Tags

Type your tag names separated by a space and hit enter

Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers.
Antimicrob Agents Chemother. 2013 Jul; 57(7):3299-306.AA

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+Show Affiliations

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23650162

Citation

Crandon, Jared L., and David P. Nicolau. "Human Simulated Studies of Aztreonam and Aztreonam-avibactam to Evaluate Activity Against Challenging Gram-negative Organisms, Including Metallo-β-lactamase Producers." Antimicrobial Agents and Chemotherapy, vol. 57, no. 7, 2013, pp. 3299-306.
Crandon JL, Nicolau DP. Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers. Antimicrob Agents Chemother. 2013;57(7):3299-306.
Crandon, J. L., & Nicolau, D. P. (2013). Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers. Antimicrobial Agents and Chemotherapy, 57(7), 3299-306. https://doi.org/10.1128/AAC.01989-12
Crandon JL, Nicolau DP. Human Simulated Studies of Aztreonam and Aztreonam-avibactam to Evaluate Activity Against Challenging Gram-negative Organisms, Including Metallo-β-lactamase Producers. Antimicrob Agents Chemother. 2013;57(7):3299-306. PubMed PMID: 23650162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-β-lactamase producers. AU - Crandon,Jared L, AU - Nicolau,David P, Y1 - 2013/05/06/ PY - 2013/5/8/entrez PY - 2013/5/8/pubmed PY - 2014/1/1/medline SP - 3299 EP - 306 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 57 IS - 7 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/23650162/Human_simulated_studies_of_aztreonam_and_aztreonam_avibactam_to_evaluate_activity_against_challenging_gram_negative_organisms_including_metallo_β_lactamase_producers_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=23650162 DB - PRIME DP - Unbound Medicine ER -