The Experts below are selected from a list of 20109 Experts worldwide ranked by ideXlab platform
Olga Lomovskaya - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of the ultra broad spectrum beta lactamase inhibitor qpx7728 in combination with Meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Michael N. Dudley, Debora Rubioaparicio, Ruslan Tsivkovski, Dongxu Sun, Maxim Totrov, Olga LomovskayaAbstract:QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of Meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for Meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in Meropenem potency, with the MIC90 of Meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the Meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of Meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of Meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of Meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of Meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of Meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with Meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.
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in vitro activity of the ultrabroad spectrum beta lactamase inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N. Dudley, Dongxu Sun, Olga LomovskayaAbstract:QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of Meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of Meropenem against CRE, with the Meropenem MIC90 decreasing from >64 μg/ml to 0.5 μg/ml for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of Meropenem against CRE with multiple resistance mechanisms; the reduction in the Meropenem MIC90 with QPX7728 (8 μg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, Meropenem with QPX7728 was the most potent beta-lactam-BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of Meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus Meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of Meropenem with QPX7728 at 8 μg/ml or lower. The combination of QPX7728 with Meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.
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Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae.
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Mojgan Sabet, Ziad Tarazi, Thomas G. Nolan, Jonathan Parkinson, Debora Rubio-aparicio, Olga Lomovskaya, Michael N. Dudley, David C. GriffithAbstract:Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate the efficacy of Meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with Meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with Meropenem alone or Meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with Meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of Meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of Meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that Meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.
David P Nicolau - One of the best experts on this subject based on the ideXlab platform.
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evaluation of plazomicin tigecycline and Meropenem pharmacodynamic exposure against carbapenem resistant enterobacteriaceae in patients with bloodstream infection or hospital acquired ventilator associated pneumonia from the care study achn 490 007
Infectious Diseases and Therapy, 2019Co-Authors: Joseph L Kuti, Aryun Kim, Daniel J Cloutier, David P NicolauAbstract:CARE was a Phase 3, randomized study evaluating the efficacy and safety of plazomicin-based combination therapy compared with colistin-based combination therapy for the treatment of patients with bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to carbapenem-resistant Enterobacteriaceae (CRE). Adjunctive therapies included either tigecycline or Meropenem. We sought to understand the contribution of tigecycline and Meropenem to plazomicin-treated-patient outcomes by determining their observed pharmacodynamic exposures against baseline pathogens. Blood samples collected for plazomicin therapeutic monitoring were assayed for tigecycline and Meropenem concentrations. Population pharmacokinetic models were constructed for each antibiotic. Using the individual Bayesian posterior or a covariate-based model, concentration time profiles were simulated to estimate the pharmacodynamic exposures for each patient. Pharmacodynamic thresholds for plazomicin, tigecycline, and Meropenem were a total area under the curve to minimum inhibitory concentration ratio (AUC/MIC) ≥ 85, free (f) AUC/MIC ≥ 0.9, and free time above the MIC (fT > MIC) of ≥ 40%, respectively. Fifteen plazomicin-treated patients were included (12 received tigecycline, 4 received Meropenem, 1 received both). Microbiological response was observed in 13 (86.7%) and clinical efficacy was achieved in 11 (73.3%). Plazomicin achieved its pharmacodynamic target in all 15 patients. Meropenem fT > MIC was 0% in all 4 patients, and tigecycline fAUC/MIC was ≥ 0.9 in 9 (75%) patients. Overall, 6 (40%) of 15 patients had a tigecycline or Meropenem exposure below the requisite thresholds. Microbiological response and clinical efficacy were observed in 100% (6/6) and 83.3% (5/6) of patients with low threshold attainment by tigecycline and Meropenem dosing regimens, respectively. Plazomicin successfully achieved its requisite pharmacodynamic exposure, and these data suggest that optimization of tigecycline and Meropenem therapy was not required for the combination to achieve microbiological response and clinical efficacy against serious CRE infections. ClinicalTrials.gov number, NCT01970371. Achaogen, Inc.
