Chagas disease reactivation in HIV-positive people is an opportunistic infection with 79 to 100% mortality. It commonly involves the central nervous system (CNS). Early treatment with trypanocidal drugs such as benznidazole (BNZ) is crucial for this severe manifestation of Trypanosoma cruzi infection. However, limited BNZ clinical pharmacology data are available, especially its concentration in the CNS. We report a series of HIV-positive patients undergoing treatment for T. cruzi meningoencephalitis, their clinical response, and cerebrospinal fluid (CSF) and plasma BNZ concentrations. Measurements were carried out using leftover samples originally obtained for routine medical care. A high-performance liquid chromatography/tandem mass spectrometry bioanalytical method designed for BNZ plasma measurements was adapted and validated for CSF samples. Six patients were enrolled in this study from 2015 to 2019. A total of 6 CSF and 19 plasma samples were obtained. Only three of the CSF samples had detectable BNZ levels, all under 1 µg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2 µg/ml, which is the putative trypanocidal level. We observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or not measurable in all patients, suggesting that the usual BNZ doses may be suboptimal in HIV-positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. These findings highlight the potential of therapeutic drug monitoring in BNZ treatment and suggest that the use of higher doses may be useful for Chagas disease CNS reactivations.

中文翻译：

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脑脊液中的苯硝唑：HIV 阳性患者的恰加斯病脑膜脑炎病例系列

HIV 阳性人群的恰加斯病再激活是一种机会性感染，死亡率为 79% 至 100%。它通常涉及中枢神经系统 (CNS)。早期使用杀锥虫药物如苯硝唑 (BNZ) 进行治疗对于克氏锥虫感染的这种严重表现至关重要。然而，可获得的 BNZ 临床药理学数据有限，尤其是其在 CNS 中的浓度。我们报告了一系列接受克氏锥虫治疗的 HIV 阳性患者脑膜脑炎、它们的临床反应以及脑脊液 (CSF) 和血浆 BNZ 浓度。使用最初为常规医疗护理获得的剩余样品进行测量。一种为 BNZ 血浆测量设计的高效液相色谱/串联质谱生物分析方法适用于脑脊液样本并进行了验证。2015-2019 年共纳入 6 名患者，共获得 6 份 CSF 和 19 份血浆样本。只有三个 CSF 样本具有可检测的 BNZ 水平，均低于 1 µg/ml。15 个血浆样本中可检测到 BNZ，其中 13 个高于 2 µg/ml，这是推定的锥虫杀灭水平。我们观察到人脑脊液和血浆中的 BNZ 浓度。所有患者的脑脊液 BNZ 浓度都很低或无法测量，T. cruzi脑膜脑炎。虽然药物-药物和药物-疾病相互作用可能是部分原因，但导致脑脊液 BNZ 水平低的因素仍有待详细研究。这些发现突出了 BNZ 治疗中治疗药物监测的潜力，并表明使用更高剂量可能对南美锥虫病中枢神经系统的再激活有用。