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2v \VETERINARY PHARMACOLOGY

\PHARMACOLOGIE VETERINAIRE

Antimicrobial therapy of skin and

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ear

infections

Patricia M. Dowling Dermatological diseases are frequently encountered in small animal practice. There are many excellent reference texts and atlases on dermatology this article will primarily emphasize antimicrobial therapy of skin and ear infections. Pyoderma is a common bacterial skin disease, most often a canine problem. Staphylococcus intermedius is the most common bacterial culprit involved in pyoderma. Staphylococcus intermedius is part of the normal skin flora and colonizes the upper respiratory tract, the oral cavity, the anal region, and the external ear canal. Most canine staphylococci produce slime, which allows the bacteria to adhere to cells, and contain protein A, which activates the complement cascade and incites inflammation. Escherichia coli, Proteus spp., and Pseudomonas spp. can transiently colonize the skin and may occasionally become involved in pyoderma, secondary to a staphylococcal infection. Actinomycetes spp., Actinobacillus spp., mycobacteria, and various fungi can also be involved in skin diseases.

Effective therapy of pyoderma Effective treatment of superficial and deep pyodermas due to S. intermedius requires systemically administered antimicrobials and topically applied antibacterial agents, along with specific treatment of any underlying cause(s). Guidelines for successful therapy include: 1) Choose an appropriate antimicrobial with activity against B-lactamase producing S. intermedius. 2) Use a sufficient dosage regimen. Get an accurate body weight and prescribe a full course of therapy. Antimicrobials should be given for 7 d past a clinical cure for superficial pyodermas, and 14 d past for deep pyodermas. Typically, 3 to 6 wk of therapy are required. Some dogs require chronic, low-dose or pulse-dose, therapy for control of recurrent pyodermas. 3) Avoid concurrent use of glucocorticoids. Pruritic pyoderma will respond to antimicrobial therapy alone. An exception is mild pyotraumatic dermatitis ("hot spots") they respond well to glucocorticoids and topical therapy. 4) Search for underlying pathology that contributes to the pyoderma; correct when possible. Despite the common perception, most dogs with pyoderma do not have hypothyroidism. Canine atopy is the most common cause of recurrent canine pyoderma. Food allergies, ectoparasites, Department of Veterinary Physiological Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4. Can Vet J Volume 37, November 1996 Volume

37,

November

1996

keratinization defects, endocrine disease, and immunodeficiencies should also be considered.

Choosing antimicrobial therapy Staphylococcus internedius does not demonstrate antimicrobial resistance comparable with the methicillinresistant S. aureus that causes major problems in human medicine. This is because S. intermedius does not readily retain antimicrobial resistance plasmids. Resistance patterns remain fairly predictable when there has been no prior antimicrobial exposure (Table 1). When concurrent gram-negative infections occur, therapy directed at S. intermedius will usually be successful. An exception is concurrent infection with Pseudomonas spp., which rapidly acquire resistance to many antimicrobials. As immunodeficiencies may be involved in the pathogenesis of the pyoderma, it is probably better to select bactericidal over bacteriostatic drugs. Also, the antimicrobial must be able to penetrate and retain activity in inflamed tissues and phagocytes (Table 2). Amoxicillin-clavulanic acid is a good first choice for treatment of pyoderma. Cephalexin or cefadroxil are comparable in spectrum of activity and pharmacokinetic characteristics with amoxicillin-clavulanic acid but, in my experience, are more likely to cause gastrointestinal upset, especially in cats. Cloxacillin is an excellent antistaphylococcal penicillin with poor activity against gram-negative bacteria. Because of its limited spectrum of activity, this is not a drug that is usually on stock in a veterinary clinic, but it can easily be prescribed from a human pharmacy. Because of poor oral bioavailability, it must be dosed 4 times/d, making client compliance difficult. Erythromycin and lincomycin are reasonable choices for first time treatment of pyoderma; recurrent infections are likely to be resistant. Erythromycin is associated with a high occurrence of gastrointestinal upset; causing vomiting in up to 70% of dogs. This can be avoided by administering the erythromycin with food, prescribing antiemetics for the first 2 to 3 d of therapy, and initiating therapy with a lower dose. I find this treatment regimen too complicated and inconvenient for most clients and prefer to use antimicrobials that do not induce vomiting. Lincomycin has the same activity as erythromycin and does not cause gastrointestinal upset; however, it is more expensive. Trimethoprim/ sulphonamide combinations (TMP/sulphas) are effective in most cases of first-time pyoderma, and have the added advantage of high volume of distribution (Vd), ensuring adequate tissue penetration. However, the

