Antimicrobial Use in Animals

Ophthalmic aminoglycoside formulations include neomycin, framycetin (neomycin B), gentamicin, and tobramycin. Injectable amikacin can be compounded into a topical formulation. As a family the aminoglycosides are all bactericidal, mainly against aerobic gram-negative bacteria. They vary in their efficacy against Pseudomonas spp. Neomycin has no activity against Pseudomonas; gentamicin has some, although there is more resistance; tobramycin and amikacin treat resistant Pseudomonas. Aminoglycosides have some gram-positive activity against staphylococci but not streptococci. They bind irreversibly to the 30S subunit and, by causing misreading of the mRNA, result in incorrect amino acid incorporation, thus inhibiting ribosomal protein synthesis. They are hydrophilic and have poor penetration across an intact cornea. High concentrations of gentamicin are epitheliotoxic, and very frequent dosing can slow corneal epithelialization during ulcer healing.

In humans, topical ophthalmic neomycin can be highly toxic and allergenic. There are reports of similar problems in animals, especially cats. Neomycin is still used commonly in combination drops; however, care needs to be taken that the presence of conjunctivitis during and after treatment is due to disease rather than a local toxic or allergic drug reaction. Gentamicin can be injected into the vitreous in dogs and horses for ciliary body ablation in animals with blind, painful eyes from chronic glaucoma. Care needs to be taken in small dogs that the toxic dose is not reached. Low dose (4 mg) intravitreal gentamicin is also used to help treat equine recurrent uveitis. Complications can include cataract formation or maturation and retinal degeneration.

Fluoroquinolones are synthetic compounds based on a 4-quinolone nucleus. Chemical modification of this nucleus by substitution with a fluorine and addition/substitution of other chemical groups has improved the drug’s spectrum. The first fluoroquinolones were efficacious against gram-negative bacteria; subsequent generations are effective against gram-positive, atypical bacterial, Mycoplasma spp, and anaerobic bacteria. As a family, fluoroquinolones are bactericidal and have a post-antimicrobial effect against some bacteria. Their efficacy does not appear to be inhibited by the presence of mucopurulent material; thus, they are effective for treating corneal or conjunctival disease or the presence of hypopyon. Fluoroquinolones act by targeting bacterial topoisomerases II (DNA gyrase) and IV. Topoisomerase II is involved in interrupting the DNA-breakage and reunion step involved in negative supercoiling of DNA within the cell. Topoisomerase IV helps with the ATP-dependent relaxation of DNA.

Members of this family have been grouped into generations based on their antibacterial spectrum. This spectrum variation against gram-positive and gram-negative bacteria is thought to be associated with the level of activity against one or both topoisomerases. Second-generation compounds such as ciprofloxacin and ofloxacin have an increased gram-negative spectrum, including Pseudomonas aeruginosa, a common cause of melting corneal ulcers. Third- and fourth-generation compounds (levofloxacin, moxifloxacin, gatofloxacin, besifloxacin) have increased activity against gram-positive bacteria such as beta-hemolytic streptococci and atypical organisms such as Chlamydophila and Mycoplasma. However, they have decreased efficacy against P aeruginosa. As a group, the fluoroquinolones are used topically for infectious conjunctivitis and corneal ulcers. All topical products are used off-label. Too-frequent use (more than every 6 hours) in the treatment of corneal ulcers can cause corneal epithelial cell toxicity and enhancement of corneal melting due to induced expression of matrix metalloproteinases.

Oral formulations include enrofloxacin, marbofloxacin, orbifloxacin (second generation), and pradofloxacin (third generation), which can be used in treatment of Rickettsia spp, Chlamydia, and Mycoplasma spp. The fluoroquinolones are lipophilic and have good intraocular penetration when used topically and systemically. Irreversible retinal toxicity has been seen in cats after administration of enrofloxacin at dosages of 20 mg/kg or higher. The manufacturer has recommended a dosage of 5 mg/kg/day. Orbifloxacin administered orally to cats at 45 mg/kg did show some retinal hyper-reflectivity in the area centralis and some photoreceptor degeneration.

