The potent bactericidal activity of streptomycin in the guinea pig model of tuberculosis ceases due to the presence of persisters
The potent bactericidal activity of streptomycin in the guinea pig model of tuberculosis ceases due to the presence of persisters
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DOI：
10.1093/jac/dkq277
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发表时间：
2010-10-01
影响因子：
5.2
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
--
作者：
Ahmad, Zahoor;Pinn, Michael L.;Karakousis, Petros C.
异烟肼对豚鼠结核分枝杆菌的双相杀伤曲线是由于持久菌株的存在而不是异烟肼耐药突变体的选择。为了确定这种现象是否与其他杀菌药物一样，我们在豚鼠结核模型中研究了链霉素的活性及其对链霉素耐药突变体的选择能力。进行药代动力学研究以确定链霉素的人体等效剂量。将豚鼠气溶胶感染结核分枝杆菌，2周后肌肉注射链霉素，每周5天。在治疗10周之前，通过均质和肺电镀cfu来评估杀菌活性。在每个时间点，分离cfu，悬浮于生理盐水中，并重新镀于含有0.5、1.0、2.0或10.0 mg/L链霉素的板上。链霉素的人体等效剂量为70 mg/kg。链霉素在治疗的前14天显示出强大的活性，使所有动物免于急性结核病相关死亡，并使肺cfu降低了4 log（10）。然而，此后链霉素活性显著降低，在接下来的56天治疗中，肺cfu仅下降了1 log（10）。虽然可以检测到链霉素耐药突变体，但它们在治疗开始时和治疗70天后的分离频率相同。在单药治疗的第二阶段，链霉素活性的降低与链霉素耐药突变体的选择无关，而是与表型耐受的“持久性”的存在有关。
The biphasic kill curve of isoniazid against Mycobacterium tuberculosis in guinea pigs is due to the presence of persisters rather than selection of isoniazid-resistant mutants. To determine whether this phenomenon is common to other bactericidal drugs, we studied the activity of streptomycin and its ability to select for streptomycin-resistant mutants in the guinea pig model of tuberculosis.Pharmacokinetic studies were performed to establish the human-equivalent dose of streptomycin. Guinea pigs were aerosol-infected with M. tuberculosis and 2 weeks later streptomycin was given for 5 days/week via intramuscular injection. Bactericidal activity was assessed by homogenizing and plating lungs for cfu until 10 weeks of treatment. At each timepoint, cfu were isolated, suspended in normal saline and re-plated on plates containing 0.5, 1.0, 2.0 or 10.0 mg/L streptomycin.The human-equivalent dose of streptomycin was determined to be 70 mg/kg. Streptomycin showed potent activity during the first 14 days of treatment, rescuing all animals from acute tuberculosis-related death and reducing lung cfu by similar to 4 log(10). However, streptomycin activity was dramatically reduced thereafter, as lung cfu declined by only similar to 1 log(10) over the next 56 days of treatment. Although streptomycin-resistant mutants were detectable, their frequency of isolation was identical at treatment initiation and after 70 days of treatment.The reduced activity of streptomycin during the second phase of monotherapy is not associated with the selection of streptomycin-resistant mutants but, rather, with the presence of phenotypically tolerant 'persisters'.