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BAK has proven history of safety, efficacy
Clinicians should consider compliance, comfort, dosage, frequency and length of treatment when choosing an ophthalmic therapeutic.
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The presence of benzalkonium chloride in eye drops, from over-the-counter dry eye remedies to glaucoma, allergy or antibiotic medications, historically has been a topic of controversy. Perhaps because of BAK’s reputation for corneal toxicity and savvy marketing, the 60-year-old ruling king of ophthalmic preservatives has often been villified and clearly needs to be better understood by clinicians.
Ophthalmic medications usually consist of the active drug, a viscosity-increasing agent, a buffer, a stabilizer and a carrier vehicle. When packaged in multidose formulations, a preservative molecule is added. Once the sterile packaging is opened and the product used, ophthalmic medications have a tendency to be contaminated by undesired microorganisms. To keep the products safe from contamination of microorganisms that can potentially harm the eye, both the European Pharmacopeia and the U.S. Pharmacopeia Convention (USP) require the presence of a preservative as part of any medicinal compound packaged for topical ophthalmic medication and intended for delivery in multidose containers.
Potential for contamination
The role of the preservative is simple: to prevent the contents of the bottle from becoming a growth culture medium for potential pathogenic microorganisms during the course of multiple uses over time. Research has shown that preservatives are necessary when products are packaged in multidose containers, with pathogenic bacterial contamination as a common occurrence. Opening and reusing medications often leads to contamination, especially by undesired microorganisms with the potential for vision-threatening ocular infections.
Contamination of medications for topical ocular use is a bigger concern in special populations, such as patients with compromised immune systems, the elderly and patients with physical problems self-administering drops. Contamination is also a concern when drops are administered improperly, such as touching the eyelashes, eyelids or the surrounding skin or when patients’ ocular surface defenses may be compromised and they are at a higher risk of infection.
Medicinal containers can be contaminated in a number of ways, from environmental contamination by simply opening and exposing the container, to touching the bottle tip to a contaminated surface. Studies centered on drop application techniques have shown that inoculation from the ocular surface seems to be the more frequent form of microorganism contamination. It has been shown that less than one third of patients are able to successfully place a drop in the eye without touching the tip of the container to the ocular surface or structures (Geyer et al., Stone et al.).
Agustin L.
Gonzalez
Contamination of topically applied medicinal containers also has a high correlation to factors such as frequency and duration of container use, containers remaining open for longer periods of time, larger-volume bottles and preservative characteristics of the compound. Increased volume of drug with a longer period and higher frequency of administration also bring a greater chance of contamination. It is noteworthy that preservative-free medications are at an even higher risk of contamination than preserved drops. The most common infectious offenders that cause contamination include Staphylococcus species, Bacillus species, Serratia species, Klebsiella species and Enterobacter species, among others (Geyer et al.).
The ideal preservative
The task of being an ideal preservative is an ambitious one. In addition to having broad antimicrobial activity against bacteria, fungi and yeasts, ideally the molecule used for preservation should be nonsensitizing, not absorbed systemically, nonirritating to ocular tissue and nontoxic to mammalian cells (McPherson et al.). An ideal preservative would prevent both biodegradation and decomposition of the active medication molecule, thus improving the storage ability of the product. It should also interact well with the molecule being delivered and perhaps improve molecule penetration while being isotonic and able to be used with multiple vehicles and formulations. The preservative should be readily soluble and maintain chemical stability at physiologic pH in both aqueous solutions and suspensions and be able to withstand autoclaving for 20 minutes at 130°C. Finally, it should have no negative interaction with the container polymers of the eye drop dispenser.
Many preservatives have been developed with relatively good safety profiles; these newer molecules include stabilized oxychloro complex, sofzia (Alcon) and sodium perborate, yet each of these preservatives has some limitations of its own in efficacy. With years of literature supporting BAK, to date it has remained the most used preservative in eye care (Abelson et al.).
It is important to note that in vitro laboratory testing on cell cultures and animals has shown BAK, in most instances, to cause significant toxicity to cell and cell cultures (Uematsu et al., De Saint et al.). It is also important to note that this may be quite different from actual clinical conditions and applications where tear volume and blink mechanics provide great barriers and exclude excess volume and immediately dilute any drug topically applied to the ocular surface. One of the most challenging obstacles to ocular drug delivery is retention of a significant volume of medication and limitation of the subsequent washing away of molecules from the ocular surface. This is a detail often overlooked in the in vitro situation when testing BAK toxicity, often providing results different than in vivo testing.
FDA and PET testing
The preservative effectiveness test (PET) is the protocol by which the U.S. Food and Drug Administration evaluates preservative performance. During the PET protocol, standardized colony concentrations of common ophthalmic pathogenic microorganisms are exposed to the preservative, and its effectiveness in killing colonies is then measured. Known ophthalmic pathogens include Escherichia coli,Staphlyococcus species and Pseudomonas species. The colonies are then measured to evaluate the effectiveness of the preservative as a function of time.
