Categories
Diseases

Diseases of the Ear: General Principles Of Management

The therapeutic plan for otitis externa requires identification of the primary disease process and perpetuating factors. Ideally management is aimed at thoroughly cleaning and drying the ear canal, removing or managing the primary factors, controlling perpetuating factors, administering appropriate topical or systemic therapy (or both), and evaluating response to therapy.

Ear Cleaning

Ear cleaning serves several functions: (1) it removes material that supports or perpetuates infection; (2) it removes bacterial toxins, white blood cells (WBCs), and free fatty acids that stimulate inflammation; (3) it allows complete evaluation of the external ear canal and tympanum; (4) it allows topical therapy to contact all portions of the ear canal; and (5) it removes material that may inactivate topical medications. Significandy painful ears may benefit from initial anti-inflammatory therapy to decrease pain and swelling of the ear canal prior to cleaning. Severe cases of otitis externa often require general anesthesia to facilitate complete cleaning and evaluation of the external and middle ear.

Many different solutions are available for removing cerumen, exudate, and debris from the ear canal (Table Otic Cleaning Solutions). If the tympanic membrane cannot be visualized, only physiologic saline solution or water should be used, because many topical cleaning agents are ototoxic or incite inflammation of the middle ear. An operating otoscope, ear loops, and alligator forceps facilitate manual removal of large amounts of cerumen or debris. Debris is carefully removed under direct visualization, and care is taken deeper in the ear canal (close to the tympanic membrane). Aggressive hair removal is not advised, because inflammation and damage to the epithelium can result in secondary bacterial colonization and infection. Flushing may be performed after large accumulations of cerumen and debris are mechanically removed from the ear canal.

Otic Cleaning Solutions

Trade Name Acetic Acid Boric Acid Salicylic Acid Isopropyl Alcohol Propylene Clycol Dss Other
Ace-Otic Cleanser 2%   0.1%       Lactic acid 2.7%
Adams Pan-Otic         X X Parachlorometaxylenol, tris EDTA, methylparaben, diazolidinyl urea, popylparaben, octoxynol
Alocetic Ear Rinse X     X     Nonoxynol-12, methylparaben, alovera gel
Cerulytic Ear Ceruminolytic         X   Benzyl alcohol, butylated hydroxytoluene
Cerumene             25% Isopropyl myristate
DermaPet Ear/Skin Cleanser for Pets X X          
Docusate Solution         X X  
Earmed Boracetic Flush X X         Aloe
Earmed Cleansing Solution & Wash         X   50A 40B alcohol, cocamidopropyl phosphatidyl and PE dimonium chloride
Earoxide Ear Cleanser             Carbamide peroxide 6.5%
Epi-Otic Ear Cleanser     X   X X Lactic acid, chitosanide
Fresh-Ear X X X X X   Lidocaine hydrochloride, glycerin, sodium docusate, lanolin oil
OtiCalm     X       Benzoic acid, malic acid, oil of eucalyptus
Otic Clear X X X X X   Glycerin, lidocaine hydrochloride
Oticlean-A Ear Cleaning Lotion X X X 35% X   Lanolin oil, glycerin
Oti-Clens     X   X   Malic acid, benzoic acid
Otipan Cleansing Solution         X   Hydroxypropyl cellulose, octoxynol
Otocetic Solution 2% 2%          
Wax-O-Sol 25%             Hexamethyltetracosane

Flushing and evacuation of solution is done under direct visualization through an operating otoscope. A bulb syringe and red rubber catheter system may be used to both flush and evacuate solutions and accumulations from the ear canal. The operator, avoiding drastic pressure changes within the external ear canal that could damage the tympanum, should carefully control suction and manual evacuation of the contents of the bulb syringe from the ear canal. Other alternatives include tomcat catheters (3.5 F) or flexible, intravenous catheters (14 gauge, Teflon); stiff, narrow catheters should be used cautiously and under direct visualization deep in the external ear canal. Other reservoir systems for delivery or evacuation of solutions include a 12 mL syringe or suction tubing attached to in-house vacuum systems. In-house vacuum systems should be used cautiously and under direct visualization. Care should be taken to avoid trauma to the tympanic membrane until its integrity can be assessed. Initial flushes should be done with physiologic saline solution or water until the integrity of the tympanic membrane is established.

Other solutions may aid in the removal of wax in the ear canal. Ceruminolytics are emulsifiers and surfactants that break down ceruminocellular aggregates by causing lysis of squamous cells. A ceruminolytic agent in an alkaline pH may more effectively lyse squamous cells via cell surface protein disruption. Oil-based products soften and loosen debris to aid in their removal but do not cause cell lysis. Water-based ceruminolytics are easier to remove and dry more quickly than oil-based solutions, which are occlusive if they remain in the ear canal. Water-based products include dioctyl sodium sulfosuccinate, calcium sulfosuccinate, and carbamate peroxide, which has a foaming action with the release of urea and oxygen. Oil-based products include squalene, triethanolamine polypeptide, hexamethyltetracosane, oleate condensate, propylene glycol, glycerin, and mineral oil. In a recent study only the combination of squalene and isopropyl myristate in a liquid petrolatum base had no adverse effects on hearing, the vestibular system, and histopathologic examination. Other agents tested contained glycerin, dioctyl sodium sulfosuccinate (2% or 6.5%), parachlorometaxylenol, carbamide peroxide (6%), propylene glycol, triethanolamine polypeptide oleate condensate (10%), and chlorobutanol (0.5%).

Alcohol-based drying agents added to ceruminolytics include boric acid, benzoic acid, and salicylic acid, which decrease the pH of the ear canal, cause keratolysis, and have a mild antimicrobial effect. Drying the ear canal is important to combat increased humidity, which potentiates infection.

If the tympanum is intact, the ear canal is filled with a ceruminolytic agent for at least 2 minutes and the pinna is cleaned at the same time. The solution is flushed twice with warm water, and the canal inspected. The procedure is repeated until cleaning is complete. Other solutions commonly advocated for ear flushing include dilute chlorhexidine solution (0.05%), dilute povidone-iodine, and acetic acid (2.5%). The first two agents are potentially ototoxic or induce inflammation and should not be used if the tympanum is ruptured. A combination of propylene glycol malic, benzoic, or salicylic acid; 2% acetic acid; or dilute povidone-iodine have been suggested for use in dogs with a ruptured tympanum.

Owners may clean the ears at home with mild preparations of ceruminolytics and drying agents if mild otitis is present without severe accumulation of cerumen or exudate. Aqueous solutions are usually recommended because they are less occlusive and easier to clean from the ear, dog, and home environment.

The ear should be filled with the solution, then massaged for 40 to 60 seconds. The pet should be allowed to shake its head to remove the majority of the solution, and the excess should be wiped from the ear canal and pinna with a tissue. Daily flushing is usually recommended, followed by every other day, weekly, then as needed, depending on the solution. Ear swabs are not recommended for home use, because cerumen and debris may be forced into the horizontal ear canal and impact against the tympanic membrane

Topical Therapy

Erythematous ceruminous otitis externa is diagnosed 2.7 times more often than acute suppurative otitis according to one report. Yeast ± cocci were identified in those cases, with cocci or rods identified in suppurative otitis. Topical therapy should be based on the cytologic examination to diminish the incidence of inappropriate treatment (Table Topical Medications Used in the Treatment of Ear Disease). Many preparations combine anti-inflammatories and antimicrobials in an attempt to decrease the inflammation and combat bacterial or yeast overgrowth. All topical medications should be considered supportive, and specific treatment should be aimed at controlling the primary disease process.

Topical Medications Used in the Treatment of Ear Disease

Generic Name Trade Name Dose Frequency Description
Fluocinolone 0.01% DMSO 60% Synotic 4-6 drops; total dose<17mL q12h initially. q48-72h maintenance Potent corticosteroid anti-inflammatory
Hydrocortisone 1.0% HB101,

