H by Histoplasma capsulatum. It primarily

Transcription

1 Itraconazole for the Treatment of Histoplasmosis in Cats Ronald D. Hodges, Alfred M. Legendre, Larry G. Adarns, Michael D. Willard, Roger P. Pitts, Kevin Monce, Conya C. Needels, and Heidi Ward Eight cats with histoplasmosis were treated with itraconazole at 5 mg/kg per dose PO bid. There were multiple sites of infection, and 2 of the cats had hypercalcemia that was attributed to the histoplasmosis. All 8 cats were eventually cured, but 2 cats experienced recurrences of disease after completion, requiring 2 to 3 additional months of itraconazole. There were no clinically relevant adverse effects during treatment. Although a limited number of cats were treated, the study suggests that itraconazole is a well-tolerated and effective drug for the treatment of histoplasmosis in the cat. J Vet Intern Med 7994;8: Copyright by the American College of Veterinary Internal Medicine. istoplasmosis is a systemic fungal disease caused H by Histoplasma capsulatum. It primarily affects dogs and is considered uncommon in cats.',* This disease is more prevalent in the subtropical regions of the United States and in the Ohio and Mississippi river valleys.' However, the organism is also ubiquitous in the state of Texas.3 The two drugs used for the treatment of most systemic fungal infections are amphotericin B (Fungizone, E.R. Squibb & Sons, New York, NY) and ketoconazole (Nizoral, Janssen Pharmaceuticals, New Brunswick, NJ). Amphotericin B is a lyene antibiotic with a broad spectrum of activity that includes H capsulatum and most of the systemic fungi that infect dogs and It binds to the fungal cell membrane and increases cellular permeability causing fungal lysis.',' Nephrotoxicosis leading to tubular acidosis, azotemia, and uremia is the most common adverse Ketoconazole, an imidazole with a broad spectrum of antifungal activity, is used to treat mycoses in people and Like amphotericin B, ketoconazole alters fungal cell membranes and increases fungal cell membrane permeabilit~.'.~ The drug takes a longer time to achieve maximum effects, and its primary adverse effects are nausea, vomiting, and hepatic injury.7 Itraconazole is a new, highly liphilic, triazolic comund that has a high molecular weight and is well absorbed from the gut.* It is active in vitro and in vivo against H capsulatum in a guinea pig m ~del,~,~ and it is effective in progressive histoplasmosis in peo- Because amphotericin B and ketoconazole produce clinically relevant adverse effects in cats, the current study was conducted to evaluate the resnse to itraconazole (Sranox, Janssen Pharmaceuticals) treatment of cats with histoplasmosis. Clinical Evaluation Eight cats with histoplasmosis treated with itraconazole were from Tennessee, Colorado, Minnesota, Texas, Ken- tucky, Virginia, and Florida. Because most cats were referred, they may represent more advanced disease than is commonly seen in pra~tice.'-~-'~-'~ In each cat, the age, breed, gender, weight, previous therapy, historical signs, and abnormal physical findings were recorded. Cats were evaluated by complete hematologic and biochemical analyses, blastomycosis/histoplasmosis agar gel immunodiffusion test, urinalysis, thoracic radiography, and ophthalmologic examination. Other diagnostic methods varied according to the organ system involvement, ie, bone marrow examination, needle aspirates. Affected cats ranged in age from 1 to 14 years. Six cats were domestic short-haired and 2 domestic long-haired; there were 2 male (castrated) and 6 spayed female cats (Table 1). Clinical signs were similar to those rerted in the literature (Table l).'.3 All cats had an insidious onset of disease, and the duration of illness before itraconazole therapy ranged from 8 to 1 1 weeks. Pulmonary involvement, manifested by labored breathing or abnormal respiratory sounds, was present in 3 cats. Disseminated histoplasmosis was diagnosed by cytologic detection of histoplasma organisms in the bone marrow in 2 cats, and by histoplasma detected in a single organ (skin and spleen, respectively) in 2 cats. There From the Department of Urban Practice, College of Veterinary Medicine, University of Tennessee (Hodges and Legendre): Small Animal Clinical Science, University ofminnesota (Adarns); Department qfsma11 Animal Medicine and Surgery, Texas A&M University (Willard); private practice, Duluth, MN (Pitts), Edgewood, KY (Monce), Nokesville, VA (Needels); and Department of Small Animal Clinical Sciences, University of Florida (Ward). Accepted December 28, The authors thank to Junssen Research Foundation,fi)r providing the itraconuzole used in this study. The authors also thank Becky Greene,for her clerical assistance. Dr Hodges' present address is Wyncote Animal Hospital, 6701 Wyncote Ave, Philadelphia, PA I9138. Reprint requests: Alfied M. Legendre, DVM, MS, Department of Urban Practice, College of Veterinarv Medicine, University of Tennessee, PO Box 1071, Knoxville, TN Copyright 0 I994 by the American College of Veterinary Internal Medicine /94/0806-0OOS$3.0O/O Journal of Veterinary Internal Medicine, Vol8, No 6 (November-DecemberJ. 1994: pp

2 410 HODGES ET AL were lesions affecting the anterior or sterior chambers of the eye in 3 cats, and multifocal lytic lesions affecting the ulna and radius in 1 cat (Table I). Method of Diagnosis The diagnosis of histoplasmosis was made by cytological, histological, or culture methods (Table I). The diagnosis was confirmed histopathologically in all 8 cats. Histoplasma organisms were detected in the bone marrow of 2 cats. Bone marrow aspirates were characterized by hypercellularity, decreased erythroiesis, normal granuloiesis, and megakaryoiesis, and increased macrophage numbers containing histoplasma organisms. In 2 cats, cytological examination of transtracheally obtained aspirates revealed histoplasma organisms, and a bronchial lavage yielded organisms in 1 cat (Table 1). Fungal cultures of cutaneous nodules identified H cupsulutum in I cat. Serology for histoplasma antigens (agar gel immunodiffusion test) was sitive in 1 of 3 cats. Previous Therapy Five cats had previously been unsuccessfully treated with a variety of doses and regimens of ketoconazole. Amphotericin B and fluconazole were used in 1 cat each. Preitraconazole Treatment Laboratory Findings All cats had complete blood counts (CBC) and serum chemistry profiles performed on 0,30,60,90, and 120 of the itraconazole treatment. Table I summarizes the pretreatment clinicopathologic abnormalities. Most cats that had been affected for 8 to 1 1 weeks had normal CBCs. High serum liver enzyme activities (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) were documented in most cats (Table 1). The increased ALT activities noted in cats no. 4 and 7 were attributed to prior ketoconazole therapy. Hypercalcemia was present in cats 1 and 2 (calcium concentration 13.9 mg/dl and 12.2 mg/dl; reference range, 8 to 10 mg/dl). In both cats the serum calcium concentrations decreased after approximately 30 of itraconazole treatment. Serum creatinine concentrations were increased in cat no. 6 (creatinine concentration 6.1 mg/dl; reference range, 0.5 to 1.2 mg/dl) and no. 8 (2.5 mg/dl; reference range, 0.7 to 1.5 mg/dl). Azotemia persisted in these 2 cats with renal insufficiency despite therapy. All cats were negative for feline leukemia virus (FeLV) serum p27 antigen, and antibodies against feline imunodeficiency virus (FIV). Resnse to Therapy Itraconazole was administered PO bid at a dose of 5 mg/kg for 60 or more (Table 1). The itraconazole capsules were opened and the pellets were mixed with food. All cats experienced clinical improvement on itraconazole therapy, but cats no. I and 6 relapsed 10 months and 6 months after discontinuation of itraconazole, respectively. Reinstitution produced clinical improvement and subsequent remission in both cats. In cat no. 8, enucleation of the left eye was used as adjuvant therapy. In this cat, itraconazole was administered for 120, and the eye was enucleated after 60 of itraconazole. Histopathology revealed histoplasma panophthalmitis. One cat was euthanized because of renal failure 42 after completion of itraconazole treatment; there was no histopathologic evidence of histoplasmosis. Posttreatment Itraconazole Laboratory Findings Three cats (cats I, 3, and 4) had mild to moderate asymptomatic increases in serum ALT activity while receiving itraconazole (Table 1). The increases occurred approximately 60 after itraconazole treatment. No other abnormal laboratory findings were observed during the period of itraconazole therapy. Discussion In our study, histoplasmosis affected cats of all ages. However, the cats most frequently affected were less than 4 and older than 7 years of age. The majority of previously rerted cases occurred in cats under 4 years of age.4 Females accounted for 80% of the cats in our series, in contrast with the lack of sex predilection previously rep~rted.~'~.'~.' I Ma ny organ systems were affected. Pulmonary disease, granulomatous chorioretinitis, and lameness caused by bone involvement were common, which is similar to the clinical findings previously rerted.133,6,10-'4 In agreement with previous rerts, all the cats were serologically negative for FeLV and FIV.2,3,12913 ocytic, normochromic, nonregenerative anemia was the most common hematologic abnormality (n = 3), and was attributed to chronic inflammation. 12,) 3,15,16 One cat was leukopenic and 1 cat had leukocytosis. Pancytopenia has been rerted in cats with histoplasm~sis.'~ The mechanism of hypercalcemia in two of the cats in this rert may be similar to that associated with blastomycosis in dogs." The prosed mechanism of hypercalcemia in granulomatous disorders is increased bone resorption. Mediators of bone resorption include prostaglandin E and osteoclast-activating

3 Table 1. Case Summaries of 8 Cats With Histoplasmosis Treated With Itraconazole Laboratory Results (normal reference range) Sites of Adverse nt Clinical Findings Involvement Method of Diagnosis Previous Rx PRE-ITRA POST-ITRA Dose/Duration Effects O Dyspnea. lethargy, Eyes. and lung Conjunctival biopsy right anorexia, and eye (organism ID), chorioretinitis transtracheal wash ou (organism ID), and Lethargy, anorexia, depression, and pyrexia Anorexia, dyspnea. weight loss, pyrexia, icterus. and vomiting Lethargy, depression, and pyrexia Bone marrow, and osteolysis; proximal radius/ ulna Bone marrow cytology buffy coat (organism ID) Amoxicillin and clavulanic acid, tetracycline HCI, and s t a n o z o I o I (AGID). Depression, anorexia, cough, and cutaneous nodules Cutaneous nodules; face, ears, nose, sneezing, wheezing. and anterior uveitis Lung and skin Skin, eye, and kidney Needle biopsy of cutaneous nodules Histopathology of cutaneous nodules and fungal culture (organism identified on histopathology and culture) Ketoconazole for 150 Ketoconazole for 60 Weight loss, jaundice. and pale