Carbenicillin

This is the final article of a three-part series that is intended to provide compounding pharmacists with the skills necessary to compound specific preparations for the treatment of common veterinary ocular diseases. This article specifically discusses ocular diseases and their treatments for dogs, cats and horses.

Common Ocular Diseases Requiring Medical Therapy

Dogs

Keratoconjunctivitis sicca (KCS), or dry eye, is a common pathologic condition in which the aqueous component of the tear film is produced in an insufficient quantity. The most common form is a breed-related, immune-mediated inflammation and subsequent degeneration of the lacrimal tissue. Clinical signs include an excessive mucous discharge, conjunctival hyperemia, blepharospasm and varying degrees of corneal scarring, the latter of which is characterized by vascularization, fibrosis, keratinization and pigmentation. Severely or chronically affected animals may lose vision from corneal scarring; and, in fact, KCS is the leading cause of blindness in some predisposed breeds, including but not limited to the:

* American Bulldog

* Dachshund

* English Bulldog

* Lhasa Apso

* Miniature Poodle

* Pug

* Shih-Tzu

* West Highland White Terrier

KCS is treated with a variety of topical artificial tear supplements, including methylcellulose, polyvinyl alcohol, hyaluronic acid and petroleum-based lubricating ointments. Adjuvant therapy may include topical antibiotics and topical acetylcysteine (a mucolytic). Over the past 10 years, treatment with topical cyclosporine A (CSA), which increases tear production by an unknown mechanism, has revolutionized the treatment of canine KCS. Topical CSA is administered twice daily and is available in 0.2% ointment (Optimune is a commercially available product) or in 1% or 2% compounded solutions (generally with an olive-oil vehicle and/or diluent). Compounding pharmacists should be aware that KB Visions, Inc. (Atlanta, Georgia) holds a use patent for topical cyclosporine for KCS, and special licensing agreements must be in place prior to compounding topical cyclosporin for dry eye in dogs. Clinical studies have suggested that the 1% concentration of cyclosporine is as effective in most patients as the 2% concentration. In the author's experience, 10% of patients have a hypersensitivity or irritant effect to the olive-oil diluent; compounding with corn oil sometime alleviates this problem. Approximately 80% to 85% of affected dogs will respond to therapy with an increase in tear production.1 If the Schirmer tear test results in a value of

Pet owners should be advised that this is generally a lifelong therapy, as tear production quickly returns to the pretreatment levels if CSA therapy is discontinued. Cases that do not respond to CSA therapy require either frequent artificial tear supplementation or a surgery that involves relocating a salivary duct to the ventral conjunctival (parotid duct transposition). A study using tacrolimus 0.03% solution in olive oil is now being conducted at the University of Tennessee College of Veterinary Medicine (Knoxville, Tennessee). So far, the results of this study show promising results of tacrolimus for the treatment of KCS in canine patients. Another investigator determined2 that dogs that failed to respond to topical CSA therapy responded positively to a topical 0.02% tacrolimus aqueous suspension. It is important to note that Protopic, the commercially available tacrolimus ointment, is preserved with propylene carbonate. Use of propylene carbonate in the eye should be avoided, as this chemical is a strong corneal irritant and is also associated with depletion of cholinesterase in vitro.

Glaucoma, an increase in intraocular pressure (IOP) to a level that causes pathologic changes in the eye, is one of the most common blinding ocular conditions in dogs. Glaucoma can be defined as primary if no antecedent cause is present and secondary if another disease process (eg, uveitis, neoplasia, bleeding into the eye, lens luxation) has caused the IOP increase. Many cases of glaucoma in dogs are primary and are caused by a breed-related abnormality in their aqueous humor outflow pathways, or the iridocorneal angle. Common breeds that are affected include the:

* American Cocker Spaniel

* Basset Hound

* Chow Chow

* Dalmation

* Miniature Poodle

* Norwegian Elkhound

* Shar-Pei

Also included are many of the brachycephalic breeds (dogs having a short, almost-round head, the width of which is at least 80% as great as the length).

