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Wright W. Nichols - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of Ceftazidime-avibactam in a rat intra-abdominal abscess model against a Ceftazidime- and meropenem-resistant isolate of Klebsiella pneumoniae carrying blaKPC-2.
Journal of chemotherapy (Florence Italy), 2017Co-Authors: Taryn Sleger, Eric Gangl, Petar Pop-damkov, Kevin M. Krause, Peter J. Laud, Andrew M. Slee, Wright W. NicholsAbstract:Efficacies of Ceftazidime-avibactam (4:1 w/w) and Ceftazidime were tested against Ceftazidime-susceptible (blaKPC-2-negative), and meropenem- and Ceftazidime-resistant (blaKPC-2-positive), Klebsiella pneumoniae in a 52-h, multiple dose, abdominal abscess model in the rat. Efficacies corresponded to minimum inhibitory concentrations (MICs) measured in vitro and were consistent with drug exposures modelled from pharmacokinetics in infected animals. The Ceftazidime, Ceftazidime-avibactam and meropenem control treatments were effective in the rat abscess model against the susceptible strain, whereas only Ceftazidime-avibactam was effective against K. pneumoniae harbouring blaKPC-2.
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in vitro susceptibility to Ceftazidime avibactam of carbapenem nonsusceptible enterobacteriaceae isolates collected during the inform global surveillance study 2012 to 2014
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Boudewijn L M De Jonge, James A Karlowsky, Krystyna M Kazmierczak, Douglas J Biedenbach, Daniel F Sahm, Wright W. NicholsAbstract:The activity of Ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptible Enterobacteriaceae Most meropenem-nonsusceptible metallo-β-lactamase (MBL)-negative isolates (97.7%) were susceptible to Ceftazidime-avibactam. Isolates that carried KPC or OXA-48-like β-lactamases, both alone and in combination with extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamases, were 98.7% and 98.5% susceptible to Ceftazidime-avibactam, respectively. Meropenem-nonsusceptible, carbapenemase-negative isolates demonstrated 94.7% susceptibility to Ceftazidime-avibactam. Ceftazidime-avibactam activity was compromised only in isolates for which carbapenem resistance was mediated through metallo-β-lactamases.
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Microbiological interaction studies between Ceftazidime-avibactam and pulmonary surfactant and between Ceftazidime-avibactam and antibacterial agents of other classes.
International journal of antimicrobial agents, 2014Co-Authors: John Dallow, Kevin M. Krause, Linda G. Otterson, Michael D. Huband, Wright W. NicholsAbstract:For an antibacterial agent to be considered for clinical studies in nosocomial pneumonia (NP), it should be active in the presence of pulmonary surfactant. Furthermore, owing to the common practice of treating such infections with more than one antibacterial agent, it should be free of antagonistic interactions with agents of other classes. The aim of this study was to demonstrate the effect of pulmonary surfactant on the activity of Ceftazidime and Ceftazidime-avibactam and to determine the interaction (if any) of Ceftazidime-avibactam and six antimicrobial agents common in the treatment of NP. Minimum inhibitory concentration (MIC) determination for Ceftazidime and Ceftazidime-avibactam was performed with and without the presence of four concentrations of bovine pulmonary surfactant, and a chequerboard assay was used to determine any interaction between Ceftazidime and Ceftazidime-avibactam with tobramycin, levofloxacin, linezolid, vancomycin, tigecycline and colistin. Here we report that the in vitro antimicrobial activity of Ceftazidime-avibactam against β-lactamase-producing Gram-negative bacteria remained unaltered in the presence of pulmonary surfactant at concentrations that antagonised the antimicrobial activity of daptomycin. Furthermore, in chequerboard interaction studies, an absence of antagonism was demonstrated between Ceftazidime-avibactam and six antimicrobial agents of different classes when tested against aerobic species frequently isolated from NP. The results support the further investigation of Ceftazidime-avibactam as a potential treatment for NP caused by susceptible bacteria.
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In Vivo Efficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates
Antimicrobial agents and chemotherapy, 2014Co-Authors: Shawn H. Macvane, Wright W. Nichols, Jared L. Crandon, David P. NicolauAbstract: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.