Burrows H,

2-12 drops, depending on ear size q12h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory
Hydrocortisone 1.0%, lactic acid Epiotic HC 5-10 drops q12h for 5 days Mild corticosteroid anti-inflammatory, drying agent
Hydrocortisone 0.5%, sulfur 2%. acetic acid 2.5% Clear X Ear Treatment 2-12 drops, depending on ear size q12-24h initially. q24-48h maintenance Mild corticosteroid anti-inflammatory, astringent, germicidal
DSS 6.5%. urea (carbamide peroxide 6%) Clear X Ear Cleansing Solution 1-2 mL per ear Once per week to as necessary Ceruminolytic, lubricating agent
Chlorhexidine 2% Nolvasan Dilute 1:40 in water As necessary Antibacterial & antifungal activity
Chlorhexidine 1.5% Nolvasan Dilute 2% in

propylene glycol

q12h Antibacterial & antifungal activity
Povidone-iodine 10% Betadine solution Dilute 1:10-1:50 in water As necessary Antibacterial activity
Polyhydroxidine iodine 0.5% Xenodyne Dilute 1:1-1:5 in water As necessary, q12h, once weekly Antibacterial activity
Acetic acid 5% White vinegar Dilute 1:1-1:3 in water As necessary; q12-24h for Pseudomonas Antibacterial activity, lowers ear canal pH
Neomycin 0.25%, triamcinolone 0.1%, thiabendazole 4% Tresaderm 2-12 drops depending on ear size q12h up to 7 days Antibacterial & antifungal activity, parasiticide (mites), moderate corticosteroid anti-inflammatory
Neomycin 0.25%, triamcinolone 0.1%, nystatin 100,000 U/mL Panalog 2-12 drops depending on ear size q12h to once weekly Antibacterial & antifungal activity, moderate corticosteroid anti-inflammatory
Chloramphenicol 0.42%. prednisone 0.17%, tetracaine 2%, squalene Liquachlor, Chlora-Otic 2-12 drops depending on ear size q12h up to 7 days Antibacterial activity, mild corticosteroid anti-inflammatory
Neomycin 1.75 & polymyxin B 5000 lU/mL, penicillin C procaine 10,000 lU/mL Forte Topical 2-12 drops depending on ear size q12h Antibacterial activity
Centamicin 0.3%, betamethasone valerate 0.1% Centocin Otic Solution, Betagen Otic Solution 2-12 drops depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone 0.1%, clotrimazole 0.1% Otomax, Obibiotic Ointment 2-12 drops depending on ear size q12h for 7 days Antibacterial & antifungal activity, potent corticosteroid anti-inflammatory
Centamicin 0.3%, betamethasone valerate 0.1%, acetic acid 2.5% Centaved Otic Solution 2-12 drops, depending on ear size q12h for 7 to 14 days Antibacterial activity, potent corticosteroid anti-inflammatory
Polymixin B 10,000 lU/mL, hydrocortisone 0.5% Otobiotic 2-12 drops, depending on ear size q12h Antibacterial activity, mild corticosteroid anti-inflammatory
Enrofloxacin 0.5%, silver sulfadiazine 1% Baytril Otic 2-12 drops, depending on ear size q12h for up to 14 days Antibacterial activity
Carbaryl 0.5%, neomycin 0.5%, tetracaine Mitox Liquid 2-12 drops, depending on ear size   Antibacterial activity, parasiticide (mites)
Pyrethrins 0.06%, piperonyl butoxide 0.6% Ear Mite and Tick Control 5 drops q12h Parasiticide (mites)
Pyrethrins 0.05%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 to 10 days Parasiticide (mites), ceruminolytic
Isopropyl alcohol 90%, boric acid 2% Panodry Fill ear canal As necessary Drying agent
Acetic acid 2%, aluminum acetate Otic Domeboro Fill ear canal q12-48h Drying agent, antibacterial activity, lowers ear canal pH
Silver sulfadiazine Silvadene Dilute 1:1 with water, 1 g powder in 100 mL water q12h for 14 days Antibacterial & antifungal activity
Tris EDTA±

gentamicin 0.03%

  2-12 drops, depending on ear size q12h for 14 days 1 L distilled water, 1.2g Tris EDTA, 1 mL glacial acetic acid; antibacterial activity
Silver nitrate   Use sparingly As necessary Cauterization of

ulcerative otitis externa

Miconazole 1%; ± topical glucocorticoid (7.5 mL of dexamethasone phosphate (4 mg/mL] to10mLof1% miconazole) Conofite 2-12 drops, depending on ear size q12-24h Antifungal activity
Ivermectin 0.01% Acarexx 0.5 mL per ear Once Parasiticide (mites)
Pyrethrins 0.15%, piperonyl butoxide 1.5% Many 2-12 drops, depending on ear size Twice at 7-day interval Parasiticide (mites)
Pyrethrins 0.05%, piperonyl butoxide 0.5%, squalene 25% Cerumite 2-12 drops, depending on ear size q24h for 7 days Parasiticide (mites), ceruminolytic
Pyrethrins 0.04%, piperonyl butoxide 0.49%, DSS 1.952%, benzocaine 1.952% Aurimite 10 drops q12h  
Rotenone 0.12%, cube resins 0.16% Many 2-12 drops, depending on ear size Every other day Parasiticide (mites)

Topical glucocorticoids benefit most cases of otitis externa by decreasing pruritus, exudation, swelling, and proliferative changes of the ear canal. The most potent glucocorticoids available in topical preparations are betamethasone valerate and fluocinolone acetonide. Less potent corticosteroids include triamcinolone acetonide and dexamethasone; the least potent is hydrocortisone. Most dogs benefit from short-term therapy with topical corticosteroids at the initiation of therapy, with concurrent therapy aimed at the primary and other perpetuating factors. Long-term therapy with topical corticosteroids can be deleterious because of systemic absorption of drug. Increased serum liver enzymes and depressed adrenal responsiveness may occur; with prolonged use iatrogenic hyperadreno-corticism is possible. Glucocorticoids alone may be of benefit for short-term therapy in cases of allergic or erythematous ceruminous otitis.

Antimicrobials are important for controlling secondary bacterial or yeast overgrowth or infection. Antimicrobials are indicated in any case with cytologic evidence of bacterial overgrowth or infection, with attention paid to the morphology and gram-staining characteristics of the bacteria. Otic preparations commonly contain aminoglycoside antibiotics. Neomycin is effective against typical otitis bacteria such as Staphylococcus intermedium. Gentamicin and polymyxin B are also appropriate initial topical treatments for gram-negative bacterial otitis externa.The significant risk of bone marrow toxicity in people limits the use of chloramphenicol for treating otitis in dogs and cats despite its antibacterial spectrum and availability.

Due to the frequency of resistant gram-negative bacteria such as Pseudomonas, other topical preparations have been developed. Enrofloxacin, ophthalmic tobramycin, and topical application of injectable ticarcillin have been used to treat otitis in dogs.< Their use should be limited to cases of resistant bacteria, and culture and susceptibility testing should be performed prior to application. Other topical agents may be used to supplement treatment of resistant Pseudomonas, such as silver sulfadiazine solution and tris EDTA. Tris EDTA can render Pseudomonas susceptible to enrofloxacin or cephalosporins by enhancing membrane permeability and altering ribosome stability. Frequent ear cleaning may also assist in the treatment of resistant bacterial otitis; ceruminolytics have antimicrobial properties, and their use in clinical cases has been evaluated. Acetic acid in combination with boric acid is effective against both Pseudomonas and Staphylococcus, depending on concentration and duration of exposure. Ear cleaning removes proinflammatory products, cells, and substances that diminish the effectiveness of topical antibiotics.

Many topical preparations control yeast organisms, which may complicate erythematous ceruminous otitis and suppurative otitis. Common active ingredients include miconazole, clotrimazole, nystatin, and thiabendazole. Preparations containing climbazole, econazole, and ketoconazole have also been evaluated. Eighty percent of yeast were susceptible to miconazole and econazole, intermediately resistant to ketoconazole, and 90% were resistant to nystatin and amphotericin B in one in vitro study. Topical ear cleaning agents have some efficacy against Malassezia organisms. Other preparations (e.g. chlorhexidine, povidone-iodine, acetic acid) are also effective in the treatment of secondary yeast overgrowth.

Response to topical therapy should be gauged by re-evaluation of physical, cytologic, and otoscopic examinations every 10 to 14 days after the initiation of therapy. Any changes in the results of these examinations should be recorded. Most cases of otitis can be managed topically; failure to respond to therapy should prompt re-evaluation of the diagnosis and treatment.

Systemic Therapy

Systemic glucocorticoid administration may be beneficial in cases of severe, acute inflammation of the ear canal, chronic proliferative changes of the ear canal, and allergic otitis. Anti-inflammatory doses should be limited to 7 to 10 days. Cases of significant thickening or proliferative changes in the external ear canal benefit from systemic antimicrobial therapy. Systemic therapy should be considered if concurrent dermatologic changes of the surrounding skin, pinna, or other regions of the body are present. Long-term administration of appropriate antimicrobials based on culture and susceptibility is required in all cases of otitis media. Systemic therapy for yeast is rarely recommended in animals with otitis alone. One study evaluated oral itraconazole therapy, and in ear samples evaluated on cytology and culture, no change in cytology score was found.

 

Categories
Diseases

Therapy For Specific Diseases Of The External Ear Canal

Ectoparasites

Thorough cleaning of the external ear canal, treatment of all household pets, and whole-body therapy should be considered in the treatment regimen for ear mites. Pets with no clinical signs may be asymptomatic carriers and a reservoir for reinfestation. Otic parasiticides such as pyrethrins, rotenone, amitraz, and carbaryl must be administered every 24 hours throughout the 20-day mite life cycle because they do not kill mite eggs. Thiabendazole eliminates all mite stages, but it must be applied every 12 hours for 14 days. Ivermectin (0.3 to 0.5 mg/kg) may be applied topically once weekly for 5 weeks. Otic administration of medication does not affect mites on adjacent or distant skin locations, and systemic or other total-body parasiticide may be indicated. Alternatively, ivermectin administered subcutaneously (0.2 to 0.3 mg/kg) 2 to 3 times at 10- to 14-day intervals or orally (0.3 mg/kg) every week for four treatments eliminates otic mites and those found elsewhere on the body. Other topicals proven safe and effective for ear mite treatment include selamectin (6 mg/kg) applied to the skin between the shoulder blades and fipronil spray. Selamectin administered once in cats and two times, 30 days apart in dogs gave results similar to topical pyrethrin therapy.

