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Ophthalmic Drugs, Old and New
IN SMALL ANIMAL MEDICINE AND SURGERY
WWW.ADVANCESINSMALLANIMAL.COM
VOLUME 24, ISSUE 1 • JANUARY 2011
Ophthalmic Drugs, Old and New
REFRACTORY CORNEAL ULCERS AND TETRACYCLINES? Refractory or indolent corneal ulcers are defects in the superficial cornea, wherein
the epithelium is absent and the adjacent corneal epithelial cells are unable to appropriately migrate across the open wound. This type of ulcer is common in middleaged to older dogs, with certain breeds of dog having an increased predilection (thus, the name “Boxer ulcer.” There has long been anecdotal evidence that indicates that the use of tetracyclines can increase the rate of corneal wound healing in these cases, but no objective, critical study has previously looked into this supposition. To this end, a prospective study was designed and performed by Chandler et al. (1). The study compared the rate of corneal wound healing between groups of dogs with refractory corneal ulcers treated with various medical treatment regimes. Ulcers deemed refractory were those that had received medical therapy without healing in an appropriate period of time (Fig. 1). All dogs in this study had manual debridement and grid keratotomy performed in hospital, followed by medical therapy at home. The control group received oral cephalexin (22 mg/kg, twice per day) and topical triple antibiotic ointment, 3 times per day. The first experimental group received oral doxycycline (5 mg/kg, twice per day) and topical triple antibiotic ophthalmic ointment, 3 times per day, and the second
Figure 1. Canine refractory corneal ulcer
Figure 2. Feline herpesvirus keratitis
CARYN E. PLUMMER, DVM, DIPLOMATE ACVO ASSISTANT PROFESSOR, COMPARATIVE OPHTHALMOLOGY DEPARTMENTS OF SMALL AND LARGE ANIMAL CLINICAL SCIENCES COLLEGE OF VETERINARY MEDICINE UNIVERSITY OF FLORIDA GAINESVILLE, FLORIDA 32610 In small animal ophthalmology, there are a number of refractory, chronic, or recurrent conditions for which there is no one standardized treatment protocol. Indolent corneal ulcers in dogs are one such condition. Another is conjunctivitis in both cats and dogs. There are as many different approaches to therapy for these conditions as there are veterinarians and veterinary ophthalmologists. Historically, few controlled or objective studies have been performed which might establish a consistently effective treatment. Recently, however, a couple of studies have been published which investigate the efficacy of some medications with regard to certain disease entities.
experimental group received oral cephalexin (22 mg/kg) and topical oxytetracycline ophthalmic ointment, 3 times per day. The experimental group receiving the topical tetracycline had a statistically shorter mean time to complete re-epithelialization of the ulcers compared to the other groups. The group receiving the oral tetracycline had a shorter healing time compared to the control group, but this difference was not significant. A fourth group of patients received oral cephalexin, topical oxytetracycline, and had a bandage contact lens placed over the affected cornea. Statistical analysis was not performed on the healing times for these patients due to a lack of appropriate control; however, these patients appeared to have had the most rapid healing rates. Further studies will be necessary to confirm
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A D VA N C E S
the beneficial effects of the bandage lens. Manual debridement and grid keratotomy were performed in all cases, since part of the pathogenesis of this condition involves the formation of an acellular hyalinized zone atop the exposed stroma and redundant epithelium that has not developed a migratory phenotype. These mechanical therapies aim to remove abnormal epithelium and disrupt the stromal membrane. Therapies for herpetic ocular disease caused by feline herpesvirus-1 (FHV-1) is a major cause of ophthalmic disease in cats (Fig. 2), as well as upper respiratory disease and occasionally dermatologic disease. It has been implicated in the development of acute conjunctivitis, recurrent conjunctivitis, ulcerative keratitis, interstitial keratitis, indolent ulcerations, eosinophilic keratoconjunctivitis, and corneal sequestra. Most of the agents developed for use in humans with herpesvirus infection are either minimally effective against FHV-1, have a low bioavailability in cats, or are toxic to them. Since the virus is so common and widespread and has so many disease manifestations, the development of safe, effective therapies for cats is important. Recently, there has been increased use of and reports of favorable responses to 2 antiviral agents for this infection. The
