial rea-

sons. Two patients receiving itraconazole,

one patient receiving fluconazole and a fur-

ther patient in whom the therapy is unclear

left hospital due to financial and social rea-

sons. Three patients discontinued all ther-

apy (itraconazole; 2 patients, fluconazole;

1 patient) whereas the forth patients con-

tinued azole therapy at home.

Prentice 1997

Methods Multicentred, international (UK, Europe) open-label randomised trial. Adult studies

(104-10) and paediatric studies (104-14) are presented in the same paper

Participants Neutropenic children and adults (ANC < 0.5x109/L) with pyrexia of unknown origin

(96 hours of fever defined as a temperature ≥ 38°C not responding to broad-spectrum

antibacterial therapy)

Interventions Liposomal amphotericin B versus conventional amphotericin B

Liposomal amphotericin B (Ambisome® 1 and 3mg/kg/day) was compared with con-

ventional amphotericin B (1mg/kg/day) Therapy was continued until resolution of fever

(<38°C), recovery of neutrophils to above or equal to 0.5x109/L for 3 consecutive days,

patient death, unresolved toxicity, patient or physician request to withdraw



Prentice 1997 (Continued)

Outcomes Primary endpoint::safety

Secondary endpoints: efficacy or treatment response which was defined by a minimum

of 3 consecutive days without fever (<38°C) that continued until study end, indicated

by recovery of neutrophils to 0.5x109/L. Failure was defined as patients who remained

febrile at the of study, patients who developed a systemic fungal infection on study and

patients in whom a further systemic fungal agent was added

Notes Paediatric and adult population.

Authors contacted for further data (5/12/2008). No further data were available

The study contains two difference concentrations of liposomal amphotericin B (1mg/

kg and 3mg/kg). These have been pooled for some comparisons.

Toxicity endpoints are only expressed as percentages without clear denominators. It was

therefore necessary to calculate numbers from percentages.

Risk of bias


Adequate sequence generation? Yes Randomisation was done centrally and

each participating centre was provided with

a set of blinded, numbered envelopes which

required sequential opening. The arms

were balanced per centre and per block of

six patients.

Allocation concealment? Yes Blinded, numbered envelopes were pro-

vided by study investigators preventing al-

location concealment.

Blinding?

All outcomes

No The trial was open labelled.


All outcomes

No Patients enrolled: 204 children and 134

adults. Of 204 randomised children, 202

reported with 2 charts not available for re-

view.

Toxicity endpoints were expressed as per-

centages in both adults and children.

Nephrotoxicity data was calculated from

305 adults and children however 338 sub-

jects were evaluable for safety. It was not

clear from the report why these patients

were not included in the analysis.

Free of selective reporting? Unclear Given the incomplete outcome data, selec-

tive reporting is potentially a problem.



Prentice 1997 (Continued)

Free of other bias? Yes The study appeared to be free from other

sources of bias.

Queiroz-Telles 2008

Methods Multicentred, international (Europe, North and South America, Thailand, India) dou-

ble-blind randomised trial (a substudy of the larger study inclusive of adults and children)

Participants Paediatric patients (0 - 16 years) with candidaemia or Invasive candidiasis

Interventions Micafungin versus liposomal amphotericin B. Micafungin was administered at a daily

dose of 2 mg/kg of body weight for patients who weighed ≤40 kg and 100 mg for

patients who weighed >40 kg. Liposomal amphotericin B was administered at a daily

dose of 3 mg/kg of body weight. The recommended minimum duration of study drug

therapy was 14 days. The period of follow up was 12 weeks

Outcomes Primary endpoint: treatment success which included both clinical and mycological end-

points. Clinical response was defined as a complete or partial resolution of signs and

symptoms, and mycologic response was defined as eradication or presumed eradication

Secondary endpoints: all-cause mortality, IFI-related mortality, toxicities

Notes Paediatric population only (range: 0 to 16 years). Neonates could not be excluded for

mortality and toxicity endpoints and so have been included in the analysis.

Authors contacted for further data (17/11/2008). No further data were available.

Risk of bias


Adequate sequence generation? Yes Randomisation was achieved by computer

generated system and stratified by centre

and baseline neutropenic status.

Allocation concealment? Yes Central allocation prevented patients and

investigators from identifying assignment.

Blinding?

All outcomes


the treatment administered. Preparation of

the study drug infusion bottle and changes

in dose were managed by an unblinded staff

member of the centre, and an unblinded

study monitor reviewed drug accountabil-

ity records.


All outcomes

Yes Patients enrolled: 109 patients. Three pa-

tients did not receive any drug. Intention

to treat population: 106 patients. Eight



Queiroz-Telles 2008 (Continued)

patients did not have candidaemia infec-

tion confirmed. Modified intention to treat

population: 98 patients.

Free of selective reporting? Yes All expected outcomes were included in the

report.


sources of bias.

Sandler 2000

Methods Multicentred, double-blind randomised trial

Participants Patients were eligible for the study if they were neutropenic following chemotherapy

or hematopoietic stem cell transplantation. Neutropenic children (ANC ≤ 0.5x109/L)

were enrolled if they had pyrexia of unknown origin (72 hours of fever not responding

to broad-spectrum antibacterial therapy)

Interventions Amphotericin B colloidal dispersion (ABCD) versus conventional amphotericin B

ABCD (4mg/kg/day) was compared with conventional amphotericin B (0.8mg/kg/day)

. A patient remained in this study until one of these events occurred: i) the patient was

no longer neutropenic (absolute neutrophil count >500/mm3), ii) the patient’s cause

of fever was identified, iii) the patient experienced a grade 3 drug-related toxicity, iv)

the patient received study drug for 14 days. To be evaluable, a patient had to receive

therapy for a minimum of 7 days and not use another systemic antifungal medication.

The period of follow up was 7 days after the last dose of trial drug

Outcomes Endpoint 1: treatment success which included: i) survival of at least 7 days after the last

dose of study drug; ii) no documented or suspected fungal infection during the study

and within 7 days post study; iii) not prematurely terminated from the study because

of any toxicities; and iv) either afebrile or with infusion-associated fever only on the last

day of therapy

Endpoint 2: toxicity


Nephrotoxicity data is reported in the paper. Other toxicity data is not reliable as de-

nominator is not specified and number of patients not calculable from percentage.

