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The Triple Combination of Meropenem,Avibactam,and a Metallo-b-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different b-Lactamase Producers

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Engineering 2024年第7期38卷 124-132页

作者： Zhuoren Ling Alistair james Macdonald Farley Aditya Lankapalli Yanfang Zhang Shonnette Premchand-Branker Kate Cook Andrei Baran Charlotte Gray-Hammerton Claudia Orbegozo Rubio Edgars Suna jordan Mathias jürgen brem.kirsty sands Maria Nieto-Rosado Maria Mykolaivna Trush Nadira Naznin Rakhi Willames Martins Yuqing Zhou Christopher joseph Schofield Timothy Walsh Department of Biology&Ineos Oxford Institute for Antimicrobial Research University of OxfordOxford OX13REUK Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial ResearchUniversity of OxfordOxford OX13TAUK Latvian Institute of Organic Synthesis Riga LV-1006Latvia Department of Medical Microbiology Division of Infection and ImmunitySchool of MedicineCardiff UniversityCardiff CF144XNUK Enzymology and Applied Biocatalysis Research Center Faculty of Chemistry and Chemical EngineeringBabes-Bolyai UniversityCluj-Napoca 400028Romania

This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution *** frequency of resistance(FoR)to MEM combined with InC58 was *** were sequenced and tested for cross resistance,fitness,and the stability of the resistance *** with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(***)and OXA-23-carrying Acinetobacter baumannii(***).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,*** mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.

关键词： Carbapenemase Metallo/serine-b-lactamase inhibitor Avibactam Meropenem Antimicrobial resistance

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A One-Health Sampling Strategy to Explore the Dissemination and Relationship Between Colistin Resistance in Human,Animal,and Environmental Sectors in Laos

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Engineering 2022年第8期8卷 45-56页

作者： Yuqing Zhou Refath Farzana Somsavanh Sihalath Sayaphet Rattanavong Manivanh Vongsouvath Mayfong Mayxay kirsty sands Paul N.Newton David A.B.Dance Brekhna Hassan Timothy R.Walsh Department of Zoology University of OxfordOxford OX13SZUK Ineos Oxford Institute for Antimicrobial Research(IOI) University of OxfordOxford OX13REUK Department of Medical Microbiology Institute of Infection and ImmunitySchool of MedicineCardiff UniversityCardiff CF144XNUK Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit Microbiology LaboratoryMahosot HospitalVientiane PO Box 292Lao PDR Centre for Tropical Medicine&Global Health Nuffield Department of MedicineUniversity of OxfordOxford OX37BNUK Institute of Research and Education Development University of Health SciencesVientiane PO Box 7444Lao PDR Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical MedicineLondon WC1E 7HTUK

This study was designed to investigate the molecular epidemiology of mobile colistin resistance(mcr)using a"One-Health"approach in Laos and to predict whether any dominant plasmid backbone and/or strain type influences the dissemination of *** collected 673 samples from humans(rectal normal flora),poultry,and the environment(water,flies,birds,etc.)in Vientiane,Lao People’s Democratic Republic(Laos),from May to September 2018.A total of 238 Escherichia coli(***)isolated from nonduplicative samples,consisting of 98 MCR-positive ***(MCRPEC)("mcr"denotes the gene encoding mobile colistin resistance,and"MCR"denotes the subsequent protein encoded by mcr)and 140 MCRnegative ***(MCRNEC),were characterized by phenotype and Illumina sequencing.A subset of MCRPEC was selected for Min ION sequencing,conjugation assay,plasmid stability,and growth kinetics in *** prevalence of MCRPEC was found to be 14.6%(98/673),with the highest prevalence in human rectal swabs(45.9%(45/98),pjugative,and a significantly high transfer rate into a hypervirulent clone ST1193 was *** containing mcr irrespective of Inc type w

关键词： Colistin resistance mcr Escherichia coli Laos Horizontal transmission

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