Single high-dose liposomal amphotericin B for the treatment of cryptococcal meningitis: guidelines recommendations and unresolved issues

In February 2024, the European Confederation of Medical Mycology (ECMM), International Society for Human and Animal Mycology (ISHAM), and American Society for Microbiology (ASM) jointly published the “Global guideline for the diagnosis and management of cryptococcosis” (1), which proposed induction therapy for cryptococcal meningitis and central nervous system infections in high-income regions. This includes administering liposomal amphotericin B (LAmB) at a dosage of 3–4 mg/kg daily, in combination with flucytosine at 25 mg/kg four times daily. For low-income regions, the guidelines recommend a single high dose of LAmB at 10 mg/kg, accompanied by a two-week regimen of flucytosine at 25 mg/kg four times daily and fluconazole at 1,200 mg daily. The recommendations apply to both people living with or without human immunodeficiency virus (HIV). However, they highlight the absence of data on the efficacy of a single high-dose LAmB in solid organ transplant (SOT) recipients, or for other cryptococcal disease syndromes.

The AMBITION study, published in NEJM in 2022, provides evidence supporting the efficacy of a single high-dose LAmB regimen (2). Conducted across eight hospitals in five African countries, the study enrolled people living with HIV to compare the efficacy of a single 10mg/kg dose of LAmB against the standard 7-day regimen of amphotericin B deoxycholate combined with flucytosine. Results indicated that the single-dose LAmB group, with a 10-week all-cause mortality rate of 24.8%, was not inferior to the standard treatment group’s 28.7%, and exhibited fewer toxic reactions. Fungal clearance rates were comparable between the two groups. A review questioned the regimen’s suitability for high-income regions, highlighting the need for cautious evidence evaluation when applying findings from low- and middle-income countries (LMICs) to high-income countries’ treatment guidelines, especially in the absence of randomized controlled trial (RCT) data (3). For instance, variations in control schemes and the ability to monitor and manage HIV- and treatment-related complications render direct mortality rate comparisons inappropriate. Nonetheless, the AMBITION study’s findings suggest that this antifungal combination effectively clears cryptococcus from cerebrospinal fluid, offering lower drug-related toxicity, reduced intravenous treatment duration, and a more convenient regimen, making it a potentially valuable treatment option in multiple settings.

Another meta-analysis which includes three RCTs and 946 people living with HIV with cryptococcal meningitis also shows that single, high-dose LAmB is associated with a lower risk of life-threatening adverse events (4). In addition, the single high-dose LAmB strategy offers an obvious financial advantage over 14 days of LAmB and it is extremely important for LMICs. In 2024, the cost of LAmB was US $160 per 50-mg vial in South Africa and US $160 in China. Thus, safety benefits of single high-dose LAmB may increase utilization of this strategy, which may help lessen the financial burden of treating invasive fungal infections in people with HIV. However, further research is needed to confirm whether such a strategy is suitable for non-HIV patients.

Investigating the efficacy of this regimen in people without HIV is valuable. Given the disparities in mortality rates, immune responses, and disease severity, studies indicate that non-HIV individuals with cryptococcal meningitis experience more severe symptoms and elevated mortality rates (5-7). Furthermore, while the AMBITION study focused on amphotericin B deoxycholate, current international guidelines predominantly recommend LAmB. The potential for lower toxicity in this regimen also merits further investigation. For example, the susceptibility of the Chinese population to drug-induced hepatotoxicity necessitates additional research into the tolerability of fluconazole at a dose of 1,200 mg/day (8-10). Lastly, future research should consider the variations in cryptococcus in vitro minimum inhibitory concentrations (MIC) reported in international studies (11-15).

In summary, the single high-dose administration of LAmB for treating cryptococcal meningitis is safe and effective. It can also significantly reduce the health economic burden in LMICs and is worthy of promotion. However, whether this strategy should be applied to people without HIV remains to be confirmed. Further large-scale RCTs are needed to determine if those patients can also benefit from this strategy. Additionally, more evidence from evidence-based medicine is required to support the new guidelines.

Acknowledgments

Funding: This work was supported by the Project of the Key Laboratory of Multiple Organ Failure, Ministry of Education (2023KF07), the Key Laboratory of Intelligent Pharmacy and Individualized Treatment in Huzhou City (HZKF-20240101), and the Guangxi Key Laboratory for Diagnosis and Treatment of Acute Respiratory Distress Syndrome (ZZH2020013-3), China.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Emergency and Critical Care Medicine. The article has undergone external peer review.

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-50/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-50/coif). Y.T.Y. serves as an unpaid executive editor of Journal of Emergency and Critical Care Medicine from September 2023 to September 2024. The other authors have no conflicts of interest to declare.

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