It is possible that Sandler et al (2000) and White et al (1998) may contain the same

patients as the sponsor is the same, the methods are very similar, many of the institutions

contributed data to both studies and number of paediatric patients enrolled are similar.

Authors contacted for further data (4/12/2008). No further data were available.

Risk of bias


Adequate sequence generation? Unclear Method of randomisation not specified.



Sandler 2000 (Continued)

Allocation concealment? Unclear Insufficient methodological information

about method of concealment to permit

judgement.

Blinding?

All outcomes




All outcomes

Unclear Patients enrolled: 49 patients. Evaluable

population: 46 patients.


report..


sources of bias.

Walsh 1999

Methods Multicentred, national (US), doubled-blind, randomised trial

Participants Paediatric and adult patients with fever and neutropenia. Neutropenia was defined as

ANC < 0.5x109/L. Pyrexia of unknown origin was defined as 120 hours of fever > 38°C

not responding to broad-spectrum antibacterial therapy

Interventions Liposomal amphotericin B versus conventional amphotericin B

Liposomal amphotericin B (Ambisome® 3mg/kg/day) was compared with conventional

amphotericin B (1mg/kg/day). Patients received study drug until recovery from neu-

tropenia. The period of follow up was 7 days following after completion of therapy

Outcomes Primary endpoint: the proportion of patients with favourable overall efficacy outcome

based on a five-part composite endpoint: i) survival for seven days after initiation of

the study drug, ii) resolution of fever during the period of neutropenia, iii) successful

treatment of baseline fungal infection, iv) the absence of breakthrough fungal infection

during therapy or within seven days after the completion of therapy and v) absence of

premature discontinuation of the study drug because of toxicity or lack of efficacy

Secondary endpoints: all-cause mortality and adverse events including severe adverse

events and drug related adverse events

Notes Paediatric and adult population (age 2 to 80 years).

Authors contacted for further data (17/11/2008). Further data was received (13/3/2008)

.

Risk of bias


Adequate sequence generation? Yes Randomisation was achieved by computer

generated system.



Walsh 1999 (Continued)



Blinding?

All outcomes

Yes All patients, investigators, industrial spon-

sors and study coordinators were blinded

to the treatment administered.


All outcomes

Yes Patients enrolled: 702 patients, intention-

to-treat population: 687 patients. The rea-

son for the exclusion of 15 patients from the

intention to treat population is not clear.

All patients in the intention to treat pop-

ulation were included in the assessment of

efficacy and toxicity.


report.


sources of bias.

White 1998

Methods Multicentred, double-blind randomised trial

Participants Patients were eligible for the study if they were neutropenic following chemotherapy for

hematologic malignancy or had undergone marrow or stem cell transplantation in the

previous 3 months. Neutropenic children and adults (ANC ≤ 0.5x109/L or ANC ≤

1x109/L and expected to decline to ≤ 0.5x109/L within 2 days ) were enrolled if they

had pyrexia of unknown origin (72 hours of fever defined as a temperature ≥ 38°C not

responding to broad-spectrum antibacterial therapy) or recrudescent fever (temperature

≥ 38°C on two or more occasions after initial defervescence with antibacterial treatment)

Interventions Amphotericin B colloidal dispersion (ABCD) versus conventional amphotericin B

ABCD (4mg/kg/day) was compared with conventional amphotericin B (0.8mg/kg/day)

. Therapy was continued until recovery of neutrophils to > 0.5x109/L for 2 consecutive

days, identification of an infection thought to be the cause of the fever, toxicity leading

to study drug discontinuation or a maximum of 14 days. The period of follow up was

28 days

Outcomes Endpoint 1: treatment success which included survival for ≥ 7 days after the last study

drug, lack of suspected or documented fungal infection during the study and within 7

days of the last dose of the study drug, lack of study drug discontinuation because of

adverse events and lack of fever on the day of discontinuation of therapy

Endpoint 2: toxicity



White 1998 (Continued)

Notes Paediatric and adult population. Authors contacted for further data (5/12/2008). No

further data were available.

The authors stated that no difference between groups (i.e. children and adults admin-

istered conventional amphotericin B and ABCD) in efficacy endpoints, breakthrough

fungal infection and drug discontinuation however data not available in the report.

Rates of infusional toxicity more frequent with ABCD but subgroup analysis not re-

ported.

It is possible that Sandler et al (2000) and White et al (1998) may contain the same

patients as the sponsor is the same, the methods were very similar, many of the institutions

contributed data to both studies and number of paediatric patients enrolled were similar.

Risk of bias


Adequate sequence generation? Yes Randomisation was performed centrally

with randomisation tables.



Blinding?

All outcomes


the treatment administered. Preparation of

the study drug was performed by an un-

blinded site pharmacist.


All outcomes

Yes Patients enrolled: 213 patients. Seventeen

patients were not evaluable because of

study drug discontinuation before reaching

a study endpoint or because of receipt of

concomitant systemic antifungal therapy.

Analysis performed on 196 patients. Three

patients lost to follow up so response was

assessed on 193 patients.


report however efficacy and infusional tox-

icity for children were not reported sepa-

rately.


sources of bias.



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Arrietta 2006 Published as Queiroz-Telles 2008.

Arrietta 2007 Published as Queiroz-Telles 2008.

Bodhe 2002 The authors were contacted for data from the included paediatric cases (11th May 2009). Data were not

available.

Bowden 2002 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Cornely 2007 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Driessen 1996 Neonatal study: Age limit of those included was 0-30 days.

Ellis 1995 Not a randomised controlled trial.

Ellis 1998 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Galgiani 2000 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Herbrecht 2002 Authors contacted for data from included neonatal and paediatric cases (18th November 2008). Data was

not available.

Khayat 2005 Retrospective comparison therefore excluded.

Kim 2007 No contact details were available for authors. Insufficient data in abstract for analysis.

Kullberg 2005 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Pizzo 1982 The authors were contacted for data from the included paediatric cases (18th November 2008). Data were

not available.

Rex 1994 The authors were contacted (18th November 2008). No children included in study.

Shikanai-Yasuda 2002 The authors were contacted for data from the included paediatric cases (11th May 2009). Data were not

available.

Viscoli 1996 The authors were contacted for data from the included paediatric cases (5th December 2008). Data were

not available.

Walsh 2002 The authors and pharmaceutical company were contacted for data from the included paediatric cases (11th

March 2009). Data were not available.



