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Patricia A Bradford - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of Aztreonam avibactam against enterobacteriaceae and pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: James A Karlowsky, Krystyna M Kazmierczak, Boudewijn L M De Jonge, Meredith Hackel, Daniel F Sahm, Patricia A BradfordAbstract:The combination of the monobactam Aztreonam and the non-β-lactam β-lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-β-lactamase (MBL)-producing Enterobacteriaceae, a difficult-to-treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n = 51,352) and Pseudomonas aeruginosa (n = 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to Aztreonam-avibactam, Aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 μg/ml in combination with 2-fold dilutions of Aztreonam. The MIC90s of Aztreonam-avibactam and Aztreonam were 0.12 and 64 μg/ml, respectively, for all Enterobacteriaceae isolates; >99.9% of all isolates and 99.8% of meropenem-nonsusceptible isolates (n = 1,498) were inhibited by Aztreonam-avibactam at a concentration of ≤8 μg/ml. PCR and DNA sequencing identified 267 Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); all Enterobacteriaceae carrying MBLs demonstrated Aztreonam-avibactam MICs of ≤8 μg/ml and a MIC90 of 1 μg/ml. Against all P. aeruginosa isolates tested, the MIC90 of both Aztreonam-avibactam and Aztreonam was 32 μg/ml; against MBL-positive P. aeruginosa isolates (n = 452), MIC90 values for Aztreonam-avibactam and Aztreonam were 32 and 64 μg/ml, respectively. The current study demonstrated that Aztreonam-avibactam possesses potent in vitro activity against a recent, sizeable global collection of Enterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of Enterobacteriaceae, for which there are few treatment options.
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pharmacokinetics pharmacodynamics of a β lactam and β lactamase inhibitor combination a novel approach for Aztreonam avibactam
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Renu Singh, Patricia A Bradford, Aryun Kim, Angela M Tanudra, Jennifer J Harris, Robert E Mclaughlin, Sara A Patey, John P Odonnell, Ann E EakinAbstract:Objectives: The combination of Aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-b-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for Aztreonam/avibactam across multiple clinical Enterobacteriaceae strains. Methods: Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollowfibre infection model (HFIM) using various dosing regimens simulating human-like PK for Aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains. Results: MIC values of Aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the Aztreonam PK/PD index was observed as % fT.MIC. Studies performed in the presence of a fixed dose of Aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2 –2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target. Conclusions: PK/PD evaluations for Aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for b-lactam/b-lactamase inhibitor combinations.
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in vitro activity of Aztreonam avibactam against a global collection of gram negative pathogens from 2012 and 2013
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Douglas J Biedenbach, Krystyna M Kazmierczak, Daniel F Sahm, S Bouchillon, Patricia A BradfordAbstract:ABSTRACT The combination of Aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producing Enterobacteriaceae strains that also produce serine β-lactamases. The in vitro activities of Aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii using the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC 90 values of Aztreonam and Aztreonam-avibactam against all collected isolates of Enterobacteriaceae ( n = 23,516) were 64 and 0.12 μg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 μg/ml of Aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 μg/ml of Aztreonam-avibactam using a fixed concentration of 4 μg/ml of avibactam. The MIC 90 was 32 μg/ml for both Aztreonam and Aztreonam-avibactam against P. aeruginosa ( n = 3,766). Aztreonam alone or in combination with avibactam had no in vitro activity against isolates of A. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against most Enterobacteriaceae isolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% of Enterobacteriaceae isolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml Aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.
Michio Ohta - One of the best experts on this subject based on the ideXlab platform.
