Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
Department of Pharmacy, Huntington Hospital, Pasadena, CA, USA.
J Antimicrob Chemother. 2024 Oct 1;79(10):2471-2478. doi: 10.1093/jac/dkae241.
Staphylococcus aureus (SA) is a leading cause of bloodstream infection. The liver represents the sentinel immune organ for clearance of bloodstream pathogens and eradication of intracellular SA from liver-resident macrophages (Kupffer cells, KCs) eliminates the likely pathogenic reservoir that contributes to persistent bacteraemia.
We assessed antimicrobial activity at phagolysosome-mimicking pH, intracellular penetration, and SA eradication within KCs in vitro for clinically prescribed antistaphylococcal agents alone or in combination: vancomycin, daptomycin, ceftaroline, ceftobiprole, oritavancin, oxacillin, cefazolin; rifampin and fosfomycin.
pH-adjusted broth microdilution assays, intracellular bioaccumulation assays, and intracellular killing assays against clinical bloodstream isolates were performed using a murine KC line with study agents.
Rifampin and β-lactams exhibited enhanced activity [2- to 16-fold minimum inhibitory concentrations (MIC) decrease] at phagolysosomal pH while vancomycin, oritavancin, daptomycin and fosfomycin demonstrated reduced activity (2- to 32-fold MIC increase in order of least to greatest potency reduction). All agents evaluated had poor to modest intracellular to extracellular concentration ratios (0.024-7.8), with exceptions of rifampin and oritavancin (intracellular to extracellular ratios of 17.4 and 78.2, respectively). Finally, we showed that the first-line treatment for SA bacteraemia (SAB), vancomycin, performed worse than all other tested antibiotics in eradicating intracellular SA at human Cmax concentration (0.20 log cfu decrease), while oritavancin performed better than all other agents alone (2.05 versus 1.06-1.36 log cfu decrease).
Our findings raise concerns about the efficacy of commonly prescribed antibiotics against intracellular SA reservoirs and emphasize the need to consider targeting pathogen eradication from the liver to achieve early control of SAB.
评估在模拟吞噬体 pH 值、细胞内渗透和体外肝细胞内金黄色葡萄球菌（SA）清除率方面，单独或联合使用临床处方抗葡萄球菌药物：万古霉素、达托霉素、头孢洛林、头孢比普、奥他万古、苯唑西林和头孢唑林；利福平及磷霉素的抗菌活性。
使用一种具有研究药物的鼠源库普弗细胞（KC）系进行 pH 调整肉汤微量稀释测定、细胞内生物蓄积测定和针对临床血流分离株的细胞内杀伤测定。
利福平及β-内酰胺类在吞噬体 pH 值时表现出增强的活性（最低抑菌浓度 [MIC] 降低 2-16 倍），而万古霉素、奥他万古、达托霉素和磷霉素则表现出活性降低（MIC 增加 2-32 倍，依次为最低至最大效力降低）。所有评估的药物都具有较差至适度的细胞内/细胞外浓度比（0.024-7.8），利福平及奥他万古是例外（细胞内/细胞外浓度比分别为 17.4 和 78.2）。最后，我们发现治疗金黄色葡萄球菌菌血症（SAB）的一线药物万古霉素在达到人类 Cmax 浓度时（cfu 减少 0.20 对数），清除细胞内 SA 的效果比所有其他测试的抗生素都差，而奥他万古的效果则优于所有其他单独用药（cfu 减少 2.05 与 1.06-1.36 对数）。
我们的研究结果对普遍处方抗生素治疗细胞内 SA 储存库的疗效提出了质疑，并强调需要考虑从肝脏靶向清除病原体，以实现 SAB 的早期控制。