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bactericidal activity absence of serum effect and time kill kinetics of Ceftazidime avibactam against β lactamase producing enterobacteriaceae and pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Tiffany R Keepers, Wright W. Nichols, M A Gomez, Chris Celeri, Kevin M. KrauseAbstract:Avibactam, a non-β-lactam β-lactamase inhibitor with activity against extended-spectrum β-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of Ceftazidime against most Ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of Ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 μg/ml) were lower than those for Ceftazidime alone (0.06 to ≥256 μg/ml) against all isolates except for 2 P. aeruginosa isolates (1 blaVIM-positive isolate and 1 blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of Ceftazidime-avibactam were ≤4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on Ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ≥3-log10 decrease in the number of CFU/ml was observed at 6 h for all Enterobacteriaceae, and a 2-log10 reduction in the number of CFU/ml was observed at 6 h for 3 of the 6 P. aeruginosa isolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of Ceftazidime-avibactam and support the continued clinical development of Ceftazidime-avibactam as a new treatment option for infections caused by Enterobacteriaceae and P. aeruginosa, including isolates resistant to Ceftazidime by mechanisms dependent on avibactam-sensitive β-lactamases.
Ronald N Jones - One of the best experts on this subject based on the ideXlab platform.
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Ceftazidime avibactam activity against multidrug resistant pseudomonas aeruginosa isolated in u s medical centers in 2012 and 2013
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Helio S Sader, Mariana Castanheira, Robert K Flamm, David J Farrell, Rodrigo E Mendes, Ronald N JonesAbstract:Pseudomonas aeruginosa isolates (n = 3,902) from 75 U.S. medical centers were tested against Ceftazidime-avibactam and comparator agents by the reference broth microdilution method. Overall, 96.9% of the strains were susceptible (MIC, ≤8 μg/ml) to Ceftazidime-avibactam, while the rates of susceptibility for Ceftazidime, meropenem, and piperacillin-tazobactam were 83.8, 81.9, and 78.5%, respectively. Multidrug-resistant and extensively drug-resistant phenotypes were observed in 14.9 and 8.7% of the strains, respectively, and 81.0 and 73.7% of the strains were susceptible to Ceftazidime-avibactam, respectively.
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antimicrobial activity of Ceftazidime avibactam against gram negative organisms collected from u s medical centers in 2012
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Helio S Sader, Mariana Castanheira, Robert K Flamm, David J Farrell, Ronald N JonesAbstract:The activities of the novel β-lactam–β-lactamase inhibitor combination Ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli—8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates—were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a Ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC ≥ 2 μg/ml) K. pneumoniae, and Ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a Ceftazidime-avibactam MIC of ≤4 μg/ml. Among P. aeruginosa strains, 96.9% were inhibited at a Ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, Ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml). Acinetobacter spp. (Ceftazidime-avibactam MIC50/MIC90, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, Ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.
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antimicrobial activity of cefepime tested against Ceftazidime resistant gram negative clinical strains from north american hospitals report from the sentry antimicrobial surveillance program 1998 2004
Diagnostic Microbiology and Infectious Disease, 2006Co-Authors: Michael A Pfaller, Helio S Sader, Thomas R Fritsche, Ronald N JonesAbstract:To assess the effect of Ceftazidime resistance on the activity of other antimicrobial agents, 3030 Ceftazidime-resistant Gram-negative bacilli (GNB) isolates (of a total of 42061 GNB) were tested against a panel of more than 30 agents. Ceftazidime resistance was observed in 40.3% of Acinetobacter spp., 16.9% of Pseudomonas aeruginosa, and 5.7% of Enterobacteriaceae isolates. The highest rates of Ceftazidime resistance among the enteric GNB were observed with Enterobacter spp. (20.9%) >Citrobacter spp. (15.3%) > indole-positive Proteae (10.1%). Overall, 90% of Ceftazidime-resistant Enterobacteriaceae and 30% of Ceftazidime-resistant P. aeruginosa remained susceptible to the "4th-generation" cephalosporin, cefepime. The activities (% susceptible) of other antimicrobials tested against Ceftazidime-resistant Enterobacteriaceae and P. aeruginosa, respectively, were as follows: amikacin, 90% and 88%; ciprofloxacin, 63% and 46%; gentamicin, 59% and 67%, imipenem, 99% and 65%; levofloxacin, 69% and 44%; and piperacillin/tazobactam only 40% and 12%. Ceftazidime-resistant GNB exhibited high rates of resistance to other antimicrobials. Cefepime was very active against Ceftazidime-resistant enteric GNB (AmpC enzyme producers), especially Enterobacter spp. (94.3% susceptible), Citrobacter spp. (96.7% susceptible), and indole-positive Proteae (89.6% susceptible), and showed activity similar to that of Ceftazidime against all P. aeruginosa and Acinetobacter spp. isolated in North American medical centers. Continued resistances surveillance monitoring will be necessary to assess the effectiveness of widely used broad-spectrum antimicrobials as novel resistance mechanisms emerge.
