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Review
. 2016 Jan 16;2016(1):CD004920.
doi: 10.1002/14651858.CD004920.pub3.

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

Andrea Cortegiani  1 , Vincenzo Russotto, Alessandra Maggiore, Massimo Attanasio, Alessandro R Naro, Santi Maurizio Raineri, Antonino Giarratano
Affiliations
Review

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

Andrea Cortegiani et al. Cochrane Database Syst Rev. .

Abstract

Background: Invasive fungal infections are important causes of morbidity and mortality among critically ill patients. Early institution of antifungal therapy is pivotal for mortality reduction. Starting a targeted antifungal therapy after culture positivity and fungi identification requires a long time. Therefore, alternative strategies (globally defined as 'untargeted antifungal treatments') for antifungal therapy institution in patients without proven microbiological evidence of fungal infections have been discussed by international guidelines. This review was originally published in 2006 and updated in 2016. This updated review provides additional evidence for the clinician dealing with suspicion of fungal infection in critically ill, non-neutropenic patients, taking into account recent findings in this field.

Objectives: To assess the effects of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) compared to placebo or no antifungal or any other antifungal drug (either systemic or nonabsorbable) in non-neutropenic, critically ill adults and children. We assessed effectiveness in terms of total (all-cause) mortality and incidence of proven invasive fungal infections as primary outcomes.

Search methods: We searched the following databases to February 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), and EMBASE (OVID). We also searched reference lists of identified studies and major reviews, abstracts of conference proceedings, scientific meetings and clinical trials registries. We contacted experts in the field, study authors and pharmaceutical companies as part of the search strategy.

Selection criteria: We included randomized controlled trials (RCTs) (irrespective of language or publication status) comparing the use of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) to placebo, no antifungal, or another antifungal agent in non-neutropenic critically ill participants.

Data collection and analysis: Three authors independently applied selection criteria, extracted data and assessed the risk of bias. We resolved any discrepancies by discussion. We synthesized data using the random-effects model and expressed the results as risk ratios (RR) with 95% confidence intervals. We assessed overall evidence quality using the GRADE approach.

Main results: We included 22 studies (total of 2761 participants). Of those 22 studies, 12 were included in the original published review and 10 were newly identified. Eleven trials compared the use of fluconazole to placebo or no antifungal treatment. Three trials compared ketoconazole versus placebo. One trial compared anidulafungin with placebo. One trial compared caspofungin to placebo. Two trials compared micafungin to placebo. One trial compared amphotericin B to placebo. Two trials compared nystatin to placebo and one trial compared the effect of clotrimazole, ketoconazole, nystatin and no treatment. We found two new ongoing studies and four new studies awaiting classification. The RCTs included participants of both genders with wide age range, severity of critical illness and clinical characteristics. Funding sources from pharmaceutical companies were reported in 11 trials and one trial reported funding from a government agency. Most of the studies had an overall unclear risk of bias for key domains of this review (random sequence generation, allocation concealment, incomplete outcome data). Two studies had a high risk of bias for key domains. Regarding the other domains (blinding of participants and personnel, outcome assessment, selective reporting, other bias), most of the studies had a low or unclear risk but four studies had a high risk of bias.There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total (all-cause) mortality (RR 0.93, 95% CI 0.79 to 1.09, P value = 0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR 0.57, 95% CI 0.39 to 0.83, P value = 0.0001; participants = 2024; studies = 17). The risk of fungal colonization was significantly reduced (RR 0.71, 95% CI 0.52 to 0.97, P value = 0.03; participants = 1030; studies = 12) but the quality of evidence was low. There was no difference in the risk of developing superficial fungal infection (RR 0.69, 95% CI 0.37 to 1.29, P value = 0.24; participants = 662; studies = 5; low grade of evidence) or in adverse events requiring cessation of treatment between the untargeted treatment group and the other group (RR 0.89, 95% CI 0.62 to 1.27, P value = 0.51; participants = 1691; studies = 11; low quality of evidence). The quality of evidence for the outcome of total (all-cause) mortality was moderate due to limitations in study design. The quality of evidence for the outcome of invasive fungal infection, superficial fungal infection, fungal colonization and adverse events requiring cessation of therapy was low due to limitations in study design, non-optimal total population size, risk of publication bias, and heterogeneity across studies.

