Major toxic ocular effects may occur with long-term oral administration of these amebicidal agents, especially in children. Because they are given orally for Entamoeba histolytica, most reports come from the Far East. Data suggest that these amebicides may cause SMON. This neurologic disease has a 19% incidence of decreased vision and a 2.5% incidence of toxic amblyopia. It has been suggested that in patients being treated for acrodermatitis enteropathica, which is a disease of inherited zinc deficiency, optic atrophy may be secondary to zinc deficiency instead of diiodohydroxyquinoline. Because long-term quinolone exposure has been shown to result in accumulation of the drug in pigmented tissues, retinal degenerative changes may be observed. The best overall review of this subject is in Grant et al (1993).

Generic Name:

Emetine hydrochloride.

Proprietary Name:

Multi-ingredient preparations only.

Primary use

This alkaloid is effective in the treatment of acute amebic dysentery, amebic hepatitis and amebic abscesses.

While this is a limited-use drug and most of the data are from the older literature, the basic ingredient in ipecac is emetine hydrochloride, which is used off label to induce vomiting in patients with anorexia nervosa. Emetine hydrochloride is somewhat unique in that somewhere between 4–10 hours after exposure in humans, the drug is probably secreted in the tears to give significant bilateral foreign-body sensation, epiphoria, photophobia, lid edema, blepharospasm and conjunctival hyperemia. Because the drug is seldom used for longer than five days, these signs and symptoms quickly resolve once the drug is discontinued (Fontana 1948). At normal dosages, these are probably the only ocular side effects; but at higher doses Jacovides (1923) described optic-nerve and retinal ischemic changes with pupillary, accommodation, vision and visual field abnormalities. These are all transitory with complete recovery.

Emetine hydrochloride is highly toxic when inadvertent direct ocular exposure occurs. This rarely causes significant scarring with permanent corneal opacities with or without iritis and secondary glaucoma.

Adverse ocular reactions due to mepacrine are common but most are reversible and fairly asymptomatic. Systemic mepacrine can stain eyelids, conjunctiva, cornea and sclera yellow, and the basal layers of the conjunctival epithelium blue-gray. This is probably due to the drug being present in the tears. The pigmentary deposition and/or corneal edema may cause complaints of decreased vision, as well as yellow, blue, green or violet vision. These changes are reversible once the drug is discontinued. This may or may not be associated with a superficial keratitis. Drug-induced corneal edema may be precipitated in sensitive individuals, especially those with hepatic dysfunction. This can occur on dosages as low as 0.10 g per day and may take several weeks of therapy to occur. If the drug is discontinued, this will resolve; but if the drug is restarted, the edema will occur again in a few days. Cumming and Mitchell (1998) in the Blue Mountain Eye Study found an association between mepacrine and posterior subcapsular cataracts. Reports of optic neuritis, scotoma and enlarged blind spots are usually single case reports over 50 years ago and are not substantiated as a cause-and-effect relationship. Direct ocular exposure to mepacrine occurs either from exposure to the dust during its manufacture (Mann 1947) or self-infection (Somerville-Large 1947). This drug can stain the eyelids, cornea and conjunctiva. Significant corneal changes, including severe edema and folds in Descemet’s membrane, may occur. Color-vision changes can also occur. These changes are reversible.

Generic Name:

Piperazine.

Proprietary Name:

Piperazine.

Primary use

This anthelmintic agent is used in the treatment of ascariasis and enterobiasis.

While thiabendazole is a potent therapeutic agent, it has surprisingly few reported ocular or systemic toxic side effects. Ocular side effects that occur are transitory, reversible, and seldom of clinical importance. However, a mother and daughter after only a few doses developed keratoconjunctivitis sicca, xerostomia, cholangiostatic hepatitis and pancreatic dysfunction. Rex et al (1983) and Davidson et al (1988) reported cases similar to this. Some feel these reactions may represent allergic responses to the dead parasites rather than direct drug effects. This agent may induce ocular pemphigoid-like syndrome.

This aminoglycoside rarely causes ocular side effects when given orally. Ophthalmologists’ interest in this antibiotic is primarily for intravitreal injections, usually in combination with a cephalosporin for management of endophthalmitis. Gentamicin has been the aminoglycoside of choice for intravitreal injections until reports of macular infarcts occurred. Amikacin was shown to be less toxic to the retina than gentamicin, so many surgeons started using it intravitreally. However, now cases of retinal infarcts have been reported with this agent, with perifoveal capillaries becoming occluded, as per fluorescein angiography. D’Amico et al (1985) found lysomal inclusions in the retinal pigment epithelium secondary to amikacin. Campochiaro (1991; 1992; 1994) pointed out the role of the dependent position of the macula at the time of intravitreal injection with the resultant potential increased concentration of this drug over the macula. Aminoglycosides have a known toxic effect on ganglion and other neural cells of the retina. Doft et al (1994; 2004), from the Endophthalmitis Vitreous Study Group, felt that the data were not compelling enough to suggest a different antibiotic, and they still continue to recommend amikacin as the empirical standard to date. The National Registry is aware of more than 30 cases of macular infarct associated with amikacin use. However, based on risk/benefit ratios, along with the available clinical data, Doft’s recommendation seems reasonable. This is, however, an area of controversy among retinal specialists shown by Galloway et al (2002; 2004).

Generic Names:

1. Amoxicillin; 2. ampicillin; 3. nafcillin sodium; 4. piperacillin; 5. ticarcillin monosodium.

Proprietary Names:

1. Amoxil, Augmentin, DisperMox, Moxatag, Trimox; 2. Principen, Unasyn; 3. Nafcil; 4. Pipracil, Zosyn; 5. Timentin.

Primary use

Semisynthetic penicillins are primarily effective against staphylococci, streptococci, pneumococci and various other Gram-positive and Gram-negative bacteria.

