Treatment of Blastomycosis With Itraconazole in 112 Dogs Alfred M. Legendre, Barton W. Rohrbach, Robert L. Toal, Michael G. Rinaldi, Linda L. Grace, and Janet B. Jones One hundred twelve client-owned dogs with blastomycosis times between dogs without lung disease or with mild lung were treated with itraconazole, 5 or 10 mg/kg/d. The first disease compared with dogs with moderate or severe lung group of 70 dogs treated in 1987 and 1988 received 10 mg/ disease. Serum itraconazole concentrations reached steady kg/d (group 1). and the second group of 42 dogs treated after state by 14 days of treatment. Dogs receiving 5 mg/kg/d of October 1988 received 5 mg/kg/d (group 2). Even though the itraconazole (group 2) had mean serum concentrations of groups were treated at different times, the dogs were similar 3.55 5 2.81 mg/mL (range, 0.67 to 10.8 pglmL), whereas in age and gender distribution, number of sites involved, dogs receiving 10 pg/kg/d (group 1) had mean concentra- and percent and severity of pulmonary involvement. The tions of 13.46 ? 8.49 pglmL (range, 1.8 to 28 pglmL) (P c proportion of dogs cured with a 60-day course of itracona- .001). There was no association between cure and serum zole was similar for both groups (53.6% versus 54.3%) and itraconazole concentrations. Dogs in group 1 had signifi- for a second historical control group treated with amphoteri- cantly more adverse effects than dogs in group 2 (P = ,046). cin B (57%); the recurrence rate was also similar, 20%. 21.4%, Anorexia was the most common adverse effect, occurring and 20%. respectively. Dogs treated with itraconazole had in 14.9% of dogs in group 1. Only 8% of dogs in group 2 had similar mortality rates (25.7% at 5 mg/kg/d; 25% at 10 mg/ adverse effects. Serum concentrations of itraconazole were kg/day) to those treated with amphotericin B (23%). Seven- positively correlated with serum alkaline phosphatase and teen of the 23 dogs that died (74%), did so during the first alanine aminotransferase activities. Our findings indicate week of treatment; these early deaths were usually attrib- that itraconazole administered at a dose of 5 mglkgld is the uted to respiratory failure. The only site of infection that was drug of choice for blastomycosis in dogs. significantly associated with failure (death or recurrence) J Vet Intern Med 1996;10:365-371. Copyright 0 1996 by the was the brain. There was a marked difference in survival American College of Veterinary Internal Medicine. lastomycosis is a systemic fungal infection of the dog. dog with neurological signs referable to the brain was considered to B The disease is common in the Mississippi, Missouri, have brain involvement. Prior to receiving itraconazole, a work sheet and Ohio river basins, as well as in Wisconsin and the central was completed by the clinician identifying the sites of infection Atlantic Amphotericin B administered IV has been found during the clinIcal evaluation. Owners were asked to return their dogs for re-evaluation after 30 and 60 days of treatment and the treatment of choice since the 1960~.~-'However, renal to report any problems. Thoracic radiographs were repeated at the toxicosis often occurs during amphotericin B treatment; end of the treatment period (60 days). therefore, an easier-to-use and less toxic treatment has been sought. Ketoconazole, an imidazole administered PO, is ef- ltraconazole Treatment fective in dogs with blastomycosis,"'" but the responses to treatment occur more slowly, and the cure rate is less than Dogs in group I (n = 70) evaluated in 1987 and 1988 received itraconazole 10 mg/kg/d PO for 60 days divided into 2 doses and that obtained with amphotericin B.'" administered with food. Starting in October of 1988, the remaining Itraconazole, a triazole, was developed by Janssen Phar- dogs in group 2 (n = 42) received itraconazole 5 mg/kg/d PO with maceutica in 1980 and became available for treatment of food. After the change in protocol, there were 7 dogs that received fungal infections in humans in October 1992. We report the a dose of 10 mg/kg/d. This occurred because participating clinicians results of treatment with itraconazole PO in 112 dogs with were unaware of the change in protocol or feared that the dogs blastomycosis. would not he adequately treated with a lower dose. Materials and Methods ltraconazole Toxicity Dogs Dogs were routinely evaluated at 30-day intervals during the itra- The 112 dogs in this study were client-owned animals. Some dogs conazole treatment, and owners were asked to notify us if the patient were brought directly to the Veterinary Teaching Hospital hut most were referred by area veterinarians. Dogs were treated from January 1987 to June 1990. From the Department of Small Animal Clinical Sciences (Leg- endre, Grace and Jones) and the Department of Large Animal Clini- Inclusion Criteria cal Sciences (Rohrbuch