The amphenicol antimicrobials include chloramphenicol, thiamphenicol, and florfenicol. Chloramphenicol inhibits protein synthesis at the 50S ribosomal subunit. The mechanism of action of thiamphenicol and florfenicol is similar to chloramphenicol. Chloramphenicol is regarded as being bacteriostatic against gram-positive (S pseudointermedius, S aureus, streptococci), some gram-negative bacteria, anaerobic bacteria, and intracellular organisms such as Mycoplasma spp and Chlamydia. Chloramphenicol is lipophilic and easily crosses the cornea into the anterior chamber. Florfenicol has a similar spectrum and may be bactericidal against S pseudointermedius. It is also effective in treating infectious bovine keratoconjunctivitis when used subcutaneously or intramuscularly. In many countries, chloramphenicol cannot be legally used in food animals. The concern is the risk of irreversible aplastic anemia in humans associated with the par-nitro group of the molecule.

The tetracycline family of drugs includes tetracycline, oxytetracycline, chlortetracycline, doxycycline, and minocycline. They act by reversibly binding to the 30S ribosome and interfere with the binding of transfer RNA to messenger RNA, subsequently inhibiting protein synthesis. They are regarded as being bacteriostatic and a constant drug concentration is required for efficacy. They are amphoteric and highly lipophilic and have good intraocular penetration when applied topically and administered orally or parenterally. They are effective against gram-positive and gram-negative bacteria as well as Chlamydia, Mycoplasma, hemoplasma, Ehrlichia, and Rickettsia. Doxycycline is used orally at 10 mg/kg once or 5 mg/kg every 12 hours for inhibition of matrix metalloproteinases in deep or melting corneal ulcers.

Erythromycin is a macrocyclic lactone. The mechanism of action for this family is binding to the 50S ribosomal subunit and inhibiting protein synthesis via disruption of the translocation of mRNA. It is regarded as being bacteriostatic but can be bactericidal at higher concentrations. The antibacterial spectrum is predominately gram positive, against staphylococci and streptococci, including beta-lactam resistance staphylococci. The few gram-negative bacteria it is effective against are not common causes of ocular disease. Chlamydia and Mycoplasma are regarded as being resistant to erythromycin, and it is not regarded as the drug of choice in treating conjunctivitis. There is no efficacy against Pseudomonas spp, and it should not be used in the treatment of complicated corneal ulcers. Azithromycin is an azalide, a subclass of macrolides and is derived from erythromycin. It has a wider spectrum than erythromycin against gram-positive, gram-negative, and atypical organisms. The drug accumulates in higher concentrations in phagocytes and has been shown to have immunomodulatory effects. Oral azithromycin is not as effective as doxycycline in the treatment of feline respiratory disease due to C felis.

Bacitracin is a polypeptide antimicrobial that in ophthalmology is only used in combination with other antimicrobials, usually an aminoglycoside and polymyxin B. It is bactericidal against most gram-positive bacteria and acts by inhibiting cell wall peptidoglycan synthesis at a different step than the beta-lactam antimicrobials. Resistance is rare.

Fusidic acid is a lipophilic steroid antimicrobial. The mechanism of action is to interfere with the function of elongation factor and inhibit protein synthesis at the 50S subunit of the ribosome. It is mainly bacteriostatic against gram-positive organisms (but is not a treatment of choice for corneal streptococci infections) and slowly bactericidal against Staphylococcus aureus. It is of limited use on its own for infections because resistance can develop quickly. In vitro, there is synergism with aminoglycosides and macrolides and can be antagonistic with fluoroquinolones.

Gramicidin is an ionophore peptide antimicrobial that creates ion channels in many gram-positive bacterial cell membranes and organelles. These channels disrupt ion concentration gradients leading to cell death. High concentrations are also toxic to mammalian cells. It is often combined with other drugs with different mechanisms of action (eg, polymyxin B, neomycin) to extend the spectrum of activity.

Fortified cefazolin (33 mg/mL), a first-generation cephalosporin, can be used in combination with an aminoglycoside or fluoroquinolone to treat stromal or melting ulcers. Cefazolin is bactericidal and like other beta-lactams, has post-antimicrobial effects. It acts by binding to penicillin-binding proteins and inhibiting the transpeptidation reaction involved in cell wall cross-linking. The spectrum is predominantly gram-positive (staphylococci and streptococci). Although there is some activity against gram-negative bacteria, most are not susceptible due to poor access to the cell wall and resistance due to beta-lactamases. Pseudomonas aeruginosa are resistant. High concentrations and too frequent topical application can be toxic to corneal epithelial cells and slow down healing.