(Continued)

Wang 2007 Manuscript was translated from Chinese to English. Paediatric subgroup analysis was not reported in

manuscript.

Wheat 2001 Not a randomised controlled trial.

Wingard 2000 The authors were contacted for data from the included paediatric cases (4th December 2008). Data was not

available.

Winston 2000 The authors were contacted for data from the included paediatric cases (5th December 2008). Data were

not available.

Yao 2000 Not a randomised controlled trial.



D A T A A N D A N A L Y S E S

Comparison 1. Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional

amphotericin B

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mortality (all cause) 1 95 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.17, 3.11]

2 Mortality (related to fungal

infection)

1 95 Risk Ratio (M-H, Random, 95% CI) 0.20 [0.01, 3.98]

3 Complete resolution of fungal

infection


4 Partial resolution of fungal

infection

0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

5 Resolution of fever in suspected

fungal infection


6 Progression of disease requiring

change / addition of an

antifungal agent


7 Breakthrough fungal infection

requiring change / addition of

an antifungal agent


8 Any clinically significant adverse

reactions attributed to the

antifungal agent resulting

in discontinuation, dose

reduction or change in therapy




antifungal agent (total)


10 Nephrotoxicity 4 371 Risk Ratio (M-H, Random, 95% CI) 0.43 [0.21, 0.90]

11 Hypokalaemia 3 345 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.45, 1.14]

12 Hepatotoxicity 3 345 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.74, 1.71]

13 Infusion-related reactions 2 284 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.59, 1.38]

13.1 Fever - Liposomal AmB

vs. Conventional Amphotericin

B


13.2 Fever - ABCD vs.

Conventional Amphotericin B


13.3 Chills - Liposomal AmB

vs. Conventional Amphotericin

B


13.4 Chills - ABCD vs.

Conventional Amphotericin B


14 Haematological disturbances 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

15 Neurological disturbances 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

16 Gastrointesitnal toxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

17 Length of Stay 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable



18 Quality of Life 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

19 Cost 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

Comparison 2. Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg)


studies

No. of


1 Mortality (all cause) 1 81 Risk Ratio (M-H, Random, 95% CI) Not estimable


infection)



infection



infection



fungal infection




antifungal agent




an antifungal agent












10 Nephrotoxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

11 Hypokalaemia 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

12 Hepatotoxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

13 Infusion-related reactions 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

14 Gastrointestinal toxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable



17 Length of Stay 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

18 Quality of Life 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable




Comparison 3. Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B


studies

No. of




infection)



infection


3.1 Age < 2 years 1 43 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.64, 1.22]

3.2 Age 2 or older 1 41 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.57, 1.31]


infection



fungal infection




antifungal agent




an antifungal agent
















14 Gastrointestinal toxicity 1 212 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.49, 2.22]

14.1 Vomiting 1 106 Risk Ratio (M-H, Random, 95% CI) 1.19 [0.46, 3.04]

14.2 Diarrhoea 1 106 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.24, 2.92]


16 Haematological disturbances 1 106 Risk Ratio (M-H, Random, 95% CI) 1.56 [0.60, 4.07]

17 Length of stay 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

18 Quality of life 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable




Comparison 4. Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole


studies

No. of




infection)



infection



infection



fungal infection




antifungal agent




an antifungal agent















13 Infusion-related reactions 1 43 Risk Ratio (M-H, Random, 95% CI) Not estimable

14 Gastrointesintal toxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable






Comparison 5. All children: echinocandin versus lipid preparation of amphotericin B


studies

No. of




infection)





infection



infection



fungal infection




antifungal agent




an antifungal agent














12 Hepatotoxicity (>2.5 X ULN) 1 55 Risk Ratio (M-H, Random, 95% CI) 1.67 [0.16, 17.32]


14 Gastrointesintal toxicity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable


16 Haematological disturbances 1 106 Risk Ratio (M-H, Random, 95% CI) 1.56 [0.60, 4.07]




Comparison 6. Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional am-

photericin B (best case for lipid)


studies

No. of





Comparison 7. Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional am-

photericin B (worst case for lipid)


studies

No. of



Analysis 1.1. Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus

conventional amphotericin B, Outcome 1 Mortality (all cause).

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

Comparison: 1 Children with fever and neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B

Outcome: 1 Mortality (all cause)

Study or subgroup Lipid preparation of AmB Conventional AmB Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Walsh 1999 3/48 4/47 100.0 % 0.73 [ 0.17, 3.11 ]

Total (95% CI) 48 47 100.0 % 0.73 [ 0.17, 3.11 ]

Total events: 3 (Lipid preparation of AmB), 4 (Conventional AmB)

Heterogeneity: not applicable

Test for overall effect: Z = 0.42 (P = 0.67)

0.01 0.1 1 10 100

Favours experimental Favours control




conventional amphotericin B, Outcome 2 Mortality (related to fungal infection).



Outcome: 2 Mortality (related to fungal infection)



Walsh 1999 0/48 2/47 100.0 % 0.20 [ 0.01, 3.98 ]

Total (95% CI) 48 47 100.0 % 0.20 [ 0.01, 3.98 ]




0.01 0.1 1 10 100



conventional amphotericin B, Outcome 3 Complete resolution of fungal infection.



Outcome: 3 Complete resolution of fungal infection



Walsh 1999 1/2 1/3 100.0 % 1.50 [ 0.18, 12.46 ]

Total (95% CI) 2 3 100.0 % 1.50 [ 0.18, 12.46 ]




0.01 0.1 1 10 100

Favours conventional AmB Favours lipid preparation




conventional amphotericin B, Outcome 5 Resolution of fever in suspected fungal infection.



Outcome: 5 Resolution of fever in suspected fungal infection

Study or subgroup Lipid preparation Conventional AmB Risk Ratio Weight Risk Ratio


Walsh 1999 32/48 26/47 41.9 % 1.21 [ 0.87, 1.67 ]

Prentice 1997 90/141 31/61 58.1 % 1.26 [ 0.95, 1.66 ]

Total (95% CI) 189 108 100.0 % 1.23 [ 1.00, 1.52 ]

Total events: 122 (Lipid preparation), 57 (Conventional AmB)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0%


0.05 0.2 1 5 20


conventional amphotericin B, Outcome 7 Breakthrough fungal infection requiring change / addition of an

antifungal agent.



