Kumaraswamy Monika, Riestra Angelica, Flores Anabel, Uchiyama Satoshi, Dahesh Samira, Bondsäter Gunnar, Nilsson Victoria, Chang Melanie, Seo Hideya, Sakoulas George, Nizet Victor
Division of Infectious Diseases and Global Public Health, Department of Medicine, UC San Diego, La Jolla, CA, USA.
Infectious Diseases Section, VA San Diego Healthcare System, San Diego, CA, USA.
bioRxiv. 2023 Mar 21:2023.03.21.533661. doi: 10.1101/2023.03.21.533661.
Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance () determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against + patients based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with + infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we report previously unrecognized bactericidal activities of COL against -+ isolates of (EC), (KP), and (SE) in standard tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the + Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed + EC, KP, and SE in freshly isolated human blood proved effective as monotherapy in a murine model of + EC bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with + Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high risk patients with limited therapeutic options.
黏菌素（COL）是一种阳离子环肽，可破坏带负电荷的细菌细胞膜，常作为对抗多重耐药革兰氏阴性菌感染的最后一道抗生素防线。水平可转移的质粒介导的黏菌素耐药性（）决定簇的出现及其向携带超广谱β-内酰胺酶和碳青霉烯酶耐药基因的革兰氏阴性菌株的传播，威胁到我们化疗药物库的有效性。基于在富集细菌生长培养基中进行的标准抗菌药敏试验（AST），COL被广泛认为对阳性患者无活性；因此，该药物不会用于阳性感染患者。然而，这些标准检测培养基很难模拟体内生理学情况，并且忽略了宿主免疫因素。在此，我们报告了在含有生理缓冲剂碳酸氢盐的标准组织培养基中，COL对大肠埃希菌（EC）、肺炎克雷伯菌（KP）和金黄色葡萄球菌（SE）的阳性分离株具有以前未被认识到的杀菌活性。此外，COL促进血清补体在阳性革兰氏阴性菌表面沉积，并在病原体杀伤方面与活性人血清产生强效协同作用。在标准给药易于达到的COL浓度下，该肽抗生素在新鲜分离的人血液中杀死了阳性EC、KP和SE，在阳性EC菌血症小鼠模型中作为单一疗法被证明有效。我们的结果表明，基于传统AST目前被忽视作为一种治疗选择的COL，实际上可能在更生理的背景下进行评估时使阳性革兰氏阴性感染患者受益。这些概念在临床微生物学实验室以及对其在治疗选择有限的高危患者中的优点进行未来临床研究时值得仔细考虑。
