Comparison of the effectiveness of a daily dose of co-trimoxazole, administered once or twice, in the treatment of murine Paracoccidioidomycosis

Introduction. Paracoccidioidomycosis (PCM) is systemic mycosis caused by thermodymorphic fungi of the genus Paracoccidioides. Trimethoprim-sulfamethoxazole, also called cotrimoxazole (CMX), is one of the main therapeutic options. In the current treatment of PCM, CMX is used in the dose of 2,400 mg of sulfamethoxazole, which corresponds to six tablets divided into two daily doses, a fact that has led to the patient's lower adherence to antifungal therapy. Experimental studies have observed that the single daily dose may be sufficient to treat PCM. Objective. This study aimed to evaluate the efficacy of murine PCM treatment with CMX administered in one and two daily doses. Methods. One hundred male, isogenic mice of the Balb / c line were randomly assigned to 4 groups: healthy control (G1), infected control (G2) and infected groups receiving CMX once (G3) and twice daily (G4). After 28 days of infection, treatment was started, with evaluation of lung and spleen fungal recovery, histopathological examination of the lungs and serum analysis of specific antibodies anti-P. brasiliensis by double agar gel immunodiffusion (DID) at weeks 8 , 12, 16 and 20 after infection. The same animals were evaluated for cumulative survival at 140 days. The Kruskal-Wallis and Mann-Whitney tests were used for comparison of medians, linear regression to analyze the parameters in the successive moments of sacrifice and Kaplan-Meier for the evaluation of survival. P values less than 0.05 were considered significant. Results. The two groups treated with CMX (G3 and G4) showed improvement in the appearance and behavior of the animal, a decrease in serum antibody levels by DID (G3: p=0.005, G4: p=0.01), reduction of lung fungal load by histopathological examination in the 16th and 20th weeks (p<0.01) and a lower percentage of collagen fibers per bronichiolar area at the 20th week (p <0.05). There was no difference in fungal recovery in lung and spleen, fungal load counted by histopathological examination of lung and percentage of collagen fiber per bronchiolar area between G3 and G4 at weeks 8, 12, 16 and 20. However, DID levels tended to be lower in G4 than in G3 at week 8 of treatment (1:4 vs. 1:16, p=0.08). G4 presented lower fungal recovery of the lungs at the 8th and 12th weeks and in the spleen at weeks 16 and 20 when compared to the infected control. There was no difference in cumulative mortality between G3 and G4 (0.0% vs 4.0%). Conclusions. These findings demonstrate efficacy of the two murine PCM treatment regimens with CMX. Although there were no direct differences between the two CMX treatment regimens, the group receiving two doses per day presented a higher response when compared to the infected control, a fact that did not occur with the single daily dose group. This suggests that differences may exist between the two schemes and that future studies are needed to better understand the efficacy of these therapeutic regimens.

Comparison of the effectiveness of a daily dose of cotrimoxazole, administered once or twice, in the treatment of murine Paracoccidioidomycosis