Servicio de Microbiología y Unidad de Investigación, Hospital Universitario Son Espases, Palma de Mallorca, Spain.
Antimicrob Agents Chemother. 2012 Dec;56(12):6349-57. doi: 10.1128/AAC.01388-12. Epub 2012 Oct 8.
Recent reports have revealed the existence of widespread extensively drug-resistant (XDR) P. aeruginosa high-risk clones in health care settings, but there is still scarce information on their specific chromosomal (mutational) and acquired resistance mechanisms. Up to 20 (10.5%) of 190 bloodstream isolates collected from 10 Spanish hospitals met the XDR criteria. A representative number (15 per group) of isolates classified as multidrug-resistant (MDR) (22.6%), resistant to 1 to 2 classes (moderately resistant [modR]) (23.7%), or susceptible to all antibiotics (multiS) (43.2%) were investigated in parallel. Multilocus sequence typing (MLST) analysis revealed that all XDR isolates belonged to sequence type 175 (ST175) (n = 19) or ST111 (n = 1), both recognized as international high-risk clones. Clonal diversity was higher among the 15 MDR isolates (4 ST175, 2 ST111, and 8 additional STs) and especially high among the 15 modR (13 different STs) and multiS (14 STs) isolates. The XDR/MDR pattern in ST111 isolates correlated with the production of VIM-2, but none of the ST175 isolates produced acquired β-lactamases. In contrast, the analysis of resistance markers in 12 representative isolates (from 7 hospitals) of ST175 revealed that the XDR pattern was driven by the combination of AmpC hyperproduction, OprD inactivation (Q142X), 3 mutations conferring high-level fluoroquinolone resistance (GyrA T83I and D87N and ParC S87W), a G195E mutation in MexZ (involved in MexXY-OprM overexpression), and the production of a class 1 integron harboring the aadB gene (gentamicin and tobramycin resistance). Of particular interest, in nearly all the ST175 isolates, AmpC hyperproduction was driven by a novel AmpR-activating mutation (G154R), as demonstrated by complementation studies using an ampR mutant of PAO1. This work is the first to describe the specific resistance markers of widespread P. aeruginosa XDR high-risk clones producing invasive infections.
最近的报告揭示了在医疗机构中广泛存在的广泛耐药（XDR）铜绿假单胞菌高危克隆，但关于其特定的染色体（突变）和获得性耐药机制的信息仍然很少。在从西班牙的 10 家医院采集的 190 株血流分离株中，有 20 株（10.5%）符合 XDR 标准。对被分类为多药耐药（MDR）（22.6%）、对 1-2 类药物耐药（中度耐药[modR]）（23.7%）或对所有抗生素敏感（multiS）（43.2%）的代表性数量（每组 15 株）分离株进行了平行研究。多位点序列分型（MLST）分析显示，所有 XDR 分离株均属于序列型 175（ST175）（n=19）或 ST111（n=1），这两种均被认为是国际高危克隆。15 株 MDR 分离株的克隆多样性较高（4 株 ST175、2 株 ST111 和 8 株其他 ST），特别是 15 株 modR（13 种不同的 ST）和 multiS（14 株 ST）分离株的克隆多样性较高。ST111 分离株的 XDR/MDR 模式与 VIM-2 的产生相关，但没有一株 ST175 分离株产生获得性β-内酰胺酶。相比之下，对来自 7 家医院的 12 株代表性 ST175 分离株的耐药标记物进行分析显示，XDR 模式是由 AmpC 过度产生、OprD 失活（Q142X）、3 个赋予高水平氟喹诺酮耐药性的突变（GyrA T83I 和 D87N 和 ParC S87W）、MexZ 中的 G195E 突变（涉及 MexXY-OprM 过表达）以及携带 aadB 基因（庆大霉素和妥布霉素耐药）的 1 类整合子的产生共同驱动的。特别值得注意的是，在几乎所有的 ST175 分离株中，AmpC 的过度产生是由一种新的 AmpR 激活突变（G154R）驱动的，这一点通过使用 PAO1 的 ampR 突变体进行互补研究得到了证实。这项工作首次描述了广泛流行的铜绿假单胞菌 XDR 高危克隆产生侵袭性感染的特定耐药标记物。
