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Myths, truths about drugs prescribed in veterinary dermatology
There has been an ongoing debate over ototoxicity produced by topical medications.
Corticosteroids and antibiotics are widely prescribed in veterinary dermatology, but there are controversies and even fears about both – over effects, dosages and other factors. Here are some common myths and what is actually known:
Corticosteroids are the most used and abused medications in veterinary medicine. To date, there has been no other type of drug with so many strong effects on the body.
Corticosteroids are considered indispensable in treating many diseases, life-threatening autoimmune disorders, anaphylaxis, transplantation rejection and allergies.
In my practice, they are an integral component in my treatment of severe allergies.
Yet they are feared by many clients (as well as some doctors), who may have unfounded suspicions about potentially life-threatening side effects.
What are these effects, and how likely are they to occur?
First, it should be noted that there is little or no detailed, scientific, peer-reviewed information about corticosteroids in veterinary medicine. What we have are basically guidelines or recommendations derived from clinicians' experiences and extrapolation from human literature. Lacking evidence-based articles, there is a plethora of misinformation.
Corticosteroids have never been proven to "shorten the lives of dogs." I believe that misguided statement probably originated from concerned veterinarians trying to convince owners to find corticosteroid alternatives. That is what I recommend if I believe their continued use would be unhealthy or the patient has experienced unwanted side effects.
I believe the quality of a dog's life may be poor if treated with long-term high dosages of corticosteroids. If not monitored, the animal may experience side effects – but an early, unexpected death is inconceivable.
Side effects are more likely in dogs than cats, more likely in older animals than younger ones and more likely with high dosages and long-term use.
But what constitutes long-term therapy? More than two months? More than six months? A year? No one really knows, but I would estimate more than three months.
The most common side effects of corticosteroids stem from the mineralocorticoid effects, not from glucocorticoid effects.
Although not as potent as the well-known mineralocorticoid aldosterone, glucocorticoids have specific effects on water and electrolyte balance in the kidney. Polyuria and polydipsia associated with glucocorticoids result from inhibition of antidiuretic hormone (ADH) secretion and decreased renal sensitivity to ADH.
Glucocorticoids also enhance potassium excretion and sodium retention by the kidney. They can increase renal excretion and decrease intestinal absorption of calcium, causing depletion of calcium stores.
Prednisone and prednisolone exert a moderate mineralocorticoid effect while methylprednisolone and triamcinolone exert a lesser effect. Since mineralocorticoids promote sodium and chloride retention (thus water retention), an increase in thirst (thus an increase in urine output) occurs.
Some literature states triamcinolone exerts no mineralocorticoid effects, but this cannot be completely true, as I have observed polydypsia and polyuria in dogs treated with oral and injectable triamcinolone.
It is possible, however, that some "pure" glucocorticoids directly exert mineralocorticoid effects. This has been documented in human patients. Polyphagia also is a relatively common side effect.
Finally, excessive panting also has been occasionally reported, but the mechanism of panting from glucocorticoid treatment is not fully determined.
Effects of long-term use
When dogs are treated with corticosteroids longer than several months, one may observe less common side effects, such as muscle wasting (mostly masticatory and dorsal trunk via the catabolic effects), pendulous abdomen (due to weak abdominal muscles and fat redistribution), truncal fat redistribution and, although controversial, proteinuria.
Less common and side effects of long-term corticosteroid therapy include signs of immunosuppression, often manifested by bacterial infections such as cystitis and bullous impetigo (superficial pyoderma). Very rarely, opportunistic microbial infections (fungal, protozoal) are documented, usually when patients are treated concurrently with other immunosuppressant agents such as cyclosporine, azathioprine or luflunomide.
Lastly, glucocorticoids have the ability to cause insulin resistance and thus (in rare instances) cause diabetes mellitus (DM). Cats may be more likely to develop DM from glucocorticoid administration.