Leanne B Gasink - One of the best experts on this subject based on the ideXlab platform.
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Ceftazidime avibactam versus doripenem for the treatment of complicated urinary tract infections including acute pyelonephritis recapture a phase 3 randomized trial program
Clinical Infectious Diseases, 2016Co-Authors: Florian M E Wagenlehner, Katrina Yates, Paul Newell, Jon Armstrong, Gregory G Stone, Jack D Sobel, Xiangning Huang, Leanne B GasinkAbstract:Background. The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of Ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis. Methods. Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to Ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia). Results. Of 1033 randomized patients, 393 and 417 treated with Ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had Ceftazidime-nonsusceptible baseline pathogens. Noninferiority of Ceftazidime-avibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, −2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) Ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against Ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of Ceftazidime alone. Conclusions. Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01595438","term_id":"NCT01595438"}}NCT01595438; {"type":"clinical-trial","attrs":{"text":"NCT01599806","term_id":"NCT01599806"}}NCT01599806.
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efficacy and safety of Ceftazidime avibactam plus metronidazole versus meropenem in the treatment of complicated intra abdominal infection results from a randomized controlled double blind phase 3 program
Clinical Infectious Diseases, 2016Co-Authors: John E Mazuski, Paul Newell, Helen Broadhurst, Leanne B Gasink, Jon Armstrong, Greg Stone, Douglas Rank, Lily Llorens, Jan PachlAbstract:Background When combined with Ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of Ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). Methods The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of Ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. Results Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with Ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with Ceftazidime-avibactam plus metronidazole for Ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against Ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. Conclusions Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by Ceftazidime-susceptible and Ceftazidime-resistant pathogens. The safety profile of Ceftazidime-avibactam plus metronidazole was consistent with that previously observed with Ceftazidime alone. Clinical trials registration NCT01499290 and NCT01500239.
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Ceftazidime avibactam or best available therapy in patients with Ceftazidime resistant enterobacteriaceae and pseudomonas aeruginosa complicated urinary tract infections or complicated intra abdominal infections reprise a randomised pathogen directed
Lancet Infectious Diseases, 2016Co-Authors: Yehuda Carmeli, Angela Wardman, Paul Newell, Peter J. Laud, Jon Armstrong, Greg Stone, Leanne B GasinkAbstract:Summary Background Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of Ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to Ceftazidime-resistant Gram-negative pathogens. Methods REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by Ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa . Patients were randomised (1:1) to 5–21 days of treatment with either Ceftazidime-avibactam (a combination of 2000 mg Ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one Ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Findings Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to Ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to Ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with Ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the Ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both Ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for Ceftazidime-avibactam. Interpretation These results provide evidence of the efficacy of Ceftazidime-avibactam as a potential alternative to carbapenems in patients with Ceftazidime-resistant Enterobacteriaceae and P aeruginosa . Funding AstraZeneca.
David P. Nicolau - One of the best experts on this subject based on the ideXlab platform.
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In Vivo Efficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates
Antimicrobial agents and chemotherapy, 2014Co-Authors: Shawn H. Macvane, Wright W. Nichols, Jared L. Crandon, David P. NicolauAbstract: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.