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Table 1. Antimicrobial resistance of Staphylococcus intermedius High Resistance (80%) penicillin ampicillin amoxicillin oxytetracycline

Moderate (15%-25%)

Low (5%-10%)

None (initially)

erythromycin clindamycin lincomycin

TMP/sulphas

cloxacillin cephalexin enrofloxacin amoxicillin/clavulanic acid

TMP - trimethoprim

Table 2. Antimicrobial therapy for initial treatment of superficial pyodermas Drug amoxicillin/clavulanic acid cephalexin or cephadroxil cloxacillin available erythromycin lincomycin TMP/sulpha

Dosage 20 mg/kg BW, PO, q8h 20 mg/kg BW, PO, q I 2h to q8h 20-40 mg/kg BW, PO, q8h 10-15 mg/kg BW, PO, q8h 20 mg/kg BW, PO, ql2h 20-30 mg/kg BW, PO, ql2h

Comments

human generics adverse GI effects

BW -body weight GI -gastrointestinal

Table 3. Antimicrobial therapy for deep pyodermas or resistant infections Drug enrofloxacin chloramphenicol clindamycin rifampin

Dosage

Comments

5-10 mg/kg BW, PO, q24h 50 mg/kg BW, PO, ql2h 11 mg/kg BW, PO, ql 2h 5-10 mg/kg BW, PO, q24h

acquires resistance easily rapid resistance, some toxicity

human health risk

BW -body weight

risk of adverse effects, such as induction of keratoconjunctivitis sicca and polysystemic drug reactions, should be considered when administering TMP/ sulphas. Additional therapy of pyoderma includes bathing the animal with antimicrobial shampoos 3 times/wk, leaving the shampoo in contact with the skin for 10 min before rinsing. Antimicrobial agents in veterinary shampoos include benzoyl peroxide, chlorhexidene, iodine, and triclosan. Benzoyl peroxide has been found to be superior to the others in prophylactic activity against S. intermedius. An additional topical therapy for localized pyoderma is mupirocin ointment. It has excellent activity against gram-positive cocci, works well in an acid environment, is not absorbed systemically, and is chemically unrelated to the other antimicrobials. It is well tolerated in cats for the treatment of feline acne. Mupirocin penetrates well into granulomatous lesions, such as interdigital abscesses. Owners can decrease the relapse rate and severity of pyodermas if they immediately apply mupirocin, q12h, when they first notice early lesions developing. Mupirocin is available as a veterinary product in the United States; however, in Canada, it is only available as the human labelled product (Bactroban, Pfizer Canada, Kirkland, Quebec). 696

Resistant pyodermas and deep pyodermas Recurrent infections with resistant bacteria and deep pyodermas indicate the presence of more severe predisposing causes compared with superficial pyodermas. Underlying factors must be thoroughly investigated and corrected when possible, but prolonged and repeated therapy with antimicrobials is usually necessary for control (Table 3). Enrofloxacin is my first choice for antimicrobial therapy of deep pyodermas and shortterm therapy of recurrent pyodermas where resistance has developed. It has excellent activity against S. intermedius, Pseudomonas spp. and Proteus spp., the bacteria most likely to be involved in problem cases. Enrofloxacin has ideal pharmacokinetic properties; its high Vd reflects its tissue penetrating ability. It accumulates in leukocytes and retains its activity in necrotic and purulent debris. Since it is a concentration-dependent killer, high-dose administration, once daily, is ideal and increases client compliance with the treatment regimen. Enrofloxacin should be avoided for chronic low-dose or pulse-dose therapy, as resistance develops by chromosomal mutations. Chloramphenicol has many of the same advantages as enrofloxacin, including a broad spectrum of activity and high Vd. Its activity against Pseudomonas spp. and Can Vet J Volume 37, November 1996

Table 4. Maintenance antimicrobials for chronic recurrent pyoderma Drug amoxicillin/clavulanic acid cephalexin cloxacillin

Table 5. Antimicrobial therapy for Malassezia dermatitis Drug ketoconazole itraconazole

