Weekly high-dose liposomal amphotericin B (L-AmB) in critically ill septic patients with multiple Candida colonization: The AmBiDex study

Abstract

BackgroundTo demonstrate the feasibility and safety of weekly high-dose liposomal amphotericin B (L-AmB) (as a pre-emptive antifungal treatment) for 2 weeks in patients with septic shock and Candida colonization.MethodsPilot, multicentre, open-label, prospective study conducted in seven French ICUs. Non-immunocompromised patients, receiving mechanical ventilation were eligible if they presented ICU-acquired severe sepsis requiring newly administered antibacterial agents and Candida colonization in at least two sites. Exclusion criteria included the need for antifungal therapy and creatinine > 220 μmol/L. All patients were to receive a high-dose L-AmB (10 mg/kg/week) for two weeks. A follow-up period of 21 days following the second administration of L-AmB was conducted. Treated patients were compared to 69 matched untreated controls admitted in the same ICUs before the study period.ResultsTwenty-one patients were included in the study, of which 20 received at least one infusion of high-dose L-AmB. A total of 24 adverse events were identified in 13(61%) patients. Fourteen adverse events were categorized as serious in 8(38%) patients. In four cases the adverse events were considered as potentially related to study drug administration and resulted in L-AmB discontinuation in one patient. Few patients experienced severe renal toxicity since no patient presented with severe hypokalemia. No patients required renal replacement therapy. Compared to matched controls, no significant increase in serum creatinine levels in patients receiving high-dose L-AmB was reported.ConclusionsWeekly administration of high-dose L-AmB has a manageable safety profile and is feasible in patients with ICU-acquired sepsis and multiple Candida colonization. Trials of L-AmB versus other antifungal agents used as pre-emptive antifungal therapy are warranted.Trial registrationClinicalTrials.gov NCT00697944

Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen

“…after one week of infusion 9,16 . However, prophylaxis or the preemptive use of high L-AmB doses once per week was associated with frequent adverse effects and was not completely safe for fungemia prevention 4,22 . Comparatively, regimens for ambulatory treatment with L-AmB 50 mg or 100 mg four to five times per week yielded median Cmin values of amphotericin B that were higher than the MIC of amphotericin B for the Cryptococcus spp.…”

Amphotericin B in the Era of New Antifungals: Where Will It Stand?

“…The AmBiDex study evaluated weekly high-dose L-AmB in critically ill septic patients with multiple Candida colonizations [173]. There was no significant increase in serum creatinine levels in patients receiving 10 mg/kg/week L-AmB compared with matched controls [173].…”

“…The AmBiDex study evaluated weekly high-dose L-AmB in critically ill septic patients with multiple Candida colonizations [173]. There was no significant increase in serum creatinine levels in patients receiving 10 mg/kg/week L-AmB compared with matched controls [173]. In a phase 3 randomized controlled trial of 537 adult patients receiving at least one dose of micafungin (100 mg/day for patients >40 kg; 2 mg/kg/day for patients ≤40 kg) or L-AmB (3 mg/kg/day), treatment success rates in ICU patients were similar for micafungin (n = 120) vs. L-AmB (n = 110), 62.5% vs. 66.4%, respectively (p = 0.5828) [174].…”

Novel evidence on sepsis-inducing pathogens: from laboratory to bedside

“…Data on resistance/ susceptibility would appear to draw a trend of inverse sensitivity between compounds of the echinocandin group and fluconazole, with C. albicans displaying higher figures of resistance to echinocandin compounds than non-albicans species and lower figures of resistance to azole compounds than non-albicans species (Al-Dorzi et al, 2018;Jung et al, 2020;Guner Ozenen et al, 2023). Nevertheless, it has been reported that empirical administration of high-dose liposomal amphotericin B (L-AmB) is associated with better management of fungal invasiveness, less ICU-acquired candidemia, less need for an antifungal agent additional to L-AmB, and ultimately a reduction in ICU mortality, emphasizing the feasibility and relative safety of a preemptive antifungal therapy strategy to combat bloodstream Candida colonization (Azoulay et al, 2017). Regardless of the advancements detailed insofar, this review emphasizes the knowledge gap in molecular factors of resistance for Candida species, particularly when compared to the bacterial agents of sepsis reviewed above.…”