Idiopathic Inflammatory or Hyperplastic Otitis in Cocker Spaniels

Treatment is aimed at decreasing the secondary ear canal changes associated with this condition. Anti-inflammatory doses of corticosteroids administered orally may be useful. Topical corticosteroid preparations in combination with antimicrobials decrease the soft tissue mass affecting the ear canal but may not be as effective as oral administration. Maintenance therapy may be required both topically and orally; however, low doses of corticosteroids should be used. Re-evaluation should include attention to the potential side effects of corticosteroid therapy. Intermittent treatment of secondary bacterial or yeast overgrowth and infection may be required. Surgery is often indicated due to the severe secondary changes within the ear canal.

Excessive Moisture (Swimmer’s Ear)

Other primary disease conditions such as allergic otitis should be ruled out in any dog with erythematous ceruminous otitis. Dogs with frequent exposure to water, however, may require ear cleaning and drying agents to diminish the humidity of the ear canal. Many cleaning and drying agents also posses antimicrobial effects. Products that combine a drying agent and corticosteroid decrease the ear canal humidity and inflammation associated with allergic otitis complicated by swimming. Care should be taken to control primary disease (i.e. allergic otitis), however, and intermittendy manage the predisposing factor (i.e. excessive moisture) as necessary. The dog’s ears should be cleaned and dried the day of water exposure and for 2 to 5 days after. For continued frequent exposure, maintenance cleaning may be required every other day to twice weekly.

Chronic Bacterial Otitis

Resistant bacteria play an important role in the development of chronic otitis externa. Any dog not responding to initial therapy should be re-evaluated for primary and perpetuating conditions such as allergic disease, foreign body, neoplasia, otitis media, and secondary anatomic changes of the ear canal. Primary disease processes identified in one study included hypothyroidism, atopy, food allergy, and immune-mediated disease. Infection with Pseudomonas species frequently occurs with repeated treatment of otitis extema, and acquired resistance is common. Culture and susceptibility testing is imperative to guide therapy. Oral antimicrobials combined with topical therapy are used in severe cases with secondary changes of the ear canal. Identification of otitis media is vital to remove the middle ear as a source of otitis extema. Otitis media requires long-term treatment.

Ear cleaning prior to the application of topical medication may increase the efficacy of the agent by decreasing exudate in the ear canal that inactivates antimicrobial drugs such as polymyxin. In cases that fail to respond to first-line drug treatments such as polymyxin or gentamicin, other topical antimicrobial agents should be tried. Ophthalmic tobramycin and injectable amikacin have been described for use as topical antimicrobials in ear disease. The integrity of the tympanic membrane should be known prior to use; the clinician should avoid these medications if the tympanic membrane cannot be proven intact. Enrofloxacin or ticarcillin injectable preparations diluted in saline or water may be applied topically for resistant Pseudomonas. Parenteral ticarcillin was used in cases with a ruptured tympanic membrane until healing was observed, at which time topical therapy was instituted; clinical response occurred in 11 of 12 cases. Enrofloxacin and silver sulfadiazine combination is also available in an otic preparation (Baytril Otic, Bayer Shawne Mission, KS).

Other topical therapy may assist in eliminating resistant Pseudomonas from the ear canal.

Decreasing the pH of the ear canal with 2% acetic acid is lethal to Pseudomonas; diluted vinegar in water (1:1 to 1:3) may be used to flush the ear canal. Acetic acid combined with boric acid is lethal to Pseudomonas and Staphylococcus, depending on the concentration of each agent. Increasing the concentration of acetic acid may broaden its spectrum of activity but causes irritation of the external and middle ear. Silver sulfadiazine in a 1% solution exceeds the minimum inhibitory concentration of Pseudomonas and may be instilled into the ear canal. One gram of silver sulfadiazine powder mixed in 100 mL of water may be used for topical therapy and is also effective against Proteus species, enterococci, and Staphylococcus intermedium. Dilute acetic acid (2%) and silver sulfadiazine (1%) have not caused adverse effects in cases with a ruptured tympanic membrane.I Tris EDTA may be applied after thorough ear cleaning to increase the susceptibility of Pseudomonas to antimicrobial agents. It must be mixed, pH adjusted, and autoclaved prior to use or is available in an otic preparation (TrizEDTA, DermaPet ®, Potomac, MD), which is used to clean the ears prior to instillation of topical antibiotic. Topical antiseptics such as chlorhexidine and povidone-iodine solutions may be helpful, but ototoxicity is an issue, particularly in cases in which the tympanum is ruptured or cannot be evaluated.

Re-evaluation of the pet is important for monitoring response to therapy. Evaluation of the ear canal for progressive secondary changes and cytologic examination will allow alterations in therapy as needed. Significant narrowing of the ear canal is an indication for surgical intervention. Yeast overgrowth may occur with aggressive medical management of bacterial otitis and should be identified to maintain proper medical management.

Refractory or Recurrent Yeast Infection

Malassezia infection is a common perpetuating factor with erythematous ceruminous otitis and alterations in the otic microenvironment. Primary causes of the otitis should be identified and treated. Cytologic examination, not culture, should be relied upon for the diagnosis of yeast infection. If a case becomes refractory to therapy, reassessment of the primary condition and perpetuating factors should be done. Miconazole, clotrimazole, cuprimyxin, nystatin, and amphotericin B have all been described for treating Malassezia otitis. Climbazole had better in vitro activity against isolates of Malassezia pachydermatis in one study. Yeast were more susceptible to azole antifungals than polyene antifungals; however, oral ketoconazole, itraconazole, or fluconazole have been recommended for refractory cases. Long-term therapy may require topical antibacterial and antifungal combinations.

Ear cleaning may aid in the elimination of yeast organisms by removing cerumen, debris, or exudate and altering the microenvironment of the ear canal. Cleaning with antimicrobial agents such as chlorhexidine, povidone-iodine, and acetic acid may be beneficial; but as always the integrity of the tympanum should be established prior to use. Ear cleaning solutions may also have some efficacy against yeast organisms both in vitro and in clinical cases of otitis.

Neoplasia

Chronic otitis externa may be the result of otic neoplasia, or otitis may be a predisposing factor in the development of neoplasia. Cocker spaniels are over-represented for benign and malignant neoplasia and otitis extema. Tumors of the skin and adenexal structures of the ear predominate. Benign tumors in dogs include sebaceous gland adenoma, basal cell tumor, polyp, ceruminous gland adenoma, and papilloma. Cats are more frequendy diagnosed with malignant neoplasms, but benign conditions include inflammatory polyps, ceruminous gland adenomas, ceruminous gland cysts, and basal cell tumors. Malignant neoplasms in both species include ceruminous gland adenocarcinoma, undifferentiated carcinoma, and squamous cell carcinoma. Ceruminous gland adenocarcinomas are the most frequendy diagnosed tumors of the ear canal in dogs and cats; however, one report stated that squamous cell carcinoma occurs with equal incidence in the cat.

The biologic behavior of otic tumors cannot be judged by their gross appearance; however, benign masses are usually nodular and pedunculated. Ulceration can be secondary to otitis associated with mass lesions, but malignant masses ulcerate more frequendy than benign masses. The tympanic bulla is involved in up to 25% of aural neoplasms, and neurologic signs occur in 10% of dogs and 25% of cats with otic neoplasia. The biologic behavior of malignant neoplasms tends to be local invasion with a low metastatic rate (e.g. 10% in dogs) to draining lymph nodes or lung.

Surgery is the mainstay treatment of otic neoplasia. Conservative excision may be possible for benign lesions, depending on the location of the tumor. Malignancies should be removed by total ear canal ablation and lateral bulla osteotomy. Incomplete excision results in recurrence of the mass and secondary otitis externa. Malignant neoplasia is associated with a median survival time (MST) of more than 58 months in dogs and 11.7 months in cats. Extensive tumor involvement and lack of aggressive management are associated with a poor prognosis in dogs. In cats a poor prognosis is associated with neurologic signs, squamous cell carcinoma or undifferentiated carcinoma, vascular or lymphatic invasion, and lack of aggressive therapy. Ceruminous gland adenocarcinoma has a median disease free interval of more than 36 months and 42 months in dogs and cats, respectively. The MST associated with squamous cell carcinoma and undifferentiated carcinoma in cats is 4 to 6 months.

Categories
Drugs

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based (Abelcet, Fungizone)

Antifungal

Highlights Of Prescribing Information

Systemic antifungal used for serious mycotic infections

Must be administered IV

Nephrotoxicity is biggest concern, particularly with the deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive

Renal function monitoring essential

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based interactions

What Is Amphotericin B Desoxycholate, Amphotericin B Lipid-Based Used For?

Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

The liposomal form of amphotericin B can be used to treat Leishmaniasis.

Pharmacology / Actions

Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out.” Because bacteria and rickettsia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp.

It has been reported that amphotericin B has immunoadjuvant properties but further work is necessary to confirm the clinical significance of this effect.

Pharmacokinetics

Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form.

