Voriconazole

Queiroz-Telles, F.1; Goldani, L. Z.2; Goodrich, J. M.3; Schlamm, H. T.4; Shikanai-Yasuda, M. A.5

1 UFPR - Hospital das Clinicas; 2 UFRGS - Hospital das Clinicas; 3 University of Wyoming, Laramie, USA - Zoology and Physiology; 4 Pfizer Global Research and Development - New York, NY, USA; 5 Fundacao Pro-Sangue - Hemocentro de São Paulo

Introduction and objectives: Paracoccidioidomycosis (PCM), a subacute to chronic systemic mycosis caused by Paracoccidioides brasiliensis. The aim of this study was to investigate the efficacy, safety, and tolerability of voriconazole in the long-term treatment of acute or chronic PCM. with itraconazole as control treatment. Methods: This was a randomized, multicenter, open-label, comparative study conducted in Brazil in 2000-2002, Subjects were randomized (2:1) to receive oral therapy with voriconazole or itraconazole from 6 to 12 months. Satisfactory global response (incorporating clinical, mycologie, radiologic, and serologic assessments) at end of treatment (EOT) was compared for the 2 treatment groups. Results: Fifty-three subjects received at least 1 dose of study drug: 35 received voriconazole and 18 received itraconazole. All but 4 subjects with confirmed PCM (3 on voriconazole. 1 on itraconazole) received at least 6 months of continuous study treatment. The response rates in these treatment-evaluable patients were 100% for both treatment groups, and there were no relapses after 8 weeks of follow-up in either group. All subjects presented lung involvement at baseline: 76% mucosal lesions, 53% lymphonode enlargement. 22% laryngeal involvement and 22%, cutaneous lesions due do P. brasiliensis. One case with both lung and CNS involvement. All subjects responded well to voriconazole.The most common treatment-related events included abnormal vision, chromatopsia. rash, and headache in the voriconazole group, and bradycardia, diarrhea, and headache in the itraconazole group. Two voriconazole subjects were withdrawn prematurely, as required by the protocol, due to study drug-related elevated alk phos and hepatic enzymes (ALT, AST, and GGT). The frequency of liver function test abnormalities was slightly higher in subjects receiving voriconazole compared to itraconazole, but the median changes in these parameters from baseline values were similar between treatment groups. One voriconazole subject expired after 52 days because of a rupture of an aortic aneurysm: an autopsy was performed and was negative for PCM. Conclusions: This is the first study to demonstrate that voriconazole is well tolerated and effective for the long-term treatment of PCM. References: [1] Brummer E, et al. Clin Microbiol Rev. 1993:6:89-117. [2] Blotta MH, et al. Am J Trop Med Hyg. 1999:61:390-4. [3] Perfect JR, et al. Clin Infect Dis. 2003:36:1122-31. [4] Almeida SM, et al. ./ Infect. 2004:48:193-8.

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