Solutions and Suspensions (“Drops”)

Ophthalmic solutions and suspensions (or “drops”) are commonly used for topical treatment of ocular disease. They are usually easily instilled in dogs and cats but not in large animals. The correct method for instilling eyedrops is shown in Figure 3-3. Drops permit the delivered dose to be controlled and varied easily, and they are alleged to interfere less with repair of corneal epithelium than ointments, although this last feature is unlikely to be clinically significant. Drops are quickly diluted and eliminated from the eye by tears, so greater frequency of application or drug concentration may be required, especially with increased lacrimation. It is important to note that systemic absorption of drugs from the conjunctival sac after topical application is rapid and may result in notable blood concentrations. This may be of clinical significance with use of phenylephrine (producing systemic hypertension) and long-term corticosteroid use (inducing iatrogenic hyperadrenocorticism).

Figure 3-3 Correct method of instilling an eyedrop. The lower eyelid is held open with the hand being used to restrain the patient’s head. The upper eyelid is retracted with the hand holding the medication. The medication container is held 1 to 2 cm from the eye, and a single drop is instilled. Care must be taken to avoid the bottle touching the eye because this may injure the ocular surface or cause contamination of the drug remaining in the bottle.

Continuous or Intermittent Ocular Surface Lavage Systems

With frequent treatment or in horses with painful eyes, a lavage system allows medications to be conveniently, safely, and frequently delivered into the conjunctival sac. Originally, such systems were placed within the nasolacrimal duct and medications were instilled in a retrograde fashion. More recently subpalpebral lavage systems have been described that are simply placed and avoid nasal irritation and risk of dislodgement. A two-hole technique through the skin of the upper eyelid has now been replaced by single-hole systems, owing to the commercial availability of lavage systems with footplates to prevent inadvertent removal. The original one-hole system was placed in the central upper lid but is associated with a relatively high risk of complications, most notably corneal ulceration due to rubbing of the footplate on the cornea. Placement of the subpalpebral lavage system in the ventromedial conjunctival fornix may be preferred because of the natural corneal protection provided by the third eyelid at that point (Figure 3-4).

Figure 3-4 Placement of a subpalpebral lavage system in the medial aspect of a horse’s lower eyelid. A, A local (subcutaneous) injection of lidocaine is administered. B, The palpebral and fornicial conjunctival surfaces are anesthetized with proparacaine-soaked cotton-tipped applicators held in place for 1 or 2 minutes. C, A trocar is used to penetrate the lower lid from the conjunctival fornix, and the lavage tube is threaded through it. D, The trocar is removed, and the lavage tube is pulled down until it lies snugly in the ventral conjunctival fornix between the third eyelid and lower lid. E, The lavage tube is sutured in place with adhesive tape tabs, and an injection port is placed at its terminus near the mane on the same side as the affected eye.

Subpalpebral lavage systems placed in the medial aspect of the lower lid are associated with less common and less severe ocular complications than those placed centrally and dorsally, even when left in place and used by owners for up to 55 days after discharge from hospital. The lavage tube leads back to the shoulder, where it is secured at the mane and where drugs can be administered with less risk of injury to the eye or the operator. Drugs are injected into the tube and either slowly propelled to the eye with a gently administered bolus of air from a syringe or continuously propelled by a gravity-fed bottle or small mechanical infusion pump connected to the tube. This method of therapy is usually reserved for horses with severe corneal or uveal disease. A protective eyecup can be applied over the lavage tube for protection of the eye and apparatus. Ointments (and some more viscous suspensions) cannot be applied through lavage systems.

Ointments

In horses the orbicularis oculi muscle is very powerful, and it is impossible to tilt the head to allow a drop of solution to enter without contaminating the bottle. Ointments are preferred in such patients. Ointments also allow longer contact between the drug and surface tissues. Finally, less drug enters the nasolacrimal apparatus. Therefore ointments achieve higher tissue concentrations than solutions or suspensions do. A soothing effect occurs on instillation, they are a more stable medium for labile antibiotics and drugs, and they also provide physical lubrication and protect against desiccation better than solutions do. However, because oily ointment bases cause severe intraocular inflammation, and because application of ointments may result in ocular trauma from the tube itself, ointments are not recommended when globe perforation has occurred or is likely. Because they make tissue handling difficult and cause granulomatous inflammation if they penetrate ocular surface structures, ointments should also not be used before ocular or adnexal surgery. Finally, owners tend to overmedicate when using ointments, resulting in loss of medication, higher cost, and lower compliance with treatment regimens. As little as 0.5cm of ointment from a fine nozzle is sufficient to medicate an eye.