The testing requires both inoculation and incubation of cultures at 25°C for up to 4 weeks. During this period there is an interval recording of infectious colony counts. Upon completion of the testing protocol, a preservative is deemed to be effective if after 2 weeks there is a reduction to less than 0.1% of the initial bacterial colony inoculum concentration while keeping the concentration of both molds and yeasts at or below their original inoculum concentration.
Broad range of efficacy
BAK is classified as a chemical detergent preservative with a long history of broad, fast-acting activity and a bactericidal that is extremely effective against a wide array of gram-positive and gram-negative bacteria and other microorganisms, some viruses, fungi and protozoa. BAK is in fact the most commonly used antimicrobial preservative for multidose packaged, topical ophthalmic solutions and recognized as the standard of preservatives. It is a chemically stable quaternary ammonium compound that does not degrade easily over time and is able to sustain high autoclaving temperatures.
BAK functions by disrupting cell membrane permeability and creating cellular lysis (Abelson et al.). For more than 50 years, BAK’s efficacy has been recorded in the ophthalmic literature. In fact, in 1963, BAK’s effectiveness was put to task against 13 different strains of Pseudomonas. In this classic and often-quoted in vitro study, BAK was proved to be extremely efficacious (Kohn et al.).
An early landmark study published by Khon et al. compared the efficacy of various preservatives, including chlorobutanol, phenylethyl alcohol, thimerosal, phenylmercuric nitrate, methylparaben/propylparaben and polymyxin B sulfate. BAK’s bactericidal efficacy in eradicating the microorganisms tested was proven in just minutes – and hours ahead of other preservatives. The profile for BAK shown in these two studies quickly made it the standard for evaluating other developing preservatives and their efficacy.
More recently, five preserved artificial tear brands were tested using the stricter European Pharmacopoeia testing protocol. Of all the drops tested, those with a BAK/EDTA combination reduced cell counts of Candida to undetectable levels within 6 hours and days before other preservatives. The same study showed BAK/EDTA took just minutes to achieve undetectable levels in the inocula of Pseudomonas aeruginosa and Staphylococcus aureus (Kohn et al.).
It is worth noting that certain strains of Pseudomonas are resistant to BAK. The addition of EDTA eliminates this acquired resistance by improving the ability of BAK to chelate to divalent cations; therefore, EDTA is often added as a preservative aid to BAK (Charnock). To date, roughly 70% of multidose, ophthalmic medications contain BAK, with varied concentration ranging from 0.004% to 0.02% (Kaur et al.).
BAK is toxic
We have to keep in mind that preservatives are meant to be bactericidal to undesired microorganisms. Even at clinically common concentrations, preservatives must maintain a delicate balance and ideally be toxic only to pathogenic bacteria, fungi and yeasts. The cytotoxic profile of BAK is unquestionable. BAK’s cytotoxicity has been documented; multiple studies have confirmed BAK’s toxicity by disrupting the cell membrane of epithelial cells and affecting cell growth and apoptosis (Uematsu et al., De Saint et al.)
Numerous studies support BAK’s toxicity to ocular tissue. A 1999 study investigated its effect on epithelial conjunctival cells; the protocol was tested in vivo. The results showed that BAK does cause cell lysis upon immediate exposure and in concentrations of 0.05% and 0.01%. Within 24 hours, cells exposed to 0.01% BAK had died. The study results indicated that BAK exposure induces cell death even in minute concentrations (0.0001%) (Kaur et al.). Yet anecdotally in our offices, at much higher concentrations and dosing exposure, we see that BAK has no significant adverse effects. They primarily occur only when the frequency of use is in excess of recommended dosages.
Studies with rabbit eyes have shown that even mild dosages of preservative-free artificial tears did not show quantitative less toxicity when compared to dosages of 0.02% BAK (Kaur et al.). Other studies have found that ophthalmic preservatives can be toxic to the ocular surface and, not surprisingly, dependent on the frequency of exposure to the preservatives. The researchers clearly showed that these toxic effects are not limited to ocular tissue but also affect pathogenic microbes (Furrer et al.).
So it seems that frequency of dosage seems to be the key to toxicity, and in vivo studies of rabbit corneas have confirmed this. Researchers studied the effect of BAK in rabbit corneas by instilling two drops of a 0.02% BAK solution every 3 minutes for a 2-hour period. This higher frequency of exposure showed to induce not only cytotoxic but also morphological changes in the corneal epithelium. The same study showed that by decreasing the dosing to two drops every 30 minutes over the same 2-hour period, BAK induced mild cytotoxic damage, no different than regular saline solution (Berdy et al.).
