Mixtures of Quaternary Ammonium Compounds and Long-chain Fatty Acids as Antifungal Agents

KULL, F. C. (CIBA Pharmaceutical Products Inc., Summit, N. J.), P. C. EISMAN, H. D. SYLWESTROWICZ, AND R. L. MAYER. Mixtures of quaternary ammonium compounds and long-chain fatty acids as antifungal agents. Appl. Microbiol. 9:538-541. 1961.-The influence of undecylenic acid on the fungistatic effect of phenoxyethyldimethyldodecylammonium bromide (Domiphen bromide) against Trichophyton mentagrophytes was investigated. The unsaturated fatty acid was found to enhance the fungistatic activity of Domiphen bromide against this organism. The ratio of concentrations of these agents has a marked influence on the results of in vitro tests for antifungal action resulting in a completely different effect than heretofore noted in combination experiments against bacteria. The enhancing phenomenon is not particular to T. mentagrophytes, it was observed also with Candida albicans. A large number of varied substances are known to counteract the germicidal activity of cationic detergents. Among these antagonists, anionic agents are the most prominent. It is generally believed that this interference is comparable to the neutralization of acids by alkalies. Notwithstanding their conspicuous lack of activity against the bacteria, a number of anionic agents, in particular, the fatty acids, possess significant antifungal activity approximating in magnitude that of the quaternary ammonium compounds. The interesting question therefore arises as to whether the combination of an active cationic detergent with one of the anionic agents having antifungal activity would result in regular abolition of antifungal properties such as is known to occur with respect to antibacterial activity. Foley and Lee (1947) found that with several preparations containing trimethylcetylammonium pentachlorphenate and undecylenic acid, a marked inhibitory effect was exerted against several dermatophytes. At certain pH levels and depending upon the nature of the solubilizing vehicles used, the mixtures were more effective against these fungi than either component I Present address: Armed Forces Institute of Pathology, Walter Reed Army Medical Center, Washington, D. C. alone. Reiss and Lustig (1948), on the other hand, found neither an additive nor an enhancing effect upon fungi with combinations of quaternary ammonium compounds and undecylenic acid. In view of these contradictory reports, an attempt was made to more precisely establish the effect of phenoxyethyldimethyldodecylammonium bromide (Domiphen bromide; Bradosol2) (Neipp and Gross, 1949; Eisman and Mayer, 1947; Eisman et al., 1947) and undecylenic acid upon each other, particularly as it relates to fungistatic activity. MATERIALS AND METHODS The quaternary ammonium compound used in this stuidy, Domiphen bromide, possesses considerable activity against a wide range of bacteria and fungi as well. The anionic agent employed, undecylenic acid, has only very slight antibacterial but considerable antifungal activity; it is a common ingredient used in many preparations for the treatment of tinea pedis. The antimicrobial activities of Domiphen bromide and undecylenic acid were evaluated by recording the presence or absence of growth in varying dilutions of either substance dissolved in suitable broth; these end points of activity were compared with those obtained with mixtures of the two agents combined in a variety of ratios. In the antibacterial tests (Staphylococcus aureus and Escherichia coli), the substances were 2 CIBA Pharmaceutical Products Inc., Summit, N. J. TABLE 1. Combined action of Domiphen bromide and undecylenic acid upon Staphylococcus aureus Domiphen bromide concn (mg/100 ml) Undecylenic acid concn 0.40 0.33 0.29 0.25 0.22 0.20 0