Abstract
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.
Highlights
Invasive fungal infections are an important cause of morbidity and mortality, especially in immunocompromised and/or hospitalized patients with serious underlying diseases [1,2]
In order to improve Pneumocystis pneumonia (PcP) treatment and to overcome the potential intolerance and adverse effects of the standard antiPneumocystis spp. drugs, the aim of the present study was to evaluate the susceptibility of Pneumocystis spp. organisms to low doses of caspofungin alone and caspofungin in association with TMPSMX, in the rodent model
Evaluation of P. murina Infection Levels The results obtained for quantitative fluorescent-based real-time PCR (qPCR) quantification of P. murina mtLSU
Summary
Invasive fungal infections are an important cause of morbidity and mortality, especially in immunocompromised and/or hospitalized patients with serious underlying diseases [1,2]. Pneumocystis pneumonia (PcP) is a common and serious life-threatening opportunistic disease in hosts with impaired/debilitated immune systems, especially HIV-positive persons, and in patients who are undergoing immunosuppressive treatments related to malignancies, connective tissue diseases or organ transplantation. These organisms are emerging as a co-morbidity factor associated with chronic diseases such as chronic obstructive pulmonary disorder (COPD) [3,4,5,6,7]. The host succumbs to respiratory failure and related organ dysfunction [6,10]
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