In general, many of these side effects are more likely when higher dosages ("immunosuppressive") of corticosteroids are administered for long-term treatment. This so-called immunosuppressive dosage can range from 2-4 mg/kg/day in the dog. Anti-inflammatory (anti-pruritic) dosages generally are half or less the lower end of the immunosuppressive dosage. Cats require about double the canine dosage to achieve the same effects.
The most common bacterium isolated from superficial and deep pyoderma in the dog is Staphylococcus intermedius (less commonly Staphylococcus schleiferi, and rarely Staphylococcus aureus). It is extremely rare to isolate other organisms from superficial lesions, but not uncommon to isolate other bacteria from lesions of deep pyoderma. Aerobic cultures from lesions of deep pyoderma can produce gram-positive (Streptococcus) and gram-negative organisms (Klebsiella, Proteus, Pseudomonas, Escherichia coli, Pasteurella). Because the focus of treatment is resolution of a Staphylococcal infection, cephalexin is the drug of choice (for reasons discussed below).
Cephalexin is a penicillin derivative, a first-generation cephalosporin or a beta-lactam antibiotic that is resistant to most penicillinases secreted by staphylococcal species. Amoxicillin and ampicillin are easily cleaved by penicillinases, rendering these drugs inactive and useless.
Cephalexin is reliable, inexpensive and generally well tolerated with little or no side effects. It is a time-dependent antibiotic, and thus plasma concentrations must remain above the minimum inhibitory concentrations (MIC) over the entire course of treatment to achieve a kill.
One of several controversies with cephalexin is the dosage and dose interval. The established dosage for dogs is 22mg/kg twice daily. It has been shown by veterinary pharmacologists that three-times daily dosages are not necessarily more effective, but that significant under-dosing often fails, as lower dosages can result in much lower plasma concentrations below the MIC.
We all realize that, when calculating a dosage based on a published dose, we never deliver the exact dosage (i.e., 22mg/kg twice daily). Instead, we deliver something a tad lower or higher, depending on the weight of the dog and availability of the drug size (i.e., 24.6 mg/kg).
This is the key to prescribing cephalexin properly to dogs: Always give the dosage at or slightly higher than the published dosage.
For example, it is tempting to prescribe 500 mg cephalexin twice daily to a 30-kilogram dog. This may result in failure, however, being well below the published dosage. Because cephalexin is safe, feel free to prescribe 750 mg orally twice daily. It's that simple.
Finally, because cefpodoxime is popular among veterinarians (and veterinary dermatologists), there are some issues to discuss.
Cefpodoxime is a beta-lactam, cephalosporin antibiotic. It is technically a third-generation cephalosporin, but, at least in the dog, kills mostly gram-positive bacteria like a first- generation cephalosporin. Thus it has virtually an identical spectrum as cephalexin and is not superior to it.
The once-daily dosaging, relatively fewer gastro-intestinal side effects and proven effectiveness have been attractive to veterinarians and clients. For dogs weighing more than 50 or 60 pounds, cefpodoxime can be cost-prohibitive to some.
Otoxicity with topical drugs
Ototoxicity is rare in the dog (most veterinarians feel its less than 1 percent of treated cases) and is mostly unpredictable. There has been, however, an ongoing debate over ototoxicity produced by topical medications applied in the ear canal when the tympanum is ruptured.
There have been many published reports of ototoxicity from topical products used on human patients (antibiotics, antifungals, polyethylene glycol, antiseptics such as chlorhexidine and acetic acid).
Moreover, it appears virtually anything (including debris, mechanical and chemical changes, ph and pus) can potentially cause damage and lead to ototoxicity.
In veterinary medicine, there have been few articles on ototoxicity due to use of chlorhexidine and gentamicin on dogs.
One publication demonstrated the lack of ototoxicity when gentamicin was instilled into ear canals with an intact or a previously mechanically ruptured tympanum.
Based on this study, it appears gentamicin-induced ototoxicity generally is idiosyncratic, but there have been reports (some anecdotal) of ototoxicity (mostly deafness) in dogs treated with gentamicin with an intact tympanum membrane (TM).