Few adverse ocular reactions due to either systemic or topical ocular use of these antibiotics are seen. Clinicians may overlook in the elderly patient the effect of these agents causing lid edema and blame it on age. Nearly all ocular side effects are transitory and reversible after the drug is discontinued. Pradhan et al (2009) reported myasthenia crisis after IV azithromycin. Dramatic improvement after IV calcium suggests azithromycin probably caused presynaptic suppression of acetylcholine release. Most adverse ocular reactions are secondary to dermatologic or hematologic conditions. Paz et al (2011) reviews occupational exposure to these macrolides showing cross-sensitivity may occur. A well-documented, rechallenged, idiosyncratic response to topical ocular application of erythromycin causing mydriasis has been reported to the National Registry. Also an interaction of erythromycin with carbamazepine causing mydriasis and gaze evoked nystagmus has been reported. Parker et al (2010) reported a case, with rechallenge data, of erythromycin ointment causing increased INR values. The National Registry has also received a case of Stevens-Johnson syndrome following topical ophthalmic erythromycin ointment application. Clarithromycin, with both oral and topical ocular exposure, has been associated with subepithelial infiltrate when treating mycobacterium avium complex. When the drug was stopped, the deposits were absorbed. Visual hallucinations due to clarithromycin have only been seen when the drug was used in peritoneal dialysis.

Generic Name:

Bacitracin.

Proprietary Names:

Ak-Tracin, Baci-IM.

Primary use

This polypeptide bactericidal agent is primarily effective against Gram-positive cocci, Neisseria and organisms causing gas gangrene.

Ocular side effects from either systemic or ocular administration of bacitracin are rare. Myasthenia gravis is more commonly seen if systemic bacitracin is used in combination with neomycin, kanamycin, polymyxin or colistin. With increasing use of “fortified” bacitracin solution (10,000 units per ml), marked conjunctival irritation and keratitis may occur, especially if the solutions are used frequently. The potential of decreased wound healing with prolonged use of any topical antibiotic, especially fortified solution, may occur. Severe ocular or periocular allergic reactions, while rare, have been seen due to topical ophthalmic bacitracin application. An anaphylactic reaction was reported after the use of bacitracin ointment. Orbital compartment syndrome, acute proptosis, chemosis, increased intraocular pressure, decreased vision and ophthalmoloplegia were reported by Castro et al (2000) immediately after endoscopic sinus surgery secondary to inadvertent bacitracin ointment.

Generic Names:

1. Benzathine benzylpenicillin (benzathine penicillin G); 2. benzylpenicillin potassium (potassium penicillin G); 3. phenoxymethylpenicillin (potassium penicillin V); 4. procaine benzylpenicillin (procaine penicillin G).

Proprietary Names:

1. Bicillin L-A, Permapen; 2. Pfizerpen; 3. Pen-Vee K, Veetids; 4. Crysticillin.

Primary use

These bactericidal penicillins are effective against streptococci, S. aureus, gonococci, meningococci, pneumococci, T. pallidum, Clostridium, B. anthracis, C. diphtheriae and several species of Actinomyces.

Systemic administration of penicillin rarely causes ocular side effects. The most serious adverse reaction is papilledema secondary to elevated intracranial pressure. The incidence of allergic reactions is greater in patients with Sjögren syndrome or rheumatoid arthritis than in other individuals. Most other ocular side effects due to penicillin are transient and reversible. Kawasaki et al (1989) showed ERG changes with intravitreal injections of penicillin. Topical ocular administration results in a high incidence of sensitivity reactions.

Proprietary Names:

1. Ceclor; 2. Duricef; 3. Biocef, Cefanex, Keflex, Keftab; 4. Ancef, Zolicef; 5. Spectracef; 6. Cefobid; 7. Claforan; 8. Generic only; 9. Mefoxin; 10. Velosef; 11. Ceptaz, Fortaz, Tazicef, Tazidime; 12. Cefi zox; 13. Rocephin; 14. Zinacef; 15. Ceftin.

Primary use

Cephalosporins are effective against streptococci, staphylococci, pneumococci and strains of Escheria coli, Pneumococci mirabilis and Klebsiella.

Rarely does this group of drugs given systemically cause ocular side effects. Kraushar et al (1994) reported an anaphylactic reaction to intravitreal cefazolin. There is significant cross-sensitivity within this group, as well as with penicillin. Platt (1990) described a generalized allergic event of Type III hypersensitivity, including reversible limbal hyperemia, mild conjunctivitis and peripheral corneal edema, in a patient taking cefaclor. The National Registry has a case of acute macular neuroretinopathy associated with Type III hypersensitivity response in a patient on cefotetan. Platt’s case and the one in the National Registry make one suspicious of a possible association of a Type III hypersensitivity ocular event.

Overdose intracameral injections have caused significant ocular trauma. Delyfer et al (2011) described six post cataract extraction patients with overdose cefuroxime causing anterior and posterior inflammation, increased intraocular pressure, retinal edema and serous retinal detachments. Surgical intervention was required in all cases to achieve satisfactory outcomes. Qureshi et al (2011) reported macular infarction following overdose of intracameral cefuroxime.

Generic Name:

Chloramphenicol.

Proprietary Names:

Ak-Chlor, Chloromycetin, Chloroptic.

Primary use

This bacteriostatic dichloracetic acid derivative is particularly effective against Salmonella typhi, H. influenzae meningitis, rickettsia and the lymphogranuloma-psittacosis group and is useful in the management of cystic fibrosis.