Dosage 5-10 mg/kg BW, PO, ql2h for 30 d 5 mg/kg BW, PO, q24h for 30 d

Proteus spp. is variable, and its use should be dictated by microbiological culture and sensitivity results. Because of human health risks (1), I am reluctant to dispense or prescribe chloramphenicol for clients to administer. Clindamycin is very active against Staphylococcus spp. and anaerobic bacteria. It also has a high Vd and retains activity in purulent material. Bacterial resistance can develop fairly rapidly, and there is usually cross resistance with lincomycin and the macrolides. Rifampin has excellent activity against Staphylococcus spp. and a high Vd. It concentrates in neutrophils and macrophages, making it useful for treating deep pyodermas with chronic, granulomatous scarring lesions. Rapid development of resistance and potential toxicity limit the use of rifampin for chronic therapy of deep pyodermas. A B-lactamase resistant antimicrobial should be given with rifampin to minimize resistance (amoxicillinclavulanic acid, cephalosporin, cloxacillin). Rifampin is antagonistic to enrofloxacin, so they should not be administered concurrently. Toxic side effects include hepatitis, immune-mediated hemolytic anemia and thrombocytopenia, vomiting, and diarrhea. Rifampin should not be given to animals with pre-existing liver disease.

Maintenance antimicrobials Maintenance antimicrobial therapy is often necessary for long-term control of recurrent pyodermas. Maintenance therapy can be by continuous low-dose or pulse-dose therapy (Table 4). For continuous low-dose therapy, the dog is given the antimicrobial on a once-daily basis. Pulse dose therapy consists of a full dose of the antimicrobial administered on a "week-on, week-off" basis. If therapy is effective, the length of time "off" the antimicrobial is gradually increased. It is not known which of these methods is more efficacious in the management of recurrent pyoderma. Both have been used successfully in dogs, with minimal resistance problems developing when appropriate antimicrobials were used. The recommended antimicrobials for maintenance therapy are amoxicillin-clavulanic acid, cephalexin, and cloxacillin.

Malassezia dermatitis Malassezia dermatitis is becoming recognized as a infection with pyoderma in dogs. It

common concurrent

Can Vet J Volume 37, November 1996 37,

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1996

Comments monitor liver enzymes

is caused by Malassezia pachydermatis (Pityrosporon canis), a lipophilic, nonmycelial yeast. It is a commensal organism of the skin, ear canal, anal sacs, vagina, and rectum of the dog. Hypersensitivity appears to play a major role in the development of dermatitis. Therapy (Table 5) is directed at killing the yeast and ameliorating the predisposing cause of the opportunistic pathogen. Topical and systemic therapies are useful. Systemic therapy is most likely to result in speedy resolution of the skin lesions, but it is expensive, especially in large dogs. Itraconazole causes fewer side effects than ketoconazole (hepatotoxicity), but it is considerably more expensive. Miconazole cream (Conofite Cream 2%, Janssen Pharmaceutica, Mississauga, Ontario) can be applied topically. Degreasing agents are used to remove oily scales and exudate associated with Malassezia dermatitis that may encourage the growth of the yeast and prevent adequate penetration of antifungal agents. Good degreasing agents include benzoyl peroxide, and sulphur or selenium sulfide shampoos. Once or twice weekly use of the degreasing shampoo can be followed by a 2% ketoconazole shampoo (Nizoral Shampoo, Janssen Pharmaceutica). The ketoconazole shampoo is left in contact with the skin for 10 to 15 min before rinsing. As this human-labelled shampoo is expensive, an alternative therapy is to bathe the dog with a degreasing shampoo and follow with a rinse of enilconazole (Imaverol, Janssen Pharmaceutica), a topical azole available in Canada as a treatment for dermatophytosis in dogs. The most inexpensive antifungal rinse is a 50:50 solution of white vinegar and water, applied as a rinse following a degreasing shampoo.

