title: In vitro activity of ceftazidime-avibactam combination in in vitro checkerboard assays.
abstract: To evaluate the in vitro effects of the combination of ceftazidime and avibactam on the MICs of both compounds, checkerboard assays were performed for 81 clinical strains, including 55 Enterobacteriaceae strains (32 Klebsiella pneumoniae, 19 Escherichia coli, 1 Citrobacter freundii, and 3 Enterobacter cloacae) and 26 strains of Pseudomonas aeruginosa, all with known resistance mechanisms such as extended-spectrum β-lactamases (ESBLs) and carbapenemases, phenotypically or molecularly determined. Phenotypically ceftazidime-resistant strains (n=69) were analyzed in more detail. For the Enterobacteriaceae strains, a concentration-dependent effect of avibactam was found for most strains with a maximum effect of avibactam at a concentration of 4 mg/liter, which decreased all ceftazidime MICs to ≤4 mg/liter. Avibactam alone also showed antibacterial activity (the MIC50 and MIC90 being 8 and 16 mg/liter, respectively). For the ceftazidime-resistant P. aeruginosa strains, considerable inhibition of β-lactamases by avibactam was acquired at a concentration of 4 mg/liter, which decreased all ceftazidime MICs except one to ≤8 mg/liter (the CLSI and EUCAST susceptible breakpoint). Increasing the concentration of avibactam further decreased the MICs, resulting in a maximum effect for most strains at 8 to 16 mg/liter. In summary, for most strains, the tested addition of avibactam of 4 mg/liter restored the antibacterial activity of ceftazidime to a level comparable to that of wild-type strains, indicating full inhibition, and strains became susceptible according to the EUCAST and CLSI criteria. Based on these in vitro data, avibactam is a promising inhibitor of different β-lactamases, including ESBLs and carbapenemases.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Johanna
authors.identifier: http://orcid.org/0000-0003-4387-4464
authors.initials: J
authors.lastname: Berkhout
authors.affiliation: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Melchers
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Anita C
authors.initials: AC
authors.lastname: van Mil
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
authors.forename: Wright W
authors.initials: WW
authors.lastname: Nichols
authors.affiliation: Department of Medical Microbiology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands jwmouton@gmail.com.
authors.forename: Johan W
authors.identifier: http://orcid.org/0000-0001-6736-4149
authors.initials: JW
authors.lastname: Mouton
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002442:Ceftazidime / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; C543519:avibactam; D002442:Ceftazidime; D001618:beta-Lactamases; C063912:carbapenemase