The intrinsic L1 metallo- and L2 serine-β-lactamases in Stenotrophomonas maltophilia make it naturally multidrug resistant and difficult to treat. There is a need to identify novel treatment strategies for this pathogen, especially against isolates resistant to first-line agents. Aztreonam in combination with avibactam has demonstrated potential, although data on other aztreonam–β-lactamase inhibitor (BLI) combinations are lacking. Additionally, molecular mechanisms for reduced susceptibility to these combinations have not been explored. The objectives of this study were to evaluate and compare the in vitro activities and to understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia. A panel of 47 clinical S. maltophilia strains nonsusceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution, and 6 isolates were then evaluated in time-kill analyses. Three isolates with various aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase PCR. Avibactam restored aztreonam susceptibility in 98% of aztreonam-resistant isolates, compared to 61, 71, and 15% with clavulanate, relebactam, and vaborbactam, respectively. The addition of avibactam to aztreonam resulted in a ≥2-log₁₀-CFU/ml decrease at 24 h versus aztreonam alone against 5/6 isolates compared to 1/6 with clavulanate, 4/6 with relebactam, and 2/6 with vaborbactam. Molecular analyses revealed that decreased susceptibility to aztreonam-avibactam was associated with increased expression of genes encoding L1 and L2, as well as the efflux pump (smeABC). Aztreonam-avibactam is the most promising BLI-combination against multidrug-resistant S. maltophilia. Decreased susceptibility may be due to the combination of overexpressed β-lactamases and efflux pumps. Further studies evaluating this combination against S. maltophilia are warranted.

中文翻译：

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氨曲南与avibactam，克拉维酸，relebactam和vaborbactam联合使用可抵抗多药性嗜麦芽窄食单胞菌。

嗜麦芽窄食单胞菌固有的L1金属和L2丝氨酸-β-内酰胺酶使其天然具有多药耐药性且难以治疗。有必要确定这种病原体的新的治疗策略，尤其是针对一线耐药菌的分离株。尽管缺乏其他氨曲南-β-内酰胺酶抑制剂（BLI）组合的数据，但氨曲南与阿维巴坦联用已显示出潜力。另外，尚未探索出降低对这些组合的敏感性的分子机制。这项研究的目的是评估和比较其体外活性，并了解抗氨曲南与阿维巴坦，克拉维酸，雷贝巴坦和vaborbactam联合使用对付嗜麦芽肿链球菌的抗性机制。。通过肉汤微量稀释测试了一组47种对左氧氟沙星和/或甲氧苄氨嘧啶-磺胺甲基异恶唑不敏感的临床链球菌的菌株，并通过肉汤微量稀释对每种氨曲南-BLI组合进行了测试，然后对6个分离株进行了时间杀灭分析。对具有各种氨曲南-BLI MIC的三种分离株进行全基因组测序和定量逆转录酶PCR。阿维巴坦在98％的抗氨曲南耐药菌株中恢复了氨曲南敏感性，而克拉维酸，雷巴坦和vaborbactam分别为61％，71％和15％。加入avibactam氨曲南的产生了≥2个对数₁₀与单独使用氨曲南的5/6菌株相比，与单独使用氨曲南的患者相比，在24 h时-CFU / ml降低，而克拉维酸盐为1/6，雷巴坦为4/6，而vaborbactam为2/6。分子分析显示，对氨曲南-avibactam的敏感性降低与编码L1和L2的基因以及外排泵（smeABC）的表达增加有关。Aztreonam-avibactam是对抗多药耐药性麦芽链球菌的最有希望的BLI组合。敏感性降低可能是由于过表达的β-内酰胺酶和外排泵的组合。评估该组合抗嗜麦芽孢杆菌的进一步研究是必要的。