Why BAK is Unnecessary in an Antibiotic
A Discussion on the Pros and Cons.
BY DAVID RITTERBAND M.D.

The preservative BAK has been used in varying concentrations in therapeutic eyedrops and contact lens solutions for many years. The paramount role for BAK has been to prevent drug decomposition in order to allow a greater shelf life for these products. While it is true BAK has bacteriostatic and fungistatic properties because of its ability to disrupt cell membrane permeability, its ability if any to improve penetration of antibiotics through the cornea is largely unknown. There are no in vivo studies demonstrating "enhanced" penetration of ocular antibiotics because of the addition of BAK. If a synergistic effect on penetration exists, it is because of disruption of the epithelial cell adhesions,which is in my opinion, an untoward side effect. Most ophthalmic drug companies have sought to reduce or eliminate BAK because of its toxicity. Allergan, especially, has made such moves recently with products such as Acular LS (ketorolac tromethamine 0.4%) and Alphagan P (brimonidine tartrate 0.15%). When evaluating a topical antibiotic, it is extremely important to take into account its potency, as well as its ability to penetrate the relevant ocular structures. In vitro potency is measured in terms of minimum inhibitory concentration (MIC). The drug with the lowest MIC for a specific pathogen will exhibit the greatest potency against that specific microbe. While important as a starting point, the pharmacokinetic properties of an antibiotic are also important.

Although the combination of gatifloxacin and BAK has been shown to have an additive effect in lowering the MIC against certain strains of bacteria,1 this study was performed in an in vivo system. It is important to recognize that the moment an antibiotic is placed into a patient's eye the commercial formulation is diluted in the tear-film. Therefore, when conducting kinetic and MIC studies of antibiotic efficacy on the ocular surface, the formulations must be diluted to closely mimic the actual concentrations achieved on the ocular surface. The Blondeau and colleagues report gives us the results as if the test had been conducted inside an antibiotic bottle and not on the ocular surface. This same flaw exists in a similar study2 in which the antimicrobial activity of gatifloxacin 0.3% with BAK was compared against self-preserved moxifloxacin 0.5% against various Staphylococcus strains. This kill-curve kinetic study does not take into effect the dilutional aspect of the tear film.

It is important to remember BAK was added to Zymar to prevent its degradation in the bottle. The experiments touting BAK's synergistic effect at lowering its MIC's1 and improving kill-curve kinetics2 were reported 1 to 2 years after its introduction to the marketplace. A savvy consumer would understand that these studies are in response to the overwhelming data that demonstrate moxifloxacin is a more potent antibiotic than gatifloxacin against gram positive organisms due to its lower MICs.3,4

Although it is true that the spectrum of BAK covers fungus and nonencysted amoeba, the incidence of contamination of ophthalmic solutions is uncommon. Most of the reports of contamination of multi-use eyedrops are caused by bacteria, which would not be of concern in an eyedrop bottle containing antibiotic.5 The data listed with the FDA have consistently shown that self-preserved moxifloxacin has inherent antifungal activity in the bottle and has exceeded the USP test results in order to attain approval.

The success of antibiotic therapy most lies in its ability to target ocular tissues at concentrations greater than the MICs of pertinent organisms. In vivo penetration studies have been conducted with all of the ophthalmic quinolones. In studies in human patients with typical ocular dosing, it has been demonstrated that moxifloxacin can safely penetrate the cornea and achieve a higher concentration in the aqueous of at least 2 to 3 times that of the other fluoroquinolones.6-8 In a recent study, Kim and colleagues8 also demonstrated that moxifloxacin was biologically more active than gatifloxacin against Staphylococcus epidermidis in aqueous humor after topical application. Further disk diffusion analysis by O'Brien and colleagues9 revealed that disks soaked with the mean moxifloxacin aqueous humor concentration resulted in a 24-mm zone of inhibition whereas gatifloxacin demonstrated no activity against the test organism Staphylococcus aureus. These two studies account for the real-world application of these drugs by considering both penetration and potency at the target site.

I am skeptical that BAK was added to Zymar specifically to improve its ability to eradicate bacteria synergistically. More likely, it was added to prevent degradation of the drug in the bottle. BAK has limited therapeutic value in the postoperative period when penetration and MIC are most important. BAK cannot penetrate into the aqueous humor and therefore would have no therapeutic effect in the postoperative dosing period when high aqueous levels of antibiotic are desired. The focus on the relevance of BAK has diverted the attention away from the pertinent issues when comparing therapeutic efficacy. Antibiotic concentration, MIC and penetration should be the issues that most warrant our attention. OM

References

1. Blondeau JM, Hedlin P, Borsos S. The antimicrobial activity of gatifloxacin with or without benzalkonium chloride (BAK) against ocular bacterial pathogens. Presented at: the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 1-5, 2005; Fort Lauderdale, Fla.

2. Eser I, Hyon JY, Hose S, O'Brien TP. Comparative antimicrobial efficacy of preserved and preservative-free topical fourth-generation fluoroquinolones against various strains of Staphylococcus. Presented at: the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); April 25-29, 2004; Fort Lauderdale, Fla.

3. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Opthalmol. 2003;136:500-505.

4. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002:133:463-466.

5. Shah M, Ritterband D, Seedor J, et al. Microbial contamination of multi-use ophthalmic medicine bottles. Presented at: The American Academy of Ophthalmology Annual Meeting, November 1998; New Orleans, La.

6. Solomon R, Donnenfeld ED, Perry HD, et al. Penetration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the aqueous humor. Ophthalmology. 2005;112:466-469.

7. Katz HR, Masket S, Lane SS, et al. Absorption of topical moxifloxacin ophthalmic solution into human aqueous humor. Cornea. 2005. In press.

8. Kim DH, Stark WJ, O'Brien TP et al. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery Patients. Ophthalmology. 2005. In Press.

9. Terrence P. O'Brien and David W. Stroman. A comparison of ccular penetration and microbiological efficacy of fourth generation fluoroquinolones in cataract surgery patients. Presented at: American Academy of Ophthalmology; October 2005; Chicago, Ill.