Saudi Journal of Ophthalmology (2014) 28, 182—187 Dry Eye and Ocular Surface Disease Balancing antimicrobial efficacy and toxicity of currently available topical ophthalmic preservatives ⇑ Elmer Y. Tu, MD Abstract Medical treatment of ophthalmic diseases relies primarily on the use of multidose drugs. Short term use is highly effective usually with little local toxicity. However, chronic use of these preparations not only increases the likelihood of microbial contamination and secondary ocular infection, but also of toxicity from the drug formulation itself. Increasing awareness of the toxicity of oph- thalmic preservatives has led to an increasing variety of preservative schemes ranging from ‘‘self-preservation’’ to ionic buffer sys- tems. Beyond outdated testing methods, the anti-microbial efficacy of most of these systems is poorly defined, potentially placing these preparations at an unknown risk of contamination by unmonitored, untested organisms. No uniformity in toxicity testing exists which further complicates the clinician’s judgment of the risk–benefit of using a particular drug formulation. In this manu- script we examine in detail each of the current employed ophthalmic preservative regimens with respect to their known antimi- crobial activity and potential toxicity, where known. We also survey the most popular ophthalmic preparations, detailing their preservation schemes as well as concentrations to help the clinician in choosing an appropriate formulation for the treatment of various ophthalmic diseases. Keywords: Antimicrobial, Preservatives, Toxicity, Ophthalmic, Eye infection, Benzalkonium chloride, Purite, Glaucoma, Keratitis Ó 2014 Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University. http://dx.doi.org/10.1016/j.sjopt.2014.06.006 Introduction trol or maintenance of disease. In this instance, side effects or toxicity from the active drug can increase in frequency. Topical ophthalmic medications are the mainstay of ther- For example, with extended use, prostaglandin analogs apy for almost all ocular disorders of the anterior segment may cause complications ranging from simple hyperemia or including dry eye, glaucoma, ocular surface infections and cosmetically troublesome pigmentation to severe prosta- tumors. Topical dosing provides direct access to higher con- glandin associated periorbitopathy.1,2 centrations of a drug at its therapeutic target while minimiz- Long term, repeated dosing of topical medications pre- ing or avoiding systemic side effects which might otherwise sents several other challenges that are common to all medi- limit their use. Several medications deemed too toxic for sys- cations. Cost and compliance for chronic use often temic use can be used safely on the eye, e.g. neomycin. Short necessitates the use of multidose preparations. Although term use of commercially available topical ophthalmic prepa- the healthy ocular surface is relatively resistant to microbial rations in an otherwise healthy eye is very safe and is associ- challenge, direct applications of a high load of microorgan- ated with few local complications. However, many drugs isms may overwhelm the normal protective mechanisms lead- require extended or chronic, repeated applications for con- ing to vision-threatening infection. Further, many of these Received 25 March 2014; received in revised form 27 May 2014; accepted 15 June 2014; available online 24 June 2014. University of Illinois Eye and Ear Infirmary, Chicago, IL, USA ⇑ Address: Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, IL 60612, USA. Tel.: +1 312 996 8937; fax: +1 312 355 4248. e-mail address: [email protected] Peer review under responsibility Access this article online: of Saudi Ophthalmological Society, www.saudiophthaljournal.com King Saud University Production and hosting by Elsevier www.sciencedirect.com Study of topical ophthalmic preservatives 183 patients have a compromised ocular surface from ocular dis- subsequent increase at 28 days. Fungi are tested at 7 and ease which leaves them more susceptible to infection. 