Outcome: 7 Breakthrough fungal infection requiring change / addition of an antifungal agent



Prentice 1997 5/141 1/61 22.7 % 2.16 [ 0.26, 18.13 ]

Sandler 2000 1/26 2/22 18.9 % 0.42 [ 0.04, 4.36 ]

Walsh 1999 3/48 6/47 58.4 % 0.49 [ 0.13, 1.84 ]

Total (95% CI) 215 130 100.0 % 0.67 [ 0.24, 1.84 ]




0.05 0.2 1 5 20




conventional amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the

antifungal agent (total).



Outcome: 9 Any clinically significant adverse reactions attributed to the antifungal agent (total)



Prentice 1997 16/141 23/63 46.7 % 0.31 [ 0.18, 0.55 ]

Walsh 1999 24/48 32/47 53.3 % 0.73 [ 0.52, 1.04 ]

Total (95% CI) 189 110 100.0 % 0.49 [ 0.21, 1.17 ]


Heterogeneity: Tau2 = 0.34; Chi2 = 6.98, df = 1 (P = 0.01); I2 =86%


0.05 0.2 1 5 20

Analysis 1.10. Comparison 1 Children with fever and neutropenia: lipid preparation of amphotericin B

versus conventional amphotericin B, Outcome 10 Nephrotoxicity.



Outcome: 10 Nephrotoxicity



Prentice 1997 12/127 12/57 29.9 % 0.45 [ 0.21, 0.94 ]

Sandler 2000 3/25 11/21 21.0 % 0.23 [ 0.07, 0.71 ]

Walsh 1999 10/48 9/47 28.2 % 1.09 [ 0.49, 2.44 ]

White 1998 3/25 11/21 21.0 % 0.23 [ 0.07, 0.71 ]

Total (95% CI) 225 146 100.0 % 0.43 [ 0.21, 0.90 ]




0.05 0.2 1 5 20




versus conventional amphotericin B, Outcome 11 Hypokalaemia.



Outcome: 11 Hypokalaemia



Prentice 1997 15/141 16/63 28.9 % 0.42 [ 0.22, 0.79 ]

Sandler 2000 13/25 11/21 33.2 % 0.99 [ 0.57, 1.73 ]

Walsh 1999 18/48 22/47 37.9 % 0.80 [ 0.50, 1.29 ]

Total (95% CI) 214 131 100.0 % 0.71 [ 0.45, 1.14 ]




0.05 0.2 1 5 20


versus conventional amphotericin B, Outcome 12 Hepatotoxicity.



Outcome: 12 Hepatotoxicity

Study or subgroup Lipid preparation of AmB Conventional AmB Risk Ratio Risk Ratio


Prentice 1997 28/141 11/63 1.14 [ 0.61, 2.14 ]

Sandler 2000 0/25 0/21 0.0 [ 0.0, 0.0 ]

Walsh 1999 17/48 15/47 1.11 [ 0.63, 1.95 ]

Total (95% CI) 214 131 1.12 [ 0.74, 1.71 ]




0.05 0.2 1 5 20




versus conventional amphotericin B, Outcome 13 Infusion-related reactions.



Outcome: 13 Infusion-related reactions



1 Fever - Liposomal AmB vs. Conventional Amphotericin B

Walsh 1999 43/48 44/48 30.5 % 0.98 [ 0.86, 1.11 ]

Subtotal (95% CI) 48 48 30.5 % 0.98 [ 0.86, 1.11 ]




2 Fever - ABCD vs. Conventional Amphotericin B

Sandler 2000 19/25 17/21 27.0 % 0.94 [ 0.69, 1.27 ]

Subtotal (95% CI) 25 21 27.0 % 0.94 [ 0.69, 1.27 ]




3 Chills - Liposomal AmB vs. Conventional Amphotericin B

Walsh 1999 11/48 30/48 20.1 % 0.37 [ 0.21, 0.64 ]

Subtotal (95% CI) 48 48 20.1 % 0.37 [ 0.21, 0.64 ]




4 Chills - ABCD vs. Conventional Amphotericin B

Sandler 2000 21/25 10/21 22.3 % 1.76 [ 1.09, 2.85 ]

Subtotal (95% CI) 25 21 22.3 % 1.76 [ 1.09, 2.85 ]




Total (95% CI) 146 138 100.0 % 0.91 [ 0.59, 1.38 ]




0.01 0.1 1 10 100




Analysis 2.1. Comparison 2 Children with fever and neutropenia: caspofungin versus liposomal

amphotericin B (3 mg/kg), Outcome 1 Mortality (all cause).


Comparison: 2 Children with fever and neutropenia: caspofungin versus liposomal amphotericin B (3 mg/kg)


Study or subgroup Caspofungin Liposomal Amphotericin B Risk Ratio Risk Ratio


Maertens 2007 0/56 0/25 0.0 [ 0.0, 0.0 ]

Total (95% CI) 56 25 0.0 [ 0.0, 0.0 ]

Total events: 0 (Caspofungin), 0 (Liposomal Amphotericin B)


Test for overall effect: Z = 0.0 (P < 0.00001)

0.5 0.7 1 1.5 2



amphotericin B (3 mg/kg), Outcome 2 Mortality (related to fungal infection).




Study or subgroup Caspofungin Liposomal Amphotericin B Risk Ratio Risk Ratio


Maertens 2007 0/56 0/25 0.0 [ 0.0, 0.0 ]

Total (95% CI) 56 25 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





amphotericin B (3 mg/kg), Outcome 5 Resolution of fever in suspected fungal infection.



Outcome: 5 Resolution of fever in suspected fungal infection

Study or subgroup Caspofungin Liposomal Amphotericin B Risk Ratio Weight Risk Ratio


Maertens 2007 24/56 8/25 100.0 % 1.34 [ 0.70, 2.56 ]

Total (95% CI) 56 25 100.0 % 1.34 [ 0.70, 2.56 ]




0.01 0.1 1 10 100


Analysis 2.7. 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.






Maertens 2007 0/56 1/25 100.0 % 0.15 [ 0.01, 3.61 ]

Total (95% CI) 56 25 100.0 % 0.15 [ 0.01, 3.61 ]




0.01 0.1 1 10 100

Favours caspofungin Favours lipid preparation




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.



Outcome: 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation, dose reduction or change in therapy



Maertens 2007 2/56 3/26 100.0 % 0.31 [ 0.06, 1.74 ]

Total (95% CI) 56 26 100.0 % 0.31 [ 0.06, 1.74 ]




0.01 0.1 1 10 100


Analysis 2.9. 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).