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Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model
Antimicrobial agents and chemotherapy, 2013Co-Authors: Seth T. Housman, Wright W. Nichols, Jared L. Crandon, David P. NicolauAbstract:This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g Ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a Ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the Ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of Ceftazidime were 8 to >128 μg/ml. The change in log10 CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using Ceftazidime-avibactam in infected and uninfected mice. Humanized Ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10 CFU against P. aeruginosa with Ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a Ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a Ceftazidime-avibactam MIC of 64 μg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with Ceftazidime against isolates with Ceftazidime MICs of 32 μg/ml (ELF fT>MIC of ≥12%), variable efficacy at Ceftazidime MICs of 64 μg/ml (ELF fT>MIC of ≥0%), and no activity at a Ceftazidime MIC of 128 μg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 μg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of Ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.
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Comparative In Vitro and In Vivo Efficacies of Human Simulated Doses of Ceftazidime and Ceftazidime-Avibactam against Pseudomonas aeruginosa
Antimicrobial agents and chemotherapy, 2012Co-Authors: Jared L. Crandon, Wright W. Nichols, Virna J. A. Schuck, Mary Anne Banevicius, Marie-eve Beaudoin, M. Angela Tanudra, David P. NicolauAbstract:The combination of Ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of Ceftazidime and Ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P. aeruginosa isolates with Ceftazidime MICs of 8 to 128 mg/liter and Ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of Ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated. In vivo activity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ≥0.5 log unit for 10/27 isolates, while Ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with Ceftazidime achieving reductions of ≥0.3 log unit for 10/15 isolates, whereas Ceftazidime-avibactam did so against all 15 isolates. In vitro, Ceftazidime resulted in regrowth by 24 h against all isolates, while Ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated Ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studied in vitro; however, no resistant mutants were detected in vivo. Against this highly Ceftazidime-nonsusceptible population of P. aeruginosa, treatment with human simulated doses of Ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularly in vivo, against isolates with MICs of ≤16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.
Helio S Sader - One of the best experts on this subject based on the ideXlab platform.
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antimicrobial activity of Ceftazidime avibactam tested against multidrug resistant enterobacteriaceae and pseudomonas aeruginosa isolates from u s medical centers 2013 to 2016
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Helio S Sader, Mariana Castanheira, Dee Shortridge, Rodrigo E Mendes, Robert K FlammAbstract:The in vitro activity of Ceftazidime-avibactam and many comparator agents was determined against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 Pseudomonas aeruginosa isolates. The isolates were consecutively collected from 94 U.S. hospitals, and all isolates were tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). Enterobacteriaceae isolates resistant to carbapenems (CRE) and/or Ceftazidime-avibactam (MIC ≥ 16 μg/ml) were evaluated for the presence of genes encoding extended-spectrum β-lactamases and carbapenemases. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 μg/ml and was active against multidrug-resistant (MDR; n = 2,953; MIC50/90, 0.25/1 μg/ml; 99.2% susceptible), extensively drug-resistant (XDR; n = 448; MIC50/90, 0.5/2 μg/ml; 97.8% susceptible), and CRE (n = 513; MIC50/90, 0.5/2 μg/ml; 97.5% susceptible) isolates. Only 82.2% of MDR Enterobacteriaceae (n = 2,953) and 64.2% of ceftriaxone-nonsusceptible Klebsiella pneumoniae (n = 1,063) isolates were meropenem susceptible. Among Enterobacter cloacae (22.2% Ceftazidime nonsusceptible), 99.8% of the isolates, including 99.3% of the Ceftazidime-nonsusceptible isolates, were Ceftazidime-avibactam susceptible. Only 23 of 36,380 Enterobacteriaceae (0.06%) isolates were Ceftazidime-avibactam nonsusceptible, including 9 metallo-β-lactamase producers and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. Ceftazidime-avibactam showed potent activity against P. aeruginosa (MIC50/90, 2/4 μg/ml; 97.1% susceptible), including MDR (MIC50/90, 4/16 μg/ml; 86.5% susceptible) isolates, and inhibited 71.8% of isolates nonsusceptible to meropenem, piperacillin-tazobactam, and Ceftazidime (n = 628). In summary, Ceftazidime-avibactam demonstrated potent activity against a large collection (n = 44,248) of contemporary Gram-negative bacilli isolated from U.S. patients, including organisms resistant to most currently available agents, such as CRE and meropenem-nonsusceptible P. aeruginosa.