mucous membranes Lung. Eyes, liver, peripheral lymph nodes (liteal/ submandibular), Rt/Lf carpus, and kidneys Tracheobronchial brushing, bronchial lavage, fine-needle lung aspirate (organism ID), and Bone marrow cytology histoplasma serology Impression smear of spleen and histopathology; spleen, liver, lymph nodes (organism ID on histopathology of spleen) Cytology, lymph node (organism ID); histopathology, eye (organism ID) Amoxicillin, prednisone, ketoconazole, trimethoprim and sulfadiazine, and Clindamycin HCI f ALT. 341 IU/L, (8-54); t AST, t ALT, 79 IU/L ( ) after IU/L, (16-40); hyperproteinemia, 8.4 g/dl ( ); hyperglobulinemia, 5.4 g/dl ( ); hypercalcemia, 13.9 mg/dl ( ) Anemia. PCV 16.9% (24-45); thrombocytopenia. 100 X 10 ; relapsed 10 mo after completion of initial treatment 60 cells/rl ( x 10 ); hyperproteinemia. 6.6 g/dl ( ); hypercalcemia, 12.2 mg/dl ( ); hyperphosphatemia. 5.7 mg/dl ( ); t AST, 78 IU/L (16-40); t ALT. 201 IU/L (8-54) Proteinuria, bilirubinuria, and t ALP, 280 IU/L (0-60) t ALT, 78 IU/L (7-6 1 I after Bone marrow Ketoconazole for 18 Leukopenia, 4.4 X 103/rL (5.5- t ALT, 201 IU/L ( ) after 60 Ketoconazole and amphotericin-b 0.5 mg/kg 3 X weekly in DEW for 10 doses Fluconazole 12.5 mg PO bid for 3 mo. prednisone ophthalmic, atropine. prednisone, and chloramphenicol HCL 16.0); t AST, 83 U/L (1 3-46); t ALT, 427 U/L (30-80); t CK, 287 (35-160) Hyperglycemia and t ALP, 50 U/L 5 mg/kg PO for 60 (2-29) Anemia 23% (24-45); t BUN 213 mg/dl (1 0-30); creatinine 6.1 mg/dl(o mg/dl); t phos 23.4 mg/dl (4-7) Anemia, PCV 20% (24-45); leukocytosis, 33.2 x 103/pL (6-19 x 1031~~); t ALT. 160 IU/L (6-3 1 ) Creatinine 2.5 mg/dl 130 ; relapsed 6 mo after initial resnse; 60 additional Rx with itraconazole with itraconazole s: Rx. treatment; ITRA, itraconazole; DSH. domestic shorthair; DLH, domestic longhair; FS. female spayed; MC, male castrated; OU, both eyes; tx. treatment; ID. identified; ALT, alanine aminotransferase; AS se; ALP, alkaline phosphatase; HCI, hydrochloride; phos. phosphorus; PCV. packed cell volume; CRF, chronic renal failure; Rt/lf, right/left; DSW. 5% dextrose in water. Euth da be CR his ev his p 0

4 412 HODGES ET AL factor (OAF) The latter is produced by normal human leukocytes, lymphoma cells, and myeloma cells.2,22 Another mechanism of hypercalcemia involves abnormal metabolism of vitamin D The resolution of the hypercalcemia in association with the resnse to itraconazole in these 2 cats suggest a cause-effect relationship. The development of ketoconazole represented an imrtant advancement in the treatment of histoplasm~sis.~~-~ However, toxic effects of ketoconazole are common and include anorexia, vomiting, and hepatosis.28 Five of the cats in this study had received ketoconazole as initial antifungal medication, but the treatment was discontinued because of adverse effects. Itraconazole is effective in many of the localized and systemic mycoses. Administered PO, itraconazole was an effective treatment for aspergillosis and meningocerebral cryptococcosis in mice.* It is often effective in the treatment of both naturally and experimentally acquired feline cryptococcosis.29~30 Itraconazole also effectively eliminated Microsvum canis dermatophytosis in a Persian cat.31 Itraconazole has advantages over ketoconazole. It is well tolerated when administered in food, and the only frequent adverse effect was an asymptomatic, mild-to-moderate increase in serum ALT activity, which was detected in 3 of the cats. In another study, 17 of 18 cats given 50 to 100 mg of itraconazole per day for 5 to 9 months had no serious adverse effects.29 However, approximately 50% of those cats had