Maertens 2007 27/56 12/26 100.0 % 1.04 [ 0.64, 1.72 ]

Total (95% CI) 56 26 100.0 % 1.04 [ 0.64, 1.72 ]




0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal

amphotericin B, Outcome 1 Mortality (all cause).


Comparison: 3 Children with candidaemia or invasive candidiasis: micafungin versus liposomal amphotericin B


Study or subgroup Micafungin Liposomal Amphotericin B Risk Ratio Weight Risk Ratio


Queiroz-Telles 2008 13/52 13/54 100.0 % 1.04 [ 0.53, 2.02 ]

Total (95% CI) 52 54 100.0 % 1.04 [ 0.53, 2.02 ]

Total events: 13 (Micafungin), 13 (Liposomal Amphotericin B)



0.01 0.1 1 10 100



amphotericin B, Outcome 2 Mortality (related to fungal infection).






Queiroz-Telles 2008 4/52 3/54 100.0 % 1.38 [ 0.33, 5.89 ]

Total (95% CI) 52 54 100.0 % 1.38 [ 0.33, 5.89 ]




0.01 0.1 1 10 100





amphotericin B, Outcome 3 Complete resolution of fungal infection.






1 Age < 2 years

Queiroz-Telles 2008 14/19 20/24 62.3 % 0.88 [ 0.64, 1.22 ]

Subtotal (95% CI) 19 24 62.3 % 0.88 [ 0.64, 1.22 ]




2 Age 2 or older

Queiroz-Telles 2008 14/22 14/19 37.7 % 0.86 [ 0.57, 1.31 ]

Subtotal (95% CI) 22 19 37.7 % 0.86 [ 0.57, 1.31 ]




Total (95% CI) 41 43 100.0 % 0.88 [ 0.68, 1.13 ]




0.01 0.1 1 10 100





amphotericin B, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.




Study or subgroup Micafungin Liposomal Amphotericin B Risk Ratio Risk Ratio


Queiroz-Telles 2008 0/52 0/54 0.0 [ 0.0, 0.0 ]

Total (95% CI) 52 54 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100



amphotericin B, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent

resulting in discontinuation, dose reduction or change in therapy.






Queiroz-Telles 2008 1/52 3/54 100.0 % 0.35 [ 0.04, 3.22 ]

Total (95% CI) 52 54 100.0 % 0.35 [ 0.04, 3.22 ]




0.01 0.1 1 10 100





amphotericin B, Outcome 9 Any clinically significant adverse reactions attributed to the antifungal agent

(total).






Queiroz-Telles 2008 19/52 23/54 100.0 % 0.86 [ 0.53, 1.38 ]

Total (95% CI) 52 54 100.0 % 0.86 [ 0.53, 1.38 ]




0.01 0.1 1 10 100


Analysis 3.10. Comparison 3 Children with candidaemia or invasive candidiasis: micafungin versus

liposomal amphotericin B, Outcome 10 Nephrotoxicity.






Queiroz-Telles 2008 0/43 0/41 0.0 [ 0.0, 0.0 ]

Total (95% CI) 43 41 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





liposomal amphotericin B, Outcome 11 Hypokalaemia.






Queiroz-Telles 2008 5/52 11/54 100.0 % 0.47 [ 0.18, 1.27 ]

Total (95% CI) 52 54 100.0 % 0.47 [ 0.18, 1.27 ]




0.01 0.1 1 10 100



liposomal amphotericin B, Outcome 12 Hepatotoxicity.






Queiroz-Telles 2008 2/29 1/28 100.0 % 1.93 [ 0.19, 20.12 ]

Total (95% CI) 29 28 100.0 % 1.93 [ 0.19, 20.12 ]




0.01 0.1 1 10 100





liposomal amphotericin B, Outcome 13 Infusion-related reactions.






Queiroz-Telles 2008 7/52 10/54 100.0 % 0.73 [ 0.30, 1.77 ]

Total (95% CI) 52 54 100.0 % 0.73 [ 0.30, 1.77 ]




0.01 0.1 1 10 100



liposomal amphotericin B, Outcome 14 Gastrointestinal toxicity.



Outcome: 14 Gastrointestinal toxicity



1 Vomiting

Queiroz-Telles 2008 8/52 7/54 64.2 % 1.19 [ 0.46, 3.04 ]

Subtotal (95% CI) 52 54 64.2 % 1.19 [ 0.46, 3.04 ]




2 Diarrhoea

Queiroz-Telles 2008 4/52 5/54 35.8 % 0.83 [ 0.24, 2.92 ]

Subtotal (95% CI) 52 54 35.8 % 0.83 [ 0.24, 2.92 ]



0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Micafungin Liposomal Amphotericin B Risk Ratio Weight Risk Ratio



Total (95% CI) 104 108 100.0 % 1.04 [ 0.49, 2.22 ]




0.01 0.1 1 10 100



liposomal amphotericin B, Outcome 15 Neurological disturbances.



Outcome: 15 Neurological disturbances



Queiroz-Telles 2008 0/52 0/54 0.0 [ 0.0, 0.0 ]

Total (95% CI) 52 54 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





liposomal amphotericin B, Outcome 16 Haematological disturbances.



Outcome: 16 Haematological disturbances



Queiroz-Telles 2008 9/52 6/54 100.0 % 1.56 [ 0.60, 4.07 ]

Total (95% CI) 52 54 100.0 % 1.56 [ 0.60, 4.07 ]




0.01 0.1 1 10 100


Analysis 4.1. Comparison 4 Children with candidaemia or invasive candidiasis: itraconazole versus

fluconazole, Outcome 1 Mortality (all cause).


Comparison: 4 Children with candidaemia or invasive candidiasis: itraconazole versus fluconazole


Study or subgroup Itraconazole Fluconazole Risk Ratio Weight Risk Ratio


Mondal 2004 2/21 4/22 100.0 % 0.52 [ 0.11, 2.56 ]

Total (95% CI) 21 22 100.0 % 0.52 [ 0.11, 2.56 ]

Total events: 2 (Itraconazole), 4 (Fluconazole)



0.01 0.1 1 10 100





fluconazole, Outcome 2 Mortality (related to fungal infection).






