• Antifungal therapy
• Aspergillosis
• Candidiasis
• Critically ill patient
• Intensive care unit
• Invasive fungal infections
• Liposomal amphotericin B
• Mold infections

• BDG
• Intra-abdominal candidiasis
• L-AmB

• Aged
• Female
• Humans
• Male
• Middle Aged
• Candidiasis/drug therapy
• Critical Illness
• Peritonitis/drug therapy
• Prospective Studies

• antifungal
• drug utilization
• intra-abdominal candidiasis
• invasive candidiasis
• surgical procedures

• Humans
• Antifungal Agents/therapeutic use
• Candidiasis/drug therapy
• Intraabdominal Infections/drug therapy
• Risk Factors
• Anti-Bacterial Agents/therapeutic use

• Antifungal prophylaxis
• Aspergillosis
• Candidiasis
• Cryptococcus
• Invasive fungal infections
• Liver transplantation

• heart transplantation
• invasive aspergillosis
• liposomal amphotericin B
• prophylaxis

• antifungal prophylaxis
• breakthrough-invasive fungal infection
• echinocandins
• liver transplant recipients

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen.

• Invasive fungal infection
• antifungal stewardship
• liposomal amphotericin B
• outpatient parenteral antibiotic treatment
• triazole resistance

Triazoles remain first-line agents for antifungal prophylaxis in high-risk haemato-oncology patients, but their use is increasingly contraindicated due to drug–drug interactions and additive toxicities with novel treatments. In this retrospective, single-centre, observational study, we present our eight-year experience of antifungal prophylaxis using intermittent high-dose liposomal Amphotericin B (L-AmB). All adults identified through our Antifungal Stewardship Programme as receiving L-AmB prophylaxis at 7.5 mg/kg once-weekly between February 2012 and January 2020 were included. Adverse reactions, including infusion reactions, electrolyte loss, and nephrotoxicity, were recorded. ‘Breakthrough’ invasive fungal infection (IFI) occurring within four weeks of L-AmB was classified using European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Moreover, 114 courses of intermittent high-dose L-AmB prophylaxis administered to 92 unique patients were analysed. Hypokalaemia was the most common grade 3–4 adverse event, with 26 (23%) courses. Grade 3 nephrotoxicity occurred in 8 (7%) and reversed in all six patients surviving to 90 days. There were two (1.8%) episodes of breakthrough IFI, one ‘probable’ and one ‘possible’. In this study, the largest evaluation of intermittent high-dose L-AmB prophylaxis conducted to date, toxicity was manageable and reversible and breakthrough IFI was rare. L-AmB prophylaxis represents a viable alternative for patients with a contraindication to triazoles.

• acute leukaemia
• amphotericin B
• antifungal prophylaxis
• graft-versus-host disease (GvHD)
• hematopoietic stem-cell transplantation (HSCT)
• triazoles

• Acute liver failure
• Acute-on-chronic liver failure
• Candidemia
• Cirrhosis
• Invasive fungal infection
• Sepsis

• Antifungal Agents/therapeutic use
• Humans
• Invasive Fungal Infections/diagnosis
• Invasive Fungal Infections/drug therapy
• Invasive Fungal Infections/epidemiology
• Liver Transplantation/adverse effects
• Mycoses/diagnosis
• Mycoses/drug therapy
• Mycoses/epidemiology

The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug.

High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1).

Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died.

By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

• clinical trial
• fungal infection
• liposomal amphotericin B
• pharmacodynamics
• pharmacokinetics

• Amphotericin B/pharmacokinetics
• Animals
• Antifungal Agents/pharmacokinetics
• Fungi/drug effects
• Humans
• Invasive Fungal Infections/drug therapy
• Invasive Fungal Infections/microbiology
• Treatment Outcome

• Fungal infections
• Solid organ transplantation

• amphotericin B
• invasive fungal infection
• liver transplant
• targeted prophylaxis

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.

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.

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.

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.

ClinicalTrials.gov NCT00697944

• Amphotericin B
• Amphotericin B (PubChem CID: 5280965)
• Antifungal drugs
• Clotrimazole (PubChem CID: 2812)
• Dendrimers
• Fluconazole (PubChem CID: 3365)
• Fungal infections
• Griseofulvin (PubChem CID: 441140)
• Itraconazole (PubChem CID: 55283)
• Ketoconazole (PubChem CID: 456201)
• Liposomes
• Micelles
• Miconazole (PubChem CID: 4189)
• Nanoemulsions
• Nanoparticles
• Nystatin (PubChem CID: 6433272)

• allergic aspergillosis
• amphotericin
• aspergillosis
• azoles
• chronic aspergillosis
• echniocandins
• fungal diagnostics
• invasive aspergillosis

• accelerated blood clearance
• biological challenges
• complement activation–related pseudoallergy
• drug delivery
• lipid-based drug delivery system
• liposomes
• nanotechnology
• translation