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Effects of Aztreonam in combination with antipseudomonal antibiotics againstPseudomonas aeruginosa isolated from patients with chronic or recurrent lower respiratory tract infection
Journal of Infection and Chemotherapy, 1998Co-Authors: Kenichi Yamaki, Kenzo Takagi, Toshihiko Tanaka, Michio OhtaAbstract:The antipseudomonal activity of Aztreonam combined with other antibiotics aas examined in vitro to suggest effective therapeutic combinations for the treatment of respiratory tract infections due to Pseudomonas aeruginosa . Twenty-five P. aeruginosa strains were newly isolated from patients with chronic or recurrent lower respiratory tract infection. The susceptibility of these strains to Aztreonam alone and to Aztreonam combined with ceftazidime, cefclidin, isepamicin and imipenem was measured using the checkerboard method. The observed MICs suggested that Aztreonam alone was not very potent against P. aeruginosa associated with chronic or recurrent lower respiratory infection, but that cefclidin had strong antipseudomonal activity. The fractionary inhibitory concentration index showed synergy in 60% of the P. aeruginosa clinical isolates with Aztreonam plus isepamicin, and antagonism in approximately 16% of strains with Aztreonam plus imipenem. When combined with isepamcin, Aztreonam may have potent activity against pseudomonal lower respiratory tract infections.
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effects of Aztreonam in combination with antipseudomonal antibiotics against pseudomonas aeruginosa isolated from patients with chronic or recurrent lower respiratory tract infection
Journal of Infection and Chemotherapy, 1998Co-Authors: Kenichi Yamaki, Kenzo Takagi, Toshihiko Tanaka, Michio OhtaAbstract:The antipseudomonal activity of Aztreonam combined with other antibiotics aas examined in vitro to suggest effective therapeutic combinations for the treatment of respiratory tract infections due toPseudomonas aeruginosa. Twenty-fiveP. aeruginosa strains were newly isolated from patients with chronic or recurrent lower respiratory tract infection. The susceptibility of these strains to Aztreonam alone and to Aztreonam combined with ceftazidime, cefclidin, isepamicin and imipenem was measured using the checkerboard method. The observed MICs suggested that Aztreonam alone was not very potent againstP. aeruginosa associated with chronic or recurrent lower respiratory infection, but that cefclidin had strong antipseudomonal activity. The fractionary inhibitory concentration index showed synergy in 60% of theP. aeruginosa clinical isolates with Aztreonam plus isepamicin, and antagonism in approximately 16% of strains with Aztreonam plus imipenem. When combined with isepamcin, Aztreonam may have potent activity against pseudomonal lower respiratory tract infections.
Luning Zhuang - One of the best experts on this subject based on the ideXlab platform.
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prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and Aztreonam combination against multidrug resistant organisms
CPT: pharmacometrics & systems pharmacology, 2017Co-Authors: Luning Zhuang, Huiming Xia, Me Beaudoin, Virna J Schuck, Hartmut DerendorfAbstract:The combination of Aztreonam-avibactam is active against multidrug-resistant Enterobacteriaceae that express metallo-β-lactamases. A complex synergistic interaction exists between Aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two-state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria-mediated degradation of Aztreonam and the inhibition of Aztreonam degradation by avibactam. The model predicted that changing regimens of 2 g Aztreonam plus 0.375 and 0.6 g avibactam as a 1-hour infusion were qualitatively similar to that observed from in vivo murine thigh infection and hollow-fiber infection models previously reported in the literature with 24-hour log kill ≥1. The current approach to characterize the effect of avibactam in enhancing Aztreonam activity from time-kill study was accomplished by shifting the half-maximal effective concentration (EC50) of Aztreonam in increasing avibactam concentration using a nonlinear equation as a function of avibactam concentration, providing a framework for translational predictions.
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in vitro pharmacokinetics pharmacodynamics of the combination of avibactam and Aztreonam against mdr organisms
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Marie-eve Beaudoin, Luning Zhuang, Kathrin I. Löblein, Clemens Lux, Marlene Kissel, Robin Tremmel, Christian Frank, Severin Strasser, Jules A. A. C. Heuberger, Midas B MulderAbstract:OBJECTIVES The combination of Aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of Aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles. METHODS The MICs of Aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass Aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects Aztreonam from degradation. RESULTS Three of the four isolates had Aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in Aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for Aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of Aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid Aztreonam degradation in two isolates. CONCLUSIONS The Aztreonam/avibactam combination protects Aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple β-lactamase-expressing strains with a wide MIC range.
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In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and Aztreonam against MDR organisms.
