title: Bactericidal and intracellular activity of β-lactams against Mycobacterium abscessus.
abstract: Cefoxitin and imipenem are the sole recommended β-lactams for the treatment of Mycobacterium abscessus pulmonary infections. Here, we investigated whether one of these drugs displays superiority in terms of killing and intracellular activity. We have also evaluated whether the use of a β-lactamase inhibitor could improve their activity.
  
  
  
  The impact of the β-lactamase BlaMab on the activity of β-lactams was assessed by comparing M. abscessus CIP104536 and its β-lactamase-deficient ΔblaMab derivative, as well as by using the β-lactamase inhibitor avibactam. The activity of cefoxitin, imipenem, amoxicillin and ceftaroline, alone and in various combinations including amikacin, was compared based on determination of time-kill curves and of intracellular proliferation in human macrophages.
  
  
  
  Imipenem was superior to cefoxitin in both the time-kill and macrophage assays. Production of BlaMab limited the activity of imipenem. The combination of imipenem and amikacin was bactericidal against the ΔblaMab mutant. Deletion of blaMab extended the spectrum of β-lactams active against M. abscessus to include amoxicillin and ceftaroline. In the absence of BlaMab, amoxicillin was as active as imipenem. These drugs were more active than ceftaroline and cefoxitin was the least active. Avibactam increased the intracellular activity of ceftaroline, but inhibition of BlaMab was only partial, as previously reported for amoxicillin.
  
  
  
  Evaluation of the killing and intracellular activities of β-lactams indicates that imipenem is superior to cefoxitin at clinically achievable drug concentrations. Inhibition of BlaMab could improve the efficacy of imipenem and extend the spectrum of drugs potentially useful to treat pulmonary infections.
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Lefebvre
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubée
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Cortes
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Dorchêne
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
authors.affiliation: INSERM, U1138, LRMA, Equipe 12 du Centre de Recherche des Cordeliers, Paris, F-75006, France Université Pierre et Marie Curie, UMR S 1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France Assistance Publique-Hôpitaux de Paris, Service de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France jean-luc.mainardi@crc.jussieu.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mainardi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D004347:Drug Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects*; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000502:physiology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C543519:avibactam