Abstract

Background

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.

Objectives

To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates.

Methods

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.

Results

Rifabutin showed excellent activity on the strain panel, with an MIC_50/90 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.

Conclusions

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.

中文翻译：

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利福布汀对293种当代抗碳青霉烯类鲍曼不动杆菌临床分离株的体外活性以及利福布汀的作用方式和耐药机制的表征。

摘要

背景

利福布丁是一种被批准用于治疗鸟分枝杆菌感染的口服药物，在利福布汀通过铁载体FhuE吸收细胞后，在营养受限的培养基中显示出对鲍曼不动杆菌的有效活性。

目标

为了确定一大批鲍曼不动杆菌中的利福布汀的体外活性和耐药机制。

方法

在2017-19年间从欧洲，美国和亚洲收集的293株对碳青霉烯类耐药的鲍曼不动杆菌临床分离株用于MIC测定。利福布汀MIC升高的分离株中fhuE，rpoB和arr-2基因的测序/基因分型与基因工程和基因表达定量相结合，用于表征利福布汀的作用方式和耐药机制。

结果

_利福布汀在菌株组中显示出优异的活性，MIC _50/90为0.008 / 1 mg / L，并且优于所有其他测试的抗生素，包括粘菌素，替加环素和头孢地洛尔（MIC ₉₀为8 mg / L）。利福布汀在耐药亚群（包括对铁载体-药物共轭头孢地洛尔耐药的菌株（MIC ₉₀为2 mg / L，n =  23））上仍然具有活性。至少需要两个独立的抗药性机制才能消除利福布汀的活性，这与在2 mg / L或以上的利福布汀浓度时剂量依赖性突变抗药性频率达到10 ^-9相符。

结论

这项研究证明了利福布汀对耐碳青霉烯的鲍曼不动杆菌的有效活性。我们建议，FhuE介导的利福布汀的主动摄取可以使抗利福平菌株的活性升高。为了达到临床上有意义的菌株覆盖范围并避免快速耐药性发展，需要利福布汀的浓度≥2mg / L，而利福布汀口服制剂无法提供这些成分。