mild anorexia or slight increases in serum ALT activity. The adverse effects seemed dose dependent and abated when the dose was reduced. Itraconazole seems to be more effective than ketoconazole in cats with histoplasmosis, because it resulted in cure in 6 of the 8 cats with a single course of treatment. This is especially relevant because 5 of these 6 cats were refractory to or could not tolerate ketoconazole therapy. Itraconazole was well tolerated and caused fewer adverse effects than ketoconazole in these cats. Itraconazole has a broader spectrum of activity than ketoconazole, even though the triazoles have a similar mode of action to the imidazoles (eg, keto~onazole).~~-~~ The free azole nitrogen competes for oxygen at the catalytic heme iron atom of cytochrome P-450 enzymes, and prevents synthesis of ergosterol in fungal cell membrane^.^' Itraconazole has a higher binding affinity for fungal than mammalian cytochrome P- 450 enzyme^.^'.^^.^^ When ergosterol synthesis is disrupted, cell wall permeability increases and fungal growth is inhibited.36 Itraconazole is a lipid-soluble drug, best absorbed when ingested with food.37 In dogs, peak plasma concentration occurs within 3 hours of a single oral dose, and the plasma half-life is 8 to 12 hours.37 In people, itraconazole has a long half-life of 17 hours, and it re- quires 10 to 14 to reach steady state.34 Itraconazole is extensively metabolized, with the biliary route being the principal route of excretion.34 In dogs and people, more than 99% of itraconazole is bound to plasma proteins, primarily albumin.37 In dogs, high concentrations are achieved in the lungs, kidneys, liver, adrenal glands, and skin.37 Small amounts ofthe drug are found in the cerebrospinal fluid, eye, and plasma.37 Despite the low intraocular concentrations of itraconazole ocular lesions resolved in all 3 cats receiving the standard dose for periods of 3 to 6 months. Itraconazole was effective in dogs with blastomycosis involving the eye.38 Itraconazole pharmacokinetics are not altered in people with renal or hepatic ins~fficiency.~~ The cats with renal failure were given the standard 5-mg/kg dose of itraconazole bid. Therapy was not halted because of renal insufficiency. In summary, itraconazole seems to be an effective and well-tolerated drug for the treatment of histoplasmosis in cats. The small number of cats treated in this study limits the conclusions that can be made regarding efficacy and toxicity of itraconazole. Our study suggests that additional clinical investigations of itraconazole in cats with histoplasmosis are warranted. References 1. Breitschwerdt EB, Halliwell WH, Burk RL, et al. Feline histoplasmosis. J Am Anim Hosp Assoc 1977; 13: Wolf AM, Troy GC. Deep mycotic diseases. In: Ettinger SJ, ed. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Philadelphia, PA: WB Saunders; 1989: Wolf AM, Belden MN. Feline histoplasmosis: A literature review and retrospective study of 20 new cases. J Am Anim Hosp Assoc I984;20: Wolf AM. Histoplasmosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. Philadelphia, PA: WB Saunders; 1990: Hermans PE. Antifungal agents used for deep-seated mycotic infections. Mayo Clin Proc 1977;52: Gwin RM, Makley TA Jr, Wyman M, et al. Multifocal ocular histoplasmosis in a dog and cat. J Am Vet Med Assoc 1980; 176: Mahaffey E, Gabbert N, Johnson D, et al. Disseminated histoplasmosis in three cats. J Am Anim Hosp Assoc 1977; 13: Van Cutsen J, Van Gerven F, Janessen PAJ. Activity oforally, topically and parenterally administered itraconazole in the treatment of superficial and deep mycoses: Animal models. Rev Infect Dis 1987;9:15-32(suppl I).