Otitis externa Bacterial, yeast, and fungal infections are usually secondary causes of ear disease. Potentially pathogenic bacteria are normally present in low numbers in the external ear canal. When a primary disease damages the ear canal, these normal flora seize the opportunity to cause a secondary infection. Just like elsewhere on the skin, the most common bacterial culprit is S. intermedius. Staphylococcus intermedius can be cultured from 30% to 50% of cases. Other commonly isolated pathogens include Proteus spp., coagulase-negative Staphylococcus spp., E. coli, Corynebacterium spp.,

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Table 6. Topical antimicrobials for otitis externa Drug

framycetin/fusidin/nystatin

Activity

Product/Company

active against Pseudomonas, Proteus,

Canaurala

Staphylococcus, Malassezia chloramphenicol

neomycin/thiabendazole

anti gram-positive and gram-negative

Choralean Dropsa

activity

Liquichlorb

active against Pseudomonas, Proteus, Staphylococcus, Microsporum and Trichophyton

Tresadermc

Comments also contains prednisolone

also for ophthalmic use also contains prednisolone and tetracaine

also contains dexamethasone Neomycin can cause

contact

hypersensitivity procaine penicillin G/ neomycin/polymixin B

anti gram-positive and gram-negative

gentamicin

anti gram-positive and gram-negative

Gentocin Otic,

activity

Topagen Ointmente

gentamicin/clotrimazole

anti gram-positive and gram-negative activity, and antifungal

Otomaxe

also contains betamethasone

neomycin/bacitracin/ nystatin

anti gram-positive and gram-negative activity, and yeasts

Oribiotic Ointmenta

also contains

neomycin/thiostrepton/

anti gram-positive and gram-negative

nystatin

activity, and yeasts

Panalog Ointmentf

also contains triamcinolone

polymixin B/miconazole

anti gram-negative activity (especially Pseudomonas) and antifungal

Surolan Dropsg

also contains prednisolone

nitrofurazone/griseofulvin

anti gram-positive and gramnegative activity, and anti dermatophytes

Fulvidex Otice

anti gram-positive and gram-negative activity, especially Pseudomonas

Amiglyde-Vh

amikacin

activity

Forte-Topicald

also contains

hydrocortisone also contains betamethasone

triamcinolone, lidocaine

also contains tetracaine topical anesthetic

as

a

Apply 3-5 drops of the 250 mg/mL amikacin injectable directly into the ear

enrofloxacin

anti gram-positive and gram-negative activity, especially Pseudomonas

Baytrili

Apply 3-5 drops of the 22.7 mg/mL enrofloxacin injectable directly into

the ear aMTC Pharmaceuticals, Cambridge, Ontario bEVSCO Pharmaceutics, Brampton, Ontario cMerck Agvet, Pointe Claire-Dorval, Qu6bec dThe Upjohn Company, Orangeville, Ontario eSchering-Plough Animal Health, Pointe Claire, Quebec fCiba-Geigy Canada, Mississauga, Ontario gJanssen Pharmaceutica, Mississauga, Ontario hAyerst Laboratories, Saint Laurent, Qudbec 'Bayer, Etobicoke, Ontario

and Pseudomonas spp. As in the urinary tract, Pseudomonas is uncommon as an initial pathogen, but it frequently plays a major role in chronic otitis externa. Again, if the underlying pathophysiology is not corrected, antimicrobial therapy alone is unlikely to "cure" a Pseudomonas infection; instead, multidrug resistance is likely to occur, leaving the practitioner without reasonable treatment options. Malassezia pachydermatis may also become significant in cases of otitis externa, especially following antimicrobial therapy. Uncomplicated cases of otitis externa are best treated with topical antimicrobials (along with appropriate therapy such as anti-inflammatories and ear cleaning) (Table 6). Therapy is selected on the basis of cytological examination, looking for cocci (Staphylococcus or Streptococcus), rods (Pseudomonas or Proteus), or 9ZQQ udo

budding yeasts (Malassezia or Candida). Microbiological culture and sensitivity testing should be carried out if the cytology examination reveals rods or if the animal has chronic otitis externa. There are many topical preparations available for the treatment of otitis externa. Most contain combinations of glucocorticoids, antimicrobials, antifungals, and parasiticides. Systemic antimicrobial therapy is only necessary when the otitis externa is so severe that topical antimicrobials can not reach the site of infection, or when otitis media or interna is present. Systemic therapy should be based on the sensitivity of the pathogen(s), with consideration of pharmacokinetic characteristics, such as a high Vd, to ensure adequate tissue penetration. The aminoglycosides (neomycin, framycetin, gentamicin, amikacin) are often chosen for their efficacy Can Vet J Volume 37, November 1996

