Kurita N, Brummer E, Oarada M, Miyaji M
Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8673, Japan.
Med Mycol. 2003 Apr;41(2):131-6. doi: 10.1080/mmy.41.2.131.136.
To better understand the in vivo efficacy of fluconazole (FCZ), we investigated the possible synergy of fungistatic FCZ with human polymorphonuclear leukocytes (PMN) against Paracoccidioides brasiliensis (Pb). The effect of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in this system was also studied. For this purpose, FCZ, PMN, PMN + FCZ, PMN + IFN-gamma, PMN + IFN-gamma + FCZ, PMN + GM-CSF and PMN + GM-CSF + FCZ were co-cultured with Pb and the cfu of Pb was measured. The antifungal effect of FCZ on yeast cells of Pb was concentration-dependent. At 0.1 microg ml(-1), FCZ had no effect on the growth of Pb. At 0.2 microg ml(-1) FCZ showed a growth-inhibitory effect on three isolates of Pb in a long-term (120 h) assay, and at 0.6 microg ml(-1) or higher FCZ was fungicidal. Fungistatic concentration of FCZ (0.4 microg ml(-1)) acted synergistically with fungistatic PMN for killing isolate Bt-4 during the first 24 h of co-culture. Moreover, IFN-gamma and GM-CSF substantially enhanced the synergistic antifungal effect of PMN and FCZ. These findings provide a better understanding of why FCZ is more efficacious in in vivo models of paracoccidioidomycosis than is predicted by in vitro susceptibility tests.
为了更好地了解氟康唑（FCZ）的体内疗效，我们研究了抑菌性FCZ与人类多形核白细胞（PMN）联合抗巴西副球孢子菌（Pb）的可能协同作用。还研究了干扰素-γ（IFN-γ）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）在该系统中的作用。为此，将FCZ、PMN、PMN + FCZ、PMN + IFN-γ、PMN + IFN-γ + FCZ、PMN + GM-CSF和PMN + GM-CSF + FCZ与Pb共培养，并测定Pb的菌落形成单位（cfu）。FCZ对Pb酵母细胞的抗真菌作用呈浓度依赖性。在0.1μg/ml时，FCZ对Pb的生长没有影响。在0.2μg/ml时，FCZ在长期（120小时）试验中对三株Pb分离株显示出生长抑制作用，在0.6μg/ml或更高浓度时FCZ具有杀菌作用。抑菌浓度的FCZ（0.4μg/ml）与抑菌性PMN在共培养的前24小时协同作用以杀死Bt-4分离株。此外，IFN-γ和GM-CSF显著增强了PMN和FCZ的协同抗真菌作用。这些发现有助于更好地理解为什么FCZ在副球孢子菌病的体内模型中比体外药敏试验预测的更有效。