Mondal 2004 1/21 1/22 100.0 % 1.05 [ 0.07, 15.69 ]

Total (95% CI) 21 22 100.0 % 1.05 [ 0.07, 15.69 ]




0.01 0.1 1 10 100



fluconazole, Outcome 3 Complete resolution of fungal infection.






Mondal 2004 17/21 18/22 100.0 % 0.99 [ 0.74, 1.32 ]

Total (95% CI) 21 22 100.0 % 0.99 [ 0.74, 1.32 ]




0.01 0.1 1 10 100





fluconazole, Outcome 7 Breakthrough fungal infection requiring change / addition of an antifungal agent.




Study or subgroup Itraconazole Fluconazole Risk Ratio Risk Ratio


Mondal 2004 0/21 0/22 0.0 [ 0.0, 0.0 ]

Total (95% CI) 21 22 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100



fluconazole, Outcome 8 Any clinically significant adverse reactions attributed to the antifungal agent resulting

in discontinuation, dose reduction or change in therapy.






Mondal 2004 0/21 0/22 0.0 [ 0.0, 0.0 ]

Total (95% CI) 21 22 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





fluconazole, Outcome 10 Nephrotoxicity.






Mondal 2004 2/17 3/18 100.0 % 0.71 [ 0.13, 3.72 ]

Total (95% CI) 17 18 100.0 % 0.71 [ 0.13, 3.72 ]




0.01 0.1 1 10 100



fluconazole, Outcome 11 Hypokalaemia.






Mondal 2004 3/17 3/18 100.0 % 1.06 [ 0.25, 4.54 ]

Total (95% CI) 17 18 100.0 % 1.06 [ 0.25, 4.54 ]




0.01 0.1 1 10 100





fluconazole, Outcome 12 Hepatotoxicity.






Mondal 2004 1/17 1/18 100.0 % 1.06 [ 0.07, 15.62 ]

Total (95% CI) 17 18 100.0 % 1.06 [ 0.07, 15.62 ]




0.01 0.1 1 10 100



fluconazole, Outcome 13 Infusion-related reactions.






Mondal 2004 0/22 0/21 0.0 [ 0.0, 0.0 ]

Total (95% CI) 22 21 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100




Analysis 5.1. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B, Outcome

1 Mortality (all cause).


Comparison: 5 All children: echinocandin versus lipid preparation of amphotericin B


Study or subgroup Echinocandin Lipid preparation of AmB Risk Ratio Risk Ratio


Maertens 2007 0/56 0/25 0.0 [ 0.0, 0.0 ]

Queiroz-Telles 2008 12/52 7/54 1.78 [ 0.76, 4.17 ]

Total (95% CI) 108 79 1.78 [ 0.76, 4.17 ]

Total events: 12 (Echinocandin), 7 (Lipid preparation of AmB)



0.01 0.1 1 10 100



8 Any clinically significant adverse reactions attributed to the antifungal agent resulting in discontinuation,

dose reduction or change in therapy.




Study or subgroup Echinocandin Lipid preparation Risk Ratio Weight Risk Ratio


Maertens 2007 2/56 3/26 62.5 % 0.31 [ 0.06, 1.74 ]

Queiroz-Telles 2008 1/52 3/54 37.5 % 0.35 [ 0.04, 3.22 ]

Total (95% CI) 108 80 100.0 % 0.32 [ 0.08, 1.27 ]

Total events: 3 (Echinocandin), 6 (Lipid preparation)



0.05 0.2 1 5 20




9 Any clinically significant adverse reactions attributed to the antifungal agent (total).




Study or subgroup Echinocandin Lipid preparation Risk Ratio Weight Risk Ratio


Maertens 2007 27/56 12/26 47.7 % 1.04 [ 0.64, 1.72 ]

Queiroz-Telles 2008 19/52 23/54 52.3 % 0.86 [ 0.53, 1.38 ]

Total (95% CI) 108 80 100.0 % 0.94 [ 0.67, 1.33 ]

Total events: 46 (Echinocandin), 35 (Lipid preparation)



0.05 0.2 1 5 20

Analysis 5.10. Comparison 5 All children: echinocandin versus lipid preparation of amphotericin B,

Outcome 10 Nephrotoxicity.






Queiroz-Telles 2008 0/43 0/41 0.0 [ 0.0, 0.0 ]

Total (95% CI) 43 41 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





Outcome 11 Hypokalaemia.




Study or subgroup Echinocandin Lipid preparation of AmB Risk Ratio Weight Risk Ratio


Queiroz-Telles 2008 5/52 11/54 100.0 % 0.47 [ 0.18, 1.27 ]

Total (95% CI) 52 54 100.0 % 0.47 [ 0.18, 1.27 ]




0.01 0.1 1 10 100



Outcome 12 Hepatotoxicity (>2.5 X ULN).



Outcome: 12 Hepatotoxicity (>2.5 X ULN)



Queiroz-Telles 2008 2/30 1/25 100.0 % 1.67 [ 0.16, 17.32 ]

Total (95% CI) 30 25 100.0 % 1.67 [ 0.16, 17.32 ]




0.01 0.1 1 10 100





Outcome 13 Infusion-related reactions.






Queiroz-Telles 2008 7/52 10/54 100.0 % 0.73 [ 0.30, 1.77 ]

Total (95% CI) 52 54 100.0 % 0.73 [ 0.30, 1.77 ]




0.01 0.1 1 10 100



Outcome 15 Neurological disturbances.



Outcome: 15 Neurological disturbances



Queiroz-Telles 2008 0/52 0/54 0.0 [ 0.0, 0.0 ]

Total (95% CI) 52 54 0.0 [ 0.0, 0.0 ]




0.01 0.1 1 10 100





Outcome 16 Haematological disturbances.



Outcome: 16 Haematological disturbances



Queiroz-Telles 2008 9/52 6/54 100.0 % 1.56 [ 0.60, 4.07 ]

Total (95% CI) 52 54 100.0 % 1.56 [ 0.60, 4.07 ]




0.01 0.1 1 10 100


Analysis 6.1. Comparison 6 Children with fever, neutropenia: lipid preparation of amphotericin B versus

conventional amphotericin B (best case for lipid), Outcome 1 Nephrotoxicity.