Another in vivo study conducted by Becquet compared a wide range of preservatives and their toxic side effects. Bequet and his researchers found that cetrimonium chloride, thimerosal, benzododecinium bromide, methyl parahydroxybenzoate and BAK all induced similar histopathological changes in the rats’ epithelial and conjunctival tissue. The conclusion was that all preservatives tested in the treatment eyes showed consistent damage to both corneal and conjunctival tissue with no significant difference found among preservatives (Becquet et al.).
More recently, a retrospective study looked medical and pharmacy claims of more than 15,000 patients using medications for ocular hypertension or open angle glaucoma preserved with either sofzia or BAK. The researchers then rated the incidence of ocular surface disease, dry eye and ocular infections in these patients. The study data failed to show a statistical difference in the rate of dry eye, ocular surface disease and ocular infections between the group treated with sofzia-preserved prostaglandins and the group treated with BAK-preserved prostaglandins (Schwartz et al.).
Again, preservatives must be cytotoxic, yet these studies suggest that toxicity to BAK, just as to any other preservative, seems to be frequency dependent. As clinicians, we must then take a careful look at preexisting corneal surface disease and distinct behavioral situations in our patients who use multiple topical medications or simply just overdose the topical medications we prescribe or they get over the counter. It would make sense why this cohort of patients is at risk to show BAK-induced adverse effects more so than the more compliant or healthier ocular surface patient.
BAK: Historical preservative of choice
We keep coming back to BAK as the preservative molecule of choice used in topical multidose ophthalmic preparations. BAK is used in medications for managing diseases that are often treated concurrently and with daily dosing for an indefinite time. As such, we have to look at ophthalmic preservatives essentially as a delicate balance of effective antimicrobial toxicity to ward away undesired contamination and realize that collateral toxicity can be an adverse event.
Sensitivity to quaternary ammonium compounds (BAK) is infrequent, but we must remember that BAK is indeed a contact irritant that can easily exacerbate any preexisting condition, especially on the ocular surface. While preservatives have the potential to cause some complications, the risk of microbial inoculation in a nonpreserved eye drop is, in fact, a bigger risk. The potential for contamination of nonpreserved solutions by improper use, multi-use or abuse of unit dose dispensers and the noncompliance with manufacturers’ application recommendation of the “single use” or “unit dose” containers has real potential for permanent and devastating effects on the eye.
Microbial contamination should be the single biggest concern in the use of multi-dosage containers; as reported by Schein et al., as much as 29% of containers can be contaminated with microorganisms. For most situations, the greatest threat to the eye comes from one of the many opportunistic microorganisms with easy access that can inoculate it and cause further damage. Clinicians should not forego the benefits of a medication by focusing on a single ingredient in it.
Often taken for granted, the much-overlooked drops used in our offices are actually safer because of the preservatives that prevent microbial contamination One of the biggest testaments to BAK efficacy, tolerability and safety is the long-term and ample use of BAK, the countless FDA submissions in formulations and the unpublished reviews of the many topical, multi-use ophthalmic solutions and formulations developed over the years. It is worth noting that product manufacturers must conduct their own independent reviews before achieving FDA clearance, and BAK is one of the many components with a proven track record.
BAK is an effective molecule that has shown versatility and longevity, and after years of research and progress with many innovations in pharmacology, there is still no great substitute that proves to be as effective and safe. The fact that BAK’s safety and efficacy is tested in the millions of yearly prescriptions of ophthalmic medications and thousands of daily instillations by optometrists and ophthalmologists, among others, is telling. While we are often concerned about recommending preservative-free drops, concern over prescribing medications with BAK is really not warranted. More than 60 years of research and many years of clinical work have shown that BAK is still the most effective preservative.
However, we still need to keep in mind the cytotoxicity of preservatives; in some situations they can increase complications or they can be beneficial by aiding penetration of the molecule being delivered (Hida et al.). In cases of trauma, the use of injectables or in patients who have undergone surgical interventions, the presence of preservatives risks further compromise of the ocular tissue by the relative toxicity. This is a situation that is not prudent or desired. On the other hand, it is also worth noting that the presence of BAK at times is desired, as it can improve the efficacy of molecule delivery to tissue (Mahendra et al.).
For the patient who occasionally uses eye drops for allergies or dry eyes, the safety that a preservative such as BAK provides is paramount and unquestionable. For others who use drops intermittently or for short periods of time, the concerns should be few. For those cases requiring chronic, frequent or multiple topical drug therapy daily, the choice of product and delivery method becomes a bit more relevant.
It is clear that compliance and comfort must be taken into account in prescribing medications, and considerations such as dosages, frequency and length of treatment should be evaluated in the therapeutic regimen of ophthalmic agents and the best appropriate molecule should be selected for each case. As physicians, we must be sensitive to select treatments that minimize ocular damage and minimize adverse events, including toxicity, all while maximizing the desired therapeutic outcome. It is important that we have the knowledge to discern between good science and urban legends and set aside perceptions that can affect the selection of therapeutic molecules to heal or treat our patients.