Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Spero Therapeutic, Inc., Cambridge, Massachusetts, USA.
Antimicrob Agents Chemother. 2018 Jun 26;62(7). doi: 10.1128/AAC.00239-18. Print 2018 Jul.
SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although isolates had minimal susceptibilities to azithromycin (AZM), the antimicrobial activity of AZM against was enhanced when it was combined with SPR741. The current study evaluated the activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) We studied 30 MDR isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance (, , , and ). activity was assessed as the change in log CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of -0.53 ± 0.82 log CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising activity against MDR isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR .
SPR741 是一种新型化合物，与多黏菌素结构相似，能够增强各种类型抗生素的活性。先前的研究表明，虽然 对阿奇霉素（AZM）的敏感性最低，但当 SPR741 与 AZM 联合使用时，AZM 对 的抗菌活性增强。本研究评估了 AZM 的人模拟方案（HSR）的 活性，相当于临床剂量的 500 mg 静脉内每 24 小时（q24h）一次（i.v.）和 SPR741 相当于临床剂量的 400 mg q8h i.v.（1 小时输注），单独使用和联合使用，针对多药耐药（MDR） 我们研究了 30 株表达广泛β-内酰胺酶（ESBL、NDM、VIM 和 KPC）的 MDR 株，包括一组对大环内酯类药物耐药基因（,,, 和 ）阳性的 株。 活性评估为与 0 小时相比，24 小时时大腿内每对数 CFU 的变化。单独使用 AZM 治疗与 2.60±0.83 log CFU/大腿的净生长有关。在 AZM MICs 为≤16 mg/liter 的 株中，AZM-SPR741 治疗与细菌负荷平均减少 -0.53±0.82 log CFU/大腿有关，并且在 11 株中的 9 株（81.8%）观察到停滞至 1 对数杀灭。AZM-SPR741 HSR 的联合治疗对 AZM MICs 为≤16 mg/liter 的 MDR 株表现出有希望的 活性，包括产生各种β-内酰胺酶的 株。这些数据支持 AZM-SPR741 在治疗由 MDR 引起的感染中的潜在作用。
