24 June 2026

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Introduction

Invasive fungal infections are life-threatening conditions that predominantly affect immunocompromised or critically ill patients, carrying high mortality and morbidity across any fungal species and disease manifestation. Given the scarcity of well-designed clinical trials and complex patient management, antifungal treatment decisions are often tradition-driven rather than evidence-based, resulting in prolonged treatment durations and reluctance to switch to oral regimens. In bacterial infections, a growing body of evidence of large, randomised trials supports shorter antibiotic courses and oral routes, even in severe diseases such as sepsis and bloodstream infections.1-4 This prompts the question: can the same shift in paradigm be applied to antifungal therapy?

Current guidelines recommend a minimum of 14 days of antifungal treatment following bloodstream clearance in uncomplicated candidemia.5 This dogma, however, is based on expert opinion rather than randomised evidence and is being increasingly questioned.

Treatment shortening in candidemia

Candidemia is a bloodstream infection most commonly affecting immunocompromised and critically ill patients. Candida species rank among the leading causes of nosocomial bloodstream infections globally.5-7 A pooled meta-analysis reported an incidence of 3.9 per 100,000 population, with a case fatality rate of approximately 45%, rising further in intensive care settings.6

Shorter treatment duration could confer meaningful patient-level benefits: decreased antifungal-induced toxicity, limiting disruption of the mycobiome with consequent reduction of resistant Candida strain emergence, and shorter hospital stay with its associated risks of nosocomial infections and functional decline.

Current guidelines recommend a minimum of 14 days of antifungal treatment following bloodstream clearance in uncomplicated candidemia.5 This dogma, however, is based on expert opinion rather than randomised evidence and is being increasingly questioned.5.8.9 Observational data support this uncertainty: A retrospective cohort study found no significant difference in 30-day mortality between patients receiving short-course (<14 days) and standard-course antifungal therapy in uncomplicated candidemia, suggesting that shorter treatment may be safe in selected patients.10 To facilitate rigorous evaluation, a consensus definition of uncomplicated candidemia has been proposed to enable patient stratification in future clinical trials.11

Shorter treatment duration could confer meaningful patient-level benefits: decreased antifungal-induced toxicity, limiting disruption of the mycobiome with consequent reduction of resistant Candida strain emergence, and shorter hospital stay with its associated risks of nosocomial infections and functional decline.9,12 Reduction of treatment duration and novel dosing strategies may also carry meaningful health-economic benefits.9,13

Three ongoing randomized controlled trials are now directly addressing this question by comparing 7- or 10- versus 14-day antifungal treatment in uncomplicated candidemia: the French CANDISHORT trial (NCT06859671), the US-based SCAT trial (NCT06907992) and the German CanTEN trial (NCT pending). Together, these studies are expected to provide the first high-quality evidence challenging the established 14-day standard. Preliminary results are anticipated within the next two years.

Reconsidering treatment duration in invasive mould infections

Invasive mould infections are most commonly represented by invasive aspergillosis, typically present as pulmonary infection in immunocompromised patients, particularly those with hematological malignancies and solid organ transplant recipients with mortality rates of up to 40 %.14

Guidelines recommend treatment of invasive aspergillosis for a minimum of 6 to 12 weeks, depending on the degree of immunosuppression and disease improvement.15,16 However, clinical practice deviates frequently, due to lack of robust decision-making tools and concern of relapse following discontinuation. In every day clinical life, treatment can extend up to several months17 often driven by persistent severe immunosuppression or the inability to reduce the current immunosuppressive regimen.

In the context of rising resistance among Aspergillus species, which may be further driven by prolonged treatment duration, reconsideration of extended treatment durations is crucial. This is particularly relevant given that azole-resistant invasive aspergillosis is associated with higher mortality rates.18 Additionally, adverse events related to prolonged treatment durations, such as photosensitivity and induction of skin cancer associated with voriconazole, are not negligible and directly impact patient quality of life.19,20

Guidance of antifungal treatment of invasive mould infections presents unique clinical challenges, particularly in resource-limited settings, including the low sensitivity of culture-based diagnostics and the limited reliability and standardisation of serum biomarkers and molecular diagnostics. Furthermore, there is a lack of prospective randomised trial data on optimal timing and criteria for antifungal treatment cessation.

While randomized controlled trials remain the gold standard to inform clinical practice, evidence from well-conducted observational and retrospective studies will continue to guide treatment durations for very rare invasive fungal infections where trial feasibility is limited.

