Activity and resistance mechanisms of the third generation tetracyclines tigecycline, eravacycline and omadacycline against nationwide Spanish collections of carbapenemase-producing Enterobacterales and Acinetobacter baumannii

Abstract

Multicenter study[Abstract] Introduction: The rise in multidrug-resistant bacteria challenges clinical microbiology. Tigecycline, eravacycline, and omadacycline show promise against carbapenem-resistant Enterobacterales and Acinetobacter baumannii. This study evaluates their activity and resistance mechanisms. Methods: Two Spanish multicentre collections of WGS-characterized carbapenemase-producing Enterobacterales (n=399) and A. baumannii (n=118) were tested. The MICs of tigecycline, eravacycline, omadacycline and classic tetracyclines were determined. WGS-guided resistome analysis, expression studies, efflux pump inhibition and cloning assays identified potential mechanisms of resistance. Results: Tigecycline and eravacycline exhibited the highest activity against the whole set of Enterobacterales (MIC50/MIC90 0.5/1 mg/L and 1/2 mg/L, respectively), and A. baumannii (MIC50/MIC90 1/2 mg/L and ≤0.25/1 mg/L, respectively). Omadacycline showed no improvement relative to classic tetracyclines (MIC50/MIC90 values of 8/32 mg/L and 8/16 mg/L for Enterobacterales and A. baumannii, respectively). Resistance mechanisms in Enterobacterales included efflux pumps (AcrAB-TolC, OqxAB) and mutation in their regulatory genes. In A. baumannii, adeS gene mutations and adeABC upregulation decreased tigecycline activity. The prevalent sequence types with reduced susceptibility to eravacycline and tigecycline were ST307 in K. pneumoniae and ST2 in A. baumannii. Conclusion: Eravacycline remains a key agent for the treatment of bacterial infections exhibiting promising efficacy against multidrug-resistant pathogens. As an empirical antibiotic it could be a good alternative for severe infections caused by CPE or CRAB, however, its clinical use is limited by the absence of standardized breakpoints. Resistance mechanisms, including efflux pumps and gene mutations, vary among isolates. High-risk clones like K. pneumoniae ST307 and A. baumannii ST2 underscore the necessity of prudent antibiotic use.This work was supported by Projects PI20/01212 and PI23/00851 awarded to A.B., Project PI21/00704 awarded to G.B., and Project PI22/01212 awarded to J.A.-S. all funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. The work was also supported by CIBER-Consorcio Centro de Investigación Biomédica en Red- de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (CB21/13/00055), Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU and by project IN607A 2020/05 awarded to G.B. and project IN607D 2021/12 awarded to A.B (GAIN-Agencia Gallega de Innovación. Consellería de Economía, Emprego e Industria). JA-S was financially supported by the Juan Rodés program (ISCIII, JR21/00026), J.C.V.-U. was financially supported by IN606B-2022/009 (Xunta de Galicia), C.L.-M. was financially supported by PI20/01212 (ISCIII), P.G.-S. was financially supported by IN606A 2021/021 Grant (Xunta de Galicia). M.O.-G. was financially supported by IN607D 2021/12. I.A.-G. was financially supported by the Juan Rodés (ISCIII, JR23/00036). T.B.-M was financially supported by the ISCIII project PI20/00686 and by the Rio Hortega program (ISCIII, CM23/00095). L.G.-P was financially supported by the ISCIII project PI21/00704 and by the PFIS program (ISCIII, FI23/00074).info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI20%2F01212/ES/DESARROLLO Y EVALUACION DE NUEVAS MOLECULAS ANTIMICROBIANAS DIRIGIDAS A PATOGENOS MULTIRRESISTENTES (INHIBIDORES DE ß-LACTAMASAS Y CONJUGADOS TETRACICLINAS-SIDEROFOROS). ESTUDIO NACIONAL ACINETOBACTER SPP.info:eu-repo/grantAgreement/ISCIII/Programa Estatal para impulsar la investigación científico-técnica y su transferencia/PI23%2F00851/ES/Actividad in vivo de nuevos inhibidores de carbapenemasas frente a patógenos críticos multirresistentes: K. pneumoniae productor de carbapenemasas y P. aeruginosa.info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI21%2F00704/ES/VACUNAS AUXOTROFAS ORALES PARA LA ERRADICACION DE BACTERIAS INTESTINALES: COLONIZACIÓN INTESTINAL POR KLEBSIELLA PNEUMONIAE MULTIRRESISTENTE COMO MODELOInstituto de Salud Carlos III; CB21/13/00055España. Ministerio de Ciencia e Innovación; IN607A 2020/05España. Ministerio de Ciencia e Innovación; IN607D 2021/1