Toxic optic neuropathy is a well-known side effect of some systemic medications. Linezolid (Zyvox; Pfizer, New York, NY) received approval from the United States Food and Drug Administration in April 2000 for the treatment of methicillin-resistant Staphylococcus (MRS), vancomycin-resistant Enterococcus, nosocomial pneumonia, and complicated skin infections (1). Its approval marked the emergence of a powerful new class of antibiotics, the oxazolidinones, to treat an expanding population of resistant pathogens. Given orally or intravenously, linezolid exerts its antibiotic activity at the level of RNA translation by binding to the 23S ribosomal RNA of the 50S ribosome subunit, thereby interfering with ribosome assembly.
We describe two patients with linezolid-associated toxic optic neuropathy. We are aware of two previous case reports describing a similar process (2,3). Our report aims to characterize the ophthalmic findings and to enhance awareness of the potentially vision-impairing side effects of this medication.
A 75-year-old woman was referred for neuro-ophthalmic evaluation of painless progressively decreasing vision OU of 5 months' duration. She also noted increasing difficulty distinguishing red from other colors. Her ocular history included cataract extraction and intraocular lens implantation OS, nuclear sclerosis OD, and macular drusen OU. She had breast cancer that was treated with radical mastectomy and chest wall radiation therapy 28 years earlier, bronchiectasis, hypothyroidism, peripheral neuropathy, osteoarthritis, and aminoglycoside-related ototoxicity. Medications included esomeprazole, ramipril, celecoxib, levothyroxine, propranolol, gabapentin, alendronate, aspirin, iron, calcium, and vitamins B12, D, and E.
Continuous administration of linezolid 600 mg orally every day had been initiated 11 months before the onset of visual symptoms for the treatment of biopsy-proven Mycobacterium abscessus pneumonia that had arisen in radiation-induced pulmonary fibrosis.
On our examination 16 months after initiation of linezolid treatment, visual acuity was 20/400 OD and counting fingers at 4 feet OS, a change from 20/25 OU noted 3 months earlier. She was unable to identify any Ishihara color plates OU. Pupils were sluggishly reactive to light without relative afferent pupil defect. Slit-lamp examination of the anterior segment showed mild nuclear sclerosis OD and a posterior chamber intraocular lens OS. Ophthalmoscopy revealed a normal optic disc OD, slight temporal pallor OS (Fig. 1), and retinal pigment epithelial changes without subretinal fluid within the macula OU. Automated perimetry revealed bilateral cecocentral and arcuate visual field defects (Fig. 1). An electroretinogram was normal OU. Pattern visual evoked potentials were extinguished at the 20/50 check size OU (Fig. 1). Magnetic resonance imaging of the brain and orbits, complete blood count, vitamin B12, and folate levels were normal.
Linezolid-associated optic neuropathy was suspected and the medication was discontinued. Four months later, visual acuity was 20/25 OD and 20/30 OS, with near-complete resolution of visual field defects (Fig. 2). The optic disc OD was now slightly pale, the optic disc OS remained unchanged (Fig. 2), and the pattern visual evoked potentials were markedly improved OU (Fig. 2).
A 73-year-old woman was referred for neuro-ophthalmic evaluation of painless progressively decreasing vision OU of 4 months' duration. She also noted increasing difficulty distinguishing colors. She had a history of biopsy-proven Mycobacterium avium pneumonia for the past 2.5 years, for which she initially used ethambutol 800 mg orally every day and clarithromycin 500 mg orally every day for 1 year. During this time, she did not notice any visual disturbances, and a routine eye examination revealed visual acuities of 20/25 OD and 20/30 OS and nuclear sclerotic cataracts. The antibiotics were discontinued for a 6-month period and another routine eye examination revealed that her vision was unchanged.
Because of persistent pulmonary symptoms, linezolid 600 mg orally every day was then initiated. Eight months later, she noticed a progressive decline in vision OU and numbness in the hands and thighs. Ten months after the linezolid was started, visual acuity was 20/50 OU. Cataract extraction OS did not improve vision.
One month later, 11 months after beginning linezolid, she was referred for neuro-ophthalmic consultation. Medications included linezolid, calcium, and prednisolone eye drops OS. Visual acuity was 20/100 OU. She was able to identify only the test plate of the Ishihara color plates OU. Pupils were sluggishly reactive to light without relative afferent pupil defect. Slit-lamp examination of the anterior segment showed nuclear sclerosis OD and a posterior chamber intraocular lens OS. Ophthalmoscopy revealed normal optic discs OU, and automated perimetry revealed bilateral cecocentral and early arcuate visual field defects (Fig. 3). An electroretinogram was normal OU. Pattern visual-evoked potentials were extinguished at the 20/50 check size OU (Fig. 3). Magnetic resonance imaging of the brain and orbits and erythrocyte sedimentation rate (ESR) were normal.
Linezolid was discontinued. Three months later, visual acuity had improved to 20/40 OD, consistent with nuclear sclerosis, and 20/25 OS. The visual field defects had resolved (Fig. 4). She identified eight of eight Ishihara color plates OU. The optic discs were slightly pale OU (Fig. 4), and the pattern visual evoked potentials were markedly improved OU (Fig. 4). The numbness in the hands and thighs remained unchanged.
The history, examination findings, and clinical course in these two patients are suggestive of toxic optic neuropathy. Both patients had symmetric, painless, progressive visual loss and cecocentral visual field defects in the setting of exposure to a medication (4). Both patients were treated for a much greater duration than is recommended by the package insert, which suggests an oral dosage of 600 mg every 12 hours for an interval not to exceed 28 days (5). Our patients received oral linezolid 600 mg per day for 16 months (Case 1) and 11 months (Case 2).