Glaucoma in dogs has a relatively guarded long-term prognosis for adequate vision and most cases require surgical treatment. Acute canine glaucoma is treated with intravenous mannitol, a topical carbonic anhydrase inhibitor (dorzolamide), a topical beta-blocker (timolol), topical miotics (pilocarpine), topical adrenergics (epinephrine, apraclonidine) and topical prostanoids (latonoprost). With the exception of mannitol and apraclonidine, the same drugs are used for maintenance therapy and often for prophylaxis in the unaffected eye. Each of these drugs may be associated with specific ocular or nonocular side effects. Surgery for affected animals with vision may include a laser or cryo-cycloablation (partial destruction of the ciliary body) or gonioimplants (a tube inserted into the anterior chamber), whereas nonvisual eyes may be treated with enucleation (removal of the eye), intrascleral prosthesis or intravitreal chemical cycloablation with gentamicin.

Cataract, or opacification of the lens, is another common ocular disorder that may cause blindness in dogs. The most common etiologies include an inherited or genetic type, senility, diabetes mellitus and retinal degeneration. Commonly affected breeds include the:

* American Cocker Spaniel

* Brachycephalic breeds

* Golden Retriever

* Labrador Retriever

* Miniature Poodle

* Miniature Schnauzer

Cataract surgery is one of the most common intraocular surgical procedures performed by veterinary ophthalmologists, with several thousand performed in the US every year. The surgical technique, use of prosthetic lens, outcome (approximately 92% to 95% success rate) and ancillary medical treatment are virtually identical to those used in humans. Pre- and postoperatively, dogs are typically treated with a topical corticosteroid and/or antibiotic, nonsteroidal anti-inflammatory agent (eg, flubriprofen) and a mydriatic (eg, atropine, tropicamide, phenylephrine). Many clinicians also use oral antibiotics and oral or parenteral nonsteroidal agents perioperatively or postoperatively. Intraoperatively, the surgeon often uses a viscoelastic material injected into the anterior chamber to maintain the shape and volume of the eye and to protect the intraocular structures. The most commonly used ocular viscoelastic materials include sodium hyaluronate, hydroxypropyl methycellulose and chondroitin sulfate.

Following cataract surgery in the dog, fibrin or blood clots (hyphema) may occasionally form in the anterior chamber from the resultant uveitis. Blood or fibrin clots may also form following severe uveitis from other causes, trauma or diseases causing bleeding (ie, blood dyscrasias, thrombocytopenia, disseminated intravascular coagulation, hypertension). Because the contracting fibrin component of a clot may cause complications in the eye, including synechia or intraocular adhesions, corneal edema and cataract, this is sometimes treated with an intracamcral injection of tissue plasminogen activator (tPA). The typical dose is 25 µg in a 0.1-mL volume (250 µg/mL). Therapy with tPA should ideally be administered 1 to 3 days following formation of the clot, although some beneficial effect may be seen up to 2 weeks following clot formation. Therapy with tPA is not recommended immediately after the insult due to the possibility of a rebleed from the injured blood vessel.

Ulcerative keratitis, or corneal ulcer, in the dog is generally caused by a variety of breed-related anatomic disorders of the eyelid, KCS or exogenous trauma. Clinical signs include an abnormal appearance of the cornea (ie, edema, vascularization, necrosis), conjunctival hyperemia, and pain from miosis (caused by secondary neuronal spasm of the iris). Once an ulcer forms, it is vulnerable to a secondary bacterial infection from the normal flora of the conjunctival sac, most commonly gram-positive cocci. Gram-negative bacterial infections, especially Pseudomonas infection, can also occur and can have devastating consequences for the cornea. Progression of a corneal ulcer may lead to perforation, iris prolapse into the wound and loss of the eye. Ulcers may be treated medically with appropriate topical antibiotic and topical atropine to relieve the secondary iris and ciliary body spasm. With active microbial infections, topical antibiotics should be administered frequently-every 2 to 3 hours for the first 24 hours and then 3 to 5 times daily thereafter.

