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Synergy Testing of Antiamoebic Agents for Acanthamoeba

Antagonistic Effect of Voriconazole

Talbott, Maya BS*; Cevallos, Vicky MT*; Chen, Michael C. MD*,†; Chin, Stephanie A. BS*; Lalitha, Prajna MD; Seitzman, Gerami D. MD*,†; Lietman, Thomas M. MD*,†; Keenan, Jeremy D. MD, MPH*,†

doi: 10.1097/ICO.0000000000002055
Basic Investigation

Purpose: To determine whether combinations of commonly used antiamoebic agents display synergy in their ability to kill Acanthamoeba cysts in vitro.

Methods: Synergy testing was performed with a microdilution checkerboard assay on 10 clinical Acanthamoeba keratitis isolates collected at the Proctor Foundation from 2008 to 2012. Each isolate was exposed to pairwise combinations of chlorhexidine, propamidine, and voriconazole. The minimum cysticidal concentration (MCC) for each drug pair was estimated for each isolate, and the summed fractional cysticidal concentration (ΣFCC) was calculated for each drug combination in the checkerboard, with synergy defined as a lack of growth at a ΣFCC ≤ 0.5 and antagonism as growth at a ΣFCC > 4.

Results: Chlorhexidine and propamidine were cysticidal, with median MCCs of 12.5 (range 1.5–50) and 11.7 (range 0.2–250), respectively. Voriconazole was not cysticidal, with a median MCC of >10,000 μg/mL. The combination of chlorhexidine and propamidine did not markedly change the cysticidal activity compared with either drug alone. By contrast, voriconazole antagonized the cysticidal activity of both chlorhexidine and propamidine, with Acanthamoeba growth observed at antagonistic ΣFCCs in 27 of 49 (55.1%, 95% confidence interval 35.7%–78.6%) checkerboard combinations of voriconazole and chlorhexidine and in 58 of 147 (39.5%, 95% confidence interval 14.3%–50.3%) combinations of voriconazole and propamidine.

Conclusions: In an in vitro assay, voriconazole reduced the cysticidal activity of 2 commonly used antiamoebic drugs. Although the in vivo drug interactions could be different, these observations may be useful in cases of nonhealing Acanthamoeba keratitis being treated with combination therapies that include voriconazole.

*Francis I Proctor Foundation;

Department of Ophthalmology, University of California, San Francisco, San Francisco, CA; and

Microbiology Department, Aravind Eye Care System, Madurai, India.

Correspondence: Jeremy D. Keenan, MD, MPH, 513 Parnassus Avenue, Med Sci S334, Francis I. Proctor Foundation, University of California, San Francisco, CA 94143 (e-mail:

This study was supported by the National Institutes of Health (NIH K23EY019071, UL1RR024131, R34EY022368) and Research to Prevent Blindness.

The authors have no conflicts of interest to disclose.

Received January 19, 2019

Received in revised form May 01, 2019

Accepted May 24, 2019

Online date: July 10, 2019

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.