Delayed parasite elimination in human infections treated with clindamycin parallels 'delayed death' of Plasmodium falciparum in vitro
Delayed parasite elimination in human infections treated with clindamycin parallels 'delayed death' of Plasmodium falciparum in vitro
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DOI：
10.1016/j.ijpara.2006.12.010
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发表时间：
2007-06-01
影响因子：
4
通讯作者：
Borrmann, Steffen
中科院分区：
文献类型：
--
作者：
Burkhardt, Dominik;Wiesner, Jochen;Borrmann, Steffen
克林霉素对于治疗恶性疟原虫疟疾是安全有效的，但其作为单一疗法的使用受到初始临床反应慢得令人无法接受的限制。为了研究这种延迟作用是由于对寄生虫生长的累积性、暴露时间依赖性还是延迟效应，我们研究了克林霉素对恶性疟原虫的体内和体外药效学特征。在体内，克林霉素治疗期间消除年轻的、循环的无性寄生虫阶段表现出不寻常的双相动力学：在成年患者和无症状儿童中，分别在72和60小时后，平台期之后，无性寄生虫密度急剧下降到几乎无法检测到的水平，这表明可以不受抑制地建立第二个而不是第三个感染周期。在体外，通过检测恶性疟原虫富组氨酸蛋白11 （PfHRP2）的产生，将实验室适应的恶性疟原虫菌株连续暴露于浓度高达100 μ M的克林霉素中2个复制周期（96 h），与无药物对照相比，没有产生bb50 %的抑制作用。第二周期（96-144h）后，PfHRP2的产生完全停止（96-144h的平均半抑制浓度比48-96 h降低了10万倍）。此外，克林霉素仅在第一个（0-48小时）和三个（0-144小时）寄生虫复制周期中孵育，导致在第三个感染周期（96-144小时）中PfHRP2产生的抑制相当（平均IC99分别为27和22 nM， P = 0.2）。当寄生虫培养物暴露于50至1,000 nM不同浓度的克林霉素中72小时，并在模拟典型3天治疗方案的实验中进行随访时，寄生虫血症最初被抑制在显微镜检测阈值以下。然而，在去除药物72小时后，寄生虫以剂量依赖的方式重新出现，但在持续暴露药物的对照组中没有出现。克林霉素的延迟但有效的抗疟作用似乎是克林霉素与快速起作用的抗疟伙伴联合使用的最大潜在益处。(C) 2007澳大利亚寄生虫学学会Elsevier Ltd.出版。版权所有。
Clindamycin is safe and effective for the treatment of Plasmodium falciparum malaria, but its use as monotherapy is limited by unacceptably slow initial clinical response rates. To investigate whether the protracted action is due to an accumulative, time of exposure-dependent or a delayed effect on parasite growth, we studied the in vivo and in vitro pharmacodynamic profiles of clindamycin against P. falciparum. In vivo, elimination of young, circulating asexual parasite stages during treatment with clindamycin displayed an unusual biphasic kinetic: a plateau phase was followed by a precipitated decline of asexual parasite densities to nearly undetectable levels after 72 and 60 h in adult patients and asymptomatic children, respectively, suggesting an uninhibited capacity to establish a second, but not third, infectious cycle. In vitro, continuous exposure of a laboratory-adapted P. falciparum strain to clindamycin with concentrations of up to 100 mu M for two replication cycles (96 h) did not produce inhibitory effects of >50% compared with drug-free controls as measured by the production of P. falciparum histidine-rich protein 11 (PfHRP2). PfHRP2 production was completely arrested after the second cycle (96-144h) (>10,000-fold decrease of mean half-inhibitory concentrations measured at 96-144h compared to 48-96 h). Furthermore, incubation with clindamycin during only the first (0-48 h) versus three (0-144 h) parasite replication cycles led to comparable inhibition of PfHRP2 production in the third infectious cycle (96-144 h) (mean IC99 of 27 and 22 nM, respectively; P = 0.2). When parasite cultures were exposed to different concentrations of clindamycin ranging from 50 to 1,000 nM for 72 h and followed up in an experiment designed to simulate a typical 3-day treatment regimen, parasitaemia was initially suppressed below the microscopic detection threshold. Nonetheless, parasites reappeared in a dose-dependent manner after removal of drug at 72 h but not in continuously drug-exposed controls. The delayed, but potent, antimalarial effect of clindamycin appears to be of greatest potential benefit in new combinations of clindamycin with rapidly acting antimalarial combination partners. (C) 2007 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.