Preservatives in eyedrops: The good, the bad and the ugly

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Abstract

There is a large body of evidence from experimental and clinical studies showing that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, corneal surface impairment, and the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been described in patients receiving antiglaucoma treatments for long periods of time. However, the mechanisms involved, i.e., allergic, toxic, or inflammatory, as well as the respective roles of the active compound and the preservative in inducing the toxic and/or proinflammatory effects of ophthalmic solutions, is still being debated. The most frequently used preservative, benzalkonium chloride (BAK), has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies. As a quaternary ammonium, this compound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, and damage to deeper ocular tissues. The mechanisms causing these effects have not been fully elucidated, although the involvement of immunoinflammatory reactions with the release of proinflammatory cytokines, apoptosis, oxidative stress, as well as direct interactions with the lipid components of the tear film and cell membranes have been well established. Preservative-induced adverse effects are therefore far from being restricted to only allergic reactions, and side effects are often very difficult to identify because they mostly occur in a delayed or poorly specific manner. Care should therefore be taken to avoid the long-term use of preservatives, otherwise a less toxic alternative to BAK should be developed, as this weakly allergenic but highly toxic compound exerts dose- and time-dependent effects. On the basis of all these experimental and clinical reports, it would be advisable to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those suffering from preexisting or concomitant ocular surface diseases, and those experiencing side effects related to the ocular surface. Indeed, mild symptoms should not be underestimated, neglected, or denied, because they may very well be the apparent manifestations of more severe, potentially threatening subclinical reactions that may later cause major concerns.

Introduction

In the recent past, a large body of evidence from experimental and clinical studies has accumulated showing that the long-term use of topical drugs may induce major and frequent ocular surface changes. Many clinical manifestations associated with low-grade chronic inflammation have been described in patients receiving antiglaucoma treatments for long periods of time. Glaucoma treatment may cause chronic inflammation or aggravate a concomitant ocular surface disease. In clinical practice, glaucoma treatment often lasts for decades. Patients may present preexisting ocular surface impairment, such as dry eye, meibomian gland dysfunction, or chronic allergy, and are very frequently treated with two or more topical ophthalmic formulations. These findings explain that clinical practice apparently often does not fit the safety profiles of drugs tested in clinical trials for short periods of time, alone, and only in patients without active ocular surface disorders.

The need for sterility in multidose eye drops requires the inclusion of an antimicrobial preservative in these solutions, most frequently the quaternary ammonium benzalkonium chloride (BAK). In some patients – on long-term treatments – allergic or inflammatory reactions are experienced, including redness, stinging, burning, irritation, eye dryness, or less frequently, conjunctivitis or corneal damage. Many studies indicate a direct correlation between the presence of preservatives and the symptoms experienced during antiglaucoma therapy. In a recent large-scale European observational study (Jaenen et al., 2007), involving 9658 patients, all recorded symptoms and signs were significantly more frequent in patients taking preserved medications compared with those taking preservative-free formulations. Most effects observed in glaucoma patients are therefore more likely to be due to the preservative than the active ingredients, since toxicity of the preservatives has been well documented experimentally, as has the harmlessness of most active compounds when unpreserved. BAK toxicity for eye structures has been reported since the 1940s (Swan, 1944) and many studies in experimental or cell models have consistently and reliably shown its toxic effects (Baudouin et al., 2008, Baudouin, 2008). Conversely, BAK is a hapten causing relatively few short-term allergic reactions and appears in clinical trials as an effective and safe agent, especially when compared to mercury derivatives or chlorhexidine, formerly used in ophthalmic preparations. Nevertheless, given that the main characteristic of a toxic compound is that it exerts time- and dose-dependent effects, these effects are most likely to occur late, with poor specificity in its manifestations, when delayed, mild, or interacting with other ocular disorders. Moreover, in most cases, the severity of glaucoma as a sight-threatening disease makes dry eye sensation or chronic ocular irritation a comparatively very mild caveat regarding the benefit of glaucoma treatment. However, ocular surface manifestations deeply impact the quality of life and may influence patient compliance, in addition to a variety of long-term consequences for the eye. This review is aimed at reviewing the long-term ocular surface side effects of topical treatments, focusing on BAK toxicity and its potential harmfulness in ophthalmic preparations.

Section snippets

Regulatory aspects

The Pharmacopoeia recommends that eye drops must contain an antimicrobial agent (preservative) to avoid or to limit microbial proliferation after opening the bottle, which could induce a risk of potentially severe eye infection as well as the alteration of the formulation. Eye drops are contaminated essentially by the hands when handling the bottle or by contact of the tip touching the eyelids, lashes, conjunctiva, or tears. There is also a risk of cross-transmission when the same eye drops are

Efficacy as a preservative

BAK was mainly used for its apparently good safety/efficacy profile. This compound is weakly allergenic and has a high rate of antimicrobial properties. In a study illustrating the potent antimicrobial properties of BAK, Charnock showed that among five preservatives, benzalkonium chloride/EDTA, parabens, chlorobutanol, silver chloride complex, and the Purite-stabilized oxychloro complex, only BAK/EDTA satisfied the major criteria for antimicrobial preservation for all the test microorganisms.

