Melioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei. Current recommended melioidosis treatment requires intravenous β-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM), or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole. Emerging antibiotic resistance could lead to therapy failure and high mortality. We performed a prospective multicenter study in northeast Thailand from 2015 to 2018 to evaluate antibiotic susceptibility and characterize β-lactam resistance in clinical B. pseudomallei isolates. A collection of 1,317 B. pseudomallei isolates from patients with primary and relapse infections were evaluated for susceptibility to CAZ, imipenem (IPM), MEM, and AMC. β-Lactam-resistant isolates were confirmed by the broth microdilution method and characterized by whole-genome sequence analysis, penA expression, and β-lactamase activity. The resistant phenotype was verified via penA mutagenesis. All primary isolates were IPM susceptible, but we observed two CAZ-resistant isolates and one CAZ-intermediate isolate, two MEM-less-susceptible isolates, and one AMC-resistant and two AMC-intermediate isolates. One of 13 relapse isolates was resistant to both CAZ and AMC. Two isolates were MEM less susceptible. Strains DR10212A (primary) and DR50054E (relapse) were multidrug resistant. Genomic and mutagenesis analyses supplemented with gene expression and β-lactamase analyses demonstrated that the CAZ-resistant phenotype was caused by PenA variants: P167S (n = 2) and penA amplification (n = 1). Despite the high mortality rate in melioidosis, our study revealed that B. pseudomallei isolates had a low frequency of β-lactam resistance caused by penA alterations. Clinical data suggest that resistant variants may emerge in patients during antibiotic therapy and may be associated with a poor response to treatment.

中文翻译：

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2015年至2018年泰国东北部临床类鼻疽伯克霍尔德氏菌分离株的抗生素敏感性以及β-内酰胺抗性分离株的基因组特征


类鼻疽是热带地区一种常见的致命感染，由环境细菌类鼻疽伯克霍尔德氏菌引起。目前推荐的类鼻疽治疗需要静脉注射 β-内酰胺类抗生素，如头孢他啶 (CAZ)、美罗培南 (MEM) 或阿莫西林克拉维酸 (AMC) 以及口服甲氧苄啶-磺胺甲恶唑。新出现的抗生素耐药性可能导致治疗失败和高死亡率。我们于 2015 年至 2018 年在泰国东北部进行了一项前瞻性多中心研究，以评估临床假鼻疽杆菌分离株的抗生素敏感性和 β-内酰胺耐药性特征。对来自原发感染和复发感染患者的 1,317 株鼻疽伯克氏菌分离株进行了评估，评估其对 CAZ、亚胺培南 (IPM)、MEM 和 AMC 的敏感性。 β-内酰胺抗性分离株通过肉汤微量稀释法进行确认，并通过全基因组序列分析、 penA表达和 β-内酰胺酶活性进行表征。通过penA诱变验证了抗性表型。所有主要分离株均对 IPM 敏感，但我们观察到 2 个 CAZ 抗性分离株和 1 个 CAZ 中间分离株、2 个 MEM 不敏感分离株、1 个 AMC 抗性分离株和 2 个 AMC 中间分离株。 13 个复发分离株之一对 CAZ 和 AMC 均具有抗性。两个分离株对 MEM 不太敏感。菌株 DR10212A（原发）和 DR50054E（复发）具有多重耐药性。基因组和诱变分析辅以基因表达和 β-内酰胺酶分析表明 CAZ 抗性表型是由 PenA 变体引起的：P167S ( n = 2) 和penA扩增 ( n = 1)。 尽管类鼻疽的死亡率很高，但我们的研究表明，类鼻疽杆菌分离株具有较低频率的由penA改变引起的 β-内酰胺耐药性。临床数据表明，抗生素治疗期间患者可能会出现耐药变异，并且可能与治疗反应不佳有关。