Antifungal agents for preventing fungal infections in critically ill adults and children with a normal number of neutrophils in the blood

Review question

We reviewed the evidence about the effect of giving antifungal medications before a definitive diagnosis of fungal infections on mortality from all causes and development of severe infections due to fungi (invasive fungal infections) in adults and children who are critically ill but non-neutropenic, i.e. with a normal number of neutrophils in their blood.

Background

Critically ill adults and children may suffer from invasive fungal infections, such as those affecting the bloodstream and other organs. Once established, such infections are difficult to treat and frequently result in death. Antifungal medications are sometimes given to critically ill adults and children most prone to developing fungal infections and to those with signs of infections when it is still unclear if a fungus is the cause.

Study characteristics

We included 22 randomized controlled trials (RCTs) (total of 2761 participants). 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. The RCTs included participants of both genders with a wide age range and severity of critical illness.

Search date

The evidence is current as of February 2015.

Study funding sources

Funding sources from drug manufacturers were reported in 11 out of 22 studies. Another study was funded by a government agency.

Key results

Results of 19 from 22 randomized trials involved 2374 participants and showed that antifungal medications given before definitive diagnosis of fungal infection did not reduce mortality from all causes. None of the studied drugs were associated with a significant reduction of mortality from all causes. However, results from 17 randomized studies involving 2024 participants showed that antifungal drugs significantly reduced the risk of developing invasive fungal infections.

We also reviewed the evidence from five trials (662 participants) about the effect of antifungal treatment on the development of superficial fungal infections but we did not find any significant difference. However, we found evidence from 12 trials (1020 participants) of a significant reduction of fungi in body sites (excluding blood) not causing an infection. Eleven trials (1691 participants) reported serious adverse events requiring cessation of therapy. We found no evidence of differences in serious adverse events requiring interruption of antifungal medications between people who received and those who did not receive them.

Quality of the evidence

The quality of evidence for the outcome of mortality (all-cause) 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 number of patients studied and results inconsistent across studies.

Conclusion

There is moderate quality evidence that the use of antifungal treatment given before definitive diagnosis of fungal infection is not associated with a significant reduction in mortality from all causes among critically ill adults and children with a normal number of neutrophils in the blood. This type of antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence on this point is low.

Further studies with high-quality design are needed to improve the evidence.

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.

Read the full 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 strategy: 

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.

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