When treating bacterial ulcerative keratitis, it is not possible to achieve high concentrations of the drug in the corneal stroma with commercially available preparations. As a result, some clinicians prefer to use fortified antibiotic solutions (from the parenteral form of the drug, diluted to the appropriate strength in the appropriate vehicle). Common examples of such solutions include:

* Amikacin (10 mg/mL)

* Carbenicillin (4 to 8 mg/mL)

* Cefazolin (50 mg/mL)

* Gentamicin (14 mg/mL)

* Tobramycin (14 mg/mL) or

* Vancomycin (50 mg/mL)

For so-called melting of ulcers, some clinicians use topical anticollagenase agents, which may include acetylcysteine 2% to 10% solution (every 1 to 4 hours), sodium or calcium ethylenediaminetetraacetic acid (EDTA) as a 1% solution, citrate or endogenously collected serum, although the efficacy of such therapy is frequently questioned. Surgical treatment of deep or progressive ulcerative keratitis typically includes conjunctival or corneal graft procedures. For pain associated with corneal ulcers, a topical solution of morphine sulfate 1% preservative-free ophthalmic solution provides analgesia without interfering with wound healing.3

Chronic superficial keratitis, or pannus, is another common type of keratitis seen in the dog. This is an immune-mediated disorder seen in the German Shepherd, which may be exacerbated by exposure to ultraviolet (UV) light. As a result, the condition is more common and proportionately more severe in the Western US (ie, in high-altitude states such as Colorado). The condition is treated with topical corticosteroids, such as dexamethasone or prednisolone acetate, and/or topical CSA and subconjunctival corticosteroids. Nonresponsive cases may receive keratectomy, local (beta) radiation therapy and cryotherapy. Because dogs that suffer from this disease require long-term or lifetime topical anti-inflammatory therapy, their risk of suffering side effects from systemic absorption of topical corticosteroids is increased.

Fungal infections that cause inflammation inside the eye, or uveitis, may also develop in dogs (and cats). These fungal infections are more common in the south and southeastern US but also occur in many parts of the country. The more common systemic mycoses and their most commonly affected geographical areas include:

* Blastomycosis: Southeastern US

* Coccidiodomycosis: Southwestern US

* Cryptococcosis: Entire US

* Histoplasmosis: Southeastern and Midwestern US

The severity of these infections and the ocular manifestations vary, and they can be fatal and/or can cause loss of the eye. Ocular mycosis resulting in uveitis or endophthalmitis requires treatment with topical anti-inflammatory therapy, atropine to treat the anterior uveitis and systemic antifungal therapy. A number of systemic antifungals are available to treat these infections, but the most widely used and effective is itraconazole, although ketoconazole and fluconazole are also used. Some animals also receive a short course of intravenous amphotericin B as adjunct therapy, although renal side effects from this drug are relatively common. A minimum of several months of antifungal therapy is necessary, and many cases require prolonged therapy of up to 2 to 3 years to prevent recurrences when oral therapy is discontinued. Blind, uveitis eyes in animals with systemic mycoses require enucleation, as they may act as a nidus for re-infection.

Cats

Feline herpesvirus-1 (FHV-1), or rhinotracheitis virus, is by far the most common cause of ocular disease in cats. This ubiquitous virus is one for which cats are commonly vaccinated. Most cats are exposed to FHV-1 early in life, often from their mother, and the primary infection results in bilateral conjunctivitis (with mucopurulent ocular discharge) and a rhinotracheitis (nasal or oral discharge, sneezing, coughing and fever). Most kittens have a one- to three-week course of infection and recover without sequellae. Approximately 80% of cats will develop a latent infection, with the virus present in a subclinical form in the trigeminal ganglion. As with herpes simplex virus infection in humans, a small percentage of these cats will then develop recurrent infection with periodic clinical signs. Ocular lesions associated with these recurrent bouts are common and often occur in the absence of chronic upper respiratory tract signs. The recurrent form of infection may cause conjunctivitis or, more seriously, keratitis (inflammation of the cornea). Recurrent corneal infection may cause progressive corneal scarring and lead to blindness and is often quite painful. Other ocular lesions associated with or attributed to chronic herpesvirus infection include symblepharon (adhesions in the conjunctiva), KCS, corneal sequestrum (a black, necrotic lesion of the cornea), eosinophilic keratitis, anterior uveitis and periocular dermatitis.

Recurrent herpesvirus infections causing only conjunctivitis are often treated solely with prophylactic topical antibiotic therapy. Two other bacterial pathogens, Chlamydia psittaci and mycoplasma spp., may also cause conjunctivitis in cats, which clinically appears identical to FHV-1 infection. Because these two pathogens are sensitive to tetracyclines, these topical antibiotics are considered the treatment of choice for feline conjunctivitis. It is important to note that tetracyclines have no direct effect on viral replication and are used simply to control secondary bacterial infection.

Recurrent corneal infection with FHV-1 can be very challenging to treat. Many clinicians use a combination of topical antibiotic and topical antiviral therapy, topical antiviral agents must be administered frequently (every 2 hours for the first 24-48 hours; 5 times daily thereafter) because they selectively inhibit synthesis, by the virus, of DNA or, in some cases, RNA. This can be a very onerous task for the owner and very stressful for the cat. Available antiviral agents that are commonly used against FPIV-1 are shown in Table 1.

It is advisable to owners of cats with recurrent FHV-1 infection to minimize stress in their pet's environment as much as possible because recurrent FHV-1 ocular signs often occur following a stressful period for the cat (ie, a move by the owners, a new cat in the household, a fight with a neighborhood cat). Annual vaccination against FHV-1 is also prudent; although this does not eliminate the viral latency, it may provide some systemic humoral immunity that can lessen clinical signs during recurrence. Cats with recurrent infection generally do not pose a threat to other cats in the household, as they have generally developed an acquired immunity from exposure and/or vaccination.

Systemic hypertension in cats has been diagnosed with increasing frequency over the past several years, perhaps owing to the increased recognition of this disease and increasing life span of cats. Causes include primary or essential hypertension (similar to the most common form in humans), secondary to chronic renal failure, hyperthyroidism, diabetes mellitus, hyperadrenocorticism and pheochromocytoma. The eye is a target organ for hypertension, especially profound hypertension from which cats often suffer, and severe ocular lesions collectively referred to as hypertensive retinopathy and sudden-onset blindness are currently the most common presenting sign for feline hypertension. Lesions result from damage to the retinal and choroidal vasculature and include retinal edema, hemorrhage and detachment. Because it is effective, relatively inexpensive and easy to administer at oral dosages of 0.625 mg/clay, amlodipine besylate has emerged as the treatment of choice for feline hypertension. Other antihypertensive therapies include systemically administered diuretics, beta blockers and adrenocortical extract inhibitors. Affected cats should also be placed on a restricted salt diet. The visual prognosis depends on severity of the lesions and response to therapy, although early cases have a favorable prognosis.

Horses

Corneal ulceration with secondary microbial infection is the most common cause of ocular morbidity in horses. Most corneal ulcers in horses are initiated by some form of trauma, and the injured cornea is extremely susceptible to secondary infection. Because of their environment and the fact that horses have a high number of both bacterial and fungal flora in the conjunctiva and tear film, secondary infection with either class of microbes is possible.

Similar to small animals, bacteria species causing keratitis in horses include Staphylococcus, Streptococcus, Corynebacterium, Pseudomonas, Klebsiella and E. coli. Principles of treatment for bacterial ulcerative keratitis are similar to small animals, and frequent antibiotic solutions are administered through a subpalpebral lavage. See the International Journal of Pharmaceutical Compounding (July/August 2004)4 for graphic and written instructions on the placement of subpalpebral lavage catheters for horses. Many forms of ulcerative keratitis in horses require surgical therapy with debridement and placement of a corneal or eonjunctival graft. Topical atropine therapy needs to be used judiciously in horses due to the possibility of systemic absorption and the development of colic. Horses also develop a moderate-to-severe secondary uveitis from microbial ulcerative keratitis and, therefore, are typically also treated with systemic, nonsteroidal anti-inflammatory agents (NSAIDs) such as flunixin meglumine or phenylbutazone.

Fungal keratitis may also develop following trauma to the cornea. This serious condition is more common in the southeastern US but may be seen as far north as Canada. Trauma with plant material or prior treatment with topical corticosteroids is a risk factor for its development. Common species include Aspergillus, Fusarium and Penicillium, all filamentous, saprohyphytic fungal flora. Candida albicans infection, the most common cause of fungal keratitis in humans, is rare in horses and small animals. Mixed fungal and bacterial keratitis may also occur. Fungal keratitis is challenging to treat, and some retrospective studies suggest up to 50% of affected animals lose vision from corneal scarring or require enucleation. The disease is treated with a combination of topical antifungal and antibiotic (prophylaxis) therapy, topical atropine, systemic nonsteroidal anti-inflammatory drugs and surgery. Topical antifungals include:

* Fluconazole

* Flucytosine

* Itraconazole

* Miconazole

* Natamycin (the only commercially available preparation approved for use)

* Silver sulfadiazine

Of these antifungals, miconazole and natamycin are the most widely used. Drug penetration into the deeper layers of the cornea is the major impediment to effective therapy. Formulation with dimethyl sulfoxide has been recommended with itraconazole to increase penetration, but, in the author's experience, this form of therapy is often very painful and irritating to the patient. Topical antifungal treatment is typically necessary for 4 to 8 weeks.

Recently, oral fluconazole therapy has been investigated as an adjunct or sole therapy for equine fungal keratitis at an oral dosage of 2 mg/kg twice daily for a minimum of 2 weeks. This drug selectively concentrates in the cornea following oral therapy, which accounts for its apparent efficacy. The expense of this form of therapy limits its widespread use.

Uveitis, or "moon blindness," is the most common ocular disease in horses, estimated to occur in 10% to 20% of horses worldwide. It is the most common cause of blindness in horses, and it generally occurs in a chronic, recurrent form called equine recurrent uveitis. Each progressive bout of uveitis results in ocular tissue injury and scarring, including:

* Cataracts

* Corneal edema and fibrosis

* Phthsis bulbi (a small shrunken eye)

* Retinal degeneration and detachment

The pathogenesis is poorly understood, but it is thought to be an immune-mediated disorder that is initiated by microbial (eg, Leptospira pomona) or parasitic infection or trauma. The active bouts of inflammation are treated with topical corticosteroids, topical atropine and systemic NSAIDs. Because of the possible side effects of laminitis in horses, systemic corticosteroicl therapy is generally reserved for more severe or nonresponsivc cases. Some clinicians use chronic low-dose oral aspirin therapy (25 mg/kg every 24 hours) as a means of reducing the recurrence rate. Recently, an intravitreal sustained-release device containing CSA has been investigated. Additionally, surgical removal of the vitreous (vitrectomy) has been investigated as a possible treatment.

Sarcoids, locally invasive fibroblastic tumors, are the most common skin tumors in horses. The disease that causes sarcoids is thought to be induced by a virus and transmitted by flies. The eyelids are one site of predilection. Surgical removal alone, or surgery and cryotherapy (another common form of therapy), have only a 50% success rate. One effective Form of therapy is intralcsional mycobacterium cell-wall extract therapy (Ribigen). This form of therapy is thought to stimulate an immune response against tumor antigens, which causes regression. The injections are given at 1 mL/cm^sup 2^ of tumor surface area, at two- to four-week intervals, until remission. Each treatment interval, following the first injection, is typically associated with a moderatc-to-severe local inflammatory response and systemic NSAIDs, or even systemic corticostcroids, are often used to control these symptoms.

