Clioquinol for Otomycosis: A Lesser Understood Antimicrobial

To the Editor: Peled et al. (1) provide a detailed analysis of their experience with otitis externa. Treatment of this disease should be augmented with knowledge of the following antimicrobial which is less well understood in comparison to more traditional topical antibacterial and antimycotic agents. Clioquinol is a halogenated 8-hydroxyquinoline (also known as iodochlorohydroxyquin) and is primarily used for its antimicrobial activity (2). It has been marketed under many different proprietary names worldwide in both otic solutions and skin creams. Since clioquinol is not a member of commonly-used and broadly active antimicrobial families, little specific knowledge of it is had by the vast majority of medical practitioners. Yet, there are many physicians that are more likely to use clioquinol anecdotally than many other antimicrobials that are formally explored in their medical training, even though the drug's indications are very limited. Introduced in the 1930s as a medicinally useful quinoline derivative for its antiseptic potential, clioquinol was intended to be a topical treatment for skin wounds and superficial infections. Clinical application became common well before rigorous clinical trials were ever completed. It then became a component of various dermatological preparations, often combined with one or more other pharmaceuticals. Clioquinol was formerly administered orally as a prophylactic agent for traveller's diarrhea and as an anti-amoebic agent. Although limited for oral absorption, blood levels have been found, and skin absorption, once thought incapable, is now acknowledged (3,4). The drug has broad antimicrobial activity including many bacteria, yeast, and molds that would be obtained from most external ear or superficial skin infections (5–7). The antibacterial spectrum is broad and includes common Gram-positive cocci, many Gram-negative bacilli, and mycobacteria. The antifungal effects are also broad spectrum (including both Candida spp. and Aspergillus spp.), although as an individual antimycotic, clioquinol is weaker than both clotrimazole and tolnaftate. The specific mechanisms of antimicrobial activity are not well understood, and the drug provides more of a microbistatic than microbicidal action (8). Nevertheless, the concentration of clioquinol in topical preparations is usually 1% to 3% which should exceed required local concentrations many-fold. As a single agent, therefore, clioquinol can be considered a broad spectrum antimicrobial with both antibacterial and antifungal properties. Although most physicians have likely never heard of clioquinol by name, it was the subject of considerable controversy by the 1970s. Given its initial promise as a traveller's diarrhea and anti-amoebic agent, prophylactic use in large populations became commonplace in some regions of the world. When used orally, however, studies found a dose- and time-related toxicity of the central nervous system including subacute myelo-optic neuropathy and amnesia (9–11). Cumulative data in regards to neurotoxicity then led to a ban on oral clioquinol use in many countries (12). Elsewhere, oral use continues to attract clinical controversy (13). Skin toxicity from local exposure, or a worsening of eczema has occurred (14,15). Some 0.7 to 2.2% of patients will develop a primary dermatitis with topical clinical applications (16,17). Fixed drug eruptions after topical or other use were also reported (18,19). Patch test sensitivity varied over 0.73 to 12% (20,21). Cross-sensitization to other halogenated compounds has been reported (22). By 1965, flumethasone became available for clinical use as a topical steroid and was thought to be an improvement over hydrocortisone. Some otic solutions contain 1% clioquinol and 0.02% flumethasone pivalate for clinical use. The latter combination with flumethasone has been successfully exploited for the treatment of otitis externa generally and specifically for mycotic otitis externa (23–26). Simultaneous efficacy against both bacterial and mycotic pathogens has attracted such therapeutic interest. Several precautions with otic use should be observed. Significant absorption of clioquinol systemically with topical ear use is unlikely, but past concerns of neurotoxicity should lead physicians to refrain use in the context of tympanic perforation. Although clioquinol has quite broad antimicrobial activity, resistance among some Gram-negative bacteria has been found. A microbial culture should be obtained when there is seemingly drug failure after 5 to 7 days of application. Given clioquinol's potential to cause a local hypersensitivity reaction, despite being compounded with flumethasone, contact dermatitis due to clioquinol should also be considered in addition to resistant infection when the outer ear pathology continues during extended application.

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