Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae.
Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae.
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DOI：
10.1093/jacamr/dlad113
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发表时间：
2023-10
影响因子：
3.4
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中科院分区：
文献类型：
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头孢他啶/阿维巴坦和美罗培南/瓦波巴坦是治疗产生碳青霉烯酶（KPC）的肺炎克雷伯菌（KPC- kp）感染的首选药物，通常与其他药物联合使用。我们的目的是表征不同ompK36基因型的KPC-Kp组合的协同作用。选择含有ompK36 WT、IS5或甘氨酸-天冬氨酸重复（GD）基因型的KPC-Kp。mic测定为三份。采用时间杀伤法评价头孢他啶/阿维巴坦和美罗培南/瓦波巴坦与粘菌素、庆大霉素、替加环素、美罗培南或磷霉素联用对1 × 108 cfu/mL KPC-Kp的协同作用。KPC-Kp窝藏ompK36 WT （n = 5）、IS5 （n = 5）或GD (n = 5)；KPC-2 11例，KPC-3 4例。所有患者均对头孢他啶/阿维巴坦和美罗培南/瓦波巴坦敏感。在时间杀伤分析中，头孢他啶/阿维巴坦和美罗培南/瓦博巴坦1 × MIC的平均24 h对数杀伤分别为- 2.01和- 0.84。头孢他啶/阿维巴坦与粘菌素联用具有协同作用，不依赖于ompK36基因型。受孔蛋白突变影响的头孢他啶/阿维巴坦组合（与WT相比）是美罗培南（- 5.18对- 6.62,P < 0.001）和磷霉素（- 3.98对- 6.58,P = 0.058）。与庆大霉素联合使用美罗培南/瓦波巴坦的平均死亡人数最多（- 5.36）。在存在孔蛋白突变的情况下，添加粘菌素（- 6.65对- 0.70,P = 0.03）和磷霉素（- 3.12对1.54,P = 0.003）可以增强美罗培南/瓦波巴坦的杀伤活性。我们的研究结果揭示了头孢他啶/阿维巴坦和美罗培南/瓦博巴坦联合治疗伴或不伴孔蛋白突变的KPC-Kp的协同作用。头孢他啶/阿维巴坦与其他细胞壁活性剂对孔蛋白突变株的杀伤活性降低。另一方面，一些美罗培南/瓦博巴坦组合在存在孔蛋白突变的情况下表现出增强的杀伤作用。
Ceftazidime/avibactam and meropenem/vaborbactam are preferred agents for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) infections and are often used in combination with other agents. We aimed to characterize the synergy of combinations against KPC-Kp with varying ompK36 genotypes. KPC-Kp that harboured ompK36 WT, IS5 or glycine-aspartic acid duplication (GD) genotypes were selected. MICs were determined in triplicate. Synergy was assessed by time-kill assays for ceftazidime/avibactam and meropenem/vaborbactam in combination with colistin, gentamicin, tigecycline, meropenem or fosfomycin against 1 × 108 cfu/mL KPC-Kp. KPC-Kp harboured ompK36 WT (n = 5), IS5 (n = 5) or GD (n = 5); 11 were KPC-2 and 4 were KPC-3. All were susceptible to ceftazidime/avibactam and meropenem/vaborbactam. In time-kill analysis, ceftazidime/avibactam and meropenem/vaborbactam 1 × MIC exhibited mean 24 h log-kills of −2.01 and −0.84, respectively. Ceftazidime/avibactam was synergistic in combination with colistin independent of ompK36 genotype. Ceftazidime/avibactam combinations impacted by porin mutations (compared to WT) were meropenem (−5.18 versus −6.62 mean log-kill, P < 0.001) and fosfomycin (−3.98 versus −6.58, P = 0.058). Mean log-kills with meropenem/vaborbactam were greatest in combination with gentamicin (−5.36). In the presence of porin mutations, meropenem/vaborbactam killing activity was potentiated by the addition of colistin (−6.65 versus −0.70, P = 0.03) and fosfomycin (−3.12 versus 1.54, P = 0.003). Our results shed new light on the synergy of ceftazidime/avibactam and meropenem/vaborbactam combinations against KPC-Kp with or without porin mutations. Killing activity of ceftazidime/avibactam with other cell wall active agents was decreased against isolates with porin mutations. On the other hand, some meropenem/vaborbactam combinations demonstrated enhanced killing in the presence of porin mutations.
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影响因子：
4.9
作者：
通讯作者：
--
影响因子：
4.9
作者：
Hernández-Allés, S;Benedí, VJ;Albertí, S
通讯作者：
Albertí, S
影响因子：
4.4
作者：
通讯作者：
--
影响因子：
7.5
作者：
Iacovelli, Alessandra;Spaziante, Martina;Venditti, Mario
通讯作者：
Venditti, Mario
影响因子：
4.9
作者：
Humphries, Romney M.;Yang, Shangxin;Gregson, Aric
通讯作者：
Gregson, Aric