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
Diseases

Diseases Of The Middle And Inner Ear

Normal Anatomy and Physiology

The middle ear consists of the tympanic membrane, three cavities (epitympanic, tympanic, and ventral), and the bony ossicles (malleus, incus, and stapes). The tympanic membrane has two parts: (1) the thin pars tensa that attaches to the manubrium of the malleus and (2), above the pars tensa, the thicker, pars flaccida. The main portion of the middle ear, the ventral tympanic bulla, has two compartments in the cat (ventromedial and dorsolateral). The air-filled bulla is lined with modified respiratory epithelium, which is either squamous or cuboidal and may be ciliated. The four openings in the middle ear are the (1) tympanic opening, (2) the vestibu-lar window, (3) the cochlear window, and (4) the ostium of the auditory tube. The auditory tube is the communication between the middle ear and caudal nasopharynx. The normal flora of the middle ear may be due to this pharyngeal communication, but the role of the auditory tube as a source of bacteria in otitis media is unknown. The tympanic opening is a common source of bacterial infection of the middle ear in dogs with otitis extema. The cochlear and vestibular windows are possible ports of entry for progression of otitis media or ototoxic substances into the inner ear.

Cranial nerve VII, or the facial nerve, the sympathetic innervation of the eye, and the parasympathetic innervation of the lacrimal gland are closely associated with the middle ear. The separation of the facial nerve from the middle ear is minimal along the rostral aspect of its course through the petrosal bone. The nerve supplies motor fibers to the superficial muscles of the head, the muscles of the external ear, the caudal belly of the digastricus, and the ossicular muscles. The nerve also supplies sensation of the vertical ear canal and concave surface of the pinna.

Postganglionic sympathetic nerve fibers course closely with those of the facial nerve to innervate the smooth muscles of the eye. Preganglionic parasympathetic fibers also pass through the middle ear to innervate the salivary and lacrimal glands.

The inner ear is located within the petrosal bone. The cochlea, vestibule (saccule and utricle), and semicircular canals form the membranous labyrinth, which is encased in bone, called the bony labyrinth. The vestibular system functions to maintain the position of the eyes, trunk, and limbs relative to the position of the head, responding to linear and rotational acceleration and tilting. The system consists of the saccule, utriculus, and semicircular canals and communicates with the middle ear via the vestibular window. Fluid within the semicircular canals tends to remain stationary during motion, bending the cilia of the cells in the utricle and saccule, causing depolarization. These stereocilia synapse with the dendrites of the vestibular portion of the eighth cranial nerve and the signal is conducted via cranial nerve VIII to vestibular nuclei in the myelencephalon, the spinal cord, centers in the cerebellum and cerebral cortex, and motor nuclei of cranial nerves III, IV, and VI. The result is coordination of the body, head, and eye movement. Projections to the vomiting centers are responsible for nausea and vomiting associated with vestibular disorders and motion. The cochlear system, involved with the translation of sound, consists of the spiral organ, or organ of Corti, cochlear duct, scala vestibule, and scala tympani. Transmission of sound through the tympanic membrane, ossicles, and cochlear window results in undulation of the basilar membrane of the spiral organ. Cilia bend and cause depolarization and transmission of a signal to cochlear nuclei, caudal colliculi, and cerebral cortex. The cochlear nuclei control reflex regulation of sound via projections to cranial nerves V and VII, which control the muscles of the ossicles. Other projections allow for conscious perception of sound.

Otitis Media

Neoplasia of the Middle Ear

Neoplasia of the middle ear is rare; most cases represent extension of tumors originating in the external ear canal.

Inflammatory Polyps

Inflammatory polyps are a non-neoplastic admixture of inflammatory and epithelial cells originating in the tympanic bulla in cats. Other sites of origin include the auditory tube and nasopharynx. Macrophages, neutrophils, lymphocytes, plasma cells, and epithelial cells are usually present on histopathologic examination. The cause is unknown, but ascending infection and congenital causes have been suggested. No age or sex predilection exists for the condition, but younger cats are more commonly affected (1 to 5 years of age). Signs can be unilateral or bilateral and depend on the location of the mass lesion. A single polyp can grow into the external ear canal, down the auditory tube into the nasopharynx, or both. Signs of concurrent otitis extema and media are common with polyps limited to the ear, but respiratory stridor, dyspnea, gagging, and dysphagia occur with growth into the pharynx.

Diagnosis is based on otoscopic and pharyngeal examinations. Radiographs of the bulla, nasal cavity, and pharynx may be considered, and CT or MRI can be used to diagnose the site and side of origin of inflammatory polyps/ Treatment consists of excision by traction or surgical excision via ventral bulla osteotomy. Regrowth is a problem in half of the cats treated by traction extraction alone, and Homer’s syndrome is common in cats after ventral bulla osteotomy.

Otitis Interna

Otitis interna is usually an extension of otitis media or neoplasia of the middle ear. A careful neurologic examination is imperative to the localization of vestibular signs. Clinical signs associated with otitis interna include head tilt, ataxia, horizontal or rotary nystagmus, circling or falling toward the side of the lesion, or ipsilateral nystagmus. The fast phase of nystagmus is usually away from the side of the lesion. Occasionally, animals will become nauseated or vomit. Homer’s syndrome or deficits in cranial nerve VII may accompany otitis media interna, but involvement of other cranial nerves, vertical or changing nystagmus, or the presence of conscious proprioceptive deficits or paresis indicate central rather than peripheral vestibular disease. Bilateral peripheral vestibular disease is rare, but the animal will not have a head tilt, nystagmus, or strabismus and may exhibit wide head excursions and a crouched stance or the inability to stand.

The diagnosis of otitis interna is based on history, clinical signs, and physical, neurological, and otoscopic examinations. Advanced imaging may be helpful in distinguishing the anatomic location of the disease process. Treatment with aggressive medical or surgical intervention appropriate to the localization is important in prevention of adjacent brain stem involvement.

Prognosis for Otitis Media and Interna

A fair prognosis can be given if aggressive surgical and medical therapy are possible. Cases with concurrent severe external ear canal changes require total ear canal ablation and lateral bulla osteotomy. Repeated infections after ventral bulla osteotomy or total ear canal ablation and lateral bulla osteotomy may be operated again with resolution of the condition. Resistant organisms, failure to respond to aggressive surgery, and significant osteomyelitis are associated with a poor prognosis. The neurologic signs associated with otitis media and interna may be permanent, but many animals learn to use visual cues and can compensate for vestibular deficits. Facial nerve deficits, Horner’s syndrome, and keratoconjunctivitis sicca are often permanent.

Ototoxicity

Ototoxic substances (Table Ototoxic Drugs) damage the cochlear or vestibular systems or both. Otic application of medication can also cause adverse effects through local inflammation of the tympanic membrane or the meatal window (or both), as well as resultant otitis media. Topical medications also cause adverse effects by systemic absorption. Ototoxic substances reach the inner ear after local application and absorption through the cochlear or vestibular windows or hematogenously. The most frequent cause of ototoxicity is the application of an ototoxic substance to the external ear canal in a pet with a ruptured tympanum, which results in distribution to the middle ear. Absorption by the inner ear is increased when inflammation of the cochlear window occurs with otitis media. Hematogenous distribution of otoioxins to the inner ear is inherent in some medications (e.g. aminoglycosides).

