Lepak A J, Seiler P, Surivet J P, Ritz D, Kohl C, Andes D R
University of Wisconsin, Madison, Wisconsin, USA.
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
Antimicrob Agents Chemother. 2016 May 23;60(6):3626-32. doi: 10.1128/AAC.00363-16. Print 2016 Jun.
ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistant Staphylococcus aureus and penicillin- and fluoroquinolone-resistant Streptococcus pneumoniae We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10 S. aureus and S. pneumoniae isolates with phenotypic resistance to beta-lactams and fluoroquinolones. The in vitro activities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 10(7.4) to 10(8) CFU/thigh at the start of therapy with ACT-387042 and 10(6.7) to 10(8.3) CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10 CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R(2), 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 against S. aureus and S. pneumoniae were 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 against S. aureus and S. pneumoniae were 69 and 25, respectively. The stasis PD targets were significantly lower for S. pneumoniae (P < 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.
ACT-387042和ACT-292706是两种新型细菌拓扑异构酶抑制剂，对革兰氏阳性菌和革兰氏阴性菌具有广谱活性，包括耐甲氧西林金黄色葡萄球菌以及对青霉素和氟喹诺酮耐药的肺炎链球菌。我们使用中性粒细胞减少小鼠大腿感染模型，来表征这些研究性化合物针对一组10株对β-内酰胺类和氟喹诺酮类具有表型耐药性的金黄色葡萄球菌和肺炎链球菌分离株的药代动力学（PK）/药效动力学（PD）。这两种化合物的体外活性非常相似（MIC范围为0.03至0.125毫克/升）。通过皮下途径给予四个递增剂量，测定每种化合物的血浆药代动力学。在治疗研究中，用ACT-387042治疗开始时小鼠大腿处有10(7.4)至10(8)CFU/大腿，用ACT-292706治疗开始时小鼠大腿处有10(6.7)至10(8.3)CFU/大腿。在整个剂量范围内，所有分离株均观察到剂量反应关系。与所检查的最高剂量治疗开始时的菌量相比，最大杀菌量接近3至4 log10 CFU/大腿。在该模型中，PK/PD指数AUC/MIC比值（稳态下24小时浓度-时间曲线下面积除以MIC）与治疗效果之间存在很强的相关性（R(2)，0.63至0.82）。ACT-387042针对金黄色葡萄球菌和肺炎链球菌与净菌量停滞相关的24小时游离药物AUC/MIC比值分别为43和10。ACT-292706针对金黄色葡萄球菌和肺炎链球菌与净菌量停滞相关的24小时游离药物AUC/MIC比值分别为69和25。两种化合物针对肺炎链球菌的菌量停滞PD靶点均显著更低（P < 0.05）。1-log杀灭AUC/MIC比值靶点比菌量停滞靶点高约2至4倍。耐甲氧西林、青霉素或环丙沙星并未改变疗效所需的AUC/MIC比值大小。这些结果应有助于拓扑异构酶抑制剂临床试验的设计。
