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Clinical Sciences |

Effect of Low Concentrations of Benzalkonium Chloride on Acanthamoebal Survival and Its Potential Impact on Empirical Therapy of Infectious Keratitis

Elmer Y. Tu, MD; Megan E. Shoff, PhD; Weihua Gao, MS; Charlotte E. Joslin, OD, PhD
JAMA Ophthalmol. 2013;131(5):595-600. doi:10.1001/jamaophthalmol.2013.1644.
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Importance The significant antiacanthamoebal effect of benzalkonium chloride, at or below concentrations used for preservation of common ophthalmic preparations, should be understood both when choosing empiric antibiotic therapy for infectious keratitis and when assessing the persistent rise in Acanthamoeba cases in the United States since 2003.

Objective To characterize the antiacanthamoebal efficacy of low concentrations of benzalkonium chloride (BAK) for drug preservation and therapeutic effect against Acanthamoeba.

Design Experimental study with a review of the literature.

Setting Laboratory.

Exposures A concentration of 104 trophozoites of 3 well-characterized clinical strains of Acanthamoeba were exposed at 0.5, 2.0, 3.5, 5.0, and 6.5 hours to BAK (0.001%, 0.002%, and 0.003%), moxifloxacin hydrochloride (0.5%), and moxifloxacin (0.5%) + BAK (0.001% and 0.003%) with hydrogen peroxide (3%) and amoeba saline controls.

Main Outcomes and Measures Amoeba survival was calculated using the most probable number method recorded as log kill values. The relationship of BAK concentration and exposure time as well as the relative effect of BAK and moxifloxacin on acanthamoebal survival were analyzed.

Results Amoebicidal activity of BAK is both time dependent and concentration dependent in pooled and strain-stratified analyses (P < .001). Moxifloxacin demonstrated no significant independent inhibitory effect or additive effect to BAK efficacy on acanthamoebal survival. The profound antiacanthamoebal effect of BAK, 0.003%, was similar to that of hydrogen peroxide for certain strains.

Conclusions and Relevance Low concentrations of BAK, previously demonstrated to concentrate and persist in ocular surface epithelium, exhibit significant antiacanthamoebal activity in vitro at or below concentrations found in commercially available ophthalmic anti-infectives. The unexplained persistence of the Acanthamoeba keratitis outbreak in the United States, clusters abroad, and clinical studies reporting resolution or modification of Acanthamoeba keratitis without specific antiacanthamoebal therapy suggests that other contributing factors should be considered, including changes in the formulations used for empirical therapy of presumed infectious keratitis occurring in the same period.

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Figures

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Figure 1. Pooled results for the log kill results of 3 strains of Acanthamoeba (Acanthamoeba castellanii, Acanthamoeba hatchetti, and Acanthamoeba polyphaga) when exposed to benzalkonium chloride (BAK) (0.001%, 0.002%, and 0.003%) and hydrogen peroxide, 3%, plotted by time. Each time point represents 3 different strains each performed in triplicate (n = 9). Error bars indicate standard deviation.

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Figure 2. Log kill results of Acanthamoeba castellanii when exposed to benzalkonium chloride (BAK) (0.001%, 0.002%, and 0.003%) and hydrogen peroxide, 3%, plotted by time. Each time point represents a single strain performed in triplicate (n = 3). Error bars indicate standard deviation.

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Figure 3. Log kill results of Acanthamoeba hatchetti when exposed to benzalkonium chloride (BAK) (0.001%, 0.002%, and 0.003%) and hydrogen peroxide, 3%, plotted by time. Each time point represents a single strain performed in triplicate (n = 3). Error bars indicate standard deviation.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 4. Log kill results of Acanthamoeba polyphaga when exposed to benzalkonium chloride (BAK) (0.001%, 0.002%, and 0.003%) and hydrogen peroxide, 3%, plotted by time. Each time point represents a single strain performed in triplicate (n = 3). Error bars indicate standard deviation.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 5. Pooled results for the log kill results of 3 strains of Acanthamoeba (Acanthamoeba castellanii, Acanthamoeba hatchetti, and Acanthamoeba polyphaga) when exposed to moxifloxacin alone, moxifloxacin + benzalkonium chloride (BAK), 0.001%, and moxifloxacin + BAK, 0.003%. Each time point represents 3 different strains each performed in triplicate (n = 9). Error bars indicate standard deviation.

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