Squamous cell carcinoma (SCC) is a common periocular neoplasia in older horses. The disease is seen most commonly in breeds of horses with sparse pigment around the eyelids and third eyelids; exposure to UV light and increasing age are other risk factors. The tumor can occur on the eyelids, conjunctiva, lateral "limbus" (junction of cornea and sciera) or third eyelid. Treatment depends on location and often involves surgery, although eyelid SCC can be treated with intralesional mycobacterium cell-wall extract, as outlined for sarcoids, or chemotherapy consisting of carboplatin or cisplatin, both formulated in sesame or peanut oil suspension. (Note: The method of preparation for a formula consisting of carboplatin is a 50-mg vial of lyophilized carboplatin reconstituted with 3.3 mL sterile mater for injection to make 15-mg/mL sterile solution. Immediately prior to injection, carboplatin is emulsified in an equal volume of sterile sesame oil via syringe-to-syringe transfer.) For cisplatin, a dosage of 1 mg/cm^sup 3^ for tumors 10-20 cm^sup 3^ in size is necessary (Note: The method of preparation for a formula consisting of cisplatin is 10 mg of cisplatin in 1 mL of water and 2 mL of purified medical-grade sesame oil). Three to six treatments are typically necessary to induce tumor regression. Topical 5-fluorouracil (1% solution applied 3 times daily) or topical mitomycin C (0.02% solution, 4 times daily) may also be used for limbal and eyelid SCC. The prognosis for early periocular SCC is favorable, although recurrence or a new second site of tumor development may be seen. Avoidance of high-intensity UV light (ie, avoidance during the middle of the day) and lid tattooing with a tattoo gun and appropriate ink colors may decrease the prevalence and recurrence of SCC. Corneal scarring may be masked by tattooing with 2% platinum chloride followed in 30 seconds by 2% hydrazine hydrate.

Conclusion

Medical treatment of eye disease in animals can be challenging, as the clinician must consider not only the pharmacologic principles of the drug being administered but also the species being treated, the behavior of the animal and the ocular disease process itself. In addition, practical and economic considerations often dictate whether the animal will receive the optimal therapy and dosing regime. The compounding pharmacist can play a valuable role in the treatment of veterinary ophthalmic disease. When equipped with an understanding of basic anatomy and physiology of the eye, pharmacologic principles of veterinary ophthalmics and awareness of drugs and devices used to treat specific veterinary diseases, the compounding pharmacist becomes an indispensable part of the veterinary care triad. Table 2 provides a quick overview of therapeutic agents utilized in treating veterinary ophthalmic disease.

References

1. Wilkie DA. Kerato conjunctivitis sicca. Proceedings of 3rd Annual Tufts Animal Expo 2002; September 13-15, 2002; Boston, MA.

2. Berdoulay A, English RV, Nadelstein B et al. The effect of topical 0.02% tacrolimus aqueous suspension of tear production in dogs with kerato-conjunctivitis sicca. In: Proceedings of the 34th Annual Conference of the American College of Veterinary Ophthalmology; October 22, 2003; Coer d' Alene, ID: 33.

3. Stiles J, Honda CN, Krohne SG et al. Effect of topical administration of 1% morphine sulfate solution on signs of pain and corneal wound healing in dogs. Am J Vet Res 2003; 64(7): 813-818.

4. Davidson GS. Veterinary ophthalmic practice: Therapeutic considerations and common ocular diseases-Part 2. IJPC 2004; 8(4): 277-283.

Gigi S. Davidson, BS, RPh, FSVHP, DICVP

North Carolina State University

College of Veterinary Medicine

Raleigh, North Carolina

Address correspondence to: Gigi S. Davidson, BS, RPh, FSVHP, DICVP, North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606. E-mail: gigi_davidson@ncsu.edu

Copyright International Journal of Pharmaceutical Compounding Sep/Oct 2004
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