Polymyxin B is a detergent (surface-active agent) that disrupts the bacterial plasma membrane by binding to phospholipids. It is bactericidal against gram-negative bacteria and has a synergistic effect with ethylenediaminetetraacetic acid (EDTA) against P aeruginosa. Resistance is rare but can occur in P aeruginosa. It is used in combination with other antimicrobials with a gram-positive spectrum, eg, bacitracin, gramicidin.

Topical antimicrobials are used to treat corneal ulcers. Unless the ulcer is deep or melting, culture and sensitivity testing is not routinely done. The rationale for treatment with topical antimicrobials is primarily to prevent the exposed stroma from becoming infected and a simple ulcer becoming complicated with the risk of corneal perforation and globe loss. Both gram-positive (beta-hemolytic Streptococcus spp) and gram-negative bacteria can cause ulcer progression; thus, combination antimicrobial drops are used. Common combinations include bacitracin (gram-positive) or gramicidin (gram-positive), neomycin (gram-positive and gram-negative) and polymyxin B (gram-negative).

Trifluridine (trifluorothymidine) is licensed for use in humans for treatment of herpetic keratitis. The mechanism of action is to inhibit DNA polymerase. Trifluridine has better binding affinity for viral DNA polymerase than for mammalian DNA polymerase. It is an analog of thymidine (pyrimidine) which, when incorporated, causes mis-sense mutations, thus stopping viral replication. As with all antiviral drugs, it is only virostatic. Trifluridine has good penetration through corneal epithelium and reaches therapeutic stromal concentrations. Frequent use can cause conjunctival irritation. Another adverse effect that can affect compliance in administration to cats is that it needs to be administered frequently and it stings on application.

Idoxuridine is only available as a topical formulation from compounding pharmacies. Concentrations are usually 0.1% solution or 0.5% ointment. Because it is very similar to thymidine and is incorporated into cells, frequent topical use can cause corneal toxicity. Corneal penetration is poor when the epithelium is intact.

Cidofovir is an analogue of cytosine (pyrimidine). It is also only available as a compounded drop, usually as a 0.5% solution. Cidofovir has a long half-life due to intracellular accumulation and so can be used less frequently. It is efficacious against feline herpesvirus when administered every 12 hours, which can improve compliance. Chronic use in humans has been associated with nasolacrimal stenosis, and care should be taken with chronic use in cats.

Acyclovir is not very efficacious against feline herpesvirus and is not the topical antiviral of choice. Ganciclovir has a similar mechanism of action to acyclovir; however, it is much more efficacious in vitro than acyclovir and cidofovir. Ganciclovir inhibits viral DNA polymerase and following incorporation into viral DNA blocks replication. It is available as a 0.15% ophthalmic gel or can be compounded as a 0.5% solution with the addition of interferon alpha-2B.

Natamycin (pimaricin) is a tetraene polyene antimicrobial. It binds to ergosterol in the cell membrane and causes permeability changes. It is fungicidal when used frequently. After topical application, it enters corneal stroma well but does not reach efficacious concentration in aqueous humor. The recommended treatment is every 2–4 hours initially, for 3 to 4 days, then decreased to every 4–6 hours. Treatment should continue for at least 21–28 days. Small animals can receive drops; equine patients require a subpalpebral lavage for this frequency of application.

Both imidazoles (miconazole) and triazoles (fluconazole, itraconazole, and voriconazole) are used. As a group, they are fungistatic. The mechanism of action is to inhibit the synthesis of ergosterol by binding to the enzyme lanosterol C-14 demethylase. Lack of ergosterol allows the incorporation of other sterols into the cell membrane, resulting in less stability and also affects its barrier function. Potency depends on the affinity of the azole for the enzyme. Triazoles have better affinity than imidazoles also resulting in fewer adverse effects. Topical azoles are all used off-label.

Miconazole has good corneal penetration and has reasonable efficacy against equine Aspergillus and Fusarium isolates. It can be used successfully in dogs and cats with keratomycosis. Miconazole is available as a 2% dermatologic or vaginal cream. The vaginal preparation is less likely to cause ocular irritation. The cream can be difficult to apply because it can make the area around the globe greasy. Ointment formulations are not recommended for use. Miconazole can also be compounded as a 1% solution.

Fluconazole is not commonly used topically because most filamentous fungi (Aspergillus, Fusarium) causing keratomycosis in horses are resistant.

