DOES BAK MATTER?

Antimicrobial effects from commercially available antibiotic drops come not only from the active antibiotic component but also from additives such as benzalkonium chloride (BAK), included in formulations as a “preservative.†These preservatives serve to maintain the 'sterility' of multi-dose eye drop bottles, exerting their effect over hours of contact time within the container. To pass FDA standards, the agent must be able to reduce bacterial counts as specified in standardised testing. Clinicians often ask about what practical antimicrobial effects we can expect from the BAK component of antibiotic solutions in the treatment or prevention of eye infections, particularly as BAK is associated with ocular irritation and potential effects on corneal wound healing. In our two previous articles, we outlined comparative antimicrobial delivery from topical eye drops to the tears and aqueous humour (AH). Here we will complete this discussion by including the antimicrobial contribution of BAK, under practical clinical circumstances, to the tears and AH.

Two studies reported that the BAK containing ZymarR product (gatifloxacin 0.3 per cent + BAK 0.005 per cent) killed bacteria faster in vitro than did VigamoxR (moxifloxacin 0.5 per cent; no BAK).1,2 The BAK component of Zymar was thought to speed bacterial kill rates and even increase efficacy against MRSA strains that might be resistant to gatifloxacin alone. Hyon and associates2 also tested BAK 0.005 per cent separately, finding that bacterial killing of staphylococcal species required one hour of exposure time to the BAK. Despite the finding that BAK increased bacterial kill rates, these results drew attention to the fact that even the full strength commercial antibiotic drops often required a 'drug-bug' contact time of more than 15 minutes, in vitro, to reliably kill common ocular pathogens such as S. aureus and S. epidermidis, with most MRSA remaining viable after a full hour's contact time when BAK was not present. These findings were notable because they highlighted a time factor requirement for BAK bacterial killing to occur. Yet, the time frames and drug concentrations tested were still not consistent with reallife clinical circumstances surrounding drop administration to the eye.

Despite this, speculation remained about potential bacterial killing effects of BAK within shorter periods of time than those tested (5-15 minutes). Another study3 then examined bactericidal effects of BAK along with diminishing concentrations of fluoroquinolone antibiotics. Rapid bacterial killing from BAK alone was observed within 5-15 minutes, but only with higher concentrations of BAK (ie: above 50mg/L [50 μg/ml] or 0.005 per cent), but not at lower concentrations such as 8-32 μg/ ml. However, Freidlander and associates4 had previously shown that after a drop of Zymar,R BAK tear concentrations fell to 6.4μg/ml by 30 seconds after instillation, and to 3.2 μg/ml by one minute after a drop. At these concentrations, the study by Haas and associates3 indicates that very little bactericidal activity in the tear3 film can be anticipated from the BAK component alone, within time frames and concentrations resembling drop administration to the eye.

BAK and the aqueous humour

Given that a bactericidal effect in tears from the BAK component of eye drops is unlikely, is there any effect from BAK in the AH after topical drops? After drop administration to normal eyes, BAK is detected in corneal tissue, mostly epithelium, and conjunctiva. However, when AH is sampled to determine drug penetration, appreciable amounts of BAK are not found. On the surface of the eye, this agent serves to increase corneal permeability, but its own molecular penetration into the anterior chamber is poor. Safely tolerated concentrations of BAK in eye drops are well defined and usually below 0.05 per cent.

Therefore, in analyses of eye drops that do, or do not, contain BAK, in vitro findings cannot be extrapolated to the AH, for example, because this chemical moiety does not pass through the normal cornea along with the active antibiotic ingredient, and so cannot exert a synergistic or additive effect with the antibiotic in the AH. In summary, BAK is a useful and effective antimicrobial when used as a preservative in multiple dose eye drop bottles. It also serves to enhance corneal permeability for many topical agents. However, literature reports that describe an additive or synergistic effect for BAK in topical antibiotic formulations did so in the context of the laboratory setting, where BAK concentrations and duration of exposure to microbes did not mimic real-life conditions on the surface of the eye. Furthermore, no appreciable diffusion of BAK occurs through a normal cornea to the AH, so that an antimicrobial additive or synergistic effect there should not be anticipated. While in selected instances, some microbial strains may prove susceptible to brief time/ concentration profiles of BAK from eye drops, the current literature suggests that such expectations may be unrealistic under clinical conditions, and certainly not for prophylaxis where the AH or anterior chamber of the eye play an important role.

References 1. Callegan MC, Novosad BD, Ramadan RT, et al. Rate of bacterial eradication by ophthalmic solutions of fourthgeneration fluoroquinolones. Adv Ther 2009;26:447-454. 2. Hyon JU, Eser I, O'Brien TP. Kill rates of preserved and preservative-free topical 8-methoxy fluoroquinolones against various strains of Staphylococcus. J Cat Refract Surg 2009;35:1609-1613. 3. Haas W, Pillar CM, Hesje CK, et al. In vitro time-kill experiments with besifloxacin, moxifloxacin and gatifloxacin in the absence and presence of benzalkonium chloride. J Antimicrob Chemother 2011;66:840-844. 4. Freidlander MH, Breshears D, Amoozgar B et al. The dilution of benzalkonium chloride (BAK) in the tear film. Advances in Therapy 2006;23:835-841.