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

Before you take Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

Contraindications / Precautions / Warnings

Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but it should be used cautiously with adequate monitoring.

Adverse Effects

Amphotericin B is notorious for its nephrotoxic effects; most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in patients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require several months to do so.

Newer forms of lipid-complexed and liposome-encapsulated amphotericin B significantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that amphotericin B lipid complex was 8-10 times less nephrotoxic than the conventional form.

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recommend stopping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dL, serum creatinine >3 mg/dL or if other clinical signs of systemic toxicity develop such as serious depression or vomiting.

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12.5 grams or 0.5-1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 mL/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “… helpful in averting renal insufficiency….”

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse.

Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hypokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regenerative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been reported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels.

Reproductive / Nursing Safety

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Prohahly safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women.)

Overdosage / Acute Toxicity

No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe minimized by administering fluids and mannitol as outlined above in the Adverse Effects section.

How to use Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

All dosages are for amphotericin B desoxycholate (regular amphotericin B) unless specifically noted for the lipid-based products.

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

A published study () demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin BIV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 mL of D5W over 3 minutes.

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for dogs:

For treatment of susceptible systemic fungal infections:

a) Two regimens can be used; after diluting vial (as outlined below in preparation of solution section), either:

1) Rapid-Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given.

2) Slow IV Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 250-500 mL of D5W. Place indwelling catheter in peripheral vein and give total volume over 4-6 hours. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

b) In dehydrated, sodium-depleted animals, must rehydrate before administration. Dosage is 0.5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 mL of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 mL or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer every other day if BUN remains below 50 mg/dl. If BUN exceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8 -10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, aspergillosis and other fungal diseases require a greater cumulative dosage. ()

c) For treating systemic mycoses using the lipid-based products: AmBisome, Amphocil or Abelcet Give test dose of 0.5 mg/ kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more resistant filamentous fungal infections (e.g., pythiosis) use the higher dose 2-2.5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

e) For systemic mycoses using amphotericin B lipid complex (Abelcet): Dilute in 5% dextrose to a final concentration of 1 mg/mL and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B 0.5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5-5 mg/kg PO once daily. If CNS/ocular involvement use ketoconazole at 20-40 mg/kg PO divided twice daily ()

c) For severe cases, using amphotericin B lipid complex (Abelcet): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg ()

For cryptococcosis (see general dosage guidelines above):

a) Amphotericin B 0.5 – 0.8 mg/kg SC 2 – 3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B 0.15 – 0.5 mg/kg IV 3 times a week with ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

b) As an alternative to ketoconazole treatment: 0.5 mg/kg IV given over 6-8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7.5-8.5 mg/kg cumulative dose is achieved ()

For Leishmaniasis:

a) Using the liposomal form of Amphotericin B: 3-3.3 mg/kg IV 3 times weekly for 3-5 treatments)

b) Using AmBisome (lipid-based product): Give initial test dose of 0.5 mg/kg, then 3-3.3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. ()

For gastrointestinal pythiosis:

a) Resect lesions that are surgically removable to obtain 5 – 6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for cats:

For treatment of susceptible systemic fungal infections: a) Rapid-Infusion Technique: After diluting vial (as outlined below in preparation of solution section), dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.25 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

For cryptococcosis (see general dosage guidelines above):

a) As an alternative therapy to ketoconazole: Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with flucytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989)

b) Amphotericin B 0.15-0.4 mg/kg IV 3 times a week with flucytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily ()

c) Amphotericin B 0.5-0.8 mg/kg SC 2-3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN increases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of duration. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0.5 mg/ kg of amphotericin B. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5 – 5 mg/kg PO once daily. If CNS/ocular involvement, use ketoconazole at 20-40 mg/kg PO divided twice daily. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for rabbits, rodents, and small mammals:

a) Rabbits: 1 mg/kg/day IV ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for horses:

For treatment of susceptible systemic fungal infections:

a) For fungal pneumonia: Day 1: 0.3 mg/kg IV; Day 2: 0.4 mg/kg IV; Day 3: 0.6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6.75 mg/kg has been administered ()

b) For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0.3 mg/kg IV; Day 2: 0.45 mg/kg IV; Day 3: 0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. ()

For intrauterine infusion: 200-250 mg. Little science is available for recommending doses, volume infused, frequency, diluents, etc. Most intrauterine treatments are commonly performed every day or every other day for 3-7 days. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for Llamas:

For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1.5 mL of B-Complex and 20 mEq of KC1 added. Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coccidioidomycosis). ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for birds:

For treatment of susceptible systemic fungal infections:

a) For raptors and psittacines with aspergillosis: 1.5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/mL of saline) for 15 minutes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. ()

b) 1.5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0.3-1 mg/mL nebulized for 15 minutes 2-4 times daily ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for reptiles:

For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intratracheally once daily for 14-28 treatments ()

Client Information

■ Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy

■ The costs associated with therapy

Chemistry / Synonyms

A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent.

Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B liposomal (ABL, L-AMB, Ambisome).

Amphotericin B may also be known as: amphotericin; amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available.

Storage / Stability / Compatibility

Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives — see directions for preparation in the Dosage Form section below).

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, Ds-lactated Ringer’s, amino acids 4.25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCL, cimetidine HCL, diphenhydramine HCL, dopamine HCL, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCL, metaraminol bitartrate, methyldopate HCL, nitrofurantoin sodium, oxytetracycline HCL, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCL, and verapamil HCL. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin (Gensia Sicor); Fungizone Intravenous (Apothecon); generic (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 mL of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/mL colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/mL with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 mL (as lipid complex) in 10 mL & 20 mL vials with 5 micron filter needles: Abelcet (Enzon); (Rx)

Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 mL vials; 100 mg (as cholesteryl) in 50 mL vials; Amphotec (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; AmBisome (Fujisawa; (Rx)

Amphotericin B is also available in topical formulations: Fungizone (Apothecon); (Rx)

Categories
Diseases

Acquired Pericardial Effusions: Specific Causes, Epidemiology, Treatment, and Prognosis

Idiopathic Pericardial Effusion

Idiopathic pericardial effusion is a diagnosis of exclusion. It is made in cases with pericardial effusion where no intrapericardial masses are identified after thorough echocardiographic evaluation and the results of ancillary tests, such as pericardial fluid analysis, fail to disclose a cause. Pericardial histopathology and immunohistochemistry from dogs with idiopathic pericardial effusion demonstrate extensive pericardial fibrosis and a mixed inflammatory response of greatest intensity at the cardiac surface of the tissue. Perivascular lymphoplasmacytic aggregates are present at the pleural surface within the fibrosed pericardium. No vascular pathology or deposition of immunoglobulin or complement within the vessel wall exists, suggesting that the pericarditis is not due to a vasculitis. Immunohistochemistry findings are consistent with a predominandy humoral immune response, but they do not support a primary immune-mediated pathogenesis. The factor or factors that initiate idiopathic pericarditis remain unknown.

As with any diagnoses of exclusion, a diagnosis of idiopathic pericardial effusion should be made with appropriate caution. Small intrapericardial tumors may elude detection, especially in cases where echocardiography is performed after pericardiocentesis. In addition, mesothelioma is a diffuse neoplasm of the pericardium and other serosal surfaces, and it does not result in appreciable thickening of the pericardium on echocardiography. Cytology of pericardial effusion cannot distinguish between idiopathic pericardial effusion and mesothelioma. Consequendy, mesothelioma should always be considered as an important differential diagnosis for idiopathic pericardial effusion. Idiopathic pericardial effusion has not been reported in cats

Idiopathic pericardial effusion was diagnosed in eight of 42 dogs (19%) with pericardial effusion in a retrospective study from the Veterinary Teaching Hospital, Colorado State University. Idiopathic pericardial effusion was provisionally diagnosed in 24 of 87 dogs with pericardial effusion at the University of Minnesota Veterinary Medical Center from January 1999 to December 2001, but mesothelioma was eventually confirmed in four of these cases. Consequently, 20 of 87 cases (23%) with pericardial effusion in the University of Minnesota Veterinary Medical Center study population were finally diagnosed as having idiopathic pericardial effusion, which is similar to the data from Colorado State University. Average age among the cases with idiopathic pericardial effusion in the University of Minnesota Veterinary Medical Center study population was 94 years (±2.2 years), average weight was 28.9 kg (±14.5 kg), and there was no apparent sex predisposition (11 males:9 females). Five of the 20 dogs (25%) were golden retrievers, and the breed was over-represented (odds ratio, 4.2; 95% confidence interval, 1.6 to 11.2).

The initial treatment for idiopathic pericardial effusion is pericardiocentesis to remove as much pericardial fluid as possible. The author’s preferred approach is to restrain the animal in left lateral recumbency and to approach the pericardium from the right side ().

The gross appearance of pericardial fluid is usually indistinguishable from blood. To confirm that the catheter is in the pericardial space, an aliquot of fluid is placed in an ACT tube. Blood will normally clot in an ACT tube within 60 to 90 seconds. In contrast, sanguineous effusions in body cavities are rapidly depleted of clotting factors and thrombocytes, and pericardial fluid will consequendy not clot. If no clots form within the activated clotting tube after 3 to 5 minutes, all of pericardial fluid is aspirated and samples are collected for fluid analysis and culture. The catheter is then removed.