Ototoxic Drugs

Aminoglycoside Antibiotics Antiseptics
Neomycin Chlorhexidine
Dihydrostreptomycin Iodine & iodophores
Gentamicin Ethanol
Streptomycin Benzalkonium chloride
Kanamycin Benzethonium chloride
Tobramycin Cantrimide
Amikacin Antineoplastic Agents
Other Antibiotics Cisplatin
Polymixin B & E Nitrogen mustard
Minocycline Miscellaneous
Erythromycin Quinine
Chloramphenicol Solicylates
Vancomycin Propylene glycol
Loop Diuretics Detergents
Furosemide Arsenic
Bumetanide Lead
Ethacrynic acid Mercury

The development of ototoxicity also depends on the vehicle of the preparation, chemical composition, drug concentration, concurrent medications, as well as the route, frequency, and duration of administration. Examples of increased risk of ototoxicity depending on the vehicle (e.g. combination of chlorhexidine and detergents) and concurrent medications (e.g. loop diuretics and aminoglycosides) have been described. Minimization of the risk of toxicity should be considered when any potentially toxic substance is administered either topically or systemically. The integrity of the tympanic membrane should be known prior to topical administration of any potentially ototoxic drug, and consequences of each drug should be considered in light of the animal’s health and concurrent therapies.

Idiopathic Vestibular and Facial Nerve Diseases

A complete neurologic examination is key to differentiating peripheral from central vestibular disorders. Head tilt, ataxia, horizontal or rotary nystagmus, and cranial nerve VII deficits may be seen with either condition. Central vestibular disease causes paraparesis, conscious proprioceptive deficits, other cranial nerve abnormalities, and vertical or changing nystagmus. Middle ear neoplasia, otitis media interna, idiopathic vestibular syndrome, and congenital vestibular disorders result in peripheral vestibular signs. Congenital vestibular disorders have been described in the German shepherd, Doberman pinscher, English cocker spaniel, Siamese, and Burmese breeds. Bilateral congenital vestibular syndrome has been described in beagles and Akitas. Clinical signs of head tilt and ataxia in these dogs and cats may be persistent or may improve; animals can be congenitally deaf.

Otitis media interna may be associated with facial paresis or paralysis if cranial nerve VII is affected by the inflammation. Otitis should be ruled out before diagnosing any animal with idiopathic facial nerve paralysis, because otitis requires aggressive management and the idiopathic condition can only be treated symptomatically or with acupuncture.

Deafness

Acquired Late-Onset Conductive Deafness

Conductive deafness is due to lack of transmission of sound through the tympanic membrane and ossicles to the inner ear. Conditions that block sound transmission through the external ear canal, tympanic membrane, or middle ear and ossicles, such as otitis externa, otitis media, and otic neoplasia, cause conductive deafness. Less common causes of conductive deafness include trauma-induced fluid accumulation in the middle ear, atresia of the tympanum or ossicles, fused ossicles, or incomplete development of the external ear canal, which results in fluid accumulation in the middle ear. An increase in hearing threshold, absence of air-conducted hearing, and the presence of bone-conducted hearing on BAER suggest conductive deafness. The application of a bone-anchored hearing aid was described in one dog with conductive deafness after total ear canal ablation. It maintained bone-conducted hearing and tolerated the hearing aid anchored to the parietal bone Use of a bone-anchored device was required, because the dog did not have an external ear canal in which to place an earpiece. The hearing aid acted as an amplifier, and the dog seemed to respond to its use.

Acquired Late-Onset Sensorineural Deafness

Presbycusis, or decline in hearing associated with aging, may be due to one of the following: loss of hair cells and degeneration in the organ of Corti, degeneration of spiral ganglion cells or neural fibers of the cochlear nerve, atrophy of the stria vascularis, or changes in the basilar membrane. Because this condition occurs in older dogs and cats from 8 to 17 years of age, animals should be evaluated for concurrent causes of conductive deafness such as chronic otitis extema or media and otic neoplasia. BAER testing may demonstrate normal waveforms in response to high-intensity sound. If conduction is intact at an increased hearing threshold, use of an amplifying hearing aid may be beneficial. Pets may not tolerate occlusive types of ear pieces often used in hearing aids, and training to the ear piece should be done prior to application of the hearing aid.

Ototoxic substances, chronic exposure to loud noise, hypothyroidism, trauma, and bony neoplasia can also cause acquired late-onset deafness in dogs and cats. Ototoxicity can result in abolition of waveforms or an increase in hearing threshold on BAER. BAER testing can be used to re-evaluate patients for return of function after withdrawal of medication after exposure to ototoxic medication.

Congenital Sensorineural Deafness

Inherited sensorineural deafness usually results in complete loss of hearing in the affected ear by 5 weeks of age. Many breeds can be affected with the condition (Box Canine Breeds Associated with Inherited Deafness). The condition has been linked to coat color in many breeds of dogs and white cats. The condition is common in white cats, and mode of inheritance is thought to be autosomal dominant with incomplete penetrance.The condition is most common in white cats with blue irides. The correlation of white coat, blue eyes, and deafness is not perfect, but cats with two blue irides have a greater risk of deafness than cats with one blue iris, which have a greater risk of deafness than cats without blue irides. Total hearing loss occurs more often in longhaired white cats. The condition is common in certain breeds of dogs, such as dalmatians, which have a nearly 30% incidence of deafness (combining unilateral and bilateral deafness).

Canine Breeds Associated with Inherited Deafness

Akita Ibizan hound
American-Canadian shepherd Italian greyhound
American cocker spaniel Jack Russell terrier
American Eskimo Kuvasz
American Staffordshire terrier Labrador retriever
Australian cattle dog Maltese
Australian shepherd Miniature pincer
Beagle Miniature poodle mongrel
Bichon frise Norwegian dunkerhound
Border collie Nova Scotia duck tolling retriever
Borzoi Old English sheepdog
Boston terrier Papillion
Boxer Pit bull terrier
Bulldog Pointer
Bull terrier Poodle (toy & miniature)
Catahoula leopard dog Puli
Chihuahua Rhodesian ridgeback
Chow chow Rottweiler
Collie Saint Bernard
Dachshund Schnauzer
Dalmatian Scottish terrier
Doberman pincer Sealyham terrier
Dogo Argentino Shetland sheepdog
English cocker spaniel Shropshire terrier
English setter Soft-coated Wheaton terrier
Foxhound Springer spaniel
Fox terrier Sussex spaniel
French bulldog Tibetan spaniel
German shepherd Tibetan terrier
Great Dane Walker American foxhound
Great Pyrenees West Highland white terrier
Greyhound Yorkshire terrier

The trait is associated with the dominant merle or dapple gene in collies, Shetland sheepdogs, Great Danes, and dachshunds. The incidence of deafness tends to increase with increasing amount of white in the coat, and dogs homozygous for the merle gene are usually deaf and may be solid white, blind, or sterile, The piebald or extreme piebald gene is associated with deafness in dalmatians, bull terriers, Great Pyrenees, Sealyham terriers, greyhounds, bulldogs, and beagles. Inheritance is thought to be autosomal recessive, but the trait may be polygenic.

Heterochromia irides and lack of retinal pigment are associated with white color in dogs and cats. Hearing loss may be associated with absence of pigment in the cochlear stria vascularis. Diminished blood supply and disorders of endolymph production, with changes in the chemical or mechanical properties of endolymph, lead to degeneration of the organ of Corti secondary to stria vascularis atrophy. Loss of hair cells and abnormalities of the cochlear duct, Reissner membrane, tectorial membrane, and internal spiral suicus are typical of cochleosaccular type of end-organ degeneration seen in these cases.,

Clinical signs of deafness may be recognized in puppies as young as 3 weeks of age by astute owners; definitive diagnosis of uni- or bilateral deafness is usually made by BAER testing at 5 to 6 weeks of age when the auditory system is completely developed and cochlear degeneration, if present, is complete.