first is famcyclovir which is metabolized to pencyclovir, a nucleoside deoxyguanosine analog with a similar mechanism of action to acyclovir.2 It is administered orally (62.5mg/cat, twice or 3 times daily or 125 mg/cat, once daily). Famcyclovir has been particularly helpful in patients with severe disease, systemic disease, or those difficult to medicate topically. It appears to be relatively safe and well-tolerated. As with any orally administered antiviral agent, it may be wise to monitor the hemogram and serum biochemical profiles prior to and during administration of this agent. The second antiviral agent is a topical preparation: cidofovir 0.5%, a nucleoside monophosphate analog of cytosine. Cidofovir should be administered twice daily, which is a distinct advantage over the more traditional antiviral agents (idoxuridine, trifluridine, and vidarabine) used for FHV-1, as these should be given at least 4 to 6 times daily for effect.3 This agent is not commercially available as an ophthalmic preparation at present, but they may be easily purchased from a compounding pharmacy. Both of these antiviral agents are intended to mitigate signs and viral replication during an active bout of disease. In an effort to decrease the incidence and severity of outbreaks of the infection, many
clinicians recommend the use of orally administered L-lysine, an amino acid that competitively inhibits arginine, which is necessary for viral replication. There have been many studies that tout the benefits of L-lysine in cats with FHV-1, but a recent study refutes this claim. It was found that susceptible cats receiving an L-lysine supplemented diet (5.7%) were not protected from infection or disease severity.4 In fact, these cats were more likely to develop severe clinical disease, and FHV-1 was more readily detectable in swabs from these cats. Every species has its own herpesviruses, but the cat is most notoriously associated with herpetic ocular disease. Recently, however, there have been reports of canines developing ocular signs similar to those suffered by their feline counterparts. Canine herpesvirus-1 (CHV-1) has been identified as a cause of conjunctivitis, as well as ulcerative keratitis in dogs (manifested by dendritic ulcers similar to those experienced by cats).5 Although not likely ever to be as ubiquitous in dogs as in cats, an herpetic etiology should be considered as a differential in any case of conjunctivitis in dogs. This is particularly true if the dog is not responsive to traditional symptomatic therapy or if the animal has been housed or exposed to large numbers of other dogs and has had opportunities for contact with bodily secretions.
A D VA N C E S
PEARLS TO CONSIDER Refractory superficial ulcers may benefit from the use of tetracyclines. When treating slow or non-healing corneal ulcers, make sure that the lesion is indeed superficial with no loss of collagen stroma. Stromal ulcers may require drastically different medical and surgical approaches and should never be treated via grid or punctate keratotomy. When in doubt, refer to a veterinary ophthalmologist. Conjunctivitides in cats and dogs, especially when minimally responsive to symptomatic treatment with topical antiinflammatory agents, and when associated with upper respiratory disease or when accompanied by keratitis and ulcerations, may be related to a herpesvirus infection. PCR testing may reveal the presence of the virus but will not confirm causation. Oral L-lysine may not be an effective way to minimize disease severity and outbreaks in FHV-1 patients. If a patient does not tolerate its administration (general aversion or GI upset), it may do more harm than good. Stay tuned on this issue! REFERENCES 1. Chandler HL, Gemensky-Metzler AJ, Bras ID, et al. In vivo effects of adjunctive tetracycline treatment on refractory corneal ulcers in dogs. J Am Vet Med Assoc 2010;4:378-386. 2. Malik R, Lessels NS, Webb S, et al. Treatment of feline herpesvirus-1 associated disease in cats with famcyclovir and related drugs. J Feline Med & Surg 2009;11:40-48. 3. Stiles J, Gwin W, Pogranichniy R. Stability of 0.5% cidofovir stored under various conditions for up to 6 months. Vet Ophthamol 2010;4:275-277. 4. Drazenovich TL, Fascetti AJ, Westermeyer HD, et al. Effects of dietary lysine supplementation on upper respiratory and ocular disease and detection of infectious organisms in cats within a animal shelter. Am J Vet Res 2009;11:1391-1400. 5. Ledbetter EC, Hornbuckle WE, Dubovi EJ. Virologic survey of dogs with naturally acquired idiopathic conjunctivitis. J Am Vet Med Assoc 2009;8:954-959.