To safely guide treatment discontinuation in invasive mould infections, stopping rules have recently been proposed encompassing clinical stability, resolution of symptoms, ≥90% radiological response, negative biomarkers and low or no grade of immunosuppression.21 Assessment of metabolic activity of fungal lesions by positron emission tomography–computed tomography (PET-CT) may hold the potential to distinguish active infection from scarring and to further support discontinuation of antifungal treatment.22 Beyond serum galactomannan, which typically normalises early in treatment-responsive patients,23 emerging diagnostic tools including metagenomic next-generation sequencing,24 new molecular diagnostic tools, host immune phenotyping25 and new antigen detection assays like fungal siderophores26 hold promise for more nuanced treatment monitoring and guiding cessation decisions. Finally, only a randomized clinical trial can shed light on optimal treatment duration.27

Towards oral strategies in invasive fungal infections

The field of antimicrobial therapy is undergoing a decisive recalibration: in bacterial infections, including endocarditis and bone and joint infections, recent trials have legitimized early switch to oral therapy, challenging the long-held primacy of intravenous treatment.28,29

This paradigm shift, however, remains conspicuously underdeveloped in invasive fungal infections, where the perceived need for early fungicidal activity to mitigate high mortality sustains a “safe-default” bias towards intravenous initiation. Yet this conservatism deserves re-examination. Most triazoles offer excellent oral bioavailability, and the burdens of intravenous therapy, including complications of vascular access lines, reduced patient autonomy, and costs are non-trivial. The central tension lies in patient selection: while oral strategies may be reasonable in clinically stable patients after adequate diagnostic work-up and source-control, relevant guidelines remain cautious in their algorithms for timing and transition, reflecting a persistent absence of high-quality data.15,29 Furthermore, oral switch is only encouraged after target plasma level in triazoles is achieved.15,16,30 The current lack of oral options in azole-resistant or breakthrough fungal infections further complicates the landscape. Looking forward, the emergence of novel oral agents such as ibrexafungerp, fosmanogepix, and olorofim could be transformative, but clinical validation is pending.31 Designing trials in this space remains challenging, given the need for large samples sizes to demonstrate non-inferiority, the logistical barriers to randomizing critically ill patients, and the limited funding for pragmatic trials. Bridging this evidence gap will be essential to redefine the oral versus intravenous debate in invasive fungal infections.

Beyond shortening fixed treatment durations, personalized, response-guided strategies represent the next logical frontier. By integrating novel biomarkers, host immune phenotyping, and functional imaging, clinicians may be able to tailor treatment duration to each patient’s individual disease trajectory

Future developments and outlook

The field of antifungal therapy stands at an inflection point. For candidemia, three ongoing randomised trials are poised to generate the first prospective evidence challenging the 14-day treatment dogma. For invasive mould infections, advances in non-culture diagnostics hold promise to enable individualised, response-guided treatment cessation. While randomized controlled trials remain the gold standard to inform clinical practice, evidence from well-conducted observational and retrospective studies will continue to guide treatment durations for very rare invasive fungal infections where trial feasibility is limited. Beyond shortening fixed treatment durations, personalized, response-guided strategies represent the next logical frontier. By integrating novel biomarkers, host immune phenotyping, and functional imaging, clinicians may be able to tailor treatment duration to each patient’s individual disease trajectory. Looking ahead, several novel antifungals in late-stage development offer activity against drug-resistant fungi alongside oral bioavailability, potentially transforming treatment sequencing. Taken together, these developments point towards a future that a “less is more” approach may become an evidence-based paradigm across the spectrum of invasive fungal infections.

Ilana Reinhold is a specialist in infectious diseases and internal medicine at the University Hospital of Cologne, Germany, where she is completing a postdoctoral fellowship. During her residency in internal medicine and infectious diseases in Fribourg and Zurich, Switzerland, she developed a particular interest in immunocompromised patients and invasive fungal infections. She is an active contributor to international registry-based cohorts in fungal infections. Her research focuses on invasive candidiasis, rare mould infections, and the conduct of clinical trials in medical mycology.

Rosanne Sprute is a physician–scientist at the University Hospital Cologne, focusing on translational strategies for the management of invasive fungal infections. Her work centres on high-risk patient populations, including those with hematologic malignancies and critically ill patients. She is involved in clinical trials investigating novel anti-infective therapies and contributes to the development of national and international clinical guidelines. In her laboratory research, Rosanne studies host immune responses to fungal pathogens, aiming to improve diagnostic approaches and develop new immunotherapeutic strategies.

Jannik Stemler is a specialist in haematology and oncology at the University Hospital of Cologne. He specialises in infections in the immunocompromised host, leads the Clinical Trial Centre for Infectious Diseases, and is Deputy Director of the Excellence Centre for Invasive Fungal Disease in Cologne. He has participated in numerous epidemiological studies and clinical trials of novel anti-infective drugs. He is an author of over 90 peer-reviewed articles and has been active in international scientific working groups and the development of guidelines in his field.

Oliver Cornely is Professor and Director of the Institute of Translational Research at CECAD, University of Cologne, and Scientific Director of the Centre for Clinical Trials. A board-certified specialist in internal medicine, infectious diseases, haematology, and oncology, he focuses on infections in immunocompromised patients, particularly invasive fungal diseases, antimicrobial resistance, and vaccine-preventable infections. He is the former President of the European Confederation of Medical Mycology (ECMM), President-elect of ISHAM, founder of the Infectious Diseases Working Group of the European Hematology Association, and leads the VACCELERATE Site Network. He also serves as Editor-in-Chief of Mycoses and is among the top 1% most cited researchers, with over 1,000 publications.

Conflict of interest:

The authors declare that they do not have any relationships or affiliations that could be construed as a potential conflict of interest.

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This article was developed collaboratively by GARDP and CMI Communications and published on both websites simultaneously. Since 2025, selected Antimicrobial Viewpoint articles have been co-published on both, REVIVE and CMI Communications, as part of this collaboration.

PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

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