title: In vivo efficacy of humanized exposures of Ceftazidime-Avibactam in comparison with Ceftazidime against contemporary Enterobacteriaceae isolates.
abstract: Ceftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of the in vivo efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant Enterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against Enterobacteriaceae exhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical Enterobacteriaceae isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10 CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the Enterobacteriaceae isolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MIC of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant Enterobacteriaceae.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Shawn H
authors.initials: SH
authors.lastname: MacVane
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Wright W
authors.initials: WW
authors.lastname: Nichols
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA david.nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D065093:beta-Lactamase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime