Antifungal therapy for newborn infants with invasive fungal infection.

RATIONALE: A variety of antifungal drugs, drug preparations and drug combinations are available to treat newborn infants with suspected or confirmed invasive fungal infection. There is a need to assess their relative merits. OBJECTIVES: To evaluate the benefits and harms of treatment with one antifungal drug or drug combination or preparation versus another on mortality and morbidity in newborn infants with suspected or confirmed invasive fungal infection. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Emcare, and three trial registers up to 14 November 2025; and CINAHL to June 2025. We searched reference lists of studies and reviews. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing one antifungal agent or combination of agents with another in newborn (preterm and term) infants with suspected or confirmed invasive fungal infection. We excluded cross-over studies and studies with placebo as a comparator. OUTCOMES: Our outcomes of interest were death (all-cause) prior to hospital discharge; moderate to severe neurodevelopmental impairment (NDI); adverse reactions attributed to the antifungal agent resulting in discontinuation of the therapy; length of hospital stay; and escalation of antimicrobial therapy. RISK OF BIAS: We used Cochrane's Risk of Bias 1 (RoB 1) tool. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis where possible, calculating risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with 95% CIs for continuous outcomes. We used GRADE to assess the certainty of evidence. INCLUDED STUDIES: We included six studies (229 infants) comparing one antifungal agent or combination of agents with another in newborns. Studies varied in the antifungal prescribed (one study compared amphotericin B with fluconazole, two studies compared amphotericin B with micafungin, two studies compared amphotericin B with caspofungin and one study compared micafungin with fluconazole). Studies were predominantly conducted in high- and middle-income countries. SYNTHESIS OF RESULTS: We downgraded the overall certainty of evidence for all outcomes because of limitations in study design (e.g. performance bias due to unblinded intervention and detection bias due to unblinded outcome assessment), indirectness and serious imprecision of results, with wide confidence intervals and few events. Fluconazole compared to amphotericin B We are very uncertain about the effect of fluconazole on death (all-cause) prior to hospital discharge (RR 0.73, 95% CI 0.26 to 2.05; I² not applicable; 1 study, 23 participants; very low-certainty evidence), adverse reactions attributed to the antifungal agent that resulted in discontinuation (RR Not estimable; 1 study, 23 participants; very low-certainty evidence), or length of hospital stay (MD -2.70, 95% CI -26.50 to 21.10; I² not applicable; 1 study, 23 participants; very low-certainty evidence), when compared to amphotericin B (plus 5-fluorocytosine if fungal meningitis was present, which was not required by any participant). No studies reported on the composite outcome of moderate to severe NDI, or escalation of antifungal therapy. Micafungin compared to amphotericin B We are very uncertain about the effect of micafungin on death (all-cause) prior to hospital discharge (RR 1.20, 95% CI 0.29 to 4.90; I² = 0%; 2 studies, 86 participants; very low-certainty evidence), adverse reactions attributed to the antifungal agent that resulted in discontinuation (RR Not estimable; 1 study, 56 participants; very low-certainty evidence), or length of hospital stay (MD -5.33, 95% CI -14.82 to 4.16; I² not applicable; 1 study, 56 participants; very low-certainty evidence). No studies reported on the composite outcome of moderate to severe NDI, or escalation of antifungal therapy. Caspofungin compared to amphotericin B We are very uncertain about the effect of caspofungin on death (all-cause) prior to hospital discharge (RR 0.43, 95% CI 0.13 to 1.48; I² = 0%; 2 studies, 82 participants; very low-certainty evidence), or adverse reactions attributed to the antifungal agent that resulted in discontinuation (RR 0.10, 95% CI 0.01 to 1.71; I² not applicable; 2 studies, 81 participants; very low-certainty evidence). No studies reported on the composite outcome of moderate to severe NDI, escalation of antifungal therapy, or length of hospital stay. Micafungin compared to fluconazole We are very uncertain about the effect of micafungin on death (all-cause) prior to hospital discharge (RR 0.67, 95% CI 0.13 to 3.53; I² not applicable; 1 study, 36 participants; very low-certainty evidence), or adverse reactions attributed to the antifungal agent that resulted in discontinuation (RR Not estimable; 1 study, 36 participants; very low-certainty evidence). No studies reported on moderate to severe NDI, escalation of antifungal therapy, or length of hospital stay. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of fluconazole or micafungin on death before hospital discharge, adverse reactions attributed to the antifungal agent that result in discontinuation, or length of hospital stay, when compared to amphotericin B. The evidence is very uncertain about the effect of caspofungin on death before hospital discharge, or adverse reactions attributed to the antifungal agent that result in discontinuation, when compared to amphotericin B. The evidence is very uncertain about the effect of micafungin on death before hospital discharge or adverse reactions attributed to the antifungal agent that result in discontinuation, when compared to fluconazole. Large RCTs with low risk of bias are required to compare antifungal drugs, drug preparations or drug combinations for treating newborn infants with invasive fungal infection. Future RCTs should stratify participants by gestational age and should also measure antifungal resistance and long-term neurodevelopmental outcomes. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol (2002) DOI: 10.1002/14651858.CD003953 Original review (2004) DOI: 10.1002/14651858.CD003953.pub2 Review update (2012) DOI: 10.1002/14651858.CD003953.pub3.