Ángel Rodríguez-Villodres1,2, María Luisa Gil-Marqués1,2, Rocío Álvarez-Marín1,2, Rémy A Bonnin3, María Eugenia Pachón-Ibáñez1,2, Manuela Aguilar-Guisado1,2, Thierry Naas3, Javier Aznar1,2,4, Jerónimo Pachón2,5, José Antonio Lepe1,2, Younes Smani1,2. 1. Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Seville, Spain. 2. Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. 3. EA7361, Université Paris-Saclay, LabEx Lermit, Bacteriology-Hygiene unit, APHP, Hôpital Bicêtre, EERA 'Evolution and Ecology of Resistance to Antibiotics' Unit, Institut Pasteur-APHP-Université Paris-Sud, Le Kremlin-Bicêtre, France. 4. Department of Microbiology, University of Seville, Seville, Spain. 5. Department of Medicine, University of Seville, Seville, Spain.
Abstract
OBJECTIVES: Escherichia coli is characterized by three resistance patterns to β-lactams/β-lactamase inhibitors (BLs/BLIs): (i) resistance to ampicillin/sulbactam and susceptibility to amoxicillin/clavulanic acid and piperacillin/tazobactam (RSS); (ii) resistance to ampicillin/sulbactam and amoxicillin/clavulanic acid, and susceptibility to piperacillin/tazobactam (RRS); and (iii) resistance to ampicillin/sulbactam, amoxicillin/clavulanic acid and piperacillin/tazobactam (RRR). These resistance patterns are acquired consecutively, indicating a potential risk of developing resistance to piperacillin/tazobactam, but the precise mechanism of this process is not completely understood. METHODS: Clinical isolates incrementally pressured by piperacillin/tazobactam selection in vitro and in vivo were used. We determined the MIC of piperacillin/tazobactam in the presence and absence of piperacillin/tazobactam pressure. We deciphered the role of the blaTEM genes in the new concept of extended-spectrum resistance to BLs/BLIs (ESRI) using genomic analysis. The activity of β-lactamase was quantified in these isolates. RESULTS: We show that piperacillin/tazobactam resistance is induced in E. coli carrying blaTEM genes. This resistance is due to the increase in copy numbers and transcription levels of the blaTEM gene, thus increasing β-lactamase activity and consequently increasing piperacillin/tazobactam MICs. Genome sequencing of two blaTEM-carrying representative isolates showed that piperacillin/tazobactam treatment produced two types of duplications of blaTEM (8 and 60 copies, respectively). In the clinical setting, piperacillin/tazobactam treatment of patients infected by E. coli carrying blaTEM is associated with a risk of therapeutic failure. CONCLUSIONS: This study describes for the first time the ESRI in E. coli. This new concept is very important in the understanding of the mechanism involved in the acquisition of resistance to BLs/BLIs.
OBJECTIVES:Escherichia coli is characterized by three resistance patterns to β-lactams/β-lactamase inhibitors (BLs/BLIs): (i) resistance to ampicillin/sulbactam and susceptibility to amoxicillin/clavulanic acid and piperacillin/tazobactam (RSS); (ii) resistance to ampicillin/sulbactam and amoxicillin/clavulanic acid, and susceptibility to piperacillin/tazobactam (RRS); and (iii) resistance to ampicillin/sulbactam, amoxicillin/clavulanic acid and piperacillin/tazobactam (RRR). These resistance patterns are acquired consecutively, indicating a potential risk of developing resistance to piperacillin/tazobactam, but the precise mechanism of this process is not completely understood. METHODS: Clinical isolates incrementally pressured by piperacillin/tazobactam selection in vitro and in vivo were used. We determined the MIC of piperacillin/tazobactam in the presence and absence of piperacillin/tazobactam pressure. We deciphered the role of the blaTEM genes in the new concept of extended-spectrum resistance to BLs/BLIs (ESRI) using genomic analysis. The activity of β-lactamase was quantified in these isolates. RESULTS: We show that piperacillin/tazobactam resistance is induced in E. coli carrying blaTEM genes. This resistance is due to the increase in copy numbers and transcription levels of the blaTEM gene, thus increasing β-lactamase activity and consequently increasing piperacillin/tazobactam MICs. Genome sequencing of two blaTEM-carrying representative isolates showed that piperacillin/tazobactam treatment produced two types of duplications of blaTEM (8 and 60 copies, respectively). In the clinical setting, piperacillin/tazobactam treatment of patients infected by E. coli carrying blaTEM is associated with a risk of therapeutic failure. CONCLUSIONS: This study describes for the first time the ESRI in E. coli. This new concept is very important in the understanding of the mechanism involved in the acquisition of resistance to BLs/BLIs.
Authors: Ángel Rodríguez-Villodres; Rémy A Bonnin; José Manuel Ortiz de la Rosa; Rocío Álvarez-Marín; Thierry Naas; Javier Aznar; Jerónimo Pachón; José Antonio Lepe; Younes Smani Journal: J Clin Med Date: 2019-12-02 Impact factor: 4.241
Authors: Thomas Edwards; Eva Heinz; Jon van Aartsen; Alex Howard; Paul Roberts; Caroline Corless; Alice J Fraser; Christopher T Williams; Issra Bulgasim; Luis E Cuevas; Christopher M Parry; Adam P Roberts; Emily R Adams; Jenifer Mason; Alasdair T M Hubbard Journal: Microb Genom Date: 2022-04