Congenital Acquired Sensorineural Deafness Exposure to bacteria, ototoxic drugs, low oxygen tension, and trauma in utero or during the perinatal period rarely causes deafness in young animals.

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
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

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.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

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
Diseases

Infective Endocarditis

Infective endocarditis (IE) is a life-threatening disorder that results from microorganisms that colonize the cardiac endocardium, which commonly causes destruction of valves or other structures within the heart. Bacteremia is by far the most common etiology, with the mitral and aortic valve most frequently affected. Vegetation may cause thromboembolism or metastatic infections, which involve multiple body organs and produce a large variety of clinical signs which makes diagnosis difficult. The incidence of infective endocarditis in necropsied dogs has been reported to range from 0.06% to 6.6%. Evaluation of clinical data from university animal hospitals points to infective endocarditis as a comparably rare condition with incidences ranging from 0.04% to 0.13%. Medium to large breed, mainly purebred, middle-aged male dogs are reported to be predisposed. The incidence in cats, based on clinical experience, is considered to be 7 to 10 times lower than in dogs. Animals with congenital heart disease have a low incidence of infective endocarditis”, but associations have been reported with subaortic stenosis and occasionally with PDA. infective endocarditis has not been found to have any association with chronic mitral valve insufficiency in dogs.

Infective Endocarditis: Pathology

Vegetation associated with by infective endocarditis mainly affects the left heart with the highest incidence involving the mitral valve. Involvement of the right heart or mural endocardium is uncommon. Pathologic findings vary and depend on the virulence of the infecting organism, the duration of infection, and the immunologic response. Intracardiac vegetation consists of different layers of fibrin, platelets, bacteria, red and white cells, and is often covered by an intact endothelium. Bacteria may continue to grow despite antibiotic therapy owing to the location deep within the vegetation and a slow metabolic rate. Necrosis and destruction of the valve stroma or chordae tendineae proceed rapidly in peracute or acute infective endocarditis, which causes valvular insufficiency and cardiac failure.

Infective Endocarditis: Etiology and Pathogenesis

Transient or persistent bacteremia is a prerequisite for the development of infective endocarditis. A large number of bacteria have been associated with bacteremia (see section on Blood Culture below) and some are known to cause infective endocarditis. Most bacteria require predisposing factors to cause infective endocarditis, such as depression of the immunosystem or endothelial damage, sometimes with depositions of platelet-fibrin complexes, to adhere to the valve and create infective endocarditis. The origin of the bacteremia may be active infection localized somewhere within the body. A proportion of cases with infective endocarditis has no clinically detectable source of infection. Possible routes for bacteria to reach and infect the endocardium are by direct contact with the surface endothelium via the bloodstream or from capillaries within the valve (vasculitis).

The consequences of infective endocarditis depend on several factors: virulence of the infective agent; site of infection; degree of valvular destruction; influence of vegetation on valvular function; production of exo- or endotoxins; interaction with the immunosystem with the formation of immunocomplexes; and development of thromboembolism and metastatic infections. Gram-negative bacteremia results often in a peracute or acute clinical manifestation, whereas gram-positive bacteremia typically results in a subacute or chronic condition. The vegetation may cause valvular insufficiency or obstruction. The destruction of valvular tissue is caused by the action of bacteria or the cellular response from the immunologic system. Deposition of immunocomplexes in different organs may cause glomerulonephritis, myositis, or polyarthritis. Septic embolization that produces clinical signs is uncommon but 84% of affected dogs had evidence of systemic embolization at necropsy and glomerulonephritis was reported in 16% of 44 dogs with infective endocarditis.

Infective Endocarditis: Case History and Clinical Signs

The diagnosis of infective endocarditis can easily be overlooked because the case history and clinical signs are not specific and there may be an absence of predisposing factors to raise the suspicion of infective endocarditis. Clinical signs are variable and occur in different combinations. Commonly reported signs include lethargy, weakness, fever (sometimes recurrent), anorexia, weight loss, GI disturbances, and lameness. Stiffness and pain originating from joints or muscles may be caused by immunomediated responses and abdominal pain may be caused by secondary renal or splenic infarction, septic embolization, or abscess formation. If the condition leads to severe valvular damage, especially of the aortic valve, signs of cardiac failure and syncope from arrhythmias may occur. Predisposing factors that in combination with the clinical signs above, should raise the suspicion of infective endocarditis are immunosuppressive drug therapy, such as cortico-steroids; aortic stenosis; recent surgery, especially in conjunction with trauma to mucosal surfaces in the oral or genital tract and infections in these body regions, especially prostatitis; indwelling catheters, infected wounds, abscesses, or pyoderma.

Physical Examination

Most clinical signs lack specificity for infective endocarditis. However, fever, heart murmur (particularly if newly developed), and lameness are considered classical signs. Fever is reported to occur in 80% to 90% in dogs with infective endocarditis. Absence of fever is reported to be more common in cases with aortic valve involvement but may also be attributed to treatment with antibiotics or corticosteroids.

Since aortic insufficiency is otherwise uncommon in dogs, the finding of a diastolic murmur and bounding peripheral pulse should raise the suspicion of infective endocarditis of the aortic valve. Systolic murmurs may be caused by destruction of the mitral valve, which results in mitral regurgitation or vegetations that obstruct the aortic outflow tract, which leads to stenosis. These murmurs are, in contrast to diastolic murmurs, poor indicators of infective endocarditis since they frequendy occur in dogs with other conditions, such as chronic mitral valve insufficiency and aortic stenosis. It should be noted that 26% of dogs with infective endocarditis are reported to lack audible murmurs. Lameness is also an inconsistent finding in infective endocarditis with an incidence of 34% in one study. A range of other physical findings may be present, depending on which organs are affected by circulating immunocomplexes or septic embolization. Possible findings are pain reactions from muscles or abdomen (spleen, intestines, or kidneys), cold extremities, cyanosis, and skin necrosis from severe embolization and a variety of neurologic disturbances if the central nervous system is affected.

Blood Culture

Positive blood cultures are crucial evidence of infective endocarditis. The theory that bacteremia from infective endocarditis is intermittent has changed in recent years to the opinion that, if existent, it is continuous. Thus negative or intermittent positive cultures are unusual when collection and handling of samples is conducted properly. The time for sampling is probably not critical, but a constant finding through repeat samplings is valuable to exclude sample contamination. The technique for obtaining samples aseptically and anaerobically is important and described in detail below. In cases of positive blood culture, it is important to evaluate if the microorganism is consistent with the diagnosis of infective endocarditis.

Microorganisms known to cause infective endocarditis in dogs are, in order of reported incidence, Stapkylococcus aureus, E. coli, betahemolytic streptococci, Pseudotnonas aeroginosa, Corynebacterium spp., Erysipelothrix rhusiopathiae (tonsillarium), and Bartonella irinsonii. B. vinsonii and related proteobacteria has recently been recognized as a potential cause for endocarditis in dogs. They have been found in dogs with cardiac arrhythmias, endocarditis, or myocarditis. Bartonella spp. are also a potential cause for infective endocarditis in cats. Furthermore, Bartonella spp. have been reported to occasionally cause infective endocarditis in immunocompromised (but also immunocompetent) humans, with the cat serving as the major reservoir (cat scratch disease). The recommended antibiotic therapy when the resistance is unknown is erythro-mycin or doxycycline. Immediate antibiotic therapy of humans after significant dog or cat bites may furthermore be motivated as commensals, such as Capnocytophaga canimorsus, in the saliva of dogs and cats have been reported to occasionally cause septicemia with a mortality as high as 30%. Negative blood cultures are fairly common and may be due to antibiotic therapy, chronic situations with “incapsulated” infections, noninfective infective endocarditis (only platelets and fibrin in vegetation), or failure to grow organisms from samples. Some bacteria may grow slowly and samples should not be regarded as definitely negative until they have been incubated for 10 days. More common is a rapid growth of microorganisms with 90% of cultures positive within 72 hours of incubation.

