Effects of Amphotericin B and Caspofungin on Histamine Expression

John D. Cleary, Pharm.D., Michael Schwartz, Pharm.D., P. David Rogers, Ph.D., Jacqueline de Mestral, Stanley W. Chapman, M.D.


Pharmacotherapy. 2003;23(8) 

In This Article

Abstract and Introduction

Study Objective: To determine the effects of amphotericin B deoxycholate and caspofungin on the release of histamine from human peripheral blood cells, mononuclear cells, and mast cells.
Design: In vitro cell culture experiments.
Setting: University medical center.
Material: Cultured human mononuclear (THP-1) and mast (HMC-1) cells from five healthy volunteers.
Measurements and Main Results: The cultured cells were incubated with increasing concentrations of amphotericin B deoxycholate, diphenhydramine, amphotericin B deoxycholate plus diphenhydramine, caspofungin, caspofungin plus diphenhydramine, and the calcium ionophore A23187 for up to 24 hours. Histamine concentrations and histamine N-Methyltransferase activity were determined at various time points throughout exposure. Cell viability was assessed by exclusion of erythrocin B. The A23187 increased histamine concentrations from baseline in peripheral blood and HMC-1 cells. No change in histamine concentrations was observed in response to amphotericin B deoxycholate, whereas caspofungin induced a significant increase in histamine release in peripheral blood cells and HMC-1 cells. No change in histamine concentrations was observed in THP-1 cells in response to any pharmacologic agent tested. Similarly, histamine N-Methyltransferase activity in peripheral blood was not affected by amphotericin B deoxycholate, but was significantly decreased by caspofungin.
Conclusion: Amphotericin B deoxycholate does not affect histamine concentrations or histamine N-Methyltransferase activity in whole blood or HMC-1 cells, suggesting that the amphotericin B-induced infusion-related reaction is not a histamine-mediated event. Conversely, caspofungin increased histamine concentrations in whole blood and HMC-1 cells and inhibited histamine N-Methyltransferase activity. These data suggest that infusion-related reactions associated with caspofungin may be mediated by histamine release secondary to caspofungin.

Amphotericin B is a polyene antifungal agent that was initially isolated from Streptomyces nodus. Over the last 10 years, several new lipid amphotericin B formulations have been developed in addition to the several generic amphotericin B formulations now being manufactured. Innovative lipid products, for example, are an amphotericin B colloidal dispersion (Amphotec; Intermune Inc., Brisbane, CA); a liposomal formulation (AmBisome; Fugisawa Healthcare, Inc., Deerfield, IL), and an amphotericin B lipid complex (Abelcet; Enzon, Fairfield, NJ). Caspofungin is a pneumocandin antifungal that was approved by the Food and Drug Administration (FDA) in 2001.

A recent comparative trial found that 2.6% and 23.2% of antifungal-treated patients were withdrawn from therapy secondary to adverse reactions attributable to caspofungin and amphotericin B, respectively.[1] Both agents are associated with infusion-related reactions; however, these reactions seldom require drug withdrawal. Reactions related to amphotericin B infusions occur in 7.3-75.0% of patients. Symptoms usually appear 45-90 minutes after the start of the infusion of either agent.[2,3] In the candidemia trial comparing these agents,[1] infusion-related reactions were identified in 20% of caspofungin-treated patients and 48.8% of amphotericin B-treated patients. The frequency of infusion-related reactions is lower with lipid amphotericin (amphotericin B lipid complex) products (7.3%) than with amphotericin B (13.5%).[3]

The mechanism responsible for this infusion-related reaction has not been proven. A proposed mechanism of amphotericin B-induced reactions is the expression of interleukin-1 (IL-1) with secondary tumor necrosis factor (TNF) and prostaglandins by human mononuclear cells (hMNCs), which then alter the hypothalamic set point, inducing fever and chills. These reactions, we believe, are quite distinct from the histamine-induced reaction. Based on the clinical observations of histamine-like reactions (hypotension, tachycardia, nausea, vomiting, flushing, and headache) and the laboratory changes observed in microarray studies of N-Methyltransferase in complementary DNA, we hypothesized that both of these antifungals alter (caspofungin increases, amphotericin B decreases) histamine release from common reactor cells (mast cells and monocytes).[4,5] The purpose of our study was to identify the characteristics of histamine release and the mechanism for release secondary to amphotericin B and caspofungin exposure.