Comparison between Itraconazole and Cotrimoxazole in the Treatment of Paracoccidiodomycosis Ricardo de Souza Cavalcante 1 *, Tatiane Fernanda Sylvestre 1 , Adriele Dandara Levorato 1 , Lı´dia Rachel de Carvalho 2 , Rinaldo Poncio Mendes 1 1 Tropical Diseases Department – Faculdade de Medicina de Botucatu – Universidade Estadual Paulista (UNESP), Botucatu, Sa ˜ o Paulo state, Brazil, 2 Instituto de Biocie ˆncias de Botucatu – UNESP, Botucatu, Sa ˜o Paulo, Brazil Abstract Background: There are no published reports on studies comparing itraconazole (ITC), sulfamethoxazole-trimethoprim (cotrimoxazole, CMX), and ITC followed by CMX (ITC/CMX) in the treatment of paracoccidiodomycosis. This study aimed to compare the efficacy, effectiveness, safety and time to clinical and serologic cure in paracoccidioidomycosis patients treated with ITC or CMX, the antifungal agents most widely used. Methodology: A quasi-experimental study was performed in 177 patients with a confirmed or probable diagnosis of paracoccidioidomycosis. Treatment was divided into two stages: 1) initial, which was continued until clinical cure was achieved and the erythrocyte sedimentation rate decreased to normal values; 2) complementary, which was continued until serologic cure was achieved. Medians were compared via the Mann-Whitney test, and frequencies were compared via the chi-squared test. The assessment of variables as a function of time was performed using Kaplan-Meier curves and Cox regression. The significance level was established as p#0.05. Principal Findings: No difference was found in the efficacy and effectiveness of the initial treatment of 47 individuals given ITC and 130 individuals given CMX; however, the time to clinical cure was shorter in the former compared with the latter group (105 vs. 159 days; p = 0.001), specifically in patients with the chronic form. Efficacy and effectiveness of the three regimens were similar in the complementary treatment; however, the time to serologic cure was shorter when ITC (161 days) or CMX (495 days) was used compared with ITC/CMX (881 days) [p = 0.02]. The independent predictors of a shorter time to serologic cure were treatment with ITC [risk ratio = 6.61 (2.01–21.75)] or with CMX [risk ratio = 5.11 (1.91–13.67)]). The prevalence of side effects was lower with ITC (6.4%) than with CMX (20.0%; p = 0.03). Conclusions: Since ITC induced earlier clinical cure and was better tolerated than CMX, such triazole should be considered the first-choice for PCM treatment. Citation: Cavalcante RdS, Sylvestre TF, Levorato AD, de Carvalho LR, Mendes RP (2014) Comparison between Itraconazole and Cotrimoxazole in the Treatment of Paracoccidiodomycosis. PLoS Negl Trop Dis 8(4): e2793. doi:10.1371/journal.pntd.0002793 Editor: Richard James Hamill, Baylor College of Medicine, United States of America Received October 7, 2013; Accepted March 3, 2014; Published April 17, 2014 Copyright: ß 2014 Cavalcante et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors received no specific funding for this study. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mip.ricardo@gmail.com Introduction Paracoccidiodomycosis (PCM) is an endemic mycosis in Latin America caused by dimorphic fungi belonging to the Paracoccid- ioides brasiliensis complex and the Paracoccidioides lutzii complex, whose natural habitat is soil [1]. PCM exhibits three main clinical forms: a) acute/subacute, which prevails among children, adoles- cents, and young adults and affects organs rich in mononuclear phagocyte system elements; b) chronic, which affects adults, mostly rural workers and men, and is characterized by the involvement of the lungs and the upper digestive and airway mucous membranes; and c) residual, which comprises the sequelae remaining after efficacious treatment, especially in the lungs, larynx, and adrenal glands [2]. The appropriate treatment of PCM began 32 years after its initial description by Adolfo Lutz (1908) [3] with sulfapyridine (1940) [4], and was followed by amphotericin B (1958) [5], trimethoprim-sulfamethoxazole combination, called cotrimoxa- zole – CMX (1973) [6], ketoconazole (1979) [7,8], itraconazole – ITC (1987) [9,10,11,12] and voriconazole (2007) [13]. Despite the development of these therapeutic agents in the last decades, only four comparative studies have been conducted to date [13,14,15,16]. In 2006, the first Brazilian guidelines on the diagnosis and treatment of PCM was published, recommending ITC and CMX as first- and second-choice agents, respectively [17]. Only two previous studies comparing ITC and CMX in the treatment of PCM patients were performed [18,19]. The aim of the present study was to compare the efficacy, effectiveness, and safety of ITC and CMX during the initial and complementary treatment of PCM and to compare the time to achieve clinical cure, the return of the erythrocyte sedimentation rate (ESR) and acute-phase reactants to the normal levels, and persistent negativation of the double immunodiffusion (DID) reaction in agar gel. PLOS Neglected Tropical Diseases | www.plosntds.org 1 April 2014 | Volume 8 | Issue 4 | e2793