In virtually all cases with pericardial effusion, pericardiocentesis results in rapid and marked hemodynamic improvement. Clinical signs, pulse quality, and mucous membrane perfusion improve, and heart rate decreases. However, ventricular and supraventricular arrhythmias (including atrial fibrillation) are common after pericardiocentesis. These arrhythmias seldom require therapy and usually resolve spontaneously. The author prefers to hospitalize and monitor cases for 12 to 24 hours after pericardiocentesis.

The author usually treats an initial episode of idiopathic pericardial effusion by pericardiocentesis alone, followed by pericardiectomy in cases that develop recurrent effusions. Recurrent effusions, effusive-constrictive, and constrictive pericarditis are well-recognized complications after pericardiocentesis in cases with idiopathic pericardial effusion. Among the 20 cases diagnosed with idiopathic pericardial effusion in the University of Minnesota Veterinary Medical Center study population, six died or were euthanized after developing recurrent effusions with tamponade within 44 days of their initial episode. Cardiac tamponade with pulmonary thromboembolism was the cause of death in one dog. Postmortem examinations were not performed in the remaining five cases, and the possibility that some dogs might have had cardiac tumors that eluded detection during echocardiography cannot be excluded. Among the remaining 14 dogs, four developed recurrent effusions necessitating pericardiectomy, and a further six developed effusive-constrictive pericarditis between 3 months and 3 years after their initial episode. Median survival time (MST) among the 20 cases was 663 days, indicating a generally good prognosis in cases with idiopathic pericardial effusion. However, the complication rate among these cases was high, and this is consistent with the results of others.

The complication rate among cases with idiopathic pericardial effusion would probably be lower if pericardiectomy was performed at the time of the initial episode rather than after recurrent effusion. Pericardiectomy would avoid the risk of recurrent life-threatening cardiac tamponade and the potential for developing effusive-constrictive and constrictive pericarditis. In addition, surgery permits examination of thoracic and intrapericardial structures to rule out other causes of pericardial effusion, including tumors and foreign bodies. Although pericardiectomy is by no means devoid of morbidity and mortality, it is an extremely successful procedure for idiopathic pericardial effusion. Consequendy, it is likely that pericardiectomy will increasingly form part of the initial treatment for cases with idiopathic pericardial effusion, especially as minimally invasive methods for the procedure become more widespread.

Colchicine, nonsteroidal anti-inflammatories, and corticosteroids are prescribed for humans with recurrent idiopathic pericarditis. Colchicine and nonsteroidal anti-inflammatories are recommended in most cases, and the use of corticosteroids is limited to very severe cases. Colchicine for the treatment of recurrent pericarditis in humans is promising, although data from large controlled prospective studies are lacking. The safety and efficacy of colchicine, nonsteroidal anti-inflammatories, corticosteroids, and any other medical therapies in the management of idiopathic pericardial effusion in small animals have yet to be established.

Mesothelioma

Mesothelioma is emerging as an increasingly important cause of pericardial effusion. Mesothelioma was confirmed in four of 87 dogs (5%) in the University of Minnesota Veterinary Medical Center study population of dogs with pericardial effusion. Average age among the affected cases at time of presentation was 9.5 years (±2.2 years), average weight was 37.5 kg (± 11.1 kg), and males and females were equally represented. No breed predisposition has been reported, and affected breeds in the University of Minnesota Veterinary Medical Center population were Akita, golden retriever, Labrador retriever, and springer spaniel. Mesothelioma causing pericardial effusion has been described in a cat, but pericardial mesothelioma is rare in this species.

The clinical course of pericardial effusion due to mesothelioma in the University of Minnesota Veterinary Medical Center study population followed a characteristic pattern. Presenting and clinical signs were no different from other cause of pericardial effusion. In all four cases, a provisional diagnosis of idiopathic pericardial effusion was made after various diagnostic procedures, including echocardiography and pericardial fluid analysis failed to disclose a cause for the pericardial effusion. Pericardiocentesis was performed, and this was repeated at 77 days (± 46 days) when the dogs developed recurrent effusions with tamponade. Pericardiectomies were then performed in all cases; histopathology of the excised pericardia was consistent with idiopathic pericarditis in three cases, and mesothelioma in one. Severe and unremitting pleural effusions requiring repeated thoracocentesis began at 103 days (±44 days) after pericardiectomy. Intracavitary cisplatin was administered in two dogs, but this did not appear to signifi-candy change the course of the disease. Thoracocentesis was necessary every 2 to 3 weeks until death or euthanasia, and MST from the initial episode of pericardial effusion was 312 days (range, 206 to 352). In all cases, mesothelioma that had spread throughout the thoracic cavity was confirmed on postmortem examination.

The signalment and clinical course among cases with pericardial effusion due to mesothelioma in the University of Minnesota Veterinary Medical Center study population are strikingly similar to those described by others. It is extremely difficult to distinguish between idiopathic pericardial effusion and pericardial effusion due to mesothelioma, even with pericardial histopathology and immunohistochemistry. The clinical course of the disease is suggestive, and accumulation of significant amounts of pleural effusion within 120 days of pericardiectomy increases the index of suspicion for mesothelioma. In addition to being a diagnostic challenge, mesothelioma is difficult to treat. However, long-term survival has been reported in a dog in which a histopathologic diagnosis of pericardial mesothelioma was made after pericardiectomy for recurrent pericardial effusion. Treatment in that case was initiated 48 hours after surgery with intracavitary cisplatin and intravenous doxoru-bicin, and the dog was free of disease 27 months later. Intracavitary cisplatin has successfully resolved pleural effusions in some dogs with pleural mesothelioma.

Cardiac Hemangiosarcoma

In a retrospective study from the Veterinary Teaching Hospital, Colorado State University, cardiac hemangiosarcoma was diagnosed in 14 of 42 dogs (33%) with pericardial effusion. At the UMVMC, cardiac hemangiosarcoma was diagnosed either by echocardiography or echocardiography and histopathology in 53 of 87 dogs (61%) in the study population with pericardial effusion. Cardiac hemangiosarcoma with pericardial effusion was nearly three times more prevalent than the second most common form of pericardial effusion, idiopathic pericardial effusion. Average age among the affected dogs was 9.8 years (± 2.1 years), and their average weight was 32.0 kg (± 12.2 kg). Males slightly outnumbered females (31 males:22 females), but the difference was not statistically significant when compared with the general hospital population. Sixteen of the 57 dogs (28%) were golden retrievers and the breed was over-represented (odds ratio, 5.3; 95% confidence interval, 2.9 to 9.4).

Two features of these data suggest that important changes have occurred in the epidemiology of cardiac hemangiosarcoma. First, the prevalence of cardiac hemangiosarcoma in the University of Minnesota Veterinary Medical Center study population was nearly twice that of the Colorado State University study population. The reasons for this are not clear; however, regional differences in the epidemiology of cardiac hemangiosarcoma may exist, or the prevalence of the disease may have increased over time. Second, the golden retriever was the only over-represented breed among the cases with cardiac hemangiosarcoma in the University of Minnesota Veterinary Medical Center study population. Cardiac hemangiosarcoma has previously been recognized most frequendy in German shepherds. More recendy, cardiac hemangiosarcoma has also been seen commonly in golden retrievers at the Veterinary Hospital, University of Pennsylvania.

Treatment for all forms of hemangiosarcoma is challenging, and a diagnosis of cardiac hemangiosarcoma confers a grave prognosis. By the time of diagnosis, cardiac hemangiosarcoma usually has metastasized and should be considered a systemic disease. At the UMVMC, the majority of owners of dogs with cardiac hemangiosarcoma elect to have their dogs treated by peri-cardiocentesis alone on one or more occasions. Pericardiocentesis is predictably associated with marked clinical improvement, but clinical signs of tamponade typically recur within a few days, often resulting in death or prompting euthanasia. In the University of Minnesota Veterinary Medical Center study population, MST among dogs with cardiac hemangiosarcoma treated by pericardiocentesis alone (n = 30) was just 11 days (range, 0 to 208). Percutaneous balloon peri-cardiotomy has been described in the dog, and the procedure may provide longer periods of palliation in cases with cardiac hemangiosarcoma.

More aggressive approaches to the treatment of cardiac hemangiosarcoma include various combinations of pericardiectomy, tumor resection, splenectomy in cases with splenic metastases, and chemotherapy. Survival data for cases managed in this manner are limited. In a case report of right atrial hemangiosarcoma treated with chemotherapy alone, survival time was 20 weeks. In dogs treated by surgery alone (tumor resection and pericardiectomy or creation of a pericardial window, or pericardiectomy alone), reported survival times range from 2 days to 8 months.. No survival data are available that compare surgery alone, with surgery and chemotherapy for dogs with cardiac hemangiosarcoma. Further, no compelling evidence suggests that survival times in dogs with either splenic or cardiac hemangiosarcoma can be significantly prolonged with adjuvant chemotherapy. Nevertheless, the management of cardiac hemangiosarcoma should always involve consultation with an oncologist to take advantage of continually emerging modalities for the treatment of this highly malignant tumor.

