Therapeutic Potential of Caspofungin Combined with Trimethoprim-Sulfamethoxazole for Pneumocystis Pneumonia: A Pilot Study in MiceReportar como inadecuado




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Pneumocystis pneumonia PcP is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole TMP-SMX which is the standard first line therapy-prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin-TMP-SMX was evaluated in Balb-c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg-kg, 0.05 mg-kg, and 0.001 mg-kg and TMP-SMX was administered by oral gavage 12.25 mg-62.5 mg-day, for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR qPCR. Serum β-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin-TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin-TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg-kg-day with TMP-SMX 12.5 mg–62.5 mg-day, which reduced the parasite burden to undetectable levels immediately at the 14th day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance.



Autor: Maria Luísa Lobo, Francisco Esteves, Bruno de Sousa, Fernando Cardoso, Melanie T. Cushion, Francisco Antunes, Olga Matos

Fuente: http://plos.srce.hr/



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