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WWW.ADVANCESINSMALLANIMAL.COM
VOLUME 24, ISSUE 1 • JANUARY 2011
Ophthalmic Drugs, Old and New
REFRACTORY CORNEAL ULCERS AND TETRACYCLINES? Refractory or indolent corneal ulcers are defects in the superficial cornea, wherein
the epithelium is absent and the adjacent corneal epithelial cells are unable to appropriately migrate across the open wound. This type of ulcer is common in middleaged to older dogs, with certain breeds of dog having an increased predilection (thus, the name “Boxer ulcer.” There has long been anecdotal evidence that indicates that the use of tetracyclines can increase the rate of corneal wound healing in these cases, but no objective, critical study has previously looked into this supposition. To this end, a prospective study was designed and performed by Chandler et al. (1). The study compared the rate of corneal wound healing between groups of dogs with refractory corneal ulcers treated with various medical treatment regimes. Ulcers deemed refractory were those that had received medical therapy without healing in an appropriate period of time (Fig. 1). All dogs in this study had manual debridement and grid keratotomy performed in hospital, followed by medical therapy at home. The control group received oral cephalexin (22 mg/kg, twice per day) and topical triple antibiotic ointment, 3 times per day. The first experimental group received oral doxycycline (5 mg/kg, twice per day) and topical triple antibiotic ophthalmic ointment, 3 times per day, and the second
Figure 1. Canine refractory corneal ulcer
Figure 2. Feline herpesvirus keratitis
CARYN E. PLUMMER, DVM, DIPLOMATE ACVO ASSISTANT PROFESSOR, COMPARATIVE OPHTHALMOLOGY DEPARTMENTS OF SMALL AND LARGE ANIMAL CLINICAL SCIENCES COLLEGE OF VETERINARY MEDICINE UNIVERSITY OF FLORIDA GAINESVILLE, FLORIDA 32610 In small animal ophthalmology, there are a number of refractory, chronic, or recurrent conditions for which there is no one standardized treatment protocol. Indolent corneal ulcers in dogs are one such condition. Another is conjunctivitis in both cats and dogs. There are as many different approaches to therapy for these conditions as there are veterinarians and veterinary ophthalmologists. Historically, few controlled or objective studies have been performed which might establish a consistently effective treatment. Recently, however, a couple of studies have been published which investigate the efficacy of some medications with regard to certain disease entities.
experimental group received oral cephalexin (22 mg/kg) and topical oxytetracycline ophthalmic ointment, 3 times per day. The experimental group receiving the topical tetracycline had a statistically shorter mean time to complete re-epithelialization of the ulcers compared to the other groups. The group receiving the oral tetracycline had a shorter healing time compared to the control group, but this difference was not significant. A fourth group of patients received oral cephalexin, topical oxytetracycline, and had a bandage contact lens placed over the affected cornea. Statistical analysis was not performed on the healing times for these patients due to a lack of appropriate control; however, these patients appeared to have had the most rapid healing rates. Further studies will be necessary to confirm
PAG E 2
A D VA N C E S
the beneficial effects of the bandage lens. Manual debridement and grid keratotomy were performed in all cases, since part of the pathogenesis of this condition involves the formation of an acellular hyalinized zone atop the exposed stroma and redundant epithelium that has not developed a migratory phenotype. These mechanical therapies aim to remove abnormal epithelium and disrupt the stromal membrane. Therapies for herpetic ocular disease caused by feline herpesvirus-1 (FHV-1) is a major cause of ophthalmic disease in cats (Fig. 2), as well as upper respiratory disease and occasionally dermatologic disease. It has been implicated in the development of acute conjunctivitis, recurrent conjunctivitis, ulcerative keratitis, interstitial keratitis, indolent ulcerations, eosinophilic keratoconjunctivitis, and corneal sequestra. Most of the agents developed for use in humans with herpesvirus infection are either minimally effective against FHV-1, have a low bioavailability in cats, or are toxic to them. Since the virus is so common and widespread and has so many disease manifestations, the development of safe, effective therapies for cats is important. Recently, there has been increased use of and reports of favorable responses to 2 antiviral agents for this infection. The
