Does use of the polyene natamycin as a food preservative jeopardise the clinical efficacy of amphotericin B? A word of concern

Abstract

Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety concern. However, highly soluble natamycin-cyclodextrin inclusion complexes have been developed for the protection of beverages. This practice leads to high drug exposures exceeding the safety level. Apart from the definition of an acceptable daily dietary exposure to natamycin, its effect on the faecal flora as a reservoir for resistance has to be examined. Consumption of food to which natamycin has been added and mixed homogeneously, such as yoghurt, and in particular the addition of cyclodextrin inclusion complexes to beverages and wine generates high faecal natamycin concentrations resulting in high drug exposures of faecal Candida spp. Development of natamycin resistance has been observed in Candida spp. colonising the intestinal tract of patients following natamycin treatment of fungal infections. Horizontal gene transfer among different Candida spp. and within Aspergillus fumigatus spreads resistance. Therefore, it cannot be denied that use of natamycin for preservation of yoghurt and beverages may foster development of resistance to polyenes in Candida spp.

For Debate: May the Use of the Polyene Macrolide Natamycin as a Food Additive Foster Emergence of Polyene-Resistance in Candida Species?

“…and jeopardizing the clinical efficacy of Amphothericin B [36] has been discussed controversially [37,38]. Evidence has been presented that Natamycin exerts a negligible in vitro resistance-selective potential in pathogenic yeasts and other probably opportunistic fungal pathogens [39].…”

“…may expose the human faecal Candida spp. flora to antimicrobially active drug concentrations [36]. Consumption of yoghurt containing the novel Natamycin formulation may result in an estimated 2-day daily intake of Natamycin from background and proposed uses for the total US population of 0.61 to 1.22 mg/day [41].…”

“…Assuming that the entire amount of Natamycin consumed with yoghurt is deposited in the faeces and is freely available and thus antifungally active, mean faecal Natamycin concentrations exceed its MICs for Candida spp. [36].…”

“…under these particular circumstances. Furthermore, fungi harbouring polyene resistance originating from environmental sources or having been selected as a consequence of Amphothericin B-or Nystatin therapy may render other faecal fungal species polyene resistant by horizontal gene transfer [36]. This hypothesis implies that first, polyene resistance can indeed be elicited in vitro and in vivo; second, that a polyene resistance reservoir does exist; third, that in case a polyene resistance reservoir does exist, Natamycin may exert a resistance selective potential thus amplifying Amphothericin B resistance, and fourth, that resistance can be spread.…”

Fast Sample Preparation Method Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry for Natamycin Determination in Wine Samples

“…1 Natamycin or pimaricin is an antibiotic belonging to the group of polyene macrolides produced by actinomycetes Streptomyces natalensis. 2,3 Several studies reported the use of natamycin for the surface treatment of cheeses and dry sausages [4][5][6] and most recently, in antimicrobial packaging systems. 7 Natamycin cannot be added to wines because it is classified as a non-permitted additive by the Code of Enological Practices of the International Organization of Vine and Wine (OIV).…”