Allergic reactions

The symptoms of conjunctival allergy (congestion, tearing, photophobia, burning and stinging sensations) induced by the instillation of preserved eyedrops are various. Simple conjunctival congestion or papillary conjunctivitis may be observed with or without eczema, the worst reaction being patent giant papillary conjunctivitis. In certain cases, a severe type IV allergic reaction may develop. Allergic manifestations are often spectacular (Fig. 2), occurring a few days after treatment

Prospective studies

Only very few prospective studies have addressed the question of the deleterious role of the preservative, in part because of the current lack of preservative-free compounds and to a large extent because a normal ocular surface will experience weak toxic effects after a short duration of treatment, especially with a monotherapy, that is at a low BAK exposure rate. Nevertheless, in healthy volunteers Ishibashi et al. demonstrated that preserved timolol caused significantly higher tear film

Chemical characteristics of BAK

Benzalkonium chloride (BAK) is a bactericidal cationic tensioactive compound used as preservative in various medical preparations in concentrations ranging from 0.004% to 0.025% in eye drops. BAK is a mixture of alkyl benzyl dimethyl ammonium chlorides with several analogs varying in the length of the aliphatic alkyl chain. In commercial preparations, the aliphatic alkyl chains possess lengths of 12, 14 and 16 carbon atoms (Gardner and Girard, 2000). At low concentrations, BAK in aqueous

Experimental data in animal models

Chemicals, cosmetics, and pharmaceuticals have to be assessed for their irritancy potential and risk to the human eye. However, the only method accepted worldwide by regulatory authorities for the assessment of acute eye irritation potential is the Draize rabbit test (Draize et al., 1944), which has been criticized by animal welfare advocates and whose relevance, validity, and precision have been challenged because of the variability and low predictiveness of the human response (Curren and

Dry eye and ocular surface diseases

BAK is a well-known irritant in dermatological and allergological investigations, but it is rarely recognized as the main allergen responsible for contact dermatitis (Uter et al., 2008). However, by truly allergenic mechanisms or as a cofactor and an irritant compound it may cause or enhance various clinical manifestations at the ocular surface level, such as allergic or nonallergenic blepharitis, meibomian gland dysfunction, chronic conjunctival inflammation, or tear film instability. Through

Eliminating the preservative

Considerable efforts have been made in the recent past by the pharmaceutical industry to develop new antiglaucomatous compounds that would bring about efficacy, safety, and compliance. As BAK toxicity is mainly dose-dependent, reducing the number of instillations has improved ocular tolerance. Long-acting preparations of timolol and prostaglandins are given once a day, mathematically reducing the amount of BAK in contact with the eye by 50%. The same has occurred for various fixed combinations

Conclusion

Over more than two decades, a huge number of animal and in vitro studies, using a considerable variety of models, cells, and tissues, have demonstrated that BAK may cause or enhance harmful consequences on the eye structures of the anterior segment, including the tear film, cornea, conjunctiva, and even trabecular meshwork. Despite these consistent and solid data, and warnings coming from observational surveys and individual case series, BAK is still used as the main preservative in eye drops

References (141)

  • S. Chandrasekaran et al.

    Associations between elevated intraocular pressure and glaucoma, use of glaucoma medications, and 5-year incident cataract: the Blue Mountains Eye Study

    Ophthalmology

    (2006)
  • J.S. Cohen et al.

    Two-year double-masked comparison of bimatoprost with timolol in patients with glaucoma or ocular hypertension

    Surv. Ophthalmol.

    (2004)
  • M. De Saint Jean et al.

    Comparison of morphological and functional characteristics of primary-cultured human conjunctival epithelium and of Wong–Kilbourne derivative of Chang conjunctival cell line

    Exp. Eye. Res.

    (2004)
  • T. Deutschle et al.

    In vitro genotoxicity and cytotoxicity of benzalkonium chloride

    Toxicol. In Vitro

    (2006)
  • O. Doucet et al.

    Reconstituted human corneal epithelium: a new alternative to the Draize eye test for the assessment of the eye irritation potential of chemicals and cosmetic products

    Toxicol. In Vitro

    (2006)
  • R.L. Fellman et al.

    Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: a 6-month, masked, multicenter trial

    Ophthalmology

    (2002)
  • S.J. Gedde et al.

    Three-year follow-up of the tube versus trabéculectomie study

    Am. J. Ophthalmol.

    (2009)
  • M. Gobbels et al.

    Corneal epithelial permeability of dry eyes before and after treatment with artificial tears

    Ophthalmology

    (1992)
  • J.M. Herreras et al.

    Ocular surface alteration after long-term treatment with an antiglaucomatous drug

    Ophthalmology

    (1992)
  • S. Hong et al.

    Effects of topical antiglaucoma application on conjunctival impression cytology specimens

    Am. J. Ophthalmol.

    (2006)
  • A. Labbe et al.