and Toal), The University of Tennessee, To he included in the itraconazole study, a cytological or histo- Knoxville, TN and the Fungus Testing Lnboratory (Rinaldi), The pathologic diagnosis of blastomycosis was required, and owners had University of Texas Health Science Center at Sun Antonio, Depart- ment of Pathology, Sun Antonio, Texas. to sign a consent form to use an investigational drug, and agree to return the dog for re-evaluation. Acceptgd March 15, 1996. The authors thank ull the clinicians who caredftw these dogs and Junssen Pharmaceuticu, which provided the itraconazole. Clinical Evaluation Reprint requests: Atfred M.Legendre, DVM, Department of Small A history, physical examination, CBC, and serum biochemical Animal Clinical Sciences, Universit?, of Tennessee, Knoxville, TN analysis were obtained in all dogs. Ophthalmic evaluation was per- 3 7901- 107 I. formed if ocular disease was suspected during initial examination. Copyright 0 1996 by the American College of Veterinary Internal Thoracic radiographs were taken in all patients, and radiographs of Medicine specific hones were taken if there was evidence of lameness. Any 0891 -6640/96/1006-0004$3.00/0 Journal of Veterinary Internal Medicine, Vol 10, No 6 (November-December), 1996: pp 365-371 365 366 LEGENDRE ET AL was anorexic, vomiting, or had other problems. In addition to physi- the authors (AML) suspected blastomycosis from a description given cal examination, serum biochemical analysis was performed to moni- by the owner, even though the diagnosis was not confirmed. Dogs tor liver enzyme activities. Increase in serum alkaline phosphatase in those cases where contact with the owners had been lost, dogs (SAP) activity was classified as mild (73 to 200 IU/L; reference that ran away from home, or dogs that died from defined causes range, 12 to 72 IU/L), moderate (201 to 400 IU/L), and severe (>400 unrelated to blastomycosis less than 426 days after the start of treat- IU/L). Increase in serum alanine aminotransferase (ALT) activity ment were classified as lost to follow-up. In our analysis, these dogs was classified as mild (76 to 200 IU/L; reference range, 20 to 75 were given credit for the time they spent under observation. For IU/L), moderate (201 to 400 IUIL), and severe (>400 IU/L). analysis of the risk factors, the groups with a negative response (death and relapse) were combined into a treatment failure group Procedures for Handling Complications and compared with the cured group (no relapse and alive and well for at least 426 days after the start of treatment). The attending clinician was given the option to continue treatment if clinical signs had not resolved at the end of the treatment period. The dose of itraconazole was usually decreased from bid to sid (10 Severity of Lung Disease mg/kg/d to 5 mg/kg/d) if signs of drug-associated toxicosis (anorexia, The severity of lung disease at the time of initial examination was lethargy, ulcerative dermatitis, increases in ALT activity above 300 determined by review of lung radiographs by one radiologist (RLT). U/L) occurred. If toxicosis was suspected in the dogs receiving 5 Severity of lung disease was classified by previously published crite- mg/kg/d (group 2), the drug was discontinued and restarted at the ria as: no lesions, 0; mild or localized lung mass, I; moderate, 2; same dose after the signs had abated. Treatment was discontinued moderate to severe, 3; severe, 4."' if toxic effects occurred late in the course of treatment (after 45 days) and the signs of blastomycosis had resolved. Statistical Analysis Interval data were tested for normal distribution using the W test Serum Itraconazole Concentrations developed by Shapiro and Wilk.12 The level of alpha error to deter- Serum itraconazole was quantified by one of the authors (MGR) mine statistical significance for all tests was >0.05. Where possible, using a yeast-nitrogen base agar diffusion bioassay method modified non-normally distributed interval data were transformed using square from the technique described by Bodet et al." Candida fefyr was root or log transformation. Differences in means of interval charac- added to a solution of yeast nitrogen base (YNB) broth and incubated teristics among groups were tested for statistical significance using at 37°C for 6 hours. The solution was adjusted to a No. 2 McFarland the t-test procedure. When we were unable to transform to a normal standard and 0.5 mL was added to 35 mL of melted YNB agar distribution, the Mann-Whitney test for nonparametric data was deeps. The YNB was poured into 150 X 15 mm Petri plates. Each used." Categorical data were evaluated using a X-square or Fisher's 7-mm well bored in the agar was tilled with standards (0.5, 2, 5, Exact Test, depending on whether expected cell values were less and 20 pg/mL), control, or patient unknowns, and the plates were than 5.