Faropenem resistance causes in vitro cross-resistance to carbapenems in ESBL-producing Escherichia coli |
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| Institution: | 1. Clinical Microbiology Laboratory, Department of Pathology, NorthShore University HealthSystem, Evanston, Illinois;2. Department of Pathology, The University of Chicago Pritzker School of Medicine, Chicago, Illinois;3. The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA;4. Sequencing Core, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois;5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA;6. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA;7. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA;1. Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland;2. Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Tx, USA;3. Saint Louis University, St Louis, Mo, USA;1. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA;2. Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, USA;2. Department of Laboratory Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China;3. Department of Laboratory Medicine, Chongqing Dazu District People''s Hospital, Chongqing, China;4. Department of Clinical Laboratory, University of Chinese Academy of Sciences Chongqing Renji Hospital, Fifth People’s Hospital of Chongqing, Chongqing, China;5. Department of Laboratory Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China;1. Aix-Marseille Université, IRD, APHM, MEPHI, IHU Méditerranée Infection, Marseille, France;2. Aix-Marseille Université, IRD, SSA, APHM, VITROME, IHU Méditerranée Infection, Marseille, France;3. Département de cardiologie, Hôpital de la Timone, AP-HM, boulevard Jean-Moulin, 13005 Marseille, France;4. Laboratoire d''hématologie, Hôpital de la Timone, APHM, boulevard Jean Moulin, 13005 Marseille, France;1. Paris-Descartes University, Faculty of Medicine, APHP, European Georges Pompidou Hospital, Parasitology-Mycology Unit, Microbiology department, Paris, France;2. Dynamyc Research Group, Paris Est Créteil University (UPEC, EnvA), France;3. Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India |
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| Abstract: | ObjectiveFaropenem is an oral penem drug with activity against Gram-positive and Gram-negative bacteria, including CTX-M-15-type extended spectrum beta-lactamase (ESBL)-producing Enterobacteriales and anaerobic bacteria. As there are structural similarities, there is concern for the development of carbapenem cross-resistance; however, there are no studies confirming this. This study examined whether in vitro development of faropenem resistance in Escherichia coli isolates would result in cross-resistance to carbapenems.MethodsFour well-characterized E. coli isolates from the US Centers for Disease Control and Prevention antibiotic resistance isolate bank were utilized. Three isolates (NSF1, NSF2 and NSF3) are ESBL producers (CTX-M-15) and one (NSF4) is pan-susceptible. Faropenem minimum inhibitory concentrations (MICs) were determined and resistance was induced by serial passaging in increasing concentrations of faropenem. Susceptibility to carbapenems was determined and whole-genome sequencing (WGS) was performed to identify the underlying genetic mechanism leading to carbapenem resistance.ResultsFaropenem MIC increased from 1 mg/L to 64 mg/L within 10 days for NSF2 and NSF4 isolates, and from 2 mg/L to 64 mg/L within 7 days for NSF1 and NSF3 isolates. Reduced carbapenem susceptibility (ertapenem MIC ≥8 mg/L, doripenem/meropenem ≥2 mg/L and imipenem ≥1 mg/L) developed among three CTX-M-15-producing isolates that were faropenem-resistant, but not in NSF4 isolate that lacked ESBL enzyme. WGS analysis revealed non-synonymous changes in the ompC gene among three CTX-M-15-producing isolates, and a single nucleotide polymorphism (SNP) in the envZ gene in NSF4 isolate.ConclusionInduced resistance to faropenem causes cross-resistance to carbapenems among E. coli isolates containing CTX-M-15-type ESBL enzymes. |
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