Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days

Joanne Livermore,Catherine Walker,Werner Müller,Andrew D Sharp,Julie A Schwartz,Bill Moser,William W Hope,Lea Gregson,John R Perfect,Thomas S Harrison,Susan J Howard,Joanne Goodwin,Timothy Felton,George L Drusano

doi:10.1128/mbio.00725-13

Abstract

ABSTRACT Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log10 CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3+ CD4+ or CD3+ CD8+ cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis.

Highlights

IntroductionInduction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings
Cryptococcal meningoencephalitis is an urgent global health problem
This paper provides the experimental basis for the efficacy of abbreviated regimens of dAmB for cryptococcal meningitis

Summary

Introduction

Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. In well-resourced health care settings, induction therapy with at least 2 weeks of amphotericin B deoxycholate (dAmB) is advocated. In well-resourced health care settings, effective antifungal regimens and combinations for cryptococcal meningitis are relatively well delineated. Because prolonged parenteral therapy is too expensive and/or there are inadequate resources to monitor for and manage drugrelated toxicity These obstacles are especially pertinent for many parts of sub-Saharan Africa, which has a disproportionate share of the world’s burden of cryptococcal meningitis.

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Results

Conclusion