antibioticsАнтибиотики и ХимиотерапияAntibiot Khimioter = Antibiotics and Chemotherapy0235-2990ООО «Издательство ОКИ»10.37489/0235-2990-2022-67-11-12-16-21antibiotics-992Research ArticleЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯEXPERIMENTAL STUDIESАктивность цефидерокола и других новых антибиотиков в отношении экстремально-антибиотикорезистентных штаммов Klebsiella pneumoniaeActivity of Cefiderocol and Other New Antibiotics Against Extensively Drug-Resistant Klebsiella pneumoniae Strainshttps://orcid.org/0000-0002-3952-6187КарповаЕ. В.KarpovaE. V.

Карпова Елена Васильевна — ассистент кафедры микробиологии, вирусологии и иммунологии.

ул. Ланге, 5, Гомель, 246050

Scopus Author ID: 57318423400

Elena V. Karpova — assistant of the Department of Microbiology, Virology and Immunology, Gomel State Medical University.

5 Lange st., Gomel, 246050

Scopus Author ID: 57318423400

https://orcid.org/0000-0002-9484-7848ТапальскийД. В.TapalskiD. V.

Тапальский Дмитрий Викторович — доктор медицинских наук, доцент, заведующий кафедрой микробиологии, вирусологии и иммунологии.

ул. Ланге, 5, Гомель, 246050

Scopus Author ID: 6506992098

Dmitry V. Tapalski — D. Sc. in medicine, Head of the Department of Microbiology, Virology and Immunology, Gomel State Medical University.

5 Lange st., Gomel, 246050

Scopus Author ID: 6506992098

tapalskiy@gsmu.byГомельский государственный медицинский университетБеларусьGomel State Medical UniversityBelarus2022110220236711-121621Copyright © Карпова Е.В., Тапальский Д.В., 20232023Карпова Е.В., Тапальский Д.В.Karpova E.V., Tapalski D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.antibiotics-chemotherapy.ru/jour/article/view/992Актуальность

Актуальность. Распространение экстремальной антибиотикорезистентности среди грамотрицательных бактерий требует поиска антибактериальных агентов с новыми  механизмами активности.

Цель

Цель. Оценить чувствительности экстремально-антибиотикорезистентных штаммов K. pneumoniae к цефидероколу и новым ингибиторозащищённым β-лактамам, а также определить генетические механизмы антибиотикорезистентности.

Методы

Методы. Отобрано 30 экстремально-антибиотикорезистентных штаммов K. pneumoniae, выделенных в 2016–2021 гг. в 4 регионах Беларуси. Детекция  генов карбапенемаз выполнена  методом ПЦР  в режиме реального времени. Определение минимальных подавляющих концентраций (МПК)  цефидерокола  и других новых антибиотиков выполнено методом микроразведений  с использованием системы  Sensititre. Для 2 резистентных  и 3 чувствительных  к цефидероколу  штаммов  выполнено высокопроизводительное секвенирование.  Сборку  геномных последовательностей и их аннотацию выполняли с помощью программного инструмента UGENE v. 37.0. Трансляцию  нуклеотидных  последовательностей в аминокислотные проводили  с помощью пакета CLC  Sequence Viewer v. 8.0 (QIAGEN). Оценку аминокислотных замен и их влияние на функциональную активность белков выполняли  с помощью ресурса PROVEAN.

Результаты

Результаты. Продуцентами  карбапенемазы KPC являлись 4 штамма,  OXA-48 — 17, KPC+OXA-48  — 1, NDM  — 7, OXA-48 + NDM  — 1. Все продуценты  KPC были чувствительны к имипенему/релебактаму  и меропенему/ваборбактаму. Устойчивость к цефтазидиму–авибактаму отмечена у всех продуцентов NDM и ко-продуцента OXA-48 + NDM.  Выявлено  9 штаммов, устойчивых  к цефидероколу.  Устойчивые штаммы являлись продуцентами  NDM либо OXA-48 и были выделены  от пациентов с инфекцией COVID-19 в стационарах  трёх регионов Беларуси. У устойчивых штаммов выявлены  функционально значимые несинонимичные замены в генах TonB-зависимых рецепторов катехолатных сидерофоров FepA (F472V, P64S) и Fiu (T92S).

Заключение

Заключение. Показана высокая микробиологическая эффективность новых ингибиторозащищённых карбапенемов и цефалоспоринов в отношении  продуцентов карбапенемаз определённых  типов. Выявлены штаммы с мутационной  устойчивостью к цефидероколу — антибиотику, ранее не применявшемуся в Беларуси.

Background

Background. The spread of extensive drug-resistance among gram-negative bacteria calls for the search for antimicrobics with new mechanisms of actions.

The aim was to assess susceptibility of extensively drug-resistant K. pneumoniae strains to cefiderocol and other new inhibitor-protected β-lactams, and to determine genetic mechanisms of antibiotic resistance.

Methods

Methods. This study included 30 extensively drug-resistant K. pneumoniae strains collected in 2016–2021 from 4 regions of Belarus. Carbapenemase genes were detected by real-time PCR. Minimum inhibitory concentrations (MICs) for cefiderocol and other new antibiotics were assessed by microdilution method using the Sensititre system. Whole genome sequencing was performed for 2 resistant and 3 cefiderocol-susceptible strains. Genome assemblies and annotation were performed using UGENE v. 37.0 software. Nucleotide sequences were translated using CLC  Sequence Viewer v. 8.0 (QIAGEN) package. The PROVEAN software was used to assess amino asides substitutions and their influence on the functional activity of proteins.

Results

Results. KPC carbapenemase-producers were 4 strains, OXA-48 — 17, KPC+OXA-48 — 1, NDM — 7, OXA-48 + NDM — 1. All KPC-producers were susceptible to imipenem/relebactam and meropenem/vaborbactam. Resistance to ceftazidime-avibactam was noted in all NDM  producers and OXA-48+NDM  co-producer. The study has identified 9 cefiderocol-resistant strains. These were NDM and OXA-48-producers isolated from hospitalized patients with COVID-19 infection from 3 regions of Belarus. Resistant strains had functionally significant nonsynonymous  substitutions in the genes of TonB-dependent receptors for catecholate siderophores FepA (F472V, P64S) and Fiu (T92S).

Conclusion

Conclusion. The study has shown high efficacy of new inhibitor-protected carbapenems and cephalosporins against certain types of carbapenemase-producers. Strains with mutational resistance to cefiderocol, an antibiotic not previously used in Belarus, have been identified.

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The authors declare that there are no conflicts of interest present.