Obtaining Blood Cultures

The referral laboratory should be contacted concerning the preferred type of preprepared vials before obtaining a sample; special additives are available if the patient has been on antibiotics. Pediatric vials are useful because less blood is required but volumes in the range of 20 to 30 mL increase the chance for growth. To avoid contamination, strictly aseptic sampling should be observed which includes thorough shaving and disinfection of the sampling site and strict use of sterile gloves. Three samples with adequately filled vials from different puncture sites should be collected. If samples are collected with a syringe, suction should cease before withdrawal of the needle from the patient to avoid contamination with skin bacteria and a new sterile needle should be used for the transfer of blood into the bottles. The bottles should be prewarmed to 37° C and, after sampling, incubated at the same temperature. Sampling through indwelling catheters should be avoided but may be used as a second choice. The former recommendation to draw samples over 24-hour periods has changed, since multiple simultaneously drawn samples in humans have been shown to be equally sensitive.

Electrocardiographic Findings

Arrhythmia is reported to occur in 50% to 75% of dogs with infective endocarditis.sn.86 Ventricular premature beats and tachyarrhythmias are the most commonly encountered arrhythmias, but they are usually not life threatening. Deviation in the ST-segment suggests myocardial hypoxia and may indicate coronary artery embolism or ischemia from heart failure. Evidence of chamber enlargement may occur in chronic infective endocarditis. All the mentioned ECG abnormalities are, however, nonspecific.

Radiogrophic Findings

Radiography often does not add any information specific for infective endocarditis. In cases of chronic infective endocarditis with aortic or mitral insufficiency, left-sided cardiac enlargement may be detected. Calcified deposits on the valve leaflets are occasionally observed in chronic cases.

Echocardiographic Findings

Echocardiography has significantly improved the possibility of diagnosis and monitoring of animals with infective endocarditis. Valvular vegetations may be detected using two-dimensional echocardiography, although minor lesions may be difficult to distinguish from myxomatous lesions. M-mode can be used to measure secondary changes in cardiac size and to detect abnormal mitral valve motion such as fluttering from aortic regurgitation. Mitral or aortic regurgitation may be detected using continous or color-flow Doppler echocardiography.

Other Laboratory Findings

Mild anemia is found in 50% to 60% of cases with infective endocarditis. The anemia is similar to those from other infections, usually being normocytic and normochromic. Leukocytosis is found in about 80% of dogs with infective endocarditis, usually due to neutrophilia and monocy-tosis (left shift). Other findings that may be encountered include elevated blood urea nitrogen (BUN) due to embolization, metastatic infection, heart failure, or immune-mediated disease.

Urine analysis may reveal pyuria, bacteriuria, or proteinuria. Elevated serum alkaline phosphatase may be found, probably caused by circulating endotoxins and reduced hepatic function, which may cause hypoalbuminemia. The serum glucose concentration may be decreased and serologic tests for immuno-mediated disease, such as Coombs test, may be positive.

Diagnosis of Infective Endocarditis

Since the clinical signs of infective endocarditis are often a result of complications, rather than reflecting the intracardiac infection, the diagnosis may easily be overlooked. Major criteria for infective endocarditis are positive blood cultures with typical microorganisms for infective endocarditis from two separate samples plus evidence of cardiac involvement. The localization and severity of cardiac lesions is confirmed by echocardiographic visualization of vegetations. In the absence of positive cultures, a tentative diagnosis of infective endocarditis can be made if there is clinical and laboratory evidence of systemic infection, such as fever and leukocytosis plus cardiac involvement and possibly signs of embolization.

Management of Infective Endocarditis

The goal of therapy is to eradicate the infective microorganism and to treat all secondary complications. A successful outcome of the therapy is based on early diagnosis and immediate and aggressive treatment. Only bactericidal antibiotics capable of penetrating fibrin should be considered. The antibiotic concentration in serum and deep within vegetations should exceed the organisms minimal inhibitory concentration (MIC), but preferably also the minimum bactericidal concentration (MBC), continuously or throughout most of the interval between doses. Treatment should continue for at least 6 weeks to eradicate dormant microorganisms.

Management of Cases with Tentative Diagnosis of infective endocarditis

A blood culture (see section above) and an antibiotic sensitivity profile should be obtained. While results from cultures and sensitivity tests are awaited, intravenous treatment with a high dosage of bactericidal antibiotic IV, such as cephalosporins (second generation), should be initiated. Alternatives to cephalosporins are combinations of ampicillin or amoxicillin for gram-positive organisms and gentamicin or amikacin for gram-negative organisms. An alternative to gentamicin and amikacin, which are potentially toxic and only recommended to be used for at most one week, is enrofloxacin for suspected gram-negative infective endocarditis. Enrofloxacin is bactericidal and may penetrate myocardium and heart valves and is also indicated for treating Bartonella infections. Choice of antibiotic should preferably depend on the suspected source of infection and the estimated resistance pattern for the primary infection. Practitioners should try to identify the source of infection and treat it as aggressively as possible, such as use of surgical drainage or debridement. Possible secondary problems should be identified, such as heart or renal failure that need therapy or may impair the prognosis.

For dogs with heart failure from aortic regurgitation, hydralazine titered to an adequate reduction of arterial blood pressure is effective and should be considered as a part of medical therapy. When results are available from blood cultures, appropriate antibiotics are selected and aggressive IV treatment continued for 5 to 10 days while renal function is monitored. If results from cultures are negative, the decision to continue antibiotic therapy should be based on clinical improvement. Depending on the early outcome of therapy, subcutaneous administration may substitute a 5 to 10 days IV treatment, and later be superseded by oral preparations. The duration of therapy should be at least 6 weeks on the effective antibiotic. Frequent clinical examinations, blood screening, and urine analyses should be performed during that period.

Prognosis of Infective Endocarditis

Factors that indicate a poor prognosis include late diagnosis and late start of therapy; vegetations on valves (especially the aortic); gram-negative infections, heart or renal failure that do not respond to therapy; septic embolization or metastatic infection; elevation of serum alkaline phosphatase and hypoalbuminemia (70% mortality is reported if this is found in cases with infective endocarditis); concurrent treatment with corticosteroids, regardless if antibiotics are given simultaneously; treatment with bacteriostatic antibiotics or premature termination of antibiotic therapy. Factors that indicate a more favorable prognosis include only mitral valve involvement (47% of dogs are reported to survive); gram-positive infections, origin of infection being the skin, abscesses, cellulitis, or wound infections.

Prevention of Infective Endocarditis

Prophylactic antibiotics may be indicated 1 to 2 hours before and 12 to 24 hours after diagnostic or surgical procedures when turbulent blood flow is suspected to have damaged the endocardium, such as aortic stenosis, patent ductus arteriosus (PDA), or ventral septal defect (VSD). In these cases, early treatment of all manifest infections is important to avoid bacteremia and reduce the risk for infective endocarditis, and caution should be observed when bleeding or infection is anticipated or evident in the oral, urogenital, intestinal, or respiratory tract. Amoxicillin may be the first choice, but other antibiotics, such as clindamycin or cephalosporins, may also be considered depending on the organ system involved and site of infection.

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Horses

Treatment of RFM

Although many mares with RFM do not become clinically ill, early prophylactic intervention is widely practiced because the complications associated with RFM may be severe and potentially life threatening. Many farm managers and horse owners with a veterinary client-patient relationship may be instructed to begin intramuscular (IM) injections of oxytocin 2 to 4 hours postpartum if the fetal membranes have not been passed. The membranes should be tied up above the hocks to prevent soiling and tearing. Tying a weight (e.g., a brick) to the membranes is not recommended because it may predispose the mare to development of a uterine horn intussusception. Injections of oxytocin should be given every hour for at least 6 treatments. The half-life of oxytocin in the mare is brief (12 min).

The initial starting dose of oxytocin should be on the low side (10-20IU/500 kg) because sensitivity to oxytocin varies widely. The dose of oxytocin can then be tailored to each individual mare. A positive response will result in passage of uterine fluid from the vagina. Mares should be monitored following injection because any obvious cramping will begin within 10 minutes of IM injection. If a 10- to 20-IU oxytocin treatment does not result in an outward manifestation of discomfort by the mare, such as sweating and restlessness, then the dose can be increased in 10- to 20-IU increments until an effect is noticed. The dose should only be high enough to elicit mild colic signs. Mares with uterine inertia because of dystocia may be initially very resistant to the effect of oxytocin and may become more sensitive in the subsequent hours. If cramping and rolling result then the dose should be reduced. Some mares become inattentive mothers during the time when they are distracted by RFM or uncomfortable from the oxytocin-induced cramping. Thus the foal should be kept in a safe place when the mare is in pain. Nursing should be encouraged to stimulate the natural release of oxytocin associated with milk letdown.

If the mare fails to respond to six oxytocin injections or if she is clinically ill, a thorough veterinary examination is indicated. One option is to start an intravenous (IV) drip of oxytocin at 0.1 IU/ml of saline (i.e., 100 IU oxytocin per 1 L saline). The IV flow rate should be set so that the mare has visible signs of contractions every S to 10 minutes. The oxytocin drip treatment protocol will, in effect, revert the mare back into labor for about 1 hour.

The technique described by Burns and colleagues () works best when the membranes are fresh. Some clinicians perform the procedure prophylacti-cally after a dystocia to reduce the likelihood of membrane retention. The clinician should wear waterproof clothing and a sterile surgical glove over a clean rectal sleeve. The perineum of the mare and external portion of the membranes are washed thoroughly. The opening at the cervical star, which leads into the allantoic cavity, is identified. A clean large-bore stomach tube is introduced, and the membranes are gathered around the tube. In addition, 4 L or more of a warm 1% povidone iodine solution is pumped or gravity fed into the chorioallantois until the fluid overflows. The tube is withdrawn as the RFM are tied shut with umbilical tape. Oxytocin may then be administered so that the uterus contracts against the distended membranes. This technique distends the endometrial crypts and often permits release of the microcotyledons. If the procedure is unsuccessful then it may be repeated several hours later. However, the retained membranes soon become autolytic and tend to tear as soon as distention starts.

If partial retention of the membranes is diagnosed, or if the membranes are badly torn, the uterus may be distended with 1% povidone iodine solution as described previously. The fluid distention and uterine contractions may help loosen the membranes. If the piece of membrane can be reached, it may be gently teased off the en-dometrium and removed. However, if the membrane tag is firmly adhered then continued traction is contraindicated. Once or twice daily flushing and the process of au-tolysis will eventually loosen the membranes. This procedure also may be carefully performed in mares that retain the membranes after a cesarean section. However, it is important to use a lower volume of infusate so that the uterine closure and fibrin seal are not disrupted.

Toxemic mares that are clinically ill and are passing a fetid uterine discharge may require systemic support with IV fluids, frequent IV treatments with oxytocin, and twice daily high-volume uterine lavage. Gentle manual removal of the fetid membranes may be necessary in these mares. Back and forth uterine lavage is performed with a clean stomach tube, bilge, or stomach pump. A dilute (1%) povidone iodine solution or sterile fluids are used to remove bacteria and inflammatory debris from the uterus. The clinician should hold the end of the tube cupped in the hand within the uterine cavity to prevent the tube from forcefully sucking against the wall when the fluid is being siphoned back. During the first few lavage procedures, persistence and patience in obtaining a clean return from the uterus is often rewarded with rapid clinical improvement and uterine involution. Lavage should be repeated once or twice daily until all debris is removed, the lavage is clear, and the uterus is well involuted.

Prophylactic administration of antibiotic and antiinflammatory medication is often prescribed early in the course of RFM in an attempt to prevent complications. Common antimicrobial choices are trimethoprim sulfa (30 mg/kg, q24h PO), or procaine penicillin G (22,000 IU/kg ql2h IM) for a minimum of 3 to 5 days. If the mare is systemically ill then broad-spectrum medications such as penicillin-aminoglycoside combinations are recommended. The formulations or derivatives of penicillin include the following: procaine penicillin (22,000 IU/kg ql2h IM), sodium and potassium penicillin (22,000 IU/kg q6h IV), ampicillin (50 mg/kg q8h IV), or ticarcillin (44 mg/kg q8h IM) for resistant cases. Aminoglycosides such as gentamicin (6 mg/kg q24h IM or IV) or amikacin (6.6 mg/kg ql2h IV or IM) are used for mixed and gram-negative infections or resistant cases. Appropriate antibiotic use is confirmed by uterine culture and sensitivity results.

The mostly commonly used antiinflammatory medication for endotoxemic mares is flunixin meglumine, 1.1 mg/kg IV. In milder cases, flunixin meglumine (0.25-0.5 mg/kg q8h IV), ketoprofen (2 mg/kg ql2h IV), vedaprofen (2 mg/kg ql2h PO), or phenylbutazone (4 mg/kg IV or PO) are used. Hyperimmune plasma is administered if it is available.

Laminitis in mares with RFM is a serious complication. Lateral radiographs of the distal phalanx will help establish the degree of rotation, and the prognosis. Symptomatic care such as hosing the hooves with cold water, or application of foam pads or special shoes to the hooves can provide extra support and promote comfort. Phenylbutazone at 2 g every 24 hours by mouth is sometimes used prophylactically.

Mares with lactation failure should be treated with domperidone at 1.1 mg/kg orally every 12 hours to encourage lactation.

Categories
Horses

General Considerations For Testing Ability Of Spermatozoa To Survive Cooled Storage

Preservation of semen begins with the collection process. Accurate assessment of semen quality relies heavily on proper semen collection techniques. Ejaculated semen is susceptible to environmental influences. Therefore mishandling semen samples before evaluation can lead to erroneous interpretation of results, thereby negating their value for representing the ability of a stallion’s spermatozoa to survive the cooling process.

Semen should be collected using a properly prepared artificial vagina. The interior of the artificial vagina should be clean and free of potentially toxic substances such as soap or tapwater residues. Between uses, artificial vaginas should be rinsed thoroughly with deionized water to remove impurities, rinsed with 70% isopropyl or ethyl alcohol to eliminate growth of microorganisms, and allowed to air dry. Before collection, artificial vaginas should be lubricated with a nonspermicidal product. Additionally, the semen collection receptacle should be nonspermicidal and fitted with a filter to allow separation of gel from the gel-free portion of the ejaculate.

After collection, semen should be processed in a careful and efficient manner. The semen should be placed immediately in a light-shielded incubator adjusted to 37° C to 38° C. All items that come in contact with raw semen should be prewarmed to 37° C to 38° C to prevent cold shock to the spermatozoa. The filtered gel-free semen should be poured into a graduated cylinder to measure volume accurately. Some types of specimen cups have inaccurate graduated markings for volume.

Sperm concentration of the gel-free semen is determined using either a hemacytometer or properly calibrated photometric instrument. The total spermatozoal number in the ejaculate is calculated by multiplying spermatozoal concentration by volume of gel-free semen. This calculation is necessary (when the percentage of progressively motile spermatozoa is taken into account) to aid in determination of the number of inseminations possible from an ejaculate and determination of the amount of semen extender that should be added to the raw semen to maximize longevity of motility following cooled storage. A portion of the gel-free semen should be diluted in a suitable prewarmed extender, then incubated at 37° C to 38° C for 5 to 10 minutes before estimation of percentage of progressively motile spermatozoa in the sample.

Motility assessment using raw (unextended) semen can yield erroneous measurements. Warmed nonfat dry skim milk-glucose (NFDSM-G) extender serves this purpose well because it sustains spermatozoal motility and does not interfere with microscopic visualization of the spermatozoa. To standardize the spermatozoal motility testing protocol, all semen samples should be diluted to a specific concentration (i.e., 25 x 106 spermatozoa/ml) with extender before analysis. Ideally, spermatozoal motility should be estimated at a magnification of 200 to 400 times, using a microscope equipped with phase-contrast optics and a warming stage.

Screening against ejaculates of poor quality is necessary to maximize success with preserved semen. If fresh stallion semen is poor quality, successful results most likely cannot be obtained by breeding with preserved semen. Extended semen from fertile stallions often can be stored in a cooled state for hours to days before insemination without a significant reduction in pregnancy rate. Longevity of spermatozoal viability in vitro may be maximized by properly diluting semen with a high quality extender, cooling the extended semen at the proper rate, and holding the cooled semen at the proper temperature until it is used.

Semen extenders contain protective ingredients that permit spermatozoal survival outside the reproductive tract. Lipoproteins, such as those contained in milk, protect spermatozoa against cold shock by stabilizing cellular membranes. Metabolizable substrates, such as glucose, provide a plentiful source of energy for spermatozoa. Antibiotics are added to extenders to retard or eliminate growth of bacterial organisms.

Osmotic pressure and pH of extenders also are adjusted to maximize spermatozoal survival. Extenders may be homemade formulations or commercially available preparations. Potassium penicillin G (1000 units per ml of extender), amikacin sulfate (100-1000 M-g/ml of extender), amikacin sulfate plus potassium penicillin G in combination, or ticarcillin (100-1000 μg/ml of extender) have been found to be acceptable antibiotics for inclusion in NFDSM-G extender formulation. These antibiotics do not impair motility of stored spermatozoa and inhibit the growth of most bacteria present in equine semen. The combination of potassium penicillin G and amikacin provides better control of bacterial growth than ticarcillin or either antibiotic used singularly.

Ideally, semen should be mixed with a prewarmed (37° C to 38° C) extender within minutes after ejaculation. A minimum of a 1:1 ratio of semen to extender is recommended if semen is to be inseminated immediately. If semen is to be stored for a period longer than 2 to 4 hours before insemination, greater dilution (i.e., more extender to semen) is required. A final concentration of 25 to 50 million spermatozoa per ml in extended semen generally maximizes spermatozoal survivability in vitro. Alternatively, extender can be added to semen at a 1:4 to 1:19 (semen: extender) ratio to reduce seminal plasma in the ejaculate to 5% to 20% of the extended volume. Seminal plasma can be detrimental to longevity of spermatozoal viability during storage of the semen if it occupies more than 20% of the total volume of extended semen; however, retention of some seminal plasma generally improves longevity of spermatozoal motility. The concentration of spermatozoa in extended semen should not be below 25 million spermatozoa per ml. When a stallion ejaculates relatively dilute semen (e.g., £100 million spermatozoa per ml), dilution in extender to arrive at a final concentration of 25 million spermatozoa per ml may fail to provide protection against environmental influences for spermatozoa, thereby resulting in a low rate of spermatozoal survival following cooled storage. In such instances, it may be beneficial to mix the raw semen with extender, then centrifuge the extended semen at 500 x g for 10 minutes, aspirate the supernatant, and resuspend the spermatozoal pellet in additional fresh extender. The majority of seminal plasma is removed after centrifugation and aspiration of the supernatant, so the remaining spermatozoal pellet can be resuspended in extender to arrive at a final concentration of 25 to 100 million spermatozoa per ml. For some stallions, centrifugation of extended semen, followed by resuspension in fresh extender, has been shown to improve spermatozoal motility characteristics after 24 hours of cooled storage at 5° C.

Categories
Horses

Endometrial Culture and Antimicrobial Therapy

Sampling of the surface of the endometrium for pathogenic microflora is an important part of the breeding soundness evaluation of the mare. Additionally, most breeding sheds and stallion owners require broodmares to have a negative uterine culture before natural mating. Breeds that allow artificial insemination may be less restrictive with this requirement. Other indications for endometrial culture include recent dystocia or retained fetal membranes, detection of intrauterine fluid by ultrasonography, or previously diagnosed endometritis.

Sampling Technique

Antimicrobial Therapy

It is imperative that any anatomic defects — such as poor perineal conformation, rectovaginal fistulas, perineal lacerations, and vesicovaginal reflux — be surgically corrected. Without doing so, endometritis will recur despite appropriate antimicrobial therapy. A list of agents used for intrauterine antimicrobial therapy in the mare is given in Table Antimicrobial Therapy for Intrauterine Use in the Mare. In most mares, a volume of 50 to 100 ml will give adequate dispersion over the entire endometrial surface. Mares whose uteri are enlarged may require volumes greater than 100 ml to achieve uniform distribution throughout both horns and the body of the uterus. Treatment once daily for 4 to 6 days during estrus is usually adequate for most cases of endometritis. It is often beneficial to precede antimicrobial infusion with uterine lavage, thereby mechanically removing organic debris, which can interfere with the efficacy of most antibiotics. Postpartum mares — or those with an especially enlarged uterus that lacks tone — benefit temporarily from lavage with warm saline before infusion with antimicrobial agents. Oxytocin is an effective tool to enhance uterine clearance of the mare. It is advisable to wait several hours after using any intrauterine antimicrobial agents before administering oxytocin; otherwise, uterine contractions will prematurely expel the antimicrobial agent. In such cases, combining uterine lavage and oxytocin with systemic antimicrobial therapy may prove more efficacious and cost-effective.

Table Antimicrobial Therapy for Intrauterine Use in the Mare*

Antimicrobial Dose Comments
amikacin sulfate 2g Gram-negative organisms; buffer with equal volume 7.5% bicarbonate
ampicillin 1-3 g  
ceftiofur ig Broad spectrum (Streptococcus zooepidemicus)
gentamicin 1-2 g Cram-negative organ-
sulfate   isms; buffer with equal volume 7.5% bicarbonate
kanamycin sulfate 1-2 g Escherichia coli; toxic to spermatozoa
penicillin 5 million units S. zooepidemicus
polymixin B 1 million units Pseudomonas spp.
ticarcillin fig Broad spectrum
ticarcillin/ clavulanic acid 6 g/200 mg Broad spectrum
nystatin 500,000 units Antimycotic; must use sterile water (precipitates in saline)
clotrimazole 500 mg Antimycotic; suspension or cream; q24-48h for 1 -2 weeks
vinegar 2% Antimycotic; 20 ml wine vinegar in 1 L of saline; used as a lavage fluid

*Parts of this table from Asbury AC, Lyle SK: Infectious causes of infertility.

The use of systemic antimicrobial therapy is becoming an increasingly popular route for treating mares with endometritis, especially in mares prone to postmating endometritis during the postovulatory period, in mares whose biopsy shows evidence of inflammation deep in the stratum spongiosum, and in mares that receive embryos by transcervical transfer. Trimethoprim/sulfa combinations (30 mg/kg q24h or divided ql2h PO) and ceftiofur (4 mg/kg IM q24h) are broad-spectrum antibiotics that should be safe for the early embryo. Enrofloxacin (7.5 mg/kg q24h PO) also has broad-spectrum activity but would not be recommended for use in pregnant or potentially pregnant mares. The bioavailability of the tablet form of enrofloxacin appears to be superior to that of the injectable preparation.

Uterine infections due to fungal or yeast infections are difficult to treat and often follow chronic bacterial endometritis with extensive intrauterine antibiotic use. Clotrimazole and uterine lavage with dilute vinegar solutions are anecdotally the most effective treatments but can require more than one course of therapy. Dilute povidone-iodine lavage solutions (0.05%) have also been suggested. Vaginal speculum examinations are important to monitor cervical inflammation. Some mares are extremely sensitive to even dilute iodine solutions, in which case severe cervicitis, vaginitis, and intraluminal uterine adhesions can result. Occasionally spontaneous recovery from fungal endometritis is seen. In most cases these infections tend to be extremely difficult to resolve; the owner should be given a guarded prognosis for fertility.

Categories
Veterinary Medicine

Canine Parvovirus

1. What are the common clinical signs in dogs with canine parvovirus (CPV)?

• Lethargy

• Vomiting

• Inappetence

• Fever

• Acute-onset diarrhea

• Profound neutropenia (white blood cells < 1000/mm3)

Puppies between the ages of 6 weeks to 6 months are most commonly affected. In a Canadian study, sexually intact dogs had a 4-fold greater risk than spayed or neutered dogs, and the months of July, August, and September had a 3-fold increase in cases of canine parvovirus.

2. What systems other than the GI tract are involved with canine parvovirus?

In a study of dogs with the GI form of canine parvovirus, arrhythmia was diagnosed in 21 of 148 cases, including supraventricular arrhythmias and conduction disturbances. Some dogs developed significant enlargement of the cardiac silhouette and other radiographic cardiac abnormalities. CPV can replicate in bone marrow, heart, and endothelial cells; replication in endothelial cells of the brain produces neurologic disease.

3. What other infectious diseases may be mistaken for canine parvovirus infection?

Infection with Salmonella sp., Campylobacter sp., or Escherichia coli may mimic canine parvovirus symptoms and also cause the shift in white blood cells. CPV infection also may be confused with hemorrhagic gastroenteritis (HGE), although HGE is seen most commonly in smaller breeds and usually resolves in 24 hours. Coronavirus often presents with GI signs, but neutropenia tends to resolve more rapidly than with canine parvovirus infection. Clinical signs of infection with coronavirus are usually seen only in dogs also infected with parvovirus.

4. What is the primary mode of transmission of canine parvovirus?

The number of viral particles in the feces is quite high; the fecal-oral route is the most likely means of transmission. No studies of vomitus have been done, but it probably contains viral particles.

5. How does canine parvovirus infect the intestines?

Viral replication occurs in the oropharynx during the first 2 days of infection, spreading to other organ systems via the blood. By the third to fifth day a marked viremia develops. The virus reaches the intestinal mucosa from the blood rather than from the intestinal lumen. Clinical signs are seen 4-5 days after exposure, and the incubation period ranges from 3-8 days, with shedding of the virus on day 3.

6. Where does canine parvovirus replicate in the body?

The virus replicates in rapidly dividing cells, which include lymph nodes, spleen, bone marrow, and intestines. In the intestines, viral replication kills the germinal epithelium of the intestinal crypts, leading to epithelial loss, shortening of the intestinal villi, vomiting, and diarrhea. Lymphoid necrosis and destruction of myeloproliferative cells result in lymphopenia and, in severe cases, panleukopenia. Only about one-third of canine parvovirus cases have defined neutropenia or lymphopenia.

7. How has the clinical presentation of CPV infection changed since the 1970s?

There are several strains of canine parvovirus, including the original strain, CPV-1; the minute virus; and the most severe strain, CPV-2 (with subtypes 2a and 2b). CPV-2b is now the most common strain in the United States. CPV-1, which dominated in the 1970s, caused a milder disease associated with fever and a larger window for treatment. CPV-2b causes a more explosive acute syndrome that affects young dogs 6-12 weeks of age, making the window between the first signs of GI upset and treatment much narrower and more critical. There have been no major changes in presentation in the past 6 years; lethargy, listlessness, and bloody diarrhea are the most common presenting signs. Other diseases associated with or mistaken for canine parvovirus are canine distemper virus, coccidial or giardial infection, hookworms, roundworms, or a combination of these.

8. When and how does one diagnose canine parvovirus?

CPV is most easily diagnosed with a fecal enzyme-linked immunosorbent assay (ELIS A). If the test is negative but canine parvovirus is still suspected, isolate the animal and run the test again in 48 hours. The virus is not usually shed until day 3, and conscientious clients may bring the animal to the hospital at the first sign of illness. The period during which canine parvovirus is shed in the feces is brief, and the virus is not usually detectable until day 10-12 after infection. Usually the acute phase of illness has passed by this time. Modified live canine parvovirus vaccines shed in the feces may give a false-positive ELISA result 4-10 days after vaccination.

One also may use a combination of ELISA, complete blood count, and radiographs to diagnose canine parvovirus. Radiographs may help to rule out the possibility of an intestinal foreign body, and detection of generalized ileus with fluid-filled loops of intestines supports the diagnosis of canine parvovirus. Be sure to have enough antigen in the fecal sample when running the ELISA; watery stools may dilute the antigen and give a false-negative result.

Conclusive proof of canine parvovirus infection is made with electron microscope identification of the virus.

9. What are the recommendations for inpatient care of dogs with CPV?

1. Aggressive fluid therapy. Correct dehydration and provide intravenous maintenance fluid volumes of a balanced crystalloid solution. Make every attempt to replace continuing losses (vomitus and diarrhea) with equal volumes of crystalloid fluids. The easiest method is simply to estimate the volume lost and double your estimate. Continuing losses need to be replaced at the time that they occur. Use Normosol with at least 20 mEq/L of potassium chloride supplementation. Monitor glucose level. If necessary, add 2.5-5% dextrose to intravenous fluids. A 5% dextrose solution creates an osmotic diuresis, but it also allows assessment of progress in dealing with a septic case (glucose increases when the animal receives 5% dextrose if the sepsis is resolving). Low levels of magnesium chloride may be added to fluids to help correct unresponsive hypokalemia.

2. Antibiotic therapy. Broad-spectrum parenteral antibiotics are recommended because of disruption of the mucosal barrier and potential sepsis. Bacteremia is identified in 25% of dogs infected with parvovirus. A combination of ampicillin and gentamicin is recommended. Most veterinarians use only a first-generation cephalosporin in dogs without neutropenia or fever and reserve ampicillin and gentamicin or amikacin for dogs with signs of sepsis. One should be cautious about using an aminoglycoside because of renal toxicity.

3. Endotoxin-neutralizing products. Endotoxin-neutralizing products may be administered along with antibiotic therapy. The rationale for their use is based on the large population of gram-negative bacteria; by killing the bacteria, antibiotic therapy may shower the body with en-dotoxin, thus exacerbating the canine parvovirus condition. Studies have shown that endotoxin-neutralizing products decrease the incidence of septic shock. They may be diluted (4 ml/kg) with an equal volume of saline and administered intravenously over 30-60 minutes. Dogs who have recovered from parvovirus infections can be a good source for serum. Serum should be collected within 4 months of infection.