According to veterinary pharmaceutical companies that manufacture gentamycin-containing topical otic drugs, geriatric dogs may be more susceptible to deafness.
What is ototoxicity?
In order for a drug to exert ototoxicity, it must reach the inner components of the middle and inner ear and must have the ability to produce toxic changes.
It is also well known that certain medications can pass through an intact or subtly damaged TM and produce the same ototoxic changes.
Drug infiltration into the middle ear is enhanced by the presence of a ruptured TM but the presence of moderate to severe inflammation (otitis media/interna) further augments the drug delivery to the inner ear. Inflammation allows an increased flow of medication through the round window membrane. The drug passes through the membrane of the round window and contacts the hair cells of the organ of Corti and causes degeneration of the perceptive/sensory or sensoneural cells, or both. Depending upon the drug and concentration, cochlear (hearing) or vestibular (balance) deficits can occur.
Drugs that affect the cochlea and cause hearing impairment are cochleotoxic; drugs that affect the vestibular system resulting in vestibular dysfunction are vestibulotoxic.
The exact mechanisms of these toxicities are not fully known but are mostly drug-type specific, concentration-dependent and relatively unpredictable.
The clinical signs of ototoxicity may reflect uni- or bilateral involvement.
Signs of vestibular damage include horizontal nystagmus, with the fast component to the affected side, strabismus, ataxia, head tilt, circling and nausea.
Improvement generally occurs over several weeks, with complete resolution sometimes within several months. The head tilt, however, may be permanent.
Clinical signs of cochlear damage occur when complete deafness is present. Dogs that have lost most or all of their hearing can appear frightened, disoriented and incapable of following owner's commands. Deafness may be reversible after cessation of the culprit drug.
Because of the lack of evidence-based research and clinical evidence of widespread toxicity in the dog, it is clear that cochlear or vestibular damage is rare.
In my practice, I routinely prescribe Amikacin (an aminoglycoside) ear drops (prepared from the injectable form of Amikacin) for severe cases of susceptible strains of pseudomonal otitis media. I have not observed otoxicity in seven years of prescribing this drug.
I have seen only three cases of deafness, all in dogs with confirmed Malassezia otitis externa, an intact TM, and treated with a gentamicin/clotrimazole/betamethasone-containing otic preparation.
Since most commercially available otic preparations contain polypharmacy, how does one know which ingredient(s) are the culprit(s)?
Clotrimazole has been implicated as the causative agent in published cases of ototoxicity in humans, but has never been reported in the dog.
As mentioned earlier, since ototoxicity is likely related to aminoglycoside and chlorhexidine-containing preparations, is it proper to prescribe these polypharmacy preparations containing an antibiotic for cases of Malassezia otitis?
In addition to exposing Staphylococcal flora to aminoglycosides as well as the concerns of ototoxicity, the practice of prescribing polypharmacy otic medications may need to be re-evaluated.
Some veterinarians have realized this and have teamed with pharmacologists to "create" their own otic preparations, either combining single-drug preparations (i.e., clotrimazole with dexamethasone) or using other forms of drugs (injectables) to create pharmacologically stable, specific topical ear medications.
Veterinary pharmaceutical companies may need to get involved and produce more therapeutics that are FDA-approved, narrow-spectrum, specific otic medications. Until then, veterinarians must continue to be cautious with known ototoxic agents but also realize that the incidence of ototoxicity is rare and can be idiosyncratic.
Dr. Vitale received his veterinary degree from Mississippi State University, College of Veterinary Medicine. He completed a residency in veterinary dermatology at the University of California, Davis and is a diplomate of the American College of Veterinary Dermatology. He is a clinical instructor/lecturer at UC-Davis and a staff dermatologist at East Bay Veterinary Specialists (formerly Encina Veterinary Hospital), Bay Area Veterinary Specialists and San Francisco Veterinary Specialists.