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efficacy of human simulated epithelial lining fluid exposure of Meropenem nacubactam combination against class a serine β lactamase producing enterobacteriaceae in the neutropenic murine lung infection model
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Tomefa E Asempa, Ana Motos, Kamilia Abdelraouf, Caterina Bissantz, Claudia Zampaloni, David P NicolauAbstract:Nacubactam is a novel, broad-spectrum, β-lactamase inhibitor that is currently under development as combination therapy with Meropenem. This study evaluated the efficacy of human-simulated epithelial lining fluid (ELF) exposures of Meropenem, nacubactam, and the combination of Meropenem and nacubactam against class A serine carbapenemase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model. Twelve clinical Meropenem-resistant Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates, all harboring KPC or IMI-type β-lactamases, were utilized in the study. Meropenem, nacubactam, and Meropenem-nacubactam (1:1) combination MICs were determined in triplicate via broth microdilution. At 2 h after intranasal inoculation, neutropenic mice were dosed with regimens that provided ELF profiles mimicking those observed in humans given Meropenem at 2 g every 8 h and/or nacubactam at 2 g every 8 h (1.5-h infusions), alone or in combination. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0-h controls. Meropenem, nacubactam, and Meropenem-nacubactam MICs were 8 to >64 μg/ml, 2 to >256 μg/ml, and 0.5 to 4 μg/ml, respectively. The average bacterial density at 0 h across all isolates was 6.31 ± 0.26 log10 CFU/lung. Relative to the 0-h control, the mean values of bacterial growth at 24 h in the untreated control, Meropenem human-simulated regimen treatment, and nacubactam human-simulated regimen treatment groups were 2.91 ± 0.27, 2.68 ± 0.42, and 1.73 ± 0.75 log10 CFU/lung, respectively. The Meropenem-nacubactam combination human-simulated regimen resulted in reductions of -1.50 ± 0.59 log10 CFU/lung. Meropenem-nacubactam human-simulated ELF exposure produced enhanced efficacy against all class A serine carbapenemase-producing Enterobacteriaceae isolates tested in the neutropenic murine lung infection model.
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in vivo efficacy of Meropenem with a novel non β lactam β lactamase inhibitor nacubactam against gram negative organisms exhibiting various resistance mechanisms in a murine complicated urinary tract infection model
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Marguerite L Monogue, Claudia Zampaloni, Caterina Bissantz, Sara Giovagnoli, David P NicolauAbstract:Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with in vitro activity against class A and class C β-lactamases. Nacubactam is being developed in combination with Meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of Meropenem-nacubactam compared with Meropenem or nacubactam alone against 10 Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had Meropenem-nacubactam MICs between 1 and 8 μg/ml. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving a ≥3 log reduction from the 48-h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed antibacterial properties, achieving a >1 log reduction against the majority of isolates. The combination of Meropenem-nacubactam further enhanced the activity of either agent alone, notably against Meropenem-resistant isolates. Against ceftazidime-avibactam-resistant isolates, Meropenem-nacubactam demonstrated increased antibacterial kill upwards of 6 log10 CFU in comparison to the 48-h control. Our data support the potential clinical utility of Meropenem-nacubactam for cUTI in humans against MDR Enterobacteriaceae, although further clinical data supporting Meropenem-nacubactam efficacy are needed.
