Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments
Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments
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DOI：
10.1128/aac.48.12.4733-4744.2004
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发表时间：
2004-12-01
影响因子：
4.9
通讯作者：
Evans, ME
中科院分区：
文献类型：
--
作者：
Campion, JJ;McNamara, PJ;Evans, ME
尽管常见病原体对现有抗菌药物的耐药性不断增加，但新型抗菌药物的开发正在减少。深入了解药效学和耐药性之间的关系可能会提供优化现有药物使用的方法。研究了两种对环丙沙星敏感的金黄色葡萄球菌菌株暴露于体外模拟临床和实验环丙沙星药代动力学曲线 96 小时后的耐药性演变。随着平均稳态浓度（C-avg ss）的增加，杀灭率接近最大值，而再生率下降。具有 grlA 突变和低水平环丙沙星耐药性的亚群的富集也根据药代动力学环境而变化。产生略高于 MIC 的 C-avg ss 值的方案选择了具有 grLA 突变的耐药变体，但这些变体并未进化到更高水平的耐药性。提供 C-avg ss 中间值至 MIC 和突变预防浓度 (MPC) 的临床方案导致出现 gyrA 突变和更高水平的耐药性亚群。产生接近 MPC 选择的 grLA 突变体的 C-avg ss 值的方案，但具有较高抗性水平的亚群的出现减少。旨在将环丙沙星浓度完全维持在 MPC 以上的方案似乎可以根除接种物中的低水平耐药变异，并防止出现更高水平的耐药性。环丙沙星浓度在 MIC 和 MPC 之间保持的时间与 grLA 或 gyrA 中出现的耐药程度或环丙沙星耐药突变的存在或类型之间没有关系。旨在根除金黄色葡萄球菌群体中低水平耐药变异的治疗方案可以防止出现更高水平的氟喹诺酮耐药性。
The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible Staphylococcus aureus strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (C-avg ss) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for C-avg ss slightly above the MIC selected resistant variants with grLA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for C-avg ss intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance. A regimen producing values for C-avg ss close to the MPC selected grLA mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in grLA or gyrA. Regimens designed to eradicate low-level resistant variants in S. aureus populations may prevent the emergence of higher levels of fluoroquinolone resistance.