Subconjunctival, Subtenons, and Retrobulbar Injection

Subconjunctival injection permits a portion of the administered drug to bypass the barrier of the corneal epithelium and penetrate transsclerally. However, a notable proportion of the injected drug leaks back out the injection tract and is absorbed as if it had been administered topically. Subconjunctival administration is used to facilitate high drug concentrations in anterior regions of the eye, whereas deeper injections beneath Tenon’s capsule allow greater diffusion of drugs through the sclera and into the eye. Mydriatics (for pupillary dilation), antibiotics, and corticosteroids are the main groups of drugs administered by this route. Some irritating drugs (e.g., polymyxin B) or any topical drug containing a preservative cannot be given subconjunctivally. Drugs with potent systemic sympathomimetic or vasopressor effects also should not be given in this manner.

In cooperative patients, subconjunctival injections can be given using topical anesthesia only. Handheld lid retractors may be helpful in all species (Figure 3-5). For horses and cattle, one should also consider tranquilization, appropriate restraint (a twitch for horses and nose grips for cattle), and an auriculopalpebral nerve block to produce akinesia of the upper lid (see Chapter 5). A few drops of topical ophthalmic anesthetic (e.g., proparacaine) are instilled into the conjunctival sac. Conjunctival anesthesia is facilitated by a cotton-tipped applicator soaked in topical anesthesia and placed against the conjunctiva at the planned injection site for about 30 seconds. The solution for subconjunctival injection then is administered through a 25- to 27-gauge needle with a 1-mL tuberculin or insulin syringe under the bulbar conjunctiva as close as possible to the lesion being treated (Figure 3-6). Injection under the palpebral conjunctiva is not effective. The needle is rotated on withdrawal to limit leakage through the needle tract. Up to 1mL of drug can be given beneath the bulbar conjunctiva, but most injections do not exceed 0.5mL. Slight hemorrhage into the injection site occasionally occurs but is absorbed within 7 to 10 days. Injections of depot preparations should be avoided at this site because they often lead to granuloma formation.

Figure 3-5 A, Handheld lid retractors. B, Retractor in use.

Figure 3-6 Subconjunctival injection technique. A, After application of a topical anesthestic, a 25- to 27-gauge needle is inserted beneath the bulbar conjunctiva. Care must be taken not to penetrate the globe. B, The medication injected forms a noticeable bleb that reduces in size over the next few minutes to hours.

(Courtesy Dr. David Ramsey.)

Retrobulbar injection is used rarely and only for treatment of disease processes in the orbit or posterior half of the globe. These areas can usually be treated adequately with safer and simpler systemic routes of treatment. Therefore this route of therapy is now generally limited to the injection of local anesthetic into the muscle cone behind the globe for removal of the bovine eye.

Systemic Drug Administration

Although there are rare exceptions, systemically administered drugs should be considered to reach only the vascular tissues of the eye and surrounding structures—that is, not the cornea, the lens, or (in the presence of an intact blood-ocular barrier) the aqueous or vitreous humor. This knowledge may be used to the clinician’s advantage. For example, systemic administration of a corticosteroid for control of uveitis in the presence of corneal ulceration is safe and effective, because the target tissue (the uvea) is vascular, but the drug will not reach the avascular cornea in quantities sufficient to retard healing. Equally, the systemic administration of an antibiotic for treatment of an ulcer in a nonvascularized cornea is of little value, and topical administration is most effective. Therefore systemically administered drugs should be reserved for treatment of diseases of the eyelids, conjunctiva, sclera, uvea (iris, ciliary body, choroid), retina, optic nerve, extraocular muscles, and orbital contents.

As with other body systems, intravenous, subcutaneous, and intramuscular injections provide relatively high plasma concentrations of a drug to the vascular components of the eye. However, because continuous treatment is necessary for many ocular disorders, oral drug administration by owners is used most frequently, particularly in dogs and cats. Continuous intramuscular administration is used occasionally in large animals. Intravenous therapy is rarely used for ocular disease, with the important exception of the administration of mannitol for reduction of intraocular pressure (IOP) and vitreous volume in acute glaucoma.

Intraocular drug concentrations attainable by systemic routes depend on the following three important factors:

Some examples reinforce these general points. Although penicillin is readily absorbed by intramuscular injection, penicillin G is poorly absorbed orally because it is destroyed by gastric acid. Even when adequate plasma concentrations are achieved, it penetrates the blood-ocular barrier poorly. By contrast, chloramphenicol is well absorbed by dogs after oral administration and, once in the plasma, passes the blood-aqueous barrier well. From these examples, it follows that the clinician must understand the properties of the individual drugs used in order to predict their applicability for ophthalmic use.