4. Antiemetics. Metoclopramide is the drug of choice. Phenothiazine derivatives should be used with caution and only after adequate volume replacement is initiated to avoid severe hypotension. Antiemetics are especially useful when continued vomiting makes it difficult to maintain hydration or electrolyte balance.

5. Motility modifiers. The use of motility modifiers is controversial. Anticholinergic anti-diarrheal medications may suppress segmental contractions and actually hasten transit time. Narcotic analgesics and synthetic opiates are better choices but should be reserved for severe or prolonged cases because slowing the flow through the intestine may increase toxin absorption.

6. Nothing per os (NPO). Begin a slow return to water 24 hours after the animal stops vomiting, and slowly progress to gruel made from a bland diet.

10. What is granulocyte colony-stimulating factor (GCSF)? What role does it have in treating dogs with CPV?

Granulocyte colony-stimulating factor selectively stimulates release of granulocytes form the bone marrow. Preliminary studies have shown that it reduces morbidity and mortality due to canine parvovirus. Unfortunately, it is available only as a human drug and is expensive, but when the positive benefits are considered, its use may be justified.

11. Does interferon benefit a dog with parvovirus infection?

Interferon given parenterally has been shown to be beneficial. The suggested dosage of human recombinant interferon is 1.3 million units/m2 subcutaneously 3 times/week.

12. How is a dog with canine parvovirus monitored?

Monitor respiration and central venous pressure (CVP) to prevent overhydration. With osmotic diarrhea the animal loses protein. If abdominal or extremity swelling is observed or if the total solids drop by 50% from admission values or go below 2.0 gm/dl, the animal should be supplemented with either 6% hetastarch or plasma to maintain colloid oncotic pressures. Blood glucose should be monitored at least 4 times/day on the first two days. Glucose level may drop precipitously and suddenly. Most importantly, weigh the dog at least twice each day. If adequate crystalloid replacement is provided, body weight does not decrease from initial values. Ideally body weight should increase at a rate comparable to the degree of dehydration originally assessed. Dogs that can hold down water for 12 hours may be offered a gruel made from bland foods. Most dogs force-fed by hand will vomit. This response may be physical or psychological (association of food with vomiting). Nasogastric tubes seem to help this problem. Metoclopramide speeds gastric emptying, acts as an antiemetic, and decreases gastric distention when added to the liquid diet. Dogs that are not vomiting should be offered food even if the diarrhea has not totally stopped. A low-fat, high-fiber diet is a good choice to stimulate intestinal motility.

13. How do you know when to send a dog home?

The dog should stay in the hospital for 12 hours after it has ingested solid food with no vomiting. Clients should report immediately any vomiting in the next 7 days or refusal to eat for 24 hours. A high-fiber diet is recommended for reducing diarrhea. A recheck appointment in 1 week with a stool sample helps the clinician to assess progress.

14. What recommendations do you offer to clients who have had a CPV-infected animal in their household and now want a new pet?

Prevention involves a proper vaccination regimen, limited exposure to other animals (especially in puppies less than 12 weeks of age), cleaning contaminated areas with bleach (allowing prolonged contact time), and vacuuming all surfaces with which the previous pet came into contact (rugs, carpet, walls, furniture). Newer higher-titer vaccines (some of which may be started as early as 4 weeks) are helpful. Generally, one should wait at least 1 month before bringing the new pet into the home. It is doubtful that the environment (especially outdoors) will ever be completely free of the virus. Canine parvovirus is a hardy and ubiquitous organism.

15. How long can a dog with CPV be expected to retain immunity?

A dog that has recovered from canine parvovirus can maintain life-long immunity.

16. What is the recommended vaccination schedule for dogs? Is it the same for every breed?

Some breeds are more susceptible to canine parvovirus than others. Rottweilers, American pitbull terriers, Doberman pinschers, and German shepherds are the most susceptible, whereas toy poodles and Cocker spaniels are less susceptible. The new higher-titer vaccines have a higher antigen level and a more virulent vaccine strain that can overcome maternal antibodies, unlike the older lower-titer vaccines. These vaccines narrow the window of infection, especially for susceptible breeds. The vaccination protocol for the new high-titer vaccines is 6, 9, and 12 weeks. Susceptible breeds should be vaccinated only with the high-titer canine parvovirus vaccine and then with a combination vaccine at 6-8, 12, and 16 weeks. For less susceptible breeds, the combination vaccines at 6-8, 12, and 16 weeks should be adequate. Some parvovirus vaccines are approved for use as early as 4 weeks of age.

17. How do you manage a sick puppy when the client is unwilling to pursue hospital treatment for CPV?

Canine parvovirus can be treated on an outpatient basis. A combination of dietary restriction, subcutaneous fluids, and, in some cases, GI medications may be used with a follow-up appointment in 1-3 days. Outpatient recommendations include the following:

• Small, frequent amounts of fluid

• Bland food

• Oral antibiotics

• Strong recommendation to have the pet reexamined and admitted for therapy if vomiting returns or anorexia persists

Nine of ten clients bring the dog back for inpatient care shortly after taking it home. Before treating an outpatient, remember that mildly depressed dogs may have a rectal temperature of 106° F and a blood glucose of 30 mg/dl in 12 hours or less.

18. Should a dog with suspected CPV be hospitalized and placed in isolation?

Undoubtedly hospitalization provides the best chance for survival. Isolation is more controversial. In most veterinary hospitals, isolation means that the animal is housed in a section of the hospital that is not staffed at all times. The adage “out of sight, out of mind” has led to the demise of many CPV-infected dogs. Experience with housing dogs with canine parvovirus in the critical care unit at the Veterinary Teaching Hospital of Colorado State University has shown that nosocomial infections can be avoided with a common-sense approach to patient management. The animal is placed in the least traveled area and has its own cleaning supplies; gowns and gloves are worn each time the animal is handled; and the animal’s cage is kept as clean as humanly possible. These procedures are no different from those in an isolation area. By being housed in an area where constant attention can be given, the animal receives adequate fluid replacement therapy and is monitored for changes, which occur rapidly.

19. How is nutrition provided for vomiting dogs?

Tough question! Dogs that have not eaten for 3-5 days are probably in a negative nitrogen balance, and certainly intestinal villi have undergone atrophy if not already destroyed by the canine parvovirus. The sooner patients begin receiving oral nutrition, the more rapidly they will recover. In addition, micronutrient therapy for the intestinal mucosa is required for maintenance of the mucosal barrier. Without this barrier, sepsis and bacteremia are more likely. Unfortunately, the only means to provide micronutrients is the oral route.

Glucose therapy does not provide nutritional support. It is best to think of dextrose as simply a source of water. One liter of 5% dextrose solution contains a mere 170 kcal. Increasing dextrose concentrations beyond 5% usually results in glycosuria and osmotic diuresis.

Patients that have not eaten for several days are primed for fat metabolism; thus, Intralipid (20%) may be added to fluids. It should be administered through a central IV catheter and requires strict aseptic management, which may be difficult if the patient is in an isolation area of the hospital.

For dogs that retain water without vomiting, glutamine may be added directly to the water bowl. Often placing electrolyte solutions in the water bowl is a good way to start the animal drinking. Placing dextrose in these fluids or even using commercial solutions such as Ensure-Plus in the bowl helps to provide intestinal nutrients.

20. Should parvovirus antibody levels be measured to check the immune status of the puppy?

Although antibodies to parvovirus can be measured, a negative titer does not necessarily mean that the dog is susceptible to canine parvovirus. Repeated revaccination of antibody-negative dogs usually does not result in significant titers.