first is famcyclovir which is metabolized to pencyclovir, a nucleoside deoxyguanosine analog with a similar mechanism of action to acyclovir.2 It is administered orally (62.5mg/cat, twice or 3 times daily or 125 mg/cat, once daily). Famcyclovir has been particularly helpful in patients with severe disease, systemic disease, or those difficult to medicate topically. It appears to be relatively safe and well-tolerated. As with any orally administered antiviral agent, it may be wise to monitor the hemogram and serum biochemical profiles prior to and during administration of this agent. The second antiviral agent is a topical preparation: cidofovir 0.5%, a nucleoside monophosphate analog of cytosine. Cidofovir should be administered twice daily, which is a distinct advantage over the more traditional antiviral agents (idoxuridine, trifluridine, and vidarabine) used for FHV-1, as these should be given at least 4 to 6 times daily for effect.3 This agent is not commercially available as an ophthalmic preparation at present, but they may be easily purchased from a compounding pharmacy. Both of these antiviral agents are intended to mitigate signs and viral replication during an active bout of disease. In an effort to decrease the incidence and severity of outbreaks of the infection, many
clinicians recommend the use of orally administered L-lysine, an amino acid that competitively inhibits arginine, which is necessary for viral replication. There have been many studies that tout the benefits of L-lysine in cats with FHV-1, but a recent study refutes this claim. It was found that susceptible cats receiving an L-lysine supplemented diet (5.7%) were not protected from infection or disease severity.4 In fact, these cats were more likely to develop severe clinical disease, and FHV-1 was more readily detectable in swabs from these cats. Every species has its own herpesviruses, but the cat is most notoriously associated with herpetic ocular disease. Recently, however, there have been reports of canines developing ocular signs similar to those suffered by their feline counterparts. Canine herpesvirus-1 (CHV-1) has been identified as a cause of conjunctivitis, as well as ulcerative keratitis in dogs (manifested by dendritic ulcers similar to those experienced by cats).5 Although not likely ever to be as ubiquitous in dogs as in cats, an herpetic etiology should be considered as a differential in any case of conjunctivitis in dogs. This is particularly true if the dog is not responsive to traditional symptomatic therapy or if the animal has been housed or exposed to large numbers of other dogs and has had opportunities for contact with bodily secretions.
A D VA N C E S
PEARLS TO CONSIDER Refractory superficial ulcers may benefit from the use of tetracyclines. When treating slow or non-healing corneal ulcers, make sure that the lesion is indeed superficial with no loss of collagen stroma. Stromal ulcers may require drastically different medical and surgical approaches and should never be treated via grid or punctate keratotomy. When in doubt, refer to a veterinary ophthalmologist. Conjunctivitides in cats and dogs, especially when minimally responsive to symptomatic treatment with topical antiinflammatory agents, and when associated with upper respiratory disease or when accompanied by keratitis and ulcerations, may be related to a herpesvirus infection. PCR testing may reveal the presence of the virus but will not confirm causation. Oral L-lysine may not be an effective way to minimize disease severity and outbreaks in FHV-1 patients. If a patient does not tolerate its administration (general aversion or GI upset), it may do more harm than good. Stay tuned on this issue! REFERENCES 1. Chandler HL, Gemensky-Metzler AJ, Bras ID, et al. In vivo effects of adjunctive tetracycline treatment on refractory corneal ulcers in dogs. J Am Vet Med Assoc 2010;4:378-386. 2. Malik R, Lessels NS, Webb S, et al. Treatment of feline herpesvirus-1 associated disease in cats with famcyclovir and related drugs. J Feline Med & Surg 2009;11:40-48. 3. Stiles J, Gwin W, Pogranichniy R. Stability of 0.5% cidofovir stored under various conditions for up to 6 months. Vet Ophthamol 2010;4:275-277. 4. Drazenovich TL, Fascetti AJ, Westermeyer HD, et al. Effects of dietary lysine supplementation on upper respiratory and ocular disease and detection of infectious organisms in cats within a animal shelter. Am J Vet Res 2009;11:1391-1400. 5. Ledbetter EC, Hornbuckle WE, Dubovi EJ. Virologic survey of dogs with naturally acquired idiopathic conjunctivitis. J Am Vet Med Assoc 2009;8:954-959.
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