Heart Base Tumors

The majority of heart base tumors in dogs are aortic body tumors. English bulldogs, boxers, and Boston terriers are predisposed, although aortic body tumors also occur in nonbrachycephalic breeds. In various studies, brachycephalic breeds have accounted for between 39% and 85% of dogs with aortic body tumors. Chronic hypoxia induces hyperplasia and neoplasia of chemoreceptors, which may explain the predisposition of brachycephalic breeds to aortic body tumors. Among the predisposed breeds, males may be at increased risk for developing aortic body tumors, but differences in sex predisposition are not statistically significant in all studies.. The age range at time of diagnosis of aortic body tumors is 6 to 15 years with an average of 10 years. Between 5% and 10% of tumors at the heart base are ectopic thyroid tumors. Aortic body tumors are reported in cats, but they are rare in this species.

Most aortic body tumors are benign and locally expansive, although local invasiveness and metastases occur in both dogs and cats. Two studies report metastases mosdy to the lungs and liver in approximately 10% to 12% of dogs with aortic body tumors. In a third study, 58% (14 of 24) of aortic body tumors were benign, 25% (6 of 24) were locally invasive, and 21% (5 of 24) were metastatic. Sites of metastases included the lungs, left atrium, pericardium, and kidneys. The biologic behavior of ectopic thyroid tumors at the heart base is less well described, and both ectopic thyroid adenomas and adenocarcinomas with metastases have been reported.

Heart base tumors were diagnosed either by echocardiography or echocardiography and histopathology in six dogs among the 87 cases (7%) with pericardial effusion in the University of Minnesota Veterinary Medical Center study population. Affected breeds were Great Dane, Labrador retriever, German shorthaired pointer, boxer, English springer spaniel, and Old English sheepdog. Average age was 11.1 years (±2.2 years), and average weight was 31.4 kg (± 13.0 kg). One dog was male and five were female. The number of dogs with heart base tumors in the University of Minnesota Veterinary Medical Center study population is small, but the epidemiologic data are reasonably in accord with those of others, with the exception of sex distribution. The prevalence of heart base tumors is consistent with a recent review of the epidemiology of cardiac tumors in dogs. In that study, aortic body tumors were approximately tenfold less common than cardiac hemangiosarcoma.

Complete surgical resection of heart base tumors is seldom possible because the tumors are highly vascular, located close to major blood vessels, and usually extensive by the time of diagnosis. However, palliation with pericardiectomy either alone or in combination with tumor resection often results in prolonged survival with an excellent quality of life. No evidence indicates that adjuvant chemotherapy improves the prognosis for dogs with heart base tumors. In a recent retrospective study in dogs with aortic body tumors in which surgery was performed, the following factors were evaluated for effect on survival time: sex; breed; presence or absence of respiratory distress; the presence of an arrhythmia other than respiratory sinus arrhythmia; the presence of pleura), pericardia), or peritoneal effusion; evidence of pulmonary metastases; treatment with pericardiectomy; and treatment with chemotherapy. No attempt was made to achieve turnorfree margins in the dogs in that study. Among the various factors evaluated, only treatment with pericardiectomy had a significant effect on survival, and the survival advantage was remarkable. MST among dogs after pericardiectomy was 730 days, whereas those that did not have a pericardiectomy had a MST of only 42 days.

Other Causes of Acquired Pericardia! Effusion

Bacterial, fungal, and viral infections are occasionally associated with pericardial effusions in small animals. Most cases of pericardial effusions due to bacterial infections are thought to arise as a consequence of intrapericardial foreign body penetration, usually by migrating foxtails (Hordeum spp.). Foxtail migration is a common and often serious problem in the western United States. Bacterial pericarditis has also been described in a puppy after a dog bite and in a young adult dog after thoracic trauma. In contrast to most other causes of pericardial effusion, pericardial fluid cytology and culture is crucial in the diagnosis of septic cases. In the largest series of infectious pericardial effusion reported in dogs (five cases), treatment involved pericardiectomy and removal of any foreign bodies, chest drainage, and antibiotic therapy for up to 6 months. All dogs recovered without complications, suggesting that dogs with bacterial pericarditis have a good prognosis when treated aggressively with a combination of surgical and medical therapy.

Systemic coccidioidomycosis in dogs has been associated with pericardial disease. In most cases the fungal infection results in effusive-constrictive or constrictive pericarditis. Coccidioidomycosis should be considered, especially in dogs with pericardial disease that reside in or have a travel history that includes areas where the soil fungus Coccidioides immitis is endemic, such as the Southwestern United States. Treatment involves pericardiectomy, chest drainage, and antifungal therapy (usually beginning with Amphotericin B). Based on limited published information and experience, the prognosis for cases of coccidioidomycosis with pericardial involvement is poor. A case of effusive-constrictive pericarditis due to Aspergillus niger has been reported in a dog.

FIP is one of the more common diseases associated with pericardial effusion in the cat. Pericardial effusions that are occasionally voluminous are present in some cats suffering from this systemic and invariably fatal viral disease.

Left atrial rupture is an uncommon cause of pericardial effusion that occurs in smaller breed dogs with chronic degenerative disease of the mitral valve. Affected cases show clinical signs of acute tamponade, and a loud left apical murmur is usually apparent despite muffling of the heart sounds. Echocardiography discloses intrapericardial fluid, a mass caudal to the left ventricle due to thrombus formation, and substantial mitral regurgitation. Pericardiocentesis is immediately necessary in most cases. Further, the possibility of continued hemorrhage exists, necessitating blood transfusion and emergency thoracotomy to remove larger clots from the pericardial space and to repair the left atrium. The prognosis in such cases is grave.

Cardiac lymphosarcoma and rhabdomyosarcoma with pericardial effusion have been reported in both dogs and cats, but these are rare. Among the various cardiac tumors, cardiac lymphosarcoma is unique because cytology of the pericardial fluid establishes the diagnosis in many cases, and the tumor is amenable to combination chemotherapy.

Pericardial effusions secondary to coagulation disorders rarely result in clinically significant tamponade. However, a case of pericardial effusion and cardiac tamponade secondary to anticoagulant rodenticide toxicity has been reported in a dog. Pericardial effusions secondary to disseminated intravas-cular coagulation, warfarin toxicity, and other coagulopathies have been reported in cats.

Pericardial effusion is frequendy detected in cases with congestive heart failure in small animals, but usually not in sufficient quantity to cause significant hemodynamic compromise. Pericardial effusion secondary to uremia has been recognized in both dogs and cats.

Categories
Drugs

Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.

Pharmacology/Actions

Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.

Pharmacokinetics

Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()

Monitoring

■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)

Categories
Drugs

Acetylcysteine (N-acetylcysteine, Mucomyst, NAC)

Antidote; Mucolytic

Highlights Of Prescribing Information

Used primarily as a treatment for acetaminophen or phenol toxicity & for its mucolytic effect; used anecdotally for treating degenerative myelopathy

Also used as a topical ophthalmic ()

Has caused hypersensitivity & bronchospasm when used in pulmonary tree

Administer via gastric- or duodenal tube for acetaminophen poisoning in animals

What Is Acetylcysteine Used For?

Acetylcysteine is used in veterinary medicine as both a mucolytic agent in the pulmonary tree and as a treatment for acetaminophen or phenol toxicity in small animals. It has been used anecdotally with aminocaproic acid to treat degenerative myelopathy in dogs.

In horses with strangles, acetylcysteine instilled into the gutteral pouch has been used to help break up chondroids and avoid the need for surgical removal. Acetylcysteine enemas have been used in neonatal foals to break up meconium refractory to repeated enemas.

Before you take Acetylcysteine

Contraindications / Precautions / Warnings

Acetylcysteine is contraindicated (for pulmonary indications) in animals hypersensitive to it. There are no contraindications for its use as an antidote.

Because acetylcysteine may cause bronchospasm in some patients when used in the pulmonary system, animals with bronchospastic diseases should be monitored carefully when using this agent.

Adverse Effects

When given orally for acetaminophen toxicity, acetylcysteine can cause GI effects (nausea, vomiting) and rarely, urticaria. Because the taste of the solution is very bad, use of taste masking agents {e.g., colas, juices) have been used. Since oral dosing of these drugs may be very difficult in animals, gastric or duodenal tubes may be necessary.

Rare adverse effects reported when acetylcysteine is administered into the pulmonary tract, include: hypersensitivity, chest tightness, bronchoconstriction, and bronchial or tracheal irritation.

Overdosage / Acute Toxicity

The LD50 of acetylcysteine in dogs is 1 g/kg (PO) and 700 mg/kg (IV). It is believed that acetylcysteine is quite safe (with the exception of the adverse effects listed above) in most overdose situations.