Selection and Administration of Antibiotics

The following factors must be considered in the selection of an antibiotic:

The ideal basis for selection of an ocular antibiotic consists of identification of the responsible organism and its antibiotic sensitivity. However, obtaining this information often cannot be justified because of expense or because treatment must be instituted before the results of such testing are available. Therefore knowledge of the most likely organisms, their sensitivity, and the most likely effective antibiotics is necessary. Treating infections on such an empirical basis, although practical and often unavoidable, does not always lead to a satisfactory result. A more rational choice of therapeutic agent can be made after examination of the staining and morphologic characteristics of organisms seen on a Gram-stained or Diff-Quik–stained sample of the affected tissue and is essential in severe or nonresponsive infections. In more severe infections (e.g., stromal corneal ulcers or endophthalmitis), the organism should be identified, and a combination of routes of administration and synergistic drugs should be considered. If ocular infections persist or recur despite treatment with the appropriate antibiotic (based on results of culture and sensitivity testing), the infection may be secondary to an underlying disorder or pathologic process. Alternatively, a fastidious bacterium or nonbacterial microbe not originally cultured (Chlamydophila spp., Mycoplasma spp., fungus, virus, etc.) may be present.

Organisms commonly isolated from the conjunctival sacs of normal and diseased animals are given in Tables 3-1 through 3-9. These tables highlight a number of important general points about ocular surface flora that are relevant when interpreting these data in an individual patient:

Table 3-1 Normal Flora of the Canine Conjunctival Sac

* Data from Bistner SI, et al. (1969): Conjunctival bacteria: clinical appearances can be deceiving. Mod Vet Pract 50:45.

† Data from Urban W, et al. (1972): Conjunctival flora of clinically normal dogs. Am J Vet Med Assoc 161:201.

‡ Data from McDonald PJ, Watson ADJ (1976): Microbial flora of normal canine conjunctivae. J Small Anim Pract 17:809.

Table 3-2 Organisms Cultured from Dogs with External Ocular Disease

* Data from Verwer MAJ, Gunnick JW (1968): The occurrence of bacteria in chronic purulent eye discharge. J Small Anim Pract 9:33.

† Data from Murphy JM, et al. (1978): Survey of conjunctival flora in dogs with clinical signs of external eye disease. J Am Vet Med Assoc 172:66.

‡ Data from Gerding PA, et al. (1988): Pathogenic bacteria and fungi associated with external ocular diseases in dogs: 131 cases (1981-1986). J Am Vet Med Assoc 193:242.

Table 3-3 Normal Flora of the Feline Conjunctival Sac

Table 3-4 Fungal Flora from Normal Horses (50 Horses)

Table 3-5 Organisms Cultured from Horses with External Ocular Disease (123 Eyes)

Table 3-6 Normal Flora of the Bovine Conjunctival Sac

Table 3-7 Normal Flora of the Ovine Conjunctival Sac

Table 3-8 Normal Bacterial Flora of South American Camelid Eyes (88 Animals)

Table 3-9 Normal Fungal Flora of South American Camelid Eyes (127 Animals)

* Percentages varied according to season and camelid species.

The following sections provide a summary of some important properties of antibiotics used commonly in veterinary ophthalmology, and Table 3-10 lists the typical Gram-staining characteristics of, and the antibiotics of choice for, common organisms.

Table 3-10 Antibiotics of Choice for Common Organisms

Penicillins

The penicillins form a large family of natural and synthetic derivatives of 6-aminopenicillanic acid that range considerably in stability, solubility, spectrum of activity, ocular penetration, and resistance to β-lactamase.

Cephalosporins

A range of cephalosporins is available. They are generally similar to the penicillins in mechanism of action and pharmacology but are less susceptible to staphylococcal β-lactamases. A type of β-lactamase (cephalosporinase) produced by some gram-negative organisms may inactivate them. Cephalosporins have had excellent results when administered subconjunctivally or topically via lavage tube to horses with corneal ulceration, particularly those infected with Streptococcus spp. They are also very useful for bacterial blepharitis. Cefazolin is the antibiotic of choice for perioperative antimicrobial prophylaxis in small animal surgery.

Chloramphenicol

Chloramphenicol is a broad-spectrum bacteriostatic antibiotic effective against a wide range of gram-positive and gram-negative organisms, Rickettsia, spirochetes, and Chlamydophila spp. However, Pseudomonas aeruginosa is often resistant. Because of its lipid solubility, chloramphenicol passes the blood-ocular barrier and through corneal epithelium better than most water-soluble antibiotics. Chloramphenicol may be administered orally, intramuscularly, subcutaneously, intravenously, subconjunctivally, or topically. Because absorption after oral administration results in high blood concentrations, this is the route of choice for infections in the posterior globe and orbit. Despite controversial toxicity studies in cats, the drug has been used clinically over many years with few ill effects except anorexia and occasional pyrexia in some cats after systemic administration, provided that administration is not prolonged. Because of its wide spectrum of activity and intraocular penetration, chloramphenicol as an ointment or drops was widely used in veterinary practice for ocular surface injuries and infections, but its use is declining in favor of bactericidal antibiotics. Polymyxin B is often added to aid in control of gram-negative organisms, especially Pseudomonas spp. It is still useful in the topical treatment of suspected Chlamydophila infections in cats, although systemically administered drugs are preferable (see Chapter 7).