PRESERVATIVES

At Glaucoma 2014 at the American Society of Cataract and Refractive Surgery annual meeting in Boston, US, presenters were asked to defend or attack the use of preservatives in topical glaucoma medications. Though his presentation did not reflect his true opinions or practice patterns, Malik Y Kahook MD of the University of Colorado, Denver, US, presented the case for preservatives, while Paul Harasymowycz MD, University of Montreal, Canada, argued against.

Dr Kahook noted that BAK is a quaternary ammonium compound with detergent properties that non-selectively disrupts cell walls. For decades it has been used quite successfully to protect multi-dose containers from microbial contamination. But studies and clinical experience also suggest that BAK exposure may complicate existing ocular surface disease or precipitate it over time, a finding supported by much clinical observation.

BAK also complicates filtration surgery, Dr Harasymowycz said. Preoperative exposure to BAK is an independent risk factor for early trabeculectomy failure (Boimer C, Birt CM. J Glaucoma. 2013 Mar 20. Epub ahead of print), though this may be reversible with pre-surgical steroid treatment (Broadway D et al. Arch Ophthalmol. 1996, 114:262-267. Breusegem C et al. Ophthalmology. 2010 Ju;117(7):1324-30).

A nuanced case for preservatives

But while such findings make a compelling case for avoiding BAK-preserved glaucoma eye drops in filtration patients, eliminating them altogether may not be practical or even desirable. According to Dr Kahook, the case against preservatives rests largely on in vitro studies showing that BAK kills cultured human corneal and conjunctival epithelial cells in concentrations found in eye drops. Further, a dose-response relationship between BAK concentration and cell death rate makes the in vitro case even more compelling. These studies also show that adding an active ingredient, such as latanoprost, to the BAK solution does not increase cell death, suggesting that the preservative is the main culprit.

However, these studies have several weaknesses. For one, in vitro exposure generally runs 25 to 30 minutes, much longer than drops remain in the eye. So unless BAK accumulates in human tissue – which has not been definitively proven – soaking cells in BAK “may not perfectly replicate clinical exposure. The leap in conclusions from the petri dish to the patient requires more investigation with better clinical metrics than those available to us today,” Dr Kahook said.

Several large randomised studies also have failed to show that BAK damages the corneal surface, at least initially, Dr Kahook noted. For example, two studies comparing latanoprost BAK with bimatoprost BAK or travoprost with sofZia, found no significant differences in conjunctival hyperaemia, corneal staining or tear break up time at three months (Whitson et al. J Ocul Pharmacol Ther. 2010 June; 26(3): 287-92) or 12 weeks (Chricton et al. Adv Ther. 2013 Mar; 30(3): 26-70).

BAK provides benefits, Dr Kahook said. It is a very effective preservative that meets global standards for multi-dose bottles. It enhances formulation options with some medications, and enhances penetration of less-lipophilic medications, increasing their efficacy. In his practice, Dr Kahook finds the majority of patients do well on generic medications that contain significant BAK. So alternative preservatives or preservative-free formulations can be reserved for patients with significant ocular surface disease.

“Like everything we debate there is always a grey zone. BAK is safe for many patients, but many others do suffer from ocular surface disease related to chronic exposure,” Dr Kahook said. He looks forward to greater use of less toxic but equally effective preservatives, such as polyquad, and lower- cost preservative-free formulations.

Malik Kahook: malik.kahook@gmail.com

Paul Harasymowycz:
pharasymowycz@sympatico.ca