Who should be treated with high dose liposomal amphotericin B?

R. Herbrecht

Author address: 

Department of Hematology and Oncology, Hôpital de Hautepierre, Strasbourg, France

Abstract: 

Liposomal amphotericin B has been on the market for many years but we still do not know the optimal daily dose for the treatment of invasive fungal infections. Most initial clinical trials were performed with a 13 mg kg1 day1 dose and did not show superior efficacy over conventional amphotericin B. To date, the only study demonstrating a higher efficacy rate of liposomal amphotericin B over conventional amphotericin B in invasive aspergillosis was conducted with a 5 mg kg1 day1 dose (Leenders et al., Br J Haematol 1998). An attempt to investigate the doseefficacy relationship failed to demonstrate the superiority of a 4 mg kg1 day1 dose over a 1 mg kg1 day 1 dose in the first line therapy of invasive aspergillosis (Ellis et al. Clin Infect Dis 1998). However only a limited number of the patients enrolled in this study had a documented infection making the conclusion of absence of difference less relevant. This study never significantly influenced clinical practice with physicians being reluctant to lower the dose to 1 mg kg1 day1. A dose escalating clinical study demonstrated that daily dosages ranging from 7.5 to 15 mg/kg were well tolerated in patients with a filamentous fungal infection (Walsh et al. Antimicrob Agents Chemother 2001). Mean maximal plasma drug concentrations of the drug have been as high as 120 lg ml1 in patients treated with a daily dose of 10 mg kg1. Interestingly, 52% of the patients treated for at least 7 days responded favourably to the treatment. These data created a rational to explore higher doses of liposomal amphotericin B in clinical practice although subsequent animal studies showed no improvement in survival between 1, 3 and 5 mg kg1 day1 in a murine model of invasive aspergillosis (Martin et al. J Antimicrob Chemother 2003). Many physicians have treated patients with doses higher than the approved 35 mg kg1 day1 regimen but with few published evaluation of this approach. An open labelled non-comparative study was conducted in Spain in 10 patients with probable or proven invasive aspergillosis treated in first line with 10 mg kg1 day1 of liposomal amphotericin B (Ruiz et al., ICAAC, 2003). Nine patients responded favourably suggesting excellent efficacy of this regimen. A similar approach is currently being explored in United Kingdom in filamentous fungi infections (Kinsey et al., Meeting of the British Society of Haematology, 2004). An interim analysis showed that 12 of 20 patients responded favourably with a 12-week survival of 60%. A large double blind trial comparing 3 vs. 10 mg kg1 day1 for 14 days followed by 3 mg kg 1 day1 in patients with invasive filamentous fungi infections has been recently completed and the results should be presented soon. A large number of the patients included had documented invasive aspergillosis. These results should definitively answer the question of a beneficial effect of high dose liposomal amphotericin B. Regarding the extremely high cost of liposomal amphotericin B, the only suggestion we can make is to stay with the standard dose of 35 mg kg1 day1 for invasive aspergillosis till more information are available and to only discuss higher doses for the most severe invasive fungal infections such as zygomycosis.
2005

abstract No: 

S13.4

Full conference title: 

2nd Trends in Medical Mycology
    • TIMM 2nd (2010)