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antibacterial activity of achievable epithelial lining fluid exposures of amikacin inhale with or without Meropenem
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Jared L Crandon, Yukihiro Hamada, David P NicolauAbstract:Objectives While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of ∼ 5000 mg/L, its target site pharmacodynamics are unknown. We evaluated the pharmacodynamics of ELF exposure of inhaled amikacin ± Meropenem. Methods ELF exposures of inhaled amikacin (400 mg every 12 h), intravenous Meropenem (2 g every 8 h) and a combination of both were studied in an in vitro pharmacodynamic model. Seven Klebsiella pneumoniae and 10 Pseudomonas aeruginosa with amikacin/Meropenem MICs of 1 to 32,768/≤ 0.125 to >128 mg/L were included. Efficacy was assessed over 24-72 h. Results The mean ± SD 0 h bacterial density was 6.5 ± 0.1 log10 cfu/mL. Controls grew to 8.0 ± 0.5 log10 cfu/mL by the end of the experiments. Simulation of inhaled amikacin monotherapy rapidly achieved and sustained bactericidal activity near the limit of detection over 24 h for all 13 isolates with amikacin MIC ≤ 256 mg/L except only ∼ 2 log10 cfu/mL reduction was observed in K. pneumoniae 375 (amikacin/Meropenem MIC 64/32 mg/L) and P. aeruginosa 1544 (amikacin/Meropenem MIC 64/128 mg/L). No activity was seen against the three isolates with amikacin MIC ≥ 2048 mg/L. Among the six isolates tested with Meropenem monotherapy, five (Meropenem MIC ≥ 16 mg/L) grew similarly to the controls while one (Meropenem MIC 2 mg/L) achieved ∼ 2.5 log10 cfu/mL decrease. Among seven isolates tested in combination, four (amikacin/Meropenem MIC ≤ 64/32 mg/L), including K. pneumoniae 375, maintained limit of detection until 72 h, whereas P. aeruginosa 1544 sustained a 1 log reduction. Combination therapy had no activity against the two isolates with amikacin MIC ≥ 2048 mg/L. Conclusions Inhaled amikacin monotherapy showed bactericidal activity against most isolates tested with amikacin MICs ≤ 256 mg/L. Adjunct inhaled amikacin plus Meropenem sustained this activity for 72 h for the tested isolates with amikacin/Meropenem MIC ≤ 64/32 mg/L.
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efficacy of humanized high dose Meropenem cefepime and levofloxacin against enterobacteriaceae isolates producing verona integron encoded metallo β lactamase vim in a murine thigh infection model
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Islam M Ghazi, Jared L Crandon, Emil Lesho, Patrick Mcgann, David P NicolauAbstract:We aimed to describe the in vivo activity of humanized pharmacokinetic exposures of Meropenem and comparators against Verona integron-encoded metallo-β-lactamase (MBL) (VIM)-producing Enterobacteriaceae in a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas Meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despite in vitro resistance, high-dose Meropenem may be a possible option against infections caused by Enterobacteriaceae producing MBL-type carbapenemases.
Michael N. Dudley - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of the ultra broad spectrum beta lactamase inhibitor qpx7728 in combination with Meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Michael N. Dudley, Debora Rubioaparicio, Ruslan Tsivkovski, Dongxu Sun, Maxim Totrov, Olga LomovskayaAbstract:QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of Meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for Meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in Meropenem potency, with the MIC90 of Meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the Meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of Meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of Meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of Meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of Meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of Meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with Meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.
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in vitro activity of the ultrabroad spectrum beta lactamase inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N. Dudley, Dongxu Sun, Olga LomovskayaAbstract:QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of Meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of Meropenem against CRE, with the Meropenem MIC90 decreasing from >64 μg/ml to 0.5 μg/ml for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of Meropenem against CRE with multiple resistance mechanisms; the reduction in the Meropenem MIC90 with QPX7728 (8 μg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, Meropenem with QPX7728 was the most potent beta-lactam-BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of Meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus Meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of Meropenem with QPX7728 at 8 μg/ml or lower. The combination of QPX7728 with Meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.
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Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae.
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Mojgan Sabet, Ziad Tarazi, Thomas G. Nolan, Jonathan Parkinson, Debora Rubio-aparicio, Olga Lomovskaya, Michael N. Dudley, David C. GriffithAbstract:Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate the efficacy of Meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with Meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with Meropenem alone or Meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with Meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of Meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of Meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that Meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.
