Bacteriophage treatment is effective against carbapenem-resistant Klebsiella pneumoniae (KPC) in a neutropenic murine model of gastrointestinal translocation and renal infection.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Antimicrobial Agents and Chemotherapy Pub Date : 2025-02-13 Epub Date: 2024-12-20 DOI:10.1128/aac.00919-24
Panagiotis Zagaliotis, Jordyn Michalik-Provasek, Eleftheria Mavridou, Ethan Naing, Ioannis S Vizirianakis, Dimitrios Chatzidimitriou, Jason J Gill, Thomas J Walsh
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Abstract

Carbapenemase-producing Klebsiella pneumoniae (KPC) are globally emerging pathogens that cause life-threatening infections. Novel treatment alternatives are urgently needed. We therefore investigated the effectiveness of three novel bacteriophages (Spivey, Pharr, and Soft) in a neutropenic murine model of KPC gastrointestinal colonization, translocation, and disseminated infection. Bacteriophage efficacy was determined by residual bacterial burden of KPC (CFU/g) in kidneys. Parallel studies were conducted of bacteriophage pharmacokinetics and resistance. Treatment of mice with 5 × 109 PFU of phage cocktail via intraperitoneal injection was effective in significantly reducing renal KPC CFU by 100-fold (P < 0.01) when administered every 24 h and 1000-fold (P < 0.01) every 12 h. Moreover, a combination of bacteriophage and ceftazidime-avibactam produced a synergistic effect, resulting in a 105-fold reduction in bacterial burden in cecum and kidney (P < 0.001 in both tissues). Prophylactic administration of bacteriophages via oral gavage did not prevent KPC translocation to the kidneys. Bacteriophage decay determined by linear regression of the ln of mean concentrations demonstrated R2 values in plasma of 0.941, kidney 0.976, and cecum 0.918, with half-lives of t1/2 = 2.5 h. Furthermore, a phage-resistant mutant displayed increased sensitivity to serum killing in vitro, but did not show significant defects in renal infection in vivo. A combination of bacteriophages demonstrated significant efficacy alone and synergy with ceftazidime/avibactam in the treatment of experimental disseminated KPC infection in neutropenic mice.

在中性粒细胞减少的小鼠胃肠道转位和肾脏感染模型中,噬菌体治疗对耐碳青霉烯类肺炎克雷伯菌(KPC)有效。
产碳青霉烯酶肺炎克雷伯菌(KPC)是全球新出现的病原体,可引起危及生命的感染。迫切需要新的治疗方案。因此,我们研究了三种新型噬菌体(Spivey、Pharr和Soft)在嗜中性粒细胞减少小鼠胃肠道定植、易位和播散感染模型中的有效性。以肾内KPC残余细菌负荷(CFU/g)测定噬菌体效果。同时进行了噬菌体药代动力学和耐药性的平行研究。腹腔注射5 × 109 PFU噬菌体混合物治疗小鼠,每24 h给药可显著降低肾KPC CFU 100倍(P < 0.01),每12 h给药可显著降低1000倍(P < 0.01)。噬菌体与头孢他啶-阿维巴坦联合用药可产生协同作用,使盲肠和肾脏细菌负荷降低105倍(P < 0.001)。通过口服灌胃预防给药噬菌体并不能阻止KPC向肾脏转移。通过对平均浓度ln的线性回归测定噬菌体衰减,血浆R2值为0.941,肾脏ln值为0.976,盲肠ln值为0.918,半衰期t1/2 = 2.5 h。此外,噬菌体抗性突变体在体外对血清杀灭的敏感性增加,但在体内对肾脏感染没有明显缺陷。在中性粒细胞减少小鼠的实验性弥散性KPC感染中,噬菌体的组合显示出单独和与头孢他啶/阿维巴坦的协同作用的显著疗效。
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来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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