Pharmacodynamic Correlates of Linezolid Activity and Toxicity in Murine Models of Tuberculosis.
Pharmacodynamic Correlates of Linezolid Activity and Toxicity in Murine Models of Tuberculosis.
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DOI：
10.1093/infdis/jiaa016
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发表时间：
2021-06-04
期刊：
影响因子：
--
通讯作者：
Nuermberger EL
中科院分区：
文献类型：
--
作者：
Bigelow KM;Deitchman AN;Li SY;Barnes-Boyle K;Tyagi S;Soni H;Dooley KE;Savic RM;Nuermberger EL
利奈唑胺(LZD)对结核分枝杆菌有杀菌作用，但具有治疗限制性毒性。更好地了解支配LZD疗效和毒性的暴露-反应关系将为给药策略提供依据。由于体外单一疗法研究产生了相互矛盾的结果，我们探索了LZD在体内对活跃和非活跃繁殖细菌的药代动力学/药效学(PK/PD)关系，包括与前甘露醇联合使用。利奈唑胺在小鼠体内的多剂量药代动力学模型。剂量分级研究在急性(细菌净生长)和慢性(无净生长)感染模型中进行。在急性模型中，LZD单独或与抑菌或杀菌前甘露醇剂量一起给药。评估PK/PD参数与肺集落形成单位(CFU)和全血计数的相关性。总体而言，超过最低抑菌浓度(T&gT；MIC)的时间与CFU下降的相关性最好。然而，在生长受限模型中(即慢性感染，每天联合应用前甘露醇50 mg/kg)，MIC浓度-时间曲线下的面积(AUC/MIC)具有类似的解释能力。红细胞计数与LZD最低浓度(Cmin)密切相关。尽管T>；MIC与疗效的相关性最一致，但当细菌增殖受到宿主免疫或甘露醇前抑制时，AUC/MIC同样具有预测性。在有效的联合方案中，较少频繁地给予相同的总剂量的LZD可能同样有效，并引起较少的Cmin依赖毒性。利奈唑胺是一种有效的结核病药物，具有剂量和时间依赖性毒性。使用动物模型，我们表明，在保持每周总剂量不变的情况下，减少给药频率可能是在降低毒性的同时保持疗效的可行策略。
Linezolid (LZD) is bactericidal against Mycobacterium tuberculosis, but it has treatment-limiting toxicities. A better understanding of exposure-response relationships governing LZD efficacy and toxicity will inform dosing strategies. Because in vitro monotherapy studies yielded conflicting results, we explored LZD pharmacokinetic/pharmacodynamic (PK/PD) relationships in vivo against actively and nonactively multiplying bacteria, including in combination with pretomanid. Linezolid multidose pharmacokinetics were modeled in mice. Dose-fractionation studies were performed in acute (net bacterial growth) and chronic (no net growth) infection models. In acute models, LZD was administered alone or with bacteriostatic or bactericidal pretomanid doses. Correlations between PK/PD parameters and lung colony-forming units (CFUs) and complete blood counts were assessed. Overall, time above minimum inhibitory concentration (T>MIC) correlated best with CFU decline. However, in growth-constrained models (ie, chronic infection, coadministration with pretomanid 50 mg/kg per day), area under the concentration-time curve over MIC (AUC/MIC) had similar explanatory power. Red blood cell counts correlated strongly with LZD minimum concentration (Cmin). Although T>MIC was the most consistent correlate of efficacy, AUC/MIC was equally predictive when bacterial multiplication was constrained by host immunity or pretomanid. In effective combination regimens, administering the same total LZD dose less frequently may be equally effective and cause less Cmin-dependent toxicity. Linezolid is an efficacious TB drug that exhibits dose- and duration-dependent toxicity. Using animal models, we show that decreasing dosing frequency while maintaining the same total weekly dose may be a viable strategy to maintain efficacy while decreasing toxicity.
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影响因子：
4.3
作者：
Lanoix JP;Lenaerts AJ;Nuermberger EL
通讯作者：
Nuermberger EL
影响因子：
5.2
作者：
Abbate, Eduardo;Vescovo, Marisa;van Soolingen, Dick
通讯作者：
van Soolingen, Dick
影响因子：
24.3
作者：
Migliori, G. B.;Eker, B.;Lange, C.
通讯作者：
Lange, C.
影响因子：
4.9
作者：
Nuermberger, Eric;Rosenthal, Ian;Grosset, Jacques H.
通讯作者：
Grosset, Jacques H.
影响因子：
5.2
作者：
Park, I-Nae;Hong, Sang-Bum;Shim, Tae Sun
通讯作者：
Shim, Tae Sun