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

Abstract

Background: To 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.

Methods: Pilot, 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.

Results: Twenty-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.

Conclusions: Weekly 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 registration: ClinicalTrials.gov NCT00697944.

Conflict of interest statement

Competing Interests: EA has been a consultant for Astellas, Alexion, Cubist, Gilead and MSD. His institution received research grants from Gilead and Pfizer. JFT has given lectures for symposiums set up by Merck, Pfizer, Gilead, and Astellas and has been a consultant involved in scientific boards for Merck. His institution received research grants from Astellas. YC has given lectures for symposiums set up by MSD, Pfizer and Astellas and has been a consultant involved in scientific boards for JFIR MSD. His institution received research grants from Pfizer and MSD. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Patient flow chart, management, and 28-day follow-up in 21 patients enrolled in the study.

Fig 2. Box plots representing serum creatinine in patients receiving high-dose L-AmB and 59 matched controls.

This figure shows six couples of boxplots, one couple for each visit days of follow up. The X axis shows the visit days of follow up (Day 1, Day 2, Day 7, Day 14, Day 21, and Day 28) and the Y axis the measured values of serum creatinine (μmol/L). The shaded box indicates the middle 50% of the data; the lower and upper ends of this box therefore indicate the 25th and 75th percentiles, respectively. The solid black horizontal line through each shaded box indicates the median of the distribution and the black cross the mean. The circles above the vertical solid black lines are individual outliers. P values are provided above each pair of combinations.