5 ITRACONAZOLE TREATMENT OF HISTOPLASMOSIS IN CATS Negroni R, Palmieri F, Karen IN, et al. Oral treatment of paracoccidioidomycosis and histoplasmosis with itraconazole in humans. Rev Infect Dis 1987;9: Pedersen NC. Fungal diseases. In: Feline Infectious Diseases. Goleta, CA: American Veterinary Publications, 1988: I Barsanti JA. Blastomycosis, histoplasmosis, cryptococcosis. In: Greene CE, ed. Clinical Microbiology and Infectious Diseases of Dog and Cat. Philadelphia, PA: WB Saunders; 1984: Clinkenbeard KD, Cowell RL, Tyler RD. Disseminated histoplasmosis in cats: 12 Cases. J Am Vet Med Assoc 1987; 190: Clinkenbeard KD, Wolf AM, Cowell RL, et al. Feline disseminated histoplasmosis. Compend Contin Educ Pract Vet 1989;11: Wolf AM. Histoplasma capsulatum osteomyelitis in the cat. J Vet Intern Med 1988; 1: Jain NC. Schalm s Veterinary Hematology, 4th ed. Philadelphia, PA: Lea & Febiger; Duncan JR, Prasse KW. Veterinary Laboratory Medicine, 2nd ed. Ames, IA: Iowa State University Press; 1986: Gabbert NH, Campbell TW, Beiermann RL. Pancytopenia associated with disseminated histoplasmosis in a cat. J Am Anim Hosp Assoc 1984;20: Dow SW, Legendre AM, Stiff M, et al. Hypercalcemia associated with blastomycosis in dogs. J Am Vet Med Assoc 1986; 188: DSouza SM, Englis DJ, Clark T, et al. A factor from mononuclear cells stimulates prostaglandin E production by human gingival cells. Biochem SOC Trans 1980;8: Dominquez JH, Mundy GR. Monocytes mediate osteoclastic bone resorption by prostaglandin production. Calcif Tissue Int 1980;31: Mundy GR. The hypercalcemia of cancer. N Engl J Med 1984;310: Lemann J, Gray RW. Calcitrol, calcium and granulomatous disease. N Engl J Med 1984;311: Stern PH. Evidence for abnormal regulation of circulating 1,24-dihydroxy vitamin D in patients with sarcoidosis and normal calcium metabolism. J Clin Invest 1980;66: Bell HN. Evidence that increased circulating I,25-dihydroxy vitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest 1979;64: National Institute of Allergy and Infectious Diseases: Mycosis Study Group. Treatment of blastomycosis and histoplasmosis with ketoconazole. Ann Intern Med 1985; 103: Negroni R, Robles AM, Arechovala A, et al. Ketoconazole treatment of paracoccidioidomycosis and histoplasmosis. Rev Infect Dis 1980; Slama TG. Treatment of disseminated and progressive cavitary histoplasmosis with ketoconazole. Am J Med 1983;74: Pentlarge VW, Martin RA. Treatment of cryptococcosis in three cats, using ketoconazole. J Am Vet Med Assoc 1986; 188: Medleau L. Treatment of feline cryptococcus with itraconazole. In: Proceedings; Annual Conference of the American Academy of Veterinary Dermatology. St Louis, MO, 1989: Medleau L, Greene CE, Rakich PM. Evaluation of ketoconazole and itraconazole for treatment of disseminated cryptococcoskin cats. Am J Vet Res 1990;51: Mundell AC. New therapeutic agents in veterinary dermatology. Vet Clin North Am Small Anim Prac 1990;20: Saag MS, Dismukes WE. Azole antifungal agents: Emphasis on new triazoles. Antimicrob Agents Chemother 1988;32: Vanden Bossche H. Biochemical targets for antifungal azole derivatives: Hythesis on the mode of action. Cum Top Med Mycol 1985; 1: Baily EM, Krakovsky DJ, et al. The triazole antifungal agents: A review of itraconazole and fluconazole. Pharmacotherap 1990; 10: Hanger DP, Land G, Mamott MS, et al. The activity and selectivity of the novel, bis triazole UK for fungal sterol 14- alpha demethylation. Program and Abstracts of the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy. Minnealis, MN: American Society for Microbiology; 1985:243 (abstr). 36. Bargers M, Van de Ven MA. Degenerative changes in fungi after itraconazole treatment. Rev lnfec Dis 1987;9: (suppl I). 37. Van Cauteren H, Heykants JDE, Caster R, et al. Itraconazole: Pharmacologic studies in animals and humans. Rev Infect Dis 1987;9:~43-~46 (SUPPI). 38. Brooks DE, Legendre AM, Gum GG, et al. The treatment of canine ocular blastomycosis with systemically administered itraconazole. Prog Vet Compar Ophthal 1991; 1 : Ringel SM. New antifungal agents for the systemic mycoses. Mycopathologia 1990; 109:75-87.