28 days with a required reduction in CFUs of 2log units at Recently, a number of severe infections have been associated 7 days without an increase from this point at 28 days.15 with pharmacy-compounded ophthalmic preparations, which are normally not preserved, because of contamination during Efficacy and toxicity of current ophthalmic compounding,3,4 but for commercially prepared topical oph- preservatives thalmic preparations, contamination usually occurs as a result of poor patient compliance.5–8 Prior to adequately preserved The number of ophthalmic solution preservatives in cur- ophthalmic drugs, several severe, blinding infections were rent use is relatively small and can be classified into two or traced to in-use contamination of multidose preparations.9,10 three categories (Table 1). Surfactants, or detergents, For these reasons, manufactured topical ophthalmic prepara- directly damage the cell wall of microbes by disrupting their tions are required to be sterilely created and to be preserved lipid component causing cell lysis. Because of their non-spe- against secondary contamination. Unfortunately, the addi- cific nature, these agents are both generally more effective tives required for preservation may themselves be toxic to with a broad spectrum of activity across different classes of the eye requiring the physician to have a thorough under- pathogens but are more toxic to human cells. Oxidizing pre- standing of the potential risks of toxicity, therapeutic efficacy servatives are small molecules that can pass the microbial cell and risk of infection for each individual patient in deciding on wall to enter the cell and disrupt internal enzymatic function. appropriate medical management. These tend to be less toxic to human ocular surface cells, but its efficacy against pathogens and pathogen classes outside Antimicrobial efficacy testing (AET) of those included in the testing regimen are either unknown or unreported. Recently, an ionic buffer system was intro- duced which acts similarly as an oxidizer while in solution. All manufactured multidose ophthalmic products are Because these compounds are highly reactive, they will rap- required to resist contamination both in the U.S., Japan idly be consumed when in contact with the ocular surface. and the European Union. Their tests differ slightly, but signif- The simplest alternative to preservation of multidose icantly in some cases. Since it would be difficult to test pre- preparations is sealed, unpreserved, single dose aliquots. servative efficacy against every possible contaminating These not only eliminate the need for preservative additives, pathogen, each involves the testing of solutions against a but also the cycle of contamination, incubation and prolifera- small number of bacteria and fungi chosen with the results tion which would increase the concentration of microbes to proxied as a general measure of contamination prevention. an infectious level. Unfortunately, the cost of production is The same general principle is applied to other ophthalmic significantly higher resulting in higher costs to the patient. products, such as contact lens disinfection systems. These Although they are labeled for single use, studies have dem- tests are clearly not perfect and, combined with minimal onstrated that repeated use of a single dose applicator over post-market surveillance, are not validated as reflective of a 10 h period results in a relatively low rate (2.4%) of contam- real world efficacy. Failures result from a number of factors ination, dependent on the type of drug and patient compli- including an inadequate representation of poor patient com- ance.16,17 Another study suggested a relatively low rate of pliance and an inadequate reflection of potentially patho- contamination even if used for a longer period of time.16 genic organisms. A recent example was the recent The contamination risk of a particular compound is depen- outbreak of Fusarium keratitis as a result of the failure of dent multiple factors including not only patient handling Renu with Moistureloc to adequately disinfect contact lenses and compliance, but also on the compound itself. Unless despite excellent antifungal activity on AET specific to con- there is gross contamination, growth and proliferation of tact lens solutions.11–14 the pathogen after inoculation of the preparation is likely Current United States Pharmacopoeia (USP) Antimicrobial required to reach an infectious threshold concentration. Effectiveness Testing involves 3 stock bacteria (Pseudomonas Some microbes have demonstrated the ability to use the aeruginosa, Staphylococcus Aureus and Escherichia coli) and base drug, such as corticosteroids, in these preparations as 2 fungi (Candida albicans and Aspergillus niger). Ophthalmic a carbon source (food) to support this growth.18 There is evi- compounds are Category 1 and the methodology is similar to dence that corticosteroids themselves further influence that specified in the Japan Pharmacopoeia. These organisms microbial growth in both an inhibitory and supportive role are cultured and added to the solution to be tested with a through hormonal action. Consequentially, corticosteroid final concentration of between 1 Â 105 and 1 Â 106 colony and corticosteroid combination medications have been forming units (CFU). The solutions are then sampled at 7, shown to have a much higher rate of contamination