In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms.
In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms.
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DOI：
10.1093/jac/dkaa370
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发表时间：
2020-12-01
期刊：
影响因子：
--
通讯作者：
Dale GE
中科院分区：
文献类型：
--
作者：
Trebosc V;Schellhorn B;Schill J;Lucchini V;Bühler J;Bourotte M;Butcher JJ;Gitzinger M;Lociuro S;Kemmer C;Dale GE
利福布汀是一种被批准用于治疗禽分枝杆菌感染的口服药物，在营养有限的介质中显示出强大的抗鲍曼不动杆菌活性，这是通过铁载体受体FhuE使利福布汀细胞摄取而实现的。目的：测定大量鲍曼不动杆菌利福布汀的体外活性及耐药机制。对从欧洲、美国和亚洲采集的293株耐碳青霉烯类鲍曼不动杆菌进行最低抑菌浓度测定。对利福布汀MIC升高菌株的fhuE、rpoB和arr-2基因进行测序和基因分型，结合基因工程和基因表达定量研究利福布汀的作用方式和耐药机制。利福布汀对菌株的MIC50/90为0.008/1 mg/L，优于粘菌素、替格环素和头孢地洛(MIC90为8 mg/L)。利福布汀对耐药亚群仍然有效，包括铁载体-药物结合物头孢地洛耐药株(MIC90为2 mg/L，n= 23)。在利福布汀浓度为2−mg/L或以上时，至少需要两种独立的耐药机制才能取消利福布汀的活性，这符合剂量依赖的突变频率达到10 9的情况。我们认为，FhuE介导的主动摄取利福平使其能够对抗利福平耐药菌株。为了实现临床上有意义的菌株覆盖并避免快速耐药，需要利福布汀浓度≥2 mg/L，这是利福布汀口服制剂无法提供的。
Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE. To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates. Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017–19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin’s mode of action and resistance mechanisms. Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore–drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10−9 at rifabutin concentrations at or above 2 mg/L. This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver.
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影响因子：
5.2
作者：
Higgins, Paul G.;Dammhayn, Cathrin;Seifert, Harald
通讯作者：
Seifert, Harald
影响因子：
5.2
作者：
Farhat, Maha R.;Sixsmith, Jaimie;Murray, Megan
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作者：
Eijkelkamp BA;Hassan KA;Paulsen IT;Brown MH
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影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John
影响因子：
5.7
作者：
Ferguson, AD;Ködding, J;Welte, W
通讯作者：
Welte, W