Pharmacokinetic determinants of the window of selection for antimalarial drug resistance
Pharmacokinetic determinants of the window of selection for antimalarial drug resistance
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DOI：
10.1128/aac.00903-07
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
White, N. J.
中科院分区：
文献类型：
--
作者：
Stepniewska, K.;White, N. J.
抗疟疾药物耐药性的选择和传播对生活在热带国家的人们的健康构成了巨大的挑战。大多数抗疟疾药物被缓慢消除，因此，在流行地区进行治疗后，新获得的寄生虫暴露在其中的浓度梯度。有一个变化期，在此期间，抗药性疟疾寄生虫的新的血液期感染可以从肝脏中出现，随后产生足以传播的配子体密度，而敏感寄生虫的再感染仍然受到抑制。这一“选择之窗”推动了阻力的蔓延。我们已经研究了决定这个窗口持续时间的因素，从而决定了阻力选择压力。持续时间从零到几个月不等，取决于寄生虫抗药性的程度、浓度-效应关系的斜率和抗疟疾药物的消除动力学。窗口打开的时间和打开的持续时间都是终端消除半衰期的线性函数。由于来自兄弟姐妹易感寄生虫的竞争，低起点数有更大的灭绝风险，以及只有当血液浓度降至MIC以下时才打开窗口，因此从头抗性的选择窗口比其他地方获得的抗药性的窗口要窄。对窗口进行了检查，寻找目前可用的抗疟疾药物。消除半衰期小于1天的药物，如青蒿素和奎宁，在消除阶段不选择耐药性。
The selection and spread of antimalarial drug resistance pose enormous challenges to the health of people living in tropical countries. Most antimalarial drugs are slowly eliminated and so, following treatment in areas of endemicity, provide a gradient of concentrations to which newly acquired parasites are exposed. There is a variable period during which a new blood-stage infection with resistant malaria parasites can emerge from the liver and subsequently produce gametocyte densities sufficient for transmission while reinfection by sensitive parasites is still suppressed. This "window of selection" drives the spread of resistance. We have examined the factors which determine the duration of this window and, thus, the resistance selection pressure. The duration ranges from zero to several months and is dependent on the degree of parasite resistance, the slope of the concentration-effect relationship, and the elimination kinetics of the antimalarial drug. The time at which the window opens and the duration of opening are both linear functions of the terminal elimination half-life. Because of competition from sibling susceptible parasites, the greater risks of extinction with low starting numbers, and opening of the window only when blood concentrations have fallen below the MIC, the window of selection for de novo resistance is narrower than that for resistance acquired elsewhere. The windows were examined for the currently available antimalarials. Drugs with elimination half-lives of less than 1 day, such as the artemisinins and quinine, do not select for resistance during the elimination phase.