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Meropenem rpx7009 concentrations in plasma epithelial lining fluid and alveolar macrophages of healthy adult subjects
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Eric Wenzler, David C. Griffith, Michael N. Dudley, Mark H Gotfried, Jeffrey S Loutit, Stephanie Durso, Keith A. RodvoldAbstract:The steady-state concentrations of Meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of Meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of Meropenem and RPX7009 determined from serial plasma concentrations were as follows: Cmax = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, Vss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of Meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0-8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for Meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of Meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by Meropenem-resistant Gram-negative pathogens susceptible to the combination of Meropenem-RPX7009.
Jan Tommassen - One of the best experts on this subject based on the ideXlab platform.
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antibiotic trapping by plasmid encoded cmy 2 β lactamase combined with reduced outer membrane permeability as a mechanism of carbapenem resistance in escherichia coli
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Wil H F Goessens, Akke K Van Der Bij, Ria Van Boxtel, Johann D D Pitout, Peter Van Ulsen, Damian C Melles, Jan TommassenAbstract:A liver transplant patient was admitted with cholangitis, for which Meropenem therapy was started. Initial cultures showed a carbapenem-susceptible (CS) Escherichia coli strain, but during admission, a carbapenem-resistant (CR) E. coli strain was isolated. Analysis of the outer membrane protein profiles showed that both CS and CR E. coli lacked the porins OmpF and OmpC. Furthermore, PCR and sequence analysis revealed that both CS and CR E. coli possessed bla(CTX-M-15) and bla(OXA-1). The CR E. coli strain additionally harbored bla(CMY-2) and demonstrated a >15-fold increase in β-lactamase activity against nitrocefin, but no hydrolysis of Meropenem was detected. However, nitrocefin hydrolysis appeared strongly inhibited by Meropenem. Furthermore, the CMY-2 enzyme demonstrated lower electrophoretic mobility after its incubation either in vitro or in vivo with Meropenem, indicative of its covalent modification with Meropenem. The presence of the acyl-enzyme complex was confirmed by mass spectrometry. By transformation of the CMY-2-encoding plasmid into various E. coli strains, it was established that both porin deficiency and high-level expression of the enzyme were needed to confer Meropenem resistance. In conclusion, carbapenem resistance emerged by a combination of elevated β-lactamase production and lack of porin expression. Due to the reduced outer membrane permeability, only small amounts of Meropenem can enter the periplasm, where they are trapped but not degraded by the large amount of the β-lactamase. This study, therefore, provides evidence that the mechanism of "trapping" by CMY-2 β-lactamase plays a role in carbapenem resistance.
Kirk Nelson - One of the best experts on this subject based on the ideXlab platform.
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in vitro activity of the ultra broad spectrum beta lactamase inhibitor qpx7728 in combination with Meropenem against clinical isolates of carbapenem resistant acinetobacter baumannii
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Michael N. Dudley, Debora Rubioaparicio, Ruslan Tsivkovski, Dongxu Sun, Maxim Totrov, Olga LomovskayaAbstract:QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of Meropenem alone and in combination with QPX7728 (1 to 16 μg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for Meropenem, 64 and >64 μg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in Meropenem potency, with the MIC90 of Meropenem alone decreasing from >64 μg/ml to 8 and 4 μg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 μg/ml, respectively. In order to identify the mechanisms that modulate the Meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of Meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of Meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 μg/ml of Meropenem when tested with a fixed 4 to 8 μg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of Meropenem tested in combination with 4 to 8 μg/ml of QPX7728 did not exceed 8 μg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 μg/ml of Meropenem with 4 or 8 μg/ml of QPX7728. The combination of QPX7728 with Meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.
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in vitro activity of the ultrabroad spectrum beta lactamase inhibitor qpx7728 against carbapenