Infections in immunocompromised pets (Proceedings)

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Infections in immunocompromised pets (Proceedings)

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Apr 01, 2008

Introduction

Immunosuppression in pets may be the result of an acquired immune deficiency, such as that due to neoplastic disease, immune-mediated disease, endocrine disease, or drug therapy; or more rarely, a congenital immune deficiency. In general, the risk of opportunistic infectious disease is associated with the level and duration of immunosuppressive disease or drug therapy. In recent years, the increasing use of potent immunosuppressive drugs such as cyclosporine to prevent renal transplant rejection and to treat immune-mediated diseases in dogs and cats has been associated with the more frequent identification of unusual opportunistic infectious diseases.

Use of Cyclosporine in Veterinary Medicine

Cyclosporine (also known as ciclosporin) is a small, cyclic peptide produced by the fungus Tolypocladium infantum Gams. It acts by binding the cytosolic protein cyclophilin in lymphocytes, in particular T-lymphocytes. This complex inhibits calcineurin, which normally activates transcription of Il-2. Transcription of Il-4 and IFN-gamma is also decreased. Inhibition of eosinophil recruitment and activation, keratinocyte cytokine production and mast cell degranulation also occurs. A number of adverse drug reactions have been associated with cyclosporine, including gingival hyperplasia, gastrointestinal signs, hepatotoxicity, nephrotoxicity, hypertension, hirsuitism, lameness, and opportunistic infectious diseases (see below), although nephrotoxicity and hypertension appear to be more commonly a problem in humans than in dogs and cats. Chronic treatment with cyclosporine may also predispose to diabetes mellitus and lymphoma. Cyclosporine interacts with drugs metabolized by the P450 system of the liver. Drugs metabolized by this route, especially the azole antifungal drug ketoconazole, may increase the concentration of cyclosporine in the blood. Metoclopromide, macrolide antibiotics and some fluoroquinolones have also been reported to increase serum levels of cyclosporine, although whether these interactions are clinically significant is unknown. Finally, cyclosporine binds to P-glycoprotein and therefore may predispose to ivermectin neurotoxicity.

Because of variable drug absorption between individuals, there is a need to monitor whole blood levels of cyclosporine in dogs and cats being treated with this drug for immunosuppression to prevent excessive or suboptimal immunosuppression. Currently, measuring trough levels is recommended; we typically would start with a dose of 3-5 mg/kg q24h and check levels 5-7 days after starting therapy or dose adjustment, with regular monitoring (every 3-6 months) for patients on long term therapy. The currently accepted target whole blood concentration for immunosuppression is 300-500 ng/mL. Cyclosporine is marketed by Novartis under the brand names Sandimmune (the original formulation), Neoral, a microemulsified formulation that has improved gastrointestinal absorption, and Atopica, a microemulsified formulation which is specifically indicated for treatment of canine atopic dermatitis. Generic preparations are now available such as Gengraf (Abbott). Dosage recommendations for Atopica for the treatment of atopic dermatitis are 5 mg/kg q24h until satisfactory clinical improvement is seen (usually within 4-8 weeks), followed by tapering of the dose to every second day then every 3-4 days, provided clinical signs do not return. It is also suggested that treatment be stopped should the clinical signs disappear on this dose, with intermittent periods of therapy if needed. Several retrospective and prospective studies have been published evaluating the safety and efficacy of cyclosporine for treatment of canine atopic dermatitis, and have found the drug to be efficacious and well tolerated, with rare adverse effects. The most common adverse effects have been gastrointestinal in nature. A study of cyclosporine pharmacokinetics and efficacy in the treatment of canine atopic dermatitis concluded that considering the large margin of safety of cyclosporine in dogs, the limited interindividual variability, and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood cyclosporine levels may not be necessary in dogs with atopic dermatitis. Blood monitoring should be considered when drugs that increase cyclosporine concentrations or potentiate immunosuppression are being used concurrently.

Diseases that cyclosporine has been reportedly effective for include vesicular cutaneous lupus erythematosus, perianal fistulae, sebaceous adenitis, pemphigus foliaceous, erythema multiforme, reactive histiocytosis, inflammatory bowel disease, immune-mediated cytopenias, myasthenia gravis, and immune-mediated polyarthritis.