How to use Acetylcysteine

Acetylcysteine dosage for dogs:

For acetaminophen toxicity:

a) A 2-3 hour wait between activated charcoal and PO administration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin, ascorbic acid and SAMe. ()

b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 additional doses ()

c) Loading dose of 140 mg/kg PO, then 70 mg/kg PO every 6 hours for 7 treatments ()

For phenol toxicity:

a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascorbic acid or methylene blue. ()

For respiratory use:

a) 50 mL/hr for 30-60 minutes every 12 hours by nebulization ()

For degenerative myelopathy:

a) 25 mg/kg PO q8h for 2 weeks, then q8h every other day. The 20% solution should be diluted to 5% with chicken broth or suitable diluent. Used in conjunction with aminocaproic acid (500 mg per dog PO q8h indefinitely). Other treatments may include prednisone (0.25-0.5 mg/kg PO daily for 10 days then every other day), Vitamin C (1000 mg PO q12h) and Vitamin E (1000 Int. Units PO q12h). Note: No treatment has been shown to be effective in published trials. ()

Acetylcysteine dosage for cats:

For acetaminophen toxicity:

a) A 2-3 hour wait between activated charcoal and PO administration of acetylcysteine (NAC) is necessary. Give NAC as an initial oral loading dose of 140 mg/kg (dilute to 5% in dextrose or sterile water), followed by 70 mg/kg PO four times daily (q6h) for 7 treatments. With ingestion of massive quantities, some authors suggest using a 280 mg/kg loading dose and continuing treatment for 12-17 doses. May also be given IV after diluting to 5% and given via slow IV over 15-20 minutes. Additional therapy may include IV fluids, blood or Oxyglobin9, ascorbic acid and SAMe. ()

b) 150 mg/kg PO or IV initially, then 50 mg/kg q4h for 17 additional doses ()

For phenol toxicity:

a) 140 mg/kg PO or IV initially, then 50 mg/kg q4h for 3 days. May be partially effective to reduce hepatic and renal injury. Resultant methemoglobinemia should be treated with ascorbic acid or methylene blue. ()

For respiratory use:

a) 50 mL/hr for 30-60 minutes every 12 hours by nebulization ()

For adjunctive treatment of hepatic lipidosis (see also Carnitine):

a) Identify underlying cause of anorexia and provide a protein replete feline diet, give acetylcysteine (NAC) at 140 mg/kg IV over 20 minutes, then 70 mg/kg IV q12h; dilute 10% NAC with saline 1:4 and administer IV using a 0.25 micron filter; correct hypokalemia and hypophosphatemia, beware of electrolyte changes with re-feeding phenomenon ()

Acetylcysteine dosage for horses:

To help break up chondroids in the gutteral pouch:

a) Instill 20% solution ()

In neonatal foals to break up meconium refractory to repeated enemas:

a) 8 grams in 20 g sodium bicarbonate in 200 mL water (pH of 7.6), give as enema as needed to effect ()

b) With foal in lateral recumbency, insert a 30 french foley catheter with a 30 cc bulb for a retention enema. Using gravity flow, infuse slowly 100-200 mL of 4% acetylcysteine solution and retain for 30-45 minutes. IV fluids and pain medication should be considered. Monitor for possible bladder distention. ()

Monitoring

When used for acetaminophen poisoning:

■ Hepatic enzymes (particularly in dogs)

■ Acetaminophen level, if available (particularly in dogs)

■ Hemogram, with methemoglobin value (particularly in cats)

■ Serum electrolytes, hydration status

Client Information

■ This agent should be used in a clinically supervised setting only

Chemistry / Synonyms

The N-acetyl derivative of L-cysteine, acetylcysteine occurs as a white, crystalline powder with a slight acetic odor. It is freely soluble in water or alcohol.

Acetylcysteine may also be known as: N-acetylcysteine or N-acetyl-L-cysteine, NAC, 5052 acetylcysteinum, NSC-111180, Acetadote, Mucomyst or ACC.

Storage / Stability/Compatibility

When unopened, vials of sodium acetylcysteine should be stored at room temperature (15-30°C). After opening, vials should be kept refrigerated and used within 96 hours. The product labeled for IV use states to use within 24 hours.

Acetylcysteine is incompatible with oxidizing agents; solutions can become discolored and liberate hydrogen sulfide when exposed to rubber, copper, iron, and during autoclaving. It does not react to aluminum, stainless steel, glass or plastic. If the solution becomes light purple in color, potency is not appreciably affected, but it is best to use non-reactive materials when giving the drug via nebulization. Acetylcysteine solutions are incompatible with amphotericin B, ampicillin sodium, erythromycin lactobionate, tetracycline, oxytetracycline, iodized oil, hydrogen peroxide and trypsin.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Acetylcysteine injection: 20% (200 mg/mL), (0.5 mg/mL EDTA in 30 mL single-dose vials, preservative free; Acetadote (Cumberland); (Rx)

Acetylcysteine Solution: 10% & 20% (as sodium) in 4 mL, 10 mL, 30 mL & 100 mL (20% only) vials; Mucomyst (Apothecon); (Rx) Note: If using this product for dilution and then intravenous dosing, it is preferable to use a 0.2 micron in-line filter.

Categories
Diseases

Fungi

Histoplasma capsulatum

Cause of Fungi

Histoplasmosis is a systemic fungal disease of dogs and cats caused by Histoplasma capsulatum. In the environment, H. histoplasma organisms are mycelial, saprophytic soil fungi. In infected tissue or when cultured at 30 to 37° C, the organism is a yeast. The fungus is endemic throughout most of the temperate and subtropic regions of the world. Most cases of histoplasmosis in the United States occur in the central states, with the geographic distribution following the Mississippi, Ohio, and Missouri Rivers.

Fungi: Pathophysiology

Infection is probably via inhalation or ingestion of infective conidia from the environment. The respiratory system is thought to be the primary route of infection in cats and dogs, although the gastrointestinal tract may also be an important route in the dog. After inhalation or ingestion, conidia transform from the mycelial phase and are phagocytized by macrophages, where they grow as facultative intracellular organisms. Hematogenous and lymphatic dissemination results in multisystemic disease. Organisms can be disseminated to any organ system, but the lungs, gastrointestinal tract, lymph nodes, liver, spleen, bone marrow, eyes, and adrenal glands are the most common organs of dissemination in the dogs; lungs, liver, lymph nodes, eyes, and bone marrow are most commonly affected in cats. Cell-mediated immunity induces a granulomatous inflammatory response in most infections.

Clinical examination

Dogs with gastrointestinal histoplasmosis typically have mild fever, anorexia, lethargy, weight loss, vomiting, diarrhea, hematochezia, and tenesmus. Cachexia is a common physical examination finding. Other historical and physical examination findings (dyspnea, cough, ascites, lameness, oropharyngeal ulcerations, chorioretinitis, neuropathy) will depend upon organ and tissue involvement. The full clinical spectrum of histoplasmosis infection is outlined in site.

Diagnosis of Fungi

Endoscopic examination usually reveals severe granulomatous inflammation of the large intestine. Organism identification is required for definitive diagnosis. The most common means of organism identification is cytology. Cytology from affected tissue reveals pyogranulomatous inflammation, often with numerous small, round to oval intracellular yeast cells (2 to 4 μm in diameter) characterized by a basophilic center and a light halo. Exfoliative cytology during colonoscopy is particularly useful in diagnosing the disease. Histopathology is helpful if cytology is nondiagnostic or inconclusive. Multiple endoscopic colonic biopsies are usually sufficient to diagnose the disease. The yeast form does not stain well with routine hematoxylineosin (H&E) stains, so special stains such as PAS and Gomori’s methenamine silver stain are often used to demonstrate organisms. Fungal culture from affected tissue can be used for diagnosis but is rarely needed in clinical cases. Currently available serologies have poor specificity and sensitivity.

Treatment of Fungi

Itraconazole (5 mg / kg orally, twice a day for 2 to 4 months) is considered the treatment of choice for feline histoplasmosis. In one study, itraconazole therapy cured histo-plasmosis infections in all eight study cats. Ketoconazole and amphotericin B have been described as the treatments of choice for canine histoplasmosis. With colonic involvement, additional gastrointestinal therapy may be useful in affected dogs (e. g., dietary modification, treatment for small intestinal bacterial overgrowth, direct antidiarrheal therapy). Corticosteroids may-have been used successfully in the treatment of airway obstruction secondary to hilar lymphadenopathy in chronically infected dogs.

Prognosis of Fungi

There may be important species differences in prognosis, although the paucity of reports, especially of prospective clinical trials, makes it difficult to generalize. It would seem that the prognosis is guarded in dogs but fair to good in cats.

Categories
Diseases

Oomycetes

Pythium insidiosum

Oomycetes: Cause

Pythium insidiosum is an aquatic oomycete that causes severe gastrointestinal pathology in a range of hosts in the tropic and subtropic climates. Based on ribosomal RNA gene sequence data, members of the Class Oomycetes are phylogenetically distinct from the Kingdom Fungi and are more closely related to algae than to fungi. The Oomycetes differ from fungi in two important properties (i. e., cell wall and cell membrane composition). Chitin is an essential component of the fungal cell wall, but it is generally lacking in the oomycete cell wall. Oomycetes also differ from fungi in that ergosterol is not a principal sterol in the oomycete cell membrane. This difference may explain why ergosterol-targeting drugs like itraconazole are less effective in the medical treatment of pythiosis.