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Marie-eve Beaudoin, Luning Zhuang, Kathrin I. Löblein, Clemens Lux, Marlene Kissel, Robin Tremmel, Christian Frank, Severin Strasser, Jules A. A. C. HeubergerAbstract:OBJECTIVES The combination of Aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of Aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles. METHODS The MICs of Aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass Aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects Aztreonam from degradation. RESULTS Three of the four isolates had Aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in Aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for Aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of Aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid Aztreonam degradation in two isolates. CONCLUSIONS The Aztreonam/avibactam combination protects Aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple β-lactamase-expressing strains with a wide MIC range.
Midas B Mulder - One of the best experts on this subject based on the ideXlab platform.
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in vitro pharmacokinetics pharmacodynamics of the combination of avibactam and Aztreonam against mdr organisms
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Marie-eve Beaudoin, Luning Zhuang, Kathrin I. Löblein, Clemens Lux, Marlene Kissel, Robin Tremmel, Christian Frank, Severin Strasser, Jules A. A. C. Heuberger, Midas B MulderAbstract:OBJECTIVES The combination of Aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of Aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles. METHODS The MICs of Aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass Aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactam concentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects Aztreonam from degradation. RESULTS Three of the four isolates had Aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in Aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with a much lower dose requirement for Aztreonam. The resulting changes in base-10 logarithm of cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of Aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid Aztreonam degradation in two isolates. CONCLUSIONS The Aztreonam/avibactam combination protects Aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple β-lactamase-expressing strains with a wide MIC range.
Kenichi Yamaki - One of the best experts on this subject based on the ideXlab platform.
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Effects of Aztreonam in combination with antipseudomonal antibiotics againstPseudomonas aeruginosa isolated from patients with chronic or recurrent lower respiratory tract infection
Journal of Infection and Chemotherapy, 1998Co-Authors: Kenichi Yamaki, Kenzo Takagi, Toshihiko Tanaka, Michio OhtaAbstract:The antipseudomonal activity of Aztreonam combined with other antibiotics aas examined in vitro to suggest effective therapeutic combinations for the treatment of respiratory tract infections due to Pseudomonas aeruginosa . Twenty-five P. aeruginosa strains were newly isolated from patients with chronic or recurrent lower respiratory tract infection. The susceptibility of these strains to Aztreonam alone and to Aztreonam combined with ceftazidime, cefclidin, isepamicin and imipenem was measured using the checkerboard method. The observed MICs suggested that Aztreonam alone was not very potent against P. aeruginosa associated with chronic or recurrent lower respiratory infection, but that cefclidin had strong antipseudomonal activity. The fractionary inhibitory concentration index showed synergy in 60% of the P. aeruginosa clinical isolates with Aztreonam plus isepamicin, and antagonism in approximately 16% of strains with Aztreonam plus imipenem. When combined with isepamcin, Aztreonam may have potent activity against pseudomonal lower respiratory tract infections.
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effects of Aztreonam in combination with antipseudomonal antibiotics against pseudomonas aeruginosa isolated from patients with chronic or recurrent lower respiratory tract infection
Journal of Infection and Chemotherapy, 1998Co-Authors: Kenichi Yamaki, Kenzo Takagi, Toshihiko Tanaka, Michio OhtaAbstract:The antipseudomonal activity of Aztreonam combined with other antibiotics aas examined in vitro to suggest effective therapeutic combinations for the treatment of respiratory tract infections due toPseudomonas aeruginosa. Twenty-fiveP. aeruginosa strains were newly isolated from patients with chronic or recurrent lower respiratory tract infection. The susceptibility of these strains to Aztreonam alone and to Aztreonam combined with ceftazidime, cefclidin, isepamicin and imipenem was measured using the checkerboard method. The observed MICs suggested that Aztreonam alone was not very potent againstP. aeruginosa associated with chronic or recurrent lower respiratory infection, but that cefclidin had strong antipseudomonal activity. The fractionary inhibitory concentration index showed synergy in 60% of theP. aeruginosa clinical isolates with Aztreonam plus isepamicin, and antagonism in approximately 16% of strains with Aztreonam plus imipenem. When combined with isepamcin, Aztreonam may have potent activity against pseudomonal lower respiratory tract infections.
