title: Efficacies of colistin and tigecycline in mice with experimental pneumonia due to NDM-1-producing strains of Klebsiella pneumoniae and Escherichia coli.
abstract: New Delhi metallo-β-lactamase-1 (NDM-1)-producing Enterobacteriaceae have emerged as a global threat. The aim of this study was to assess the efficacies of colistin and tigecycline in an experimental model of pneumonia caused by NDM-1-producing Escherichia coli and Klebsiella pneumoniae. The susceptibilities of K. pneumoniae NDM, E. coli NDM and K. pneumoniae ATCC 29665 were determined using the broth microdilution technique. The pharmacokinetics of colistin and tigecycline in an experimental model of pneumonia were performed using immunocompetent C57BL/6 mice. Mice were treated with colistin (60 mg/kg/day) or tigecycline (10 mg/kg/day). Mortality, bacteraemia and lung bacterial concentrations were recorded. The strains were susceptible to colistin and tigecycline. The ratio of area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) for colistin was 158.5 (all three strains) and that for tigecycline was 18.5 (K. pneumoniae NDM) and 37 (K. pneumoniae ATCC 29665 and E. coli NDM). In vivo, colistin decreased bacterial lung concentrations of K. pneumoniae NDM and K. pneumoniae ATCC 29665 by 1.16 log colony-forming units (CFU)/g and 2.23 logCFU/g, respectively, compared with controls (not significant). Tigecycline reduced K. pneumoniae NDM and K. pneumoniae ATCC 29665 load by 2.67 logCFU/g and 4.62 logCFU/g (P<0.05). Colistin and tigecycline decreased lung concentrations of E. coli NDM by 2.27 logCFU/g and 4.15 logCFU/g (P<0.05), respectively, compared with controls, and was more active than colistin (P<0.05). In conclusion, these results suggest that colistin is inappropriate for treating pneumonia due to NDM-1-producing K. pneumoniae and its efficacy was suboptimal against NDM-1-producing E. coli. A high tigecycline dose was efficacious for treating experimental pneumonia due to NDM-1-producing E. coli and K. pneumoniae.
authors.affiliation: Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Universidad de Sevilla/CSIC, Sevilla, Spain. fdocobop@yahoo.es
authors.forename: Fernando
authors.initials: F
authors.lastname: Docobo-Pérez
authors.forename: Patrice
authors.initials: P
authors.lastname: Nordmann
authors.forename: Juan
authors.initials: J
authors.lastname: Domínguez-Herrera
authors.forename: Rafael
authors.initials: R
authors.lastname: López-Rojas
authors.forename: Younes
authors.initials: Y
authors.lastname: Smani
authors.forename: Laurent
authors.initials: L
authors.lastname: Poirel
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Pachón
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity*; D005260:Female; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity*; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000078304:Tigecycline; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000078304:Tigecycline; C004691:colistinmethanesulfonic acid; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D008911:Minocycline; D003091:Colistin