Authors' conclusions: There is moderate quality evidence that the use of untargeted antifungal treatment is not associated with a significant reduction in total (all-cause) mortality among critically ill, non-neutropenic adults and children compared to no antifungal treatment or placebo. The untargeted antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence is low, and both the heterogeneity and risk of publication bias is high.Further high-quality RCTs are needed to improve the strength of the evidence, especially for more recent and less studied drugs (e.g. echinocandins). Future trials should adopt standardized definitions for microbiological outcomes (e.g. invasive fungal infection, colonization) to reduce heterogeneity. Emergence of resistance to antifungal drugs should be considered as outcome in studies investigating the effects of untargeted antifungal treatment to balance risks and benefit.

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Conflict of interest statement

Andrea Cortegiani: none known

Vincenzo Russotto: none known

Alessandra Maggiore: none known

Alessandro R Naro: none known

Massimo Attanasio: none known

Antonino Giarratano: received grants, fees for educational presentation and advisory board membership, without any relationship to the submitted work, from Pfizer, Merck and Gilead. His institution received a grant from Gilead, Pfizer and Merck Sharp without any relationship to the submitted work.

Figures

1
1
Flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Untargeted treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal, outcome: 1.1 Mortality.
5
5
Forest plot of comparison: 1 Untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal, outcome: 1.2 Proven invasive fungal infection
6
6
Funnel plot of comparison: 1 Untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal, outcome: 1.2 Proven invasive fungal infection.
1.1
1.1. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 2 Proven invasive fungal infection.
1.3
1.3. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 3 Proven or suspected invasive fungal infection.
1.4
1.4. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 4 Suspected invasive fungal infection.
1.5
1.5. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 5 Superficial fungal infection.
1.6
1.6. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 6 Fungal colonization.
1.7
1.7. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 7 Proven invasive fungal infection (azole‐resistant Candida species).
1.8
1.8. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 8 Fungal colonization (azole‐resistant Candida species).
1.9
1.9. Analysis
Comparison 1 Primary analysis: untargeted antifungal treatment with any antifungal drug (systemic or nonabsorbable) compared to placebo/no antifungal/any other antifungal drug, Outcome 9 Adverse events requiring cessation.
2.1
2.1. Analysis
Comparison 2 Subgroup analysis, Outcome 1 Mortality. Types of participants.
2.2
2.2. Analysis
Comparison 2 Subgroup analysis, Outcome 2 Mortality. Fluconazole dose.
2.3
2.3. Analysis
Comparison 2 Subgroup analysis, Outcome 3 Mortality. Systemic or non‐absorbable antifungal drug.
2.4
2.4. Analysis
Comparison 2 Subgroup analysis, Outcome 4 Mortality. Drug class.
2.5
2.5. Analysis
Comparison 2 Subgroup analysis, Outcome 5 Mortality. Type of intervention.
2.6
2.6. Analysis
Comparison 2 Subgroup analysis, Outcome 6 Mortality. Type of control group.
2.7
2.7. Analysis
Comparison 2 Subgroup analysis, Outcome 7 Proven IFI. Type of participants.
2.8
2.8. Analysis
Comparison 2 Subgroup analysis, Outcome 8 Proven IFI. Fluconazole dose.
2.9
2.9. Analysis
Comparison 2 Subgroup analysis, Outcome 9 Proven IFI. Systemic or non‐absorbable antifungal drug.
2.10
2.10. Analysis
Comparison 2 Subgroup analysis, Outcome 10 Proven IFI. Drug class.
2.11
2.11. Analysis
Comparison 2 Subgroup analysis, Outcome 11 Proven IFI. Type of intervention.
2.12
2.12. Analysis
Comparison 2 Subgroup analysis, Outcome 12 Proven IFI. Type of control group.
3.1
3.1. Analysis
Comparison 3 Sensitivity analysis, Outcome 1 Mortality. Fixed‐effect model meta‐analysis.
3.2
3.2. Analysis
Comparison 3 Sensitivity analysis, Outcome 2 Mortality. Risk of bias for key domains: all studies.
3.3
3.3. Analysis
Comparison 3 Sensitivity analysis, Outcome 3 Mortality. Studies without any high risk of bias..
3.4
3.4. Analysis
Comparison 3 Sensitivity analysis, Outcome 4 Proven IFI. Fixed‐effect model meta‐analysis.
3.5
3.5. Analysis
Comparison 3 Sensitivity analysis, Outcome 5 Proven IFI. Risk of bias for key domains: all studies.
3.6
3.6. Analysis
Comparison 3 Sensitivity analysis, Outcome 6 Proven IFI. Studies without any high risk of bias.
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