Comparison: 6 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B (best case for lipid)




Prentice 1997 13/141 13/63 29.9 % 0.45 [ 0.22, 0.91 ]

Sandler 2000 3/27 12/22 21.2 % 0.20 [ 0.07, 0.63 ]

Walsh 1999 10/48 9/47 27.8 % 1.09 [ 0.49, 2.44 ]

White 1998 3/26 11/21 21.1 % 0.22 [ 0.07, 0.69 ]

Total (95% CI) 242 153 100.0 % 0.42 [ 0.20, 0.89 ]




0.05 0.2 1 5 20



Analysis 7.1. Comparison 7 Children with fever, neutropenia: lipid preparation of amphotericin B versus

conventional amphotericin B (worst case for lipid), Outcome 1 Nephrotoxicity.


Comparison: 7 Children with fever, neutropenia: lipid preparation of amphotericin B versus conventional amphotericin B (worst case for lipid)




Prentice 1997 13/141 6/30 25.2 % 0.46 [ 0.19, 1.12 ]

Sandler 2000 5/27 11/22 24.8 % 0.37 [ 0.15, 0.91 ]

Walsh 1999 10/48 9/47 28.0 % 1.09 [ 0.49, 2.44 ]

White 1998 4/26 11/21 22.0 % 0.29 [ 0.11, 0.79 ]

Total (95% CI) 242 120 100.0 % 0.50 [ 0.28, 0.90 ]




0.05 0.2 1 5 20

A P P E N D I C E S

Appendix 1. MEDLINE search strategy

1. Antifungal Agents/

2. exp amphotericin B/

3. fungizon$.tw

4. ampho$.tw.

5. anfo$.tw.

6. candipres$.tw.

7. ABLC$.tw.

8. ABCD$.tw.

9. abelcet$.tw.

10. ambisome$.tw.

11. exp triazoles/

12. triazole$.tw.

13. exp fluconazole/

14. flucon$.tw.

15. diflucan$.tw.

16. exp Itraconazole/

17. itracon$.tw.

18. sporanox$.tw.

19. voriconazol$.tw.

20. vfend$.tw.



21. posaconazol$.tw.

22. posafilin$.tw.

23. posanin$.tw.

24. ravuconazol$.tw.

25. exp Flucytosine/

26. flucytosin$.tw.

27. ancotil$.tw.

28. 5FC$.tw.

29. 5-fluorocytosin$.tw.

30. ancobon$.tw.

31. ancotil$.tw.

32. alcobon$.tw.

33. echinocandin$.tw.

34. caspofungin$.tw.

35. cancidas$.tw.

36. micafungin$.tw.

37. funguard$.tw.

38. mycamine$.tw.

39. anidulafungin$.tw.

40. anidrasona$.tw.

41. anidrosan$.tw.

42. HSP90$.tw.

43. mycograb$.tw.

44. antibodies, Monoclonal/tu

45. or/1-44

46. randomized controlled trial.pt.

47. controlled clinical trial.pt.

48. randomized.ab.

49. placebo.ab.

50. clinical trials as topic.sh.

51. randomly.ab.

52. trial.ti.

53. or/46-52

54. humans.sh.

55. 53 and 54

56. boy$.tw.

57. girl$.tw.

58. infant.tw.

59. pediatr$.tw.

60. paediatr$.tw.

61. infant/

62. exp child/

63. exp adolescent/

64. or/56-63

65. 45 and 55 and 64



Appendix 2. CENTRAL search strategy



3. fungizon$.tw

4. ampho$.tw.

5. anfo$.tw.

6. candipres$.tw.

7. ABLC$.tw.

8. ABCD$.tw.

9. abelcet$.tw.

10. ambisome$.tw.

11. exp triazoles/

12. triazole$.tw.


14. flucon$.tw.

15. diflucan$.tw.


17. itracon$.tw.

18. sporanox$.tw.


20. vfend$.tw.


22. posafilin$.tw.

23. posanin$.tw.



26. flucytosin$.tw.

27. ancotil$.tw.

28. 5FC$.tw.


30. ancobon$.tw.

31. ancotil$.tw.

32. alcobon$.tw.



35. cancidas$.tw.

36. micafungin$.tw.

37. funguard$.tw.

38. mycamine$.tw.


40. anidrasona$.tw.

41. anidrosan$.tw.

42. HSP90$.tw.

43. mycograb$.tw.


45. or/1-44

46. boy$.tw.

47. girl$.tw.

48. infant.tw.

49. child.tw

50. pediatr.tw.

51. chill$.tw



52. pediatr$.tw

53. paediatr$.tw.

54. infant/

55. exp child

56. or/46-55

57. 45 and 56

Appendix 3. EMBASE search strategy



3. fungizon$.tw

4. ampho$.tw.

5. anfo$.tw.

6. candipres$.tw.

7. ABLC$.tw.

8. ABCD$.tw.

9. abelcet$.tw.

10. ambisome$.tw.

11. exp triazoles/

12. triazole$.tw.


14. flucon$.tw.

15. diflucan$.tw.


17. itracon$.tw.

18. sporanox$.tw.


20. vfend$.tw.


22. posafilin$.tw.

23. posanin$.tw.



26. flucytosin$.tw.

27. ancotil$.tw.

28. 5FC$.tw.


30. ancobon$.tw.

31. ancotil$.tw.

32. alcobon$.tw.



35. cancidas$.tw.

36. micafungin$.tw.

37. funguard$.tw.

38. mycamine$.tw.


40. anidrasona$.tw.

41. anidrosan$.tw.

42. HSP90$.tw.

43. mycograb$.tw.




45. or/1-44

46. exp controlled study/ or controlled study.ti,ab,hw,tn,mf.

47. exp statistical analysis/ or clinical study.ti,ab,hw,tn,mf.

48. exp major clinical study/ or major clinical study.ti,ab,hw,tn,mf.

49. exp randomised controlled trial/ or randomised controlled study.ti,ab,hw,tn,mf.

50. exp randomized controlled trial/ or randomized controlled study.ti,ab,hw,tn,mf.

51. random$.ti,ab,hw,tn,mf.

52. exp double blind procedure/ or double blind procedure.ti,ab,hw,tn,mf.

53. exp single blind procedure/ or single blind procedure.ti,ab,hw,tn,mf.

54. exp multicenter study/ or multicenter study.ti,ab,hw,tn,mf.

55. exp placebo/ or placebo.ti,ab,hw,tn,mf.

56. or/46-55

57. boy$.tw.

58. girl$.tw.

59. infant.tw.

60. child.tw

61. pediatr.tw.