    Epithelial basement membrane dystrophy: evaluation with the HRT II Rostock Cornea Module

    Ophthalmology

    (2006)
  • A. Labbe et al.

    In vivo confocal microscopy and anterior segment optical coherence tomography analysis of the cornea in nephropathic cystinosis

    Ophthalmology

    (2009)
  • B.C. Leal et al.

    Conjunctival hyperemia associated with bimatoprost use: a histopathologic study

    Am. J. Ophthalmol.

    (2004)
  • S. Majumdar et al.

    Effect of chitosan, benzalkonium chloride and ethylenediaminetetraacetic acid on permeation of acyclovir across isolated rabbit cornea

    Int. J. Pharm.

    (2008)
  • D.P. Metz et al.

    T-cell cytokines in chronic allergic eye disease

    J. Allergy Clin. Immunol.

    (1997)
  • K. Miyake et al.

    ESCRS Binkhorst lecture 2002: pseudophakic preservative maculopathy

    J. Cataract Refract. Surg.

    (2003)
  • C. Baudouin et al.

    Short-term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers

    Br. J. Ophthalmol.

    (1998)
  • C. Baudouin et al.

    In vitro studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • C. Baudouin

    Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma

    Acta Ophthalmol.

    (2008)
  • J.D. Brandt

    Does benzalkonium chloride cause cataract?

    Arch. Ophthalmol.

    (2003)
  • E. Brasnu et al.

    In vitro effects of preservative-free tafluprost and preserved latanoprost, travoprost, and bimatoprost in a conjunctival epithelial cell line

    Curr. Eye. Res.

    (2008)
  • E. Brasnu et al.

    Comparative study on the cytotoxic effects of benzalkonium chloride on the Wong–Kilbourne derivative of Chang conjunctival and IOBA-NHC cell lines

    Mol. Vis.

    (2008)
  • D.C. Broadway et al.

    Trabeculectomy, risk factors for failure and the preoperative state of the conjunctiva

    J. Glaucoma

    (2001)
  • D.C. Broadway et al.

    Adverse effects of topical antiglaucoma medication. I. The conjunctival cell profile

    Arch. Ophthalmol.

    (1994)
  • D.C. Broadway et al.

    Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery

    Arch. Ophthalmol.

    (1994)
  • A. Bron et al.

    Efficacy and safety of substituting a twice-daily regimen of timolol with a single daily instillation of nonpreserved beta-blocker in patients with chronic glaucoma or ocular hypertension

    J. Fr. Ophtalmol.

    (2003)
  • N. Buron et al.

    Differential mechanisms of conjunctival cell death induction by ultraviolet irradiation and benzalkonium chloride

    Invest. Ophthalmol. Vis. Sci.

    (2006)
  • P. Campagna et al.

    Chronic topical eye preservative-free beta-blocker therapy effect on the ocular surface in glaucomatous patients

    Acta Ophthalmol. Scand. Suppl.

    (1997)
  • E. Champeau et al.

    Effect of ophthalmic preservatives on the ocular surface: conjunctival and corneal uptake and distribution of benzalkonium chloride and chlorhexidine digluconate

  • C. Charnock

    Are multidose over-the-counter artificial tears adequately preserved?

    Cornea

    (2006)
  • H. Chibret

    Conservateurs et préparation ophtalmiques: réalités et perspectives

    Ann. Pharmaceutiques Françaises

    (1997)
  • S.H. Chung et al.

    Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin

    Mol. Vis.

    (2006)
  • M. Ciancaglini et al.

    An in vivo confocal microscopy and impression cytology analysis of preserved and unpreserved levobunolol-induced conjunctival changes

    Eur. J. Ophthalmol.

    (2008)
  • R.D. Curren et al.

    Ocular safety: a silent (in vitro) success story

    Altern. Lab. Anim.

    (2002)
  • C. de Jong et al.

    Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma

    Graefes Arch. Clin. Exp. Ophthalmol.

    (1994)
  • M. De Saint Jean et al.

    Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells

    Invest. Ophthalmol. Vis. Sci.

    (1999)
  • M. De Saint Jean et al.

    Toxicity of preserved and unpreserved antiglaucoma topical drugs in an in vitro model of conjunctival cells

    Curr. Eye Res.

    (2000)
  • C. Debbasch et al.

    Quaternary ammoniums and other preservatives’ contribution in oxidative stress and apoptosis on Chang conjunctival cells

    Invest. Ophthalmol. Vis. Sci.

    (2001)
  • C. Debbasch et al.

    Mitochondrial activity and glutathione injury in apoptosis induced by unpreserved and preserved beta-blockers on Chang conjunctival cells

    Invest. Ophthalmol. Vis. Sci.

    (2001)
  • C. Debbasch et al.

    Cytoprotective effects of hyaluronic acid and Carbomer 934P in ocular surface epithelial cells

    Invest. Ophthalmol. Vis. Sci.

    (2002)
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    Financial disclosure: Christophe Baudouin is consultant for or has received research grants from: Alcon, Allergan, MSD, Pfizer, Santen and Théa. The other authors have benefitted from research grants from the same companies.

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