[Advances in phage therapy for pneumonia caused by Klebsiella pneumoniae].

内容摘要

Klebsiella pneumoniae (KP) has emerged as a formidable nosocomial pathogen in the era of antimicrobial resistance, with mortality from pneumonia caused by carbapenem-resistant strains exceeding 50%. Phage therapy has re-emerged as a promising alternative or adjunctive strategy for managing refractory KP infections. This review consolidates the current preclinical and clinical evidence base, outlines the molecular mechanisms of phage-host interactions, and appraises evolving therapeutic approaches. Preclinical investigations in murine pneumonia models have consistently demonstrated that intranasal or nebulization phage administration markedly reduces pulmonary bacterial burden, attenuates inflammatory lung injury, and improves survival, often exhibiting synergistic effects when combined with conventional antibiotics. Clinical case reports and small compassionate-use series have further provided preliminary yet compelling evidence supporting the safety and therapeutic promise of personalized phage formulations in critically ill patients with multidrug-resistant KP pneumonia who have exhausted standard treatment options. Mechanistically, phage tropism is mediated through the specific recognition of bacterial surface receptors-principally capsular polysaccharide and, to a lesser extent, lipopolysaccharide-by phage-encoded receptor-binding proteins, culminating in bacterial lysis. In response, KP has evolved a multilayered defensive arsenal encompassing receptor modification to impede adsorption, nucleic acid interference systems (e.g., CRISPR-Cas and restriction-modification), and abortive infection mechanisms that curtail phage propagation at the population level. To surmount the inherent limitations of narrow host range and the inevitable emergence of phage-resistant mutants, a suite of optimization strategies is under active refinement, including rationally designed phage cocktails, genetically engineered phages with extended tropism, artificial intelligence-assisted host-range prediction, and innovative delivery platforms such as hydrogel encapsulation to enhance pulmonary bioavailability. Despite ongoing challenges in mechanistic complexity, manufacturing standardization, and regulatory uncertainty, current initiatives- such as the establishment of geographically diverse phage libraries, real-time surveillance of phage resistance, and the development of phage-derived enzyme products-hold promise for establishing precision phage therapy as a viable and sustainable component of the antimicrobial stewardship armamentarium. 在抗菌药物耐药时代，肺炎克雷伯菌（Klebsiella pneumoniae，KP）已成为一种棘手的院内病原体，碳青霉烯耐药菌株所致肺炎的病死率超过50%。噬菌体疗法已重新成为治疗难治性KP感染的替代或辅助策略。本综述系统梳理了当前临床前与临床证据基础，阐明了噬菌体-宿主相互作用的分子机制，并评估了不断演进的治疗策略。尽管在机制复杂性、生产标准化及监管不确定性方面仍面临持续挑战，但正在推进的各项举措——包括建立覆盖不同地域的噬菌体库、开展噬菌体耐药性的实时监测以及开发噬菌体衍生酶类产品——有望使精准噬菌体疗法成为抗菌药物管理体系中切实可行且可持续的组成部分。.