62. child$.tw.

63. pediatr$.tw.

64. paediatr$.tw.

65. infant/

66. exp child/

67. exp adolescent/

68. or/57-67

69. 45 and 56 and 68

Appendix 4. CINAHL search strategy

1. Antifungal agents/

2. Triazoles

3. Amphotericin B

4. Fluconazole

5. Itraconazole

6. Flucytosine

7. or/1-6

8. Clinical trials

9. 7 and 8

Limit to Infant (1 to 23 month) or Child (preschool 2 to 5) or Child (6 to 12) or Adolescent (13 to18)

Appendix 5. Data extraction form 1

Reference

First author Journal

Year Source (medline, cochrane etc)



(Continued)

Title

Language

Reference available (Yes or No) Additional data provided (Yes/No)

Authors contacted (date 1) Additional data received (date)

Authors contacted (date 2)

Disease (e.g. candidaemia)

Age limits (years)

Comparator A Comparator B

Drug Drug

Formulation Formulation

Dose Dose

Assessment of risk of bias (yes, no or unclear)

(1) Was the allocation sequence adequately generated?

(2) Was allocation adequately concealed?

(3) Was knowledge of the allocation interventions adequately prevented during

the study?

(4) Were incomplete outcome data adequately addressed?

(5) Are reports of the study free of suggestion of selective outcome reporting?

(6) Was the study apparently free of other problems that could put it at a risk

of bias?



(Continued)

Participants (characteristics of patient population)

Inclusion criteria

Exclusion criteria

Follow up period

Flow diagram (children only) Total Comparator A Comparator B

Number eligible

Excluded pre-allocation

Numbers entered

Excluded post-allocation

Number analysed

Appendix 6. Data extraction form 2

Reference

Dichotomous

variables

Definition Time point Comparator A Comparator B

Number assessed Number with

outcome

Number assessed Number with

outcome

Primary outcomes

(1) All cause

mortality

Death of

any randomised

patient regard-

less of cause

End of therapy

Other time point

˙˙˙˙˙˙˙˙˙˙˙˙˙˙

(2) IFI related

mortality

Death of a pa-

tient diagnosed

with

IFI whose death

is attributable to

IFI

End of therapy



(Continued)

Other time point

˙˙˙˙˙˙˙˙˙˙˙˙˙˙

(3) Com-

plete resolution

of fungal infec-

tion

Complete reso-

lution of clinical

symptoms +/- ra-

diological or mi-

crobi-

ological findings

that led to diag-

nosis of IFI and

enabling cessa-

tion of anti-fun-

gal medication

End of therapy

Secondary outcomes

(4) Complete or

partial resolution

of fungal infec-

tion

Any improve-

ment in clinical

symptoms +/- ra-

diological find-

ings that led to

diagnosis of IFI

yet not fulfilling

criteria for com-

plete resolution

End of therapy

(5) Resolution of

fever

in suspected fun-

gal infection

Absence of temperature > 38°C for

more than 72 hours

(6) Progression

of disease requir-

ing change / ad-

dition of an anti-

fungal agent

Progression of existing symptoms +/-

radiological or microbiological find-

ings that are of enough concern for a

clinician to change anti-fungal dose

or add a new anti-fungal agent

(7) Break-

through fungal

infection requir-

ing change / ad-

dition of an anti-

fungal agent

New clinical symptoms or signs +/-

radiological or microbiological find-

ings that are of enough concern for

clinicians to change antifungal dose

or add a new anti-fungal agent

(8) Any clini-

cally significant

adverse reactions

attributed to the



(Continued)

antifungal agent

resulting in dis-

continua-

tion, dose reduc-

tion or change in

therapy

(9) Any adverse

re-

action attributed

to the antifungal

agent including

(9a) Abnormal

renal function

≥ 100% rise in serum creatinine

Other definition of nephrotoxicity

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙

(9b) electrolyte

imbalance

hypokalaemia < 3.0mmol/L

other definition of hypokalaemia

other definitions of electrolyte im-

balance

(9c) abnormal

hepatic function

transaminases > 2x normal values for

age

Other definition of hepatotoxicity

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙

(9d) infusion re-

lated reactions

Any infusion related reactions

Chills (definition

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

Fevers (definition

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

Other infusion related reaction (def-

inition ˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

(9e) gas-

trointestinal dis-

turbances such as

nausea, vomiting

or diarrhoea

Any gastrointestinal disturbances



(Continued)

Nausea

Vomiting

Diarrhoea

(9f ) neurologi-

cal disturbances

such as blurred

vision or dizzi-

ness

Any neurological disturbances

Blurred vision

Dizziness

Other neurological disturbances

(9g) Haema-

tological distur-

bances such as

anaemia, granu-

locytopae-

nia or thrombo-

cytopaenia

Any haematological disturbances

Anaemia (definition

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

Granulocytopaenia (definition

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

Thrombocytopaenia (definition

˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

Dichotomous

variables

Definition Time point Comparator A Comparator B

Number assessed Mean (SD) Number assessed Mean (SD)

Secondary outcomes

(10) Length of

stay

number of days

(11) Quality of

life

QOL (defini-

tion˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙)

(12) Cost $US



W H A T ’ S N E W

Last assessed as up-to-date: 17 January 2010.

Date Event Description

21 February 2011 Amended Assessed as Up-to-date date amended.

H I S T O R Y

Protocol first published: Issue 1, 2007

Review first published: Issue 2, 2010

C O N T R I B U T I O N S O F A U T H O R S

All authors were involved in writing and reviewing the review.

D E C L A R A T I O N S O F I N T E R E S T

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.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

• The age range published in the original protocol was between 28 days and 18 years. This has been amended to between 28 days

and 16 years as this reflects the more frequently used age range in clinical trials.

• The sensitive search strategy was modified as per the Cochrane Handbook of Systematic Reviews of Intervention, Version 5.0.1,

September 2008, Chapter 6.4.11.

I N D E X T E R M SMedical Subject Headings (MeSH)

Adolescent; Amphotericin B [therapeutic use]; Antifungal Agents [∗therapeutic use]; Candidiasis [drug therapy]; Echinocandins [ther-

apeutic use]; Fever [drug therapy]; Mycoses [∗drug therapy; mortality]; Neutropenia [drug therapy]; Randomized Controlled Trials as

Topic



MeSH check words

Child; Child, Preschool; Humans; Infant



Documents

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