Re-assessing Evidence for Adverse Ocular Reactions Associated with Fluoroquinolones: Implications for Intracameral Use

Moxifloxacin is an 8-methoxyfluoroquinolone bactericidal antibiotic which inhibits DNA gryase and topisomerase IV. Moxifloxacin has broad spectrum activity against Gram-positive and Gram-negative bacteria, anaerobic bacteria and atypical organisms. Fluoroquinolone antibiotics are indicated for the treatment of complicated intra-abdominal infections, community acquired pneumonia, bacterial skin infections, acute bacterial exacerbations of chronic bronchitis, active tuberculosis, plague and conjunctivitis. Adverse events associated with systemic use of fluoroquinolones include tendonitis, tendon rupture, peripheral neuropathy and diplopia. Uveitis was not reported in pre-marketing trials of moxifloxacin, which was approved by the Food and Drug Administration in 1999.¹ The first report of uveitis associated with orally administered moxifloxacin occurred in 2004. Subsequent reports expanded our understanding of clinical features of the condition and implicated additional drugs within the fluoroquinolone class.^2,3

Two rare conditions may arise following systemic fluoroquinolone therapy, Bilateral Acute Depigmentation of the Iris (BADI) and Bilateral Acute Iris Transillumination (BAIT).⁴ BADI and BAIT lie on a severity spectrum of the same condition; cases of BADI affecting one eye and BAIT the fellow eye exist. There is a lack of consensus regarding the etiology. Clinical and experimental data implicates quinolone toxicity but some investigators hypothesize an unidentified (possibly viral) pathogen is to blame, citing cases in which prior fluoroquinolone exposure could not be identified. Three large, retrospective studies undertaken to investigate the risk of uveitis following exposure to quinolone antibiotics yielded conflicting results.^5–7

The majority of individuals diagnosed with BAIT are female, suggesting a possible autoimmune predisposition. Phakic patients present with photophobia and loss of accommodation which may be irreversible and visually disabling and suggests both the iris and ciliary body are affected. Examination reveals atonic, mid-dilated pupils which react poorly to light and accommodation. Elevated intraocular pressure secondary to pigment dispersion may be mild and transient or severe and persistent with development of diffuse iris transillumination over the course of weeks to months. Posterior synechiae are present in some eyes but keratic precipitates do not develop and corticosteroid therapy is of negligible benefit.^2,3 Complications may include cataract and glaucoma, requiring surgery in some cases.^4,8

Phototoxicity, a class-effect of fluoroquinolones, has been postulated to cause iris transillumination although moxifloxacin is not known to cause dermal phototoxicity in individuals affected with BADI, BAIT and is generally considered less phototoxic than other fluoroquinolones. In 2012, based on application of World Health Organization (WHO) criteria to case reports in the literature and spontaneously reporting databases, an association between fluoroquinolones and uveitis was determined to be “possible,” meaning the adverse event occurred with a reasonable time sequence to administration of the drug but could also be plausibly explained by concurrent disease, other drugs or chemicals, or underlying disease.³

Off-label use of intracameral moxifloxacin (ICM) is employed in prophylaxis against post-operative endophthalmitis for several reasons, including the move toward “dropless” cataract surgery. Several large studies have reported the efficacy of ICM in reducing the rate of post-cataract surgery endophthalmitis, although at least one of these had several flaws.⁹ Unlike intracameral cefuroxime and vancomycin, moxifloxacin is commercially available in a sterile, preservative free preparation and does not require access to a compounding facility. Intracameral vancomycin is associated with rare cases of potentially visually devastating hemorrhagic occlusive retinal vasculitis.¹⁰ Vancomycin and cefuroxime lack gram-negative coverage and penicillin allergy may be a contra-indication for intracameral use of cefuroxime.

Enthusiasm for ICM must be tempered by case reports of post-operative endophthalmitis occurring despite its use. This is not surprising because cases of endopthalmitis were observed in the ICM treatment arm of the aforementioned endopthalmitis prophylaxis studies. Identification of moxifloxacin resistant staphylococcal species implicated in one report calls into question the efficacy of ICM in preventing endophthalmitis.

Although corneal endothelial toxicity studies are reassuring that intracameral moxifloxacin is safe, several studies suggest moxifloxacin may be toxic to iris melanocytes and retinal vascular cells.^11–13 Topical preparations of moxifloxacin penetrate the cornea and achieve higher aqueous concentrations than older, commercially available fluoroquinolones. There are reports of unilateral forms of BADI following topical ophthalmic fluoroquinolone use alone and two reports (5 eyes) detailing the unilateral equivalent of BAIT following intracameral moxifloxacin administration; one patient developed elevated intraocular pressure which could not be controlled medically, necessitating glaucoma surgery.^8,14–16 Because there is no re-challenge data at this time, the WHO Causality Assessment cannot yet be considered “certain”, but should be changed to “probable/likely” as evidence now suggests that the reaction is unlikely to be attributable to concurrent disease or other drugs. Surgeons, patients and medical liability insurers must reassess the risks, benefits and medicolegal ramifications of future ICM use until factors which place patients at increased risk of developing ocular morbidity are more clearly elucidated.

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.