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Ceftazidime avibactam activity against multidrug resistant pseudomonas aeruginosa isolated in u s medical centers in 2012 and 2013
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Helio S Sader, Mariana Castanheira, Robert K Flamm, David J Farrell, Rodrigo E Mendes, Ronald N JonesAbstract:Pseudomonas aeruginosa isolates (n = 3,902) from 75 U.S. medical centers were tested against Ceftazidime-avibactam and comparator agents by the reference broth microdilution method. Overall, 96.9% of the strains were susceptible (MIC, ≤8 μg/ml) to Ceftazidime-avibactam, while the rates of susceptibility for Ceftazidime, meropenem, and piperacillin-tazobactam were 83.8, 81.9, and 78.5%, respectively. Multidrug-resistant and extensively drug-resistant phenotypes were observed in 14.9 and 8.7% of the strains, respectively, and 81.0 and 73.7% of the strains were susceptible to Ceftazidime-avibactam, respectively.
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antimicrobial activity of Ceftazidime avibactam against gram negative organisms collected from u s medical centers in 2012
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Helio S Sader, Mariana Castanheira, Robert K Flamm, David J Farrell, Ronald N JonesAbstract:The activities of the novel β-lactam–β-lactamase inhibitor combination Ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli—8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates—were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a Ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC ≥ 2 μg/ml) K. pneumoniae, and Ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a Ceftazidime-avibactam MIC of ≤4 μg/ml. Among P. aeruginosa strains, 96.9% were inhibited at a Ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, Ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml). Acinetobacter spp. (Ceftazidime-avibactam MIC50/MIC90, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, Ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.
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antimicrobial activity of cefepime tested against Ceftazidime resistant gram negative clinical strains from north american hospitals report from the sentry antimicrobial surveillance program 1998 2004
Diagnostic Microbiology and Infectious Disease, 2006Co-Authors: Michael A Pfaller, Helio S Sader, Thomas R Fritsche, Ronald N JonesAbstract:To assess the effect of Ceftazidime resistance on the activity of other antimicrobial agents, 3030 Ceftazidime-resistant Gram-negative bacilli (GNB) isolates (of a total of 42061 GNB) were tested against a panel of more than 30 agents. Ceftazidime resistance was observed in 40.3% of Acinetobacter spp., 16.9% of Pseudomonas aeruginosa, and 5.7% of Enterobacteriaceae isolates. The highest rates of Ceftazidime resistance among the enteric GNB were observed with Enterobacter spp. (20.9%) >Citrobacter spp. (15.3%) > indole-positive Proteae (10.1%). Overall, 90% of Ceftazidime-resistant Enterobacteriaceae and 30% of Ceftazidime-resistant P. aeruginosa remained susceptible to the "4th-generation" cephalosporin, cefepime. The activities (% susceptible) of other antimicrobials tested against Ceftazidime-resistant Enterobacteriaceae and P. aeruginosa, respectively, were as follows: amikacin, 90% and 88%; ciprofloxacin, 63% and 46%; gentamicin, 59% and 67%, imipenem, 99% and 65%; levofloxacin, 69% and 44%; and piperacillin/tazobactam only 40% and 12%. Ceftazidime-resistant GNB exhibited high rates of resistance to other antimicrobials. Cefepime was very active against Ceftazidime-resistant enteric GNB (AmpC enzyme producers), especially Enterobacter spp. (94.3% susceptible), Citrobacter spp. (96.7% susceptible), and indole-positive Proteae (89.6% susceptible), and showed activity similar to that of Ceftazidime against all P. aeruginosa and Acinetobacter spp. isolated in North American medical centers. Continued resistances surveillance monitoring will be necessary to assess the effectiveness of widely used broad-spectrum antimicrobials as novel resistance mechanisms emerge.