Mutant prevention concentrations, in vitro resistance evolution dynamics, and mechanisms of resistance to imipenem and imipenem/relebactam in carbapenem-susceptible Klebsiella pneumoniae isolates showing ceftazidime/avibactam resistance
Year: 2024
Type: article
Abstract: ABSTRACT Klebsiella pneumoniae carbapenemase (KPC) variants selected during ceftazidime/avibactam treatment usually develop susceptibility to carbapenems and carbapenem/β-lactamase inhibitors, such as imipenem and imipenem/relebactam. We analyzed imipenem and imipenem/relebactam single-step mutant frequencies, resistance development trajectories and differentially selected resistance mechanisms using two representative K. pneumoniae isolates that had developed ceftazidime/avibactam resistance during therapy (ST512/KPC-31 and ST258/KPC-35). Mutant frequencies and mutant prevention concentrations were measured in Mueller–Hinton agar plates containing incremental concentrations of imipenem or imipenem/relebactam. Resistance dynamics were determined after incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic or combination, up to 64 times their baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing and whole genome sequencing. The impact of KPC variants identified in resistant mutants on β-lactam resistance was investigated by cloning experiments. Imipenem/relebactam suppressed the emergence of resistant mutants at lower concentrations than imipenem, slowed down resistance development for both strains, and the resulting mutants yielded lower MICs of carbapenems and carbapenem/β-lactamase inhibitors than those selected with imipenem alone. Characterization of resistant mutants revealed that imipenem resistance was mainly caused by inactivation of OmpK36 and mutations in the KPC β-lactamase. Imipenem/relebactam-resistant mutants also maintained OmpK36 alterations, but mutations in KPC were much less frequent compared with those selected with imipenem alone. Genetic and biochemical characterization of the KPC derivatives identified in the resistant mutants confirmed their role in carbapenem resistance. Our data positions imipenem/relebactam as an attractive therapeutic option for combating ceftazidime/avibactam-resistant KPC-producing K. pneumoniae infections.
DOI: 10.1128/aac.01120-24
Authors: Tania Blanco-Martín, Lucía González-Pinto, Pablo Aja-Macaya, Salud Rodríguez-Pallares, Lucía Sánchez-Peña, Eva Gato, María del Carmen Fernández-López, Michelle Outeda-García, Arianna Rodríguez-Coello, Rosa Pedraza-Merino, Isaac Alonso-García, Juan Carlos Vázquez-Ucha, Luis Martínez-Martínez, Jorge Arca-Suárez, Alejandro Beceiro, Germán Bou
Institutions: Complexo Hospitalario Universitario A Coruña, Instituto de Investigación Biomédica de A Coruña, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red Enfermedades Infecciosas, University of Córdoba
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: hybrid
Awards: G1018507005, G113891353, G1300322159, G1302679915, G1670048366, G1704884201, G1911648367, G2047982920, G2111024134, G2549797331, G2842353929, G2874540823, Vacunas auxótrofas orales para la erradicación de bacterias intestinales: colonización intestinal por Klebsiella pneumoniae multirresistente como modelo, G306770859, G3183606106, G3477070971, G3847047809, G4316060540, Actividad in vivo de nuevos inhibidores de carbapenemasas frente a patógenos críticos multirresistentes: K. pneumoniae productor de carbapenemasas y P. aeruginosa., G4987700822, G5089057386, G5195802681, G5210856704, Desarrollo y evaluación de nuevas moléculas antimicrobianas dirigidas a patógenos multirresistentes (inhibidores de ß-lactamasas y conjugados tetraciclinas-sideróforos). Estudio nacional Acinetobacter spp., G5921404938, Inhibidores de carbapenemasas: actividad frente a Enterobacterales productores de carbapenemasas, mecanismos e impacto en la evolución de la resistencia antimicrobiana (PROTECT), G6023180733, G6246111646, DETECCIÓN RÁPIDA DE RESISTENCIAS ANTIBIÓTICAS MEDIANTE ESPECTROMETRÍA DE MASAS MALDI-TOF, MARCADORES MICROBIOLÓGICOS DE LA ACTIVIDAD IN VITRO DE NUEVAS COMBINACIONES DE BETALACTÁMICOS/INHIBIDORES DE BETALACTAMASAS FRENTE A CEPAS DE K. PNEUMONIAE PRODUCTORAS DE KPC/OXA-48, G7071269994, La medicina de precisión contra la resistencia a antimicrobianos: Proyecto MePRAM, G8233566012, G8687712442, G8725042212, G8888136783
OpenAlex ID: W4404394291