Itraconazole has a somewhat better spectrum against Aspergillus and other filamentous fungi than fluconazole; however, most Fusarium isolates are resistant. Its poor solubility prevents good corneal penetration. A 1% itraconazole/30% DMSO formulation provides high corneal levels of itraconazole ; however, aqueous humor levels are not detectable.

Voriconazole is a newer triazole, similar in structure to fluconazole. Used as a 1% solution, it has better corneal penetration and reaches therapeutic concentrations in aqueous humor. It has a much better spectrum against Aspergillus and Fusarium isolates than other azoles. A 5% solution has been used intrastromally for treatment of stromal abscesses (5%). Intravitreal injection can be administered to dogs with intraocular disease from systemic blastomycosis.

Silver sulfadiazine (1%) is available in a cream for topical treatment of burns. The silver ions bind to DNA and inhibit synthesis. The ions also bind to surface membranes and proteins causing membrane leakage. Silver sulfadiazine has been associated with eye irritation; however, it may be a treatment of last resort in some cases of equine keratomycosis.

Amphotericin B is a polyene antimicrobial that works by binding ergosterol in the fungal plasma membrane. This causes leakage of fungal cell electrolytes resulting in cell death. It is effective against most systemic fungal pathogens (Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Candida spp, and some Aspergillus spp). Efficacy is concentration dependent. Administration can be oral or intravenous. The oral formulations have variable bioavailability, so intravenous administration is preferred. Various formulations are available (phospholipids, cholesteryl sulfate complex, liposomal complexes). Lipid formulations may cause less toxicity. A number of dosing protocols are published for use, usually diluted in 5% dextrose. Dose-dependent renal toxicity is the most common adverse effect. Pretreatment fluid loading with 0.9% sodium chloride is recommended.

Azoles have fewer adverse effects than amphotericin B. Fluconazole and itraconazole are used for treatment of systemic fungal disease (blastomycosis, coccidiomycosis, cryptococcosis and histoplasmosis) in small animals and in horses as part of a treatment regimen for keratomycosis.  

Fluconazole is highly water soluble, has good distribution throughout the body, and is excreted primarily via the kidneys, so dose adjustment is needed in animals with kidney disease. It penetrates well into the aqueous humor and is used to treat blastomycosis in dogs (up to 10–12 mg/kg/day), although itraconazole is more efficacious. For treatment of systemic cryptococcosis, dosages in cats range from 2.5–5 mg/kg every 24 hours, 50 mg/cat/day or 100 mg/cat/day (single or divided dose). In dogs, the dosage is 2.5–10 mg/kg/day. Coccidiomycosis can be treated with 2.5–10 mg/kg/day. Treatment may be required for 6–12 months.

Itraconazole is lipophilic and available as capsules and an oral solution. Oral bioavailability can be variable depending on the formulation. Bioavailability increases when administered with food. In a number of species, compounded itraconazole formulations have been shown to not be bioequivalent and are not recommended. Dosages of 10 mg/kg every 24 hours and 5 mg/kg every 12 hours for 2 months are equally as effective against ocular and systemic blastomycosis. Other regimens are 5 mg/kg every 12 hours for 5 days and then every 24 hours for 90 days. Urine antigen levels can be used to monitor disease resolution. A dosage of 10 mg/kg/day can be used in coccidiomycosis and histoplasmosis.

Voriconazole is well absorbed in horses and, when used at 3 mg/kg every 12 hours for 10 days, reaches therapeutic concentration in the precorneal tear film and aqueous humor. In dogs, voriconazole has been used infrequently for the treatment of systemic fungal infections. After oral dosing, it has a short half-life, and chronic dosing can result in decreased plasma concentration from induction of metabolic enzymes. Oral dosing every 12 hours is likely needed. Adverse effects are usually GI with inappetance and diarrhea. Intravenous use in dogs causes severe toxicity. It should not be used in cats because notable adverse reactions involving the GI tract, eyes and neurologic function (ataxia and hindlimb paresis) have been reported.

Posaconazole is similar in structure to itraconazole and has been used in cats and dogs. Bioavailability increases when taken with food. It is available as a 40 mg/mL suspension or 100 mg slow-release tablets. Dose ranges for animals have not been established based on pharmacokinetic data. In dogs, use of the oral suspension requires dosing (5 mg/kg) every 12 hours. Because of the 42-hour half-life in dogs dosed with the slow-release tablets, every-other-day dosing (5 mg/kg) is recommended. Cats have been treated with 5 mg/kg/day using the oral suspension with doses of 12–15 mg/kg/day also recommended.