Absorption of oral linezolid is extensive and oxidation creates two metabolic products, the accumulation of which has unknown clinical effects (6). Because similar pharmacokinetics are seen in adult and geriatric patients, the identical dosage is recommended for both populations.
The postmarketing experience disclosed by the manufacturer mentions myelosuppression, lactic acidosis, peripheral neuropathy, and optic neuropathy occurring in some cases when treatment was administered for more than 28 days. The precise mechanism for linezolid-induced optic neuropathy is unknown, and no explanation for the development of the neurologic symptoms is described within the package insert. Impairment of mitochondrial function within the retinal nerve fiber layer was suggested in one report (2) based on the assumption that the pathophysiology is similar to that of other toxic optic neuropathies. The papillomacular bundle has a higher energy requirement because of rapid action potential generation. Impaired oxidative phosphorylation in the synthesis of adenosine triphosphate (ATP) may create an energy imbalance such that the energy demands of this active tissue are not met (7). Our Case 2 had visual loss more than 1 year after discontinuing ethambutol, a well-known cause of toxic optic neuropathy (8). Perhaps previous treatment with ethambutol predisposed this patient to neurotoxicity.
Our Case 1 had a presumably idiopathic peripheral neuropathy that was present before initiation of linezolid, and that remained unchanged throughout the course of therapy. Our Case 2 had numbness in the hands and thighs that did not improve after discontinuing linezolid, consistent with previous reports of linezolid-induced peripheral neuropathy (9). Treatment with vitamin B6 in patients with linezolid-associated toxicity has been reported to improve the hematologic abnormalities (cytopenia) but not the peripheral neuropathy (10).
Cessation of linezolid led to visual improvement in both of our patients without alteration of their other medications or additional treatment. One report (2) has noted visual improvement on discontinuation of linezolid in two patients who were prescribed the drug on a long-term basis at an unstated dosage. The first patient, a 71-year-old man, was reported to have a visual acuity of counting fingers at 150 cm OU and extinguished visual evoked potentials 10 months into treatment of an MRS infection in a prosthetic joint. Visual acuity improved to 20/30 OU 2 months after discontinuing the linezolid. The second patient from the same report, a 45-year-old man, was reported to have visual acuities of counting fingers at 300 cm OU 10 months into linezolid therapy for a chronic spinal hardware-associated Staphylococcus aureus infection. Visual acuities improved to 20/30 OD and 20/40 OS 3 weeks after drug cessation. One additional report (3) described a patient with peripheral and optic neuropathies that developed 6 months into the course of oral linezolid 600 mg administered twice per day for treatment of an MRS-infected joint prosthesis. This 76-year-old man had visual field testing showing "patchy field damage" but other ophthalmic details were not included. The patient declined comprehensive ophthalmic examination but gave a subjective report of resolution of blurred vision 5 months after discontinuing linezolid.
We found three other brief references to visual dys-function related to linezolid treatment. A 27-year-old woman with systemic lupus erythematosus (SLE) received 1,200 mg/d of linezolid to treat an MRS bone marrow infection and had a decline in visual acuity to 20/30 OU 3 months into antibiotic therapy (11). Bilateral optic disc edema and central scotomas were reported in that case. The vision continued to decline to 20/200 OU even after she received a single intravenous dose of 1,000 mg of methylprednisolone for presumed SLE optic neuropathy. Two months after discontinuing linezolid, visual acuities recovered to 20/20 OD and 20/25 OS with normal-appearing optic discs. A 72-year-old woman treated with an unspecified dose of linezolid, rifampicin, and ciprofloxacin had bilateral visual loss from "optic neuritis" 41 weeks after the onset of antibiotic therapy, but details of the ophthalmic examination were not included (12). Finally, in a report of linezolid-associated peripheral neuropathy, a 69-year-old man treated with linezolid 600 mg twice daily had "blurred vision" and was noted to have visual acuities of 20/50 OU with normal ophthalmoscopy (9). The timing of the visual symptoms and details of the visual course were not provided.
Linezolid joins a growing list of medications that may cause a progressive vision-impairing optic neuropathy. Early discontinuation of this antibiotic may be associated with a gradual but not necessarily full recovery in visual function.
2. Lee E, Burger S, Shah J, et al. Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis.
3. Corallo CE, Paull AE. Linezolid-induced neuropathy [letter]. Med J Aust
4. Brazis PW, Lee AG. Neuro-ophthalmic problems caused by medications. Am Acad Ophthalmol Focal Points.
5. Package Insert. Zyvox (Linezolid). Copyright Pharmacia and Upjohn Company. 2003 Kalamazoo, MI. Revised November 2003.
6. Physician's Desk Reference,
ed. Montvale, NJ: Thomson Health Care; 2004.
7. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int.
8. Barron GJ, Tepper L, Iovine G. Ocular toxicity from ethambutol. Am J Ophthalmol
9. Rho JP, Sia IG, Crum BA, Dekutoski MB, Trousdale RT. Linezolid-associated peripheral neuropathy. Mayo Clin Proc.
10. Spellberg B, Yoo T, Bayer AS. Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6. J Antimicrob Chemother.
11. Chuman H. 41st Annual Meeting of the Japanese Neuro-Ophthalmology Society, Kyoto, Japan, December 12-13, 2003. J Neuro-ophthalmol.
12. Frippiat F, Bergiers C, Michel C, Dujardin JP, Derue G. Severe bilateral optic neuritis associated with prolonged linezolid therapy. J Antimicrob Chemother.