title: Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers.
abstract: Secondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-β-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-β-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, ≤ 32 μg/ml; fT>MIC, ≥ 38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥ 128 μg/ml; fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, ≤16 μg/ml; fT>MIC, ≥ 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P. aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤ 16 μg/ml and variable efficacy noted when the MICs were ≥ 32 μg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.
authors: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors: Jared L
authors: JL
authors: Crandon
authors: David P
authors: DP
authors: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001398:Aztreonam / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000188:drug therapy; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000302:isolation & purification; D051379:Mice; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; C543519:avibactam; C533914:metallo-beta-lactamase (VIM-13), Pseudomonas aeruginosa; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; D001398:Aztreonam
references: Antimicrob Agents Chemother. 1998 Sep;42(9):2375-9
references: 9736566
references: Antimicrob Agents Chemother. 2012 Dec;56(12):6137-46
references: 22985878
references: Clin Microbiol Rev. 2007 Jul;20(3):440-58, table of contents
references: 17630334
references: Antimicrob Agents Chemother. 2011 Jan;55(1):390-4
references: 21041502
references: Lancet Infect Dis. 2011 May;11(5):381-93
references: 21530894
references: J Antimicrob Chemother. 2010 Nov;65 Suppl 4:iv33-9
references: 21115453
references: Antimicrob Agents Chemother. 1983 Jun;23(6):852-6
references: 6684412
references: Clin Infect Dis. 2010 Mar 1;50(5):625-63
references: 20175247
references: Antimicrob Agents Chemother. 2007 Sep;51(9):3049-55
references: 17576827
references: Curr Opin Pharmacol. 2012 Oct;12(5):527-34
references: 22748801
references: Can J Infect Dis Med Microbiol. 2008 Jan;19(1):19-53
references: 19145262
references: Antimicrob Agents Chemother. 2011 Jul;55(7):3220-5
references: 21518838
references: Clin Infect Dis. 2007 Jan 1;44(1):79-86
references: 17143821
references: J Antimicrob Chemother. 2008 Nov;62(5):1053-6
references: 18689875
references: Infect Dis Clin North Am. 2003 Sep;17(3):479-501
references: 14711073
references: Antimicrob Agents Chemother. 2009 Dec;53(12):5046-54
references: 19770275
references: Clin Infect Dis. 2005 Nov 15;41(10):1373-406
references: 16231249