Interest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB). The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution. 19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC. MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition. 18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates. 10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 μg/mL). Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status. The lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation. No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging. This work highlighted some of the limitations of carbapenem use. More evidence is needed to clarify their true impact in TB treatment and outcome, considering the financial burden, complications and microbiota changes associated with their use.

中文翻译：

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厄他培南和法罗培南对抗结核分枝杆菌：宏观和微量稀释的体外测试和比较。

由于耐药结核病的出现，对碳青霉烯类药物的兴趣在过去几年一直在上升。厄他培南 (ETP) 每天一次肠胃外给药，法罗培南 (FAR) 口服给药比美罗培南 (MEM)、亚胺培南 (IPM) 和多利培南 (DOR) 更好。添加阿莫西林-克拉维酸 (AMC) 可抑制结核分枝杆菌 (MTB) 中存在的碳青霉烯酶的水解。本研究的目的是通过两种广泛使用的方法，即 BACTEC960 MGIT 和微量稀释，确定 ETP 和 FAR 对易感和耐药临床 MTB 菌株的体外活性。包括具有不同易感性特征和 H37Rv 的 19 种临床分离株。最小抑制浓度 (MIC) 测试使用两种不同浓度的 ETP 和 FAR 方法进行，有和没有 AMC。两种方法在有和没有 AMC 的情况下，FAR 的 MIC50 为 2 和 8。MIC90 通过微量稀释和 MGIT 分别 > 16 和 > 8，并且在添加 AMC 后没有变化。18/20 样品对最高浓度的 ETP 具有抗性，有和没有 AMC。一半的样本对 FAR 有一定的敏感性；添加 AMC 进一步降低了七个分离株的 MIC 水平。10/20 分离株表现出对 FAR 的敏感性，添加 AMC 进一步降低了 7 个分离株的 MIC。然而，大多数 MIC 接近有效性极限 (8 μg/mL)。对 FAR 的耐药性与对 MEM 的耐药性相关（p = 0.04），但与其他药物的耐药性相关，包括 M/XDR 状态。ETP 活性的缺乏可能与其在培养过程中的降解有关，而与碳青霉烯酶无关。没有对传统药物的敏感性模式可以预测对 FAR 的敏感性，并且敏感性测试不是常规可用的。由于达到这些实验中测试的浓度可能具有挑战性，因此需要进行 PK/PD 研究。这项工作突出了碳青霉烯使用的一些局限性。考虑到与它们的使用相关的经济负担、并发症和微生物群变化，需要更多的证据来阐明它们对结核病治疗和结果的真正影响。