title: A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae.
abstract: The spread of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether β-lactam/β-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.).
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Gutiérrez-Gutiérrez
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Pérez-Galera
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Salamanca
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: de Cueto
authors.affiliation: Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Calbo
authors.affiliation: Hospital Universitari Vall d'Hebrón, Barcelona, Spain.
authors.forename: Benito
authors.initials: B
authors.lastname: Almirante
authors.affiliation: Teaching Hospital Policlinico S. Orsola Malpighi, Bologna, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
authors.affiliation: Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
authors.affiliation: Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Pintado
authors.affiliation: Corporacio Sanitaria Parc Taulí, Sabadell, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Gasch
authors.affiliation: Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Martínez
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Canada.
authors.forename: Johann
authors.initials: J
authors.lastname: Pitout
authors.affiliation: Hacettepe University School of Medicine, Ankara, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Akova
authors.affiliation: Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Carmen
authors.identifier: 0000-0002-6673-2883
authors.initials: C
authors.lastname: Peña
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Molina
authors.affiliation: Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Hernández
authors.affiliation: Policlinico Umberto I, University of Rome La Sapienza, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Venditti
authors.affiliation: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Prim
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Origüen
authors.affiliation: Complejo Hospitalario Universitario A Coruña, A Coruña, Spain.
authors.forename: German
authors.initials: G
authors.lastname: Bou
authors.affiliation: Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Evelina
authors.initials: E
authors.lastname: Tacconelli
authors.affiliation: Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Tumbarello
authors.affiliation: Institut für Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Köln, Cologne, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hamprecht
authors.affiliation: Hygeia General Hospital, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Giamarellou
authors.affiliation: Hospital Clinic, Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Almela
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Pérez
authors.affiliation: Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, and National Center for Infection Control, Israel Ministry of Health, Tel Aviv, Israel.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Schwaber
authors.affiliation: Hospital Español, Rosario, Argentina.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Bermejo
authors.affiliation: Wits Donald Gordon Medical Centre, Johannesburg, South Africa.
authors.forename: Warren
authors.initials: W
authors.lastname: Lowman
authors.affiliation: National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Po-Ren
authors.initials: PR
authors.lastname: Hsueh
authors.affiliation: Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Mora-Rillo
authors.affiliation: Hospital Universitario Reina Sofia-IMIBIC-UCO, Córdova, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Natera
authors.affiliation: University General Hospital Attikon, Chaidari, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Souli
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA Departments of Medicine, Pharmacology, Biochemistry, Molecular Biology, and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Division of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, and National Center for Infection Control, Israel Ministry of Health, Tel Aviv, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Carmeli
authors.affiliation: University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Brisbane, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain Departamento de Microbiología, Universidad de Sevilla, Seville, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual
authors.affiliation: Unidad Clínica Intercentros de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospitales Universitarios Virgen Macarena y Virgen del Rocío-IBIS, Seville, Spain Departamento de Medicina, Universidad de Sevilla, Seville, Spain jesusrb@us.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Rodríguez-Baño
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D015780:Carbapenems / Q000627:therapeutic use; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D012189:Retrospective Studies; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use*; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases