The European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published 2019 guidelines for management of invasive candidiasis. For a non-neutropenic, critically ill patient with invasive candidiasis, echinocandins (caspofungin, micafungin, anidulafungin) are the preferred first-line empirical therapy, particularly for patients with septic shock or multiple organ failure. This recommendation is supported by their fungicidal activity, broader spectrum against non-albicans species like C. glabrata and C. krusei, and studies showing a potential mortality benefit in critically ill populations. However, fluconazole is considered a suitable first-line option for critically ill patients with low disease severity (without septic shock) in settings with low fluconazole resistance, provided the patient has had no recent azole exposure. Its value lies in its tolerability and lower cost. If fluconazole is used, a weight-based loading dose of 12 mg/kg, followed by 6 mg/kg maintenance dosing, is strongly recommended to overcome the pharmacokinetic variability common in ICU patients and achieve target drug levels. [1]
According to the 2016 IDSA guidelines for management of candidiasis, echinocandins (caspofungin, micafungin, anidulafungin) are favored as initial therapy for most adult patients with candidemia due to their fungicidal efficacy, favorable safety profile, and the rising concern of fluconazole resistance. Fluconazole is considered an acceptable first-line alternative only for patients who are not critically ill, have had no recent azole exposure, and are at low risk for infection with C. glabrata. For patients who respond well to initial echinocandin therapy, have documented clearance of Candida from the bloodstream, and are infected with a susceptible isolate, step-down therapy to oral fluconazole (or voriconazole for C. krusei) is recommended, typically after 5-7 days. This guideline also notes that while C. parapsilosis has higher echinocandin MICs in vitro, clinical data do not show superiority of fluconazole at the time, so echinocandins remain a recommended first-line option even for this species. [2]
Per the 2025 ECMM guidelines, echinocandins are also strongly recommended as first-line treatment for candidemia, favored for their broad spectrum (including against C. auris), safety, and limited drug interactions. Fluconazole is only marginally recommended for initial therapy due to high rates of treatment failure and increasing antifungal resistance in many regions. However, switching to oral fluconazole or voriconazole is a moderately recommended option for step-down therapy after at least 5 days of echinocandin treatment, provided the patient is hemodynamically stable, has documented bloodstream clearance, and the isolate is susceptible. [3]
Based on the 2017 European Conference on Infections in Leukemia (ECIL) guidelines, echinocandins (anidulafungin, caspofungin, micafungin) are strongly recommended as the first-line therapy for invasive candidiasis, including in hematologic and neutropenic patients, though the quality of evidence is lower for this specific group due to limited trial data. Fluconazole and voriconazole are considered potential alternatives for first-line treatment only in non-severe cases where there has been no prior azole exposure. After species identification, echinocandins remain the preferred drug class for most species. The guideline notes that, while fluconazole was traditionally considered more appropriate for C. parapsilosis, recent observational data showed no difference in outcomes with echinocandin-based regimens, so continuing an echinocandin is acceptable if the patient is responding. Step-down therapy to oral fluconazole (or voriconazole for C. krusei) is recommended after five days of intravenous therapy in stable patients with a susceptible isolate. A critical accompanying recommendation is the prompt removal of central venous catheters, which is independently associated with decreased mortality. [4]
A 2021 Australasian consensus guideline for the diagnosis and management of invasive candidiasis recommends echinocandins as first-line therapy for most adults with candidemia, particularly those who are critically ill, neutropenic, or at higher risk of poor outcomes. This recommendation is based on randomized controlled trials and meta-analyses demonstrating higher overall treatment success with echinocandins compared with azoles, including in patients infected with azole-susceptible isolates. Azole therapy (most commonly fluconazole) is considered appropriate in selected patients who are clinically stable, non-neutropenic, and have no risk factors for azole resistance, and remains a key option for step-down therapy once blood cultures have cleared, the patient is hemodynamically stable, able to tolerate oral therapy, and the infecting Candida species is confirmed to be azole-susceptible. The guidelines also note that species-specific susceptibility is central to treatment selection, as reduced fluconazole susceptibility is more common in Candida glabrata complex and Candida tropicalis, while Pichia kudriavzevii is intrinsically resistant to fluconazole. Liposomal amphotericin B is presented as an alternative option with comparable efficacy to echinocandins but higher toxicity, reserved for situations where echinocandins cannot be used or resistance is suspected. For uncomplicated candidemia, a minimum treatment duration of 14 days after documented bloodstream clearance is recommended, with antifungal choice and de-escalation guided by clinical response and susceptibility results. [5]