against staphylococci and gram-negative bacteria. When bacteria are resistant to amikacin, they will also be resistant to the other aminoglycosides. The reverse is not true, as many strains resistant to the other aminoglycosides will remain sensitive to amikacin. Antimicrobial activity of aminoglycosides is reduced by nucleic acid material released by decaying white blood cells. Therefore, their efficacy is less in the acidic, hyperosmolar, anaerobic environment of infected and inflamed tissues. Contact hypersensitivity can occur from topical application of neomycin. Cutaneous absorption is negligible in mild cases of otitis externa, but the aminoglycosides are potentially ototoxic with prolonged use in chronic otitis with ruptured tympanums. Many products for the treatment of otitis externa contain antimicrobial agents that are not used for systemic therapy. Fusidin is a lipid-soluble, steroid antibiotic, included in otic preparations for its activity against staphylococci. Resistance develops rapidly during treatment; therefore, it is always used as part of a combination. Polymixin B is an antimicrobial noted for its activity against Pseudomonas aeruginosa and other gram-negative pathogens, by binding to and disrupting the phospholipid (endotoxin) component of the gram-negative cell membrane. It has no activity against gram-positive bacteria. Because it causes nephrotoxicity and neurotoxicity with parenteral use, polymixin B is limited to topical therapy. It is usually combined with other antimicrobials to extend the spectrum of activity. Thiostrepton is a topical antimicrobial with gram-positive and gram-negative antimicrobial activity. Bacitracin is an antimicrobial that is bactericidal to gram-positive bacteria by interfering with the formation of the cell wall. It has little activity against gram-negative bacteria. Bacitracin is highly nephrotoxic, so its use is limited to topical therapy. Chloramphenicol has the appropriate spectrum of activity and pharmacokinetic properties for the treatment of otitis externa. In addition, it can stimulate excessive granulation tissue in the middle ear and should not be used in ears with ruptured tympanums. Otic products also commonly contain antifungal drugs. The azole drugs (thiabendazole, miconozole, and clotrimazole) are excellent broad-spectrum antifungal agents with some activity against gram-positive bacteria. The dewormer, thiabendazole, has some antifungal activity, so it is used in otic preparations and can be applied topically for dermatophytes. Clotrimazole and miconazole are not suitable for systemic therapy, but they are very broad spectrum topical antifungal drugs. Nystatin is a topical antifungal, with a more narrow spectrum of activity than the azoles. It is effective against the yeasts Candida, Pityrosporum, and Malassezia. Griseofulvin is a fungistatic antibiotic that is effective against virtually all dermatophytes, but it is not active against yeasts. For chronic infections with Pseudomonas spp., extralabel treatments may be considered, along with correction of the underlying pathophysiology by surgical procedures. Injectable amikacin and enrofloxacin have been administered directly into the external ear canal. Clinically, some Pseudomonas spp. infections that have failed to respond to other therapies have responded to Can Vet J Volume 37, November 1996

amikacin in Tris EDTA solution. The Tris EDTA can be prepared by a pharmacist from 1.2 g of EDTA disodium, 6.05 g of Tris buffer, and deionized water qs to 1 L. The pH is adjusted to 8.0 with 1.0 N HCI or NaOH, and the solution autoclaved. Then 1 .1 mL of amikacin (250 mg/mL) is added to 28.9 mL of Tris EDTA. Three to 4 drops of this solution are placed into the affected ear(s), q8h. References 1. Page SW. Chloramphenicol 1. Hazards of use and the current regulatory environment. Aust Vet J 1991; 68: 1-2.

Bibliography 1. Hill PB, Moriello KA. Canine pyoderma. J Am Vet Med Assoc 1994; 204: 334-340. 2. Lloyd D. Treating staphylococcal skin disease in the dog. Proc North Am Vet Conf 1995: 13-19. 3. Ihrke PJ. Experiences with enrofloxacin in small animal dermatology. Proc North Am Vet Conf 1995: 27-32. 4. Rosenkrantz WS. Otic manifestations of general dermatologic conditions. Trenton, New Jersey: Vet Learning Systems, 1994 (Clinical classroom: Dermatology series, Schering Plough Animal Health). 5. Bevier DE. Pyoderma in the dog and cat. Trenton, New Jersey: Vet Learning Systems, 1994 (Clinical classroom: Dermatology series, Schering Plough Animal Health).

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