Pathophysiology

The infective state of Pythium insidiosum is thought to be the motile zoospore, which is released into stagnant water in warm environments and likely causes infection either by encysting in the skin or by being ingested into the gastrointestinal tract. Ingested zoospores encyst and adhere to the gastric, jejunal, and colonic epithelium with a polarity oriented toward the submucosa for rapid tissue penetration after germ tube eruption. Pythium induces a chronic pyogranulomatous response in the gastrointestinal tract and mesenteric lymph nodes. The gastric outflow tract and ileocolonic junction are the most frequendy affected portions of the gastrointestinal tract, and it is not uncommon to find two or more segmental lesions in the same patient. Inflammation in affected regions is typically centered on the submucosa, with variable mucosal ulceration and occasional extension of disease through serosal surfaces, resulting in adhesion formation and peritonitis.

Clinical examination

Weight loss, vomiting, diarrhea, and hematochezia are the most important clinical signs. Physical examination often reveals emaciated body condition and a palpable abdominal mass. Signs of systemic illness such as lethargy and depression are not typically present unless intestinal obstruction, infarction, or perforation occurs.

Oomycetes: Diagnosis

Ileocolonic wall thickening, obliteration of the normal layered appearance, and regional lymphadenopathy are common ultrasonographic features of canine intestinal pythiosis. Of course, these findings cannot be readily differentiated from those associated with intestinal malignancy. Definitive diagnosis requires histologic demonstration or immunohistochemical staining of the organism, positive enzyme-linked immunosorbent assay or polymerase chain reaction assays, or a combination of these techniques. The histologic findings associated with pythiosis generally are characterized by eosinophilic granulomatous to pyogranulomatous inflammation with fibrosis. Affected tissue typically contains multiple foci of necrosis surrounded and infiltrated by neutrophils, eosinophils, and macrophages. Discrete granulomas composed of epithelioid macrophages, plasma cells, multinucleate giant cells, and neutrophils and eosinophils may also be observed. Pythium zoospores may be cultured directly from affected tissue in antibiotic-containing (e. g., streptomycin, ampicillin) media. More recently, sensitive and specific enzyme-linked immunosorbent assay and polymerase chain reaction assays have been developed for the accurate diagnosis of pythiosis in dogs.

Oomycetes: Treatment

Aggressive surgical resection remains the treatment of choice for pythiosis in dogs. Because it provides the best opportunity for long-term cure, complete resection of infected tissue should be pursued whenever possible. Segmental lesions of the gastrointestinal tract should be resected with 3 to 4 cm margins whenever possible. Medical therapy for the oomycetes has not been very promising. This may relate to the absence of ergosterol (cell membrane target of most currently available antifungal drugs) in the oomycete cell membrane. Clinical and serologic cures have been obtained in a small number of dogs after therapy with amphotericin B lipid complex (2 to 3 mg / kg every other day, administered to a cumulative dose of 24 to 27 mg / kg) or itraconazole (5 mg / kg every 12 hours for 6 to 9 months).

Oomycetes; Prognosis

Unfortunately, most dogs with gastrointestinal pythiosis are not presented to the veterinarian until late in the course of the disease, when complete excision is not possible. The anatomic site of the lesion (e. g., pylorus, ileocolic sphincter) may also prevent complete excision. Consequently, the prognosis is usually grave in most animals.

Categories
Diseases

Algae

Prototheca zopfii and Prototheca wickerhatnii

Algae: Cause

Three species have been recognized within the genus Prototheca: P. stagnosa, P. wickerhatnii, and P. zopfii; a fourth species, P. salmonis, has been proposed. Of these three species, P. wickerhatnii and P. zopfii have demonstrated pathogenicity. Prototheca spp. are ubiquitous in nature and are found in sewage systems, soil, lakes, rivers, ponds, and in feces. The organism has been documented to cause disease in dogs and cats and a variety of other species. P. wickerhamii is the causative organism in virtually all instances of cutaneous protothecosis, and P. zopfii is the causative organism in most instances of disseminated disease.

Algae: Pathophysiology

Cutaneous infection with granuloma formation is the most common manifestation of protothecosis in most species, including cats and humans. Dissemination does not readily occur in cats or humans, but the infection readily disseminates to distant sites in dogs.

Clinical examination

Of the 26 canine cases reported in the veterinary literature, 20 either had ocular signs on presentation or developed them later. Sixteen cases had gastrointestinal signs, usually colitis-type diarrhea, vomiting, and weight loss. Six cases had neurologic signs in the form of paresis, head tilt, cervical pain, circling, and ataxia. P. zopfii accounts for most of the cases of canine disseminated protothecosis.

Diagnosis of Algae

Contrast radiography or abdominal ultra-sonography may reveal diffuse colonic wall thickening or obstruction, but these are nonspecific findings. Fecal parasitologic examination is generally of little use in demonstrating the organism, but exfoliative cytology, histology, or both readily identifies the organism. Aqueous or vitreous centesis can also be performed in dogs with ocular pathology and is generally useful in documenting organisms in the ocular fluid.

Treatment of Algae

The management of systemic protothecosis has been challenging in all animal species. Amphotericin B and itraconazole (5 mg / kg orally, twice a day for 1 month and then 5 mg / kg orally, once a day thereafter) have been used in several patients. Short-term improvement was reported in orjly two dogs.

Prognosis

Like pythiosis, the prognosis for protothecosis is grave. The course of the disease is so insidious that, by the time a definitive diagnosis has been reached, the organism has often disseminated throughout the body.

Categories
Veterinary Drugs

Anti-infective eye preparations

Care should be taken to distinguish superficial ocular disease caused by infections from other conditions that may result in a red or inflamed eye. Where possible the causative organism should be identified and any initial choice of a broad-spectrum antibacterial, or combination of antibacterials, modified according to bacterial sensitivity data. The severity of an infection may determine the choice of drug and frequency of application. When dispensing antibacterials, it is considered preferable to choose topical preparations of drugs that are not usually used to treat systemic infections. Primary bacterial conjunctivitis is usually acute and corticosteroids are unnecessary. The normal conjunctival flora of the dog consists of a number of species whereas the cat conjunctiva harbours relatively few micro-organisms. Hence, with the exception of conjunctivitis due to Chlamydophila (Chlamydia) infection, primary bacterial conjunctivitis is rare in cats; viral infections are the more frequent cause of conjunctivitis seen in this species. Where only one eye is involved but, for prophylactic reasons, the other eye is also being treated, medication should be applied first to the unaffected eye to minimise the possibility of cross-infection.

Antibacterial preparations

Antifungal preparations

Ocular fungal infections may be superficial, for example mycotic keratitis, or intra-ocular such as mycotic endophthalmitis; both conditions are rare in the UK. Intra-ocular manifestations of systemic mycotic infections in dogs and cats, such as blastomycosis, cryptococcosis, geotrichosis, and histoplasmosis, usually present as a focal granulomatous posterior uveitis, often involving the retina and other tissues of the eye.

Specialist antifungal preparations are available from Moor-fields Eye Hospital, after identification of specific fungi by appropriate laboratory procedures.

Most topical antifungal drugs have poor corneal penetration and systemic antifungals such as ketoconazole and amphotericin B are used for treatment.

Antiviral preparations

Feline herpesvirus (FHV) is a common cause of acute conjunctivitis and chronic keratitis and is also a potential respiratory pathogen. Trifluridine has been shown to be efficacious against feline herpesvirus-1 in vitro and appears to be clinically useful. Aciclovir has very limited in vitro effect thus its clinical use is limited in cats. Ganciclovir has been shown to be effective in human herpes simplex keratitis but its use in cats remains to be investigated. Oral lysine has been shown in vitro to inhibit virus replication and uncontrolled studies in both humans and cats seem to show a beneficial effect. Clinical trials in cats are currently in progress to test the efficacy of this amino acid in FHV-1 infections.

Some forms of equine superficial punctate keratitis may be due to equine herpesvirus infection; aciclovir may be effective in these cases.

ACICLOVIR

(Acyclovir)

Indications. See notes above

Dose: Horses, cats: eye ointment, apply 5-6 times daily

Prescription-only medicine:® Zovirax (GSK) UK Eye ointment, aciclovir 3%

GANCICLOVIR

Indications. See notes above

Side-effects. Local irritation, conjunctival hyperaemia

Dose:

Cats: apply 1 drop 4-6 times daily. Maximum period of treatment 21 days

Prescription-only medicine:® Virgan (Chauvin) UK

Eye drops, ganciclovir 0.15% in gel basis

LYSINE

(L-Lysine)

Indications. Feline herpesvirus infection, see notes above

Warnings. Formulations containing propylene glycol are toxic to cats and must not be used

Dose:

Cats: by mouth, 250 mg daily. May be given during clinical episode of FHV 1 infection and also long-term in carrier cats. Higher doses of 500 mg have also been used

Preparations containing lysine are available from health food shops

TRIFLURIDINE

(Trifluorothymidine)

Indications. See notes above

Dose:

Cats: eye drops, apply 4-6 times daily for 3-4 days until clinical improvement, then apply 3 times daily

Prescription-only medicine: ® Trifluridine Eye Drops 1%

Eye drops containing trifluridine are not generally available. Contact the local pharmacist or Moorfields Eye Hospital to obtain a supply in the UK