According to a 2025 comprehensive review, echinocandins are strongly recommended as first-line treatment for severe candidemia in non-neutropenic patients, supported by a 2012 meta-analysis evidence showing they reduce mortality (odds ratio [OR] 0.50) and improve therapeutic success compared to other antifungals. This recommendation is based on their broad spectrum, favorable safety profile, and low resistance risk. However, the review highlights a critical challenge in intra-abdominal candidiasis, a common presentation in ICU patients. In this specific scenario, echinocandins may have suboptimal efficacy due to significantly lower drug concentrations in peritoneal fluid (up to 33% lower than in serum), which often fail to reach target levels needed to treat common species like C. albicans and N. glabratus. This pharmacokinetic limitation, compounded by physiological changes in critically ill patients, creates a niche for developing antifungal resistance. Consequently, the review suggests optimization strategies such as dose adjustment in obesity or considering amphotericin B formulations for their better peritoneal penetration and anti-biofilm activity in complex abdominal infections. [6], [7]
A 2015 review concluded from a literature review that while echinocandins and fluconazole each have distinct roles in managing candidemia, neither is ideal for every scenario. Based on the available evidence at the time, primarily from the single randomized trial comparing anidulafungin to fluconazole and a patient-level meta-analysis, the authors state that echinocandins had not been shown to be clearly superior to fluconazole for overall treatment, though anidulafungin was at least non-inferior and possibly more effective. The authors note significant nuance for specific situations: for C. glabrata, echinocandins were associated with better clinical success but not improved survival, and emerging echinocandin resistance linked to prior drug exposure was a concerning trend; for C. parapsilosis, despite higher echinocandin MICs, clinical outcomes appeared similar to fluconazole. In critically ill patients, they highlight conflicting data from subgroup analyses. Ultimately, their recommendations advocate for using institution-specific resistance patterns to guide empirical therapy, suggesting an echinocandin is reasonable for critically ill patients or where fluconazole-resistant C. glabrata is prevalent, while fluconazole remains appropriate for stable, non-immunosuppressed patients and for specific sites like endophthalmitis. They strongly endorse a strategy of starting with an echinocandin and stepping down to fluconazole for stable patients with susceptible isolates and emphasize the critical importance of proper, often weight-based, fluconazole dosing. The authors ultimately argue that optimizing the use of existing antifungal agents through better diagnostics and stewardship is paramount, as rapid treatment initiation may be more crucial than the specific agent choice. [8]
A 2012 individual patient-level quantitative review of seven RCTs evaluating antifungal therapy for candidemia and other forms of invasive candidiasis analyzed outcomes in 1,915 patients and assessed the impact of host, organism, and treatment-related factors on mortality and clinical success. In this pooled analysis, overall 30-day mortality was 31.4%, and multivariable logistic regression demonstrated that treatment with an echinocandin antifungal was independently associated with reduced mortality compared with polyenes or triazoles (OR 0.65; 95% confidence interval [CI] 0.45 to 0.94; p= 0.02), while triazole therapy was not associated with a survival benefit. Similar associations were observed for the composite endpoint of clinical and microbiologic success. The survival benefit of echinocandins was consistent across patients with candidemia due to Candida albicans and non-albicans Candida species and across a range of disease severities, as measured by APACHE II scores, although drug class did not significantly affect outcomes in patients with the highest severity of illness. In addition to antifungal choice, removal of a central venous catheter during treatment was independently associated with improved survival (OR 0.50; 95% CI 0.35 to 0.72; p= 0.0001). These findings support the use of an echinocandin as initial therapy for candidemia, particularly when compared with azole therapy, based on observed associations with improved mortality and treatment success in randomized trial data. [9]
A 2015 review concluded that while echinocandins and fluconazole each have distinct roles in managing candidemia, neither is ideal for every scenario. Based on the available evidence at the time, primarily from the single randomized trial comparing anidulafungin to fluconazole and a patient-level meta-analysis, the authors state that echinocandins had not been shown to be clearly superior to fluconazole for overall treatment, though anidulafungin was at least non-inferior and possibly more effective. They note significant nuance for specific situations: for C. glabrata, echinocandins were associated with better clinical success but not improved survival, and emerging echinocandin resistance linked to prior drug exposure was a concerning trend; for C. parapsilosis, despite higher echinocandin MICs, clinical outcomes appeared similar to fluconazole. In critically ill patients, they highlight conflicting data from subgroup analyses. Their recommendations advocate for using institution-specific resistance patterns to guide empirical therapy, suggesting an echinocandin is reasonable for critically ill patients or where fluconazole-resistant C. glabrata is prevalent, while fluconazole remains appropriate for stable, non-immunosuppressed patients and for specific sites like endophthalmitis. They strongly endorse a strategy of starting with an echinocandin and stepping down to fluconazole for stable patients with susceptible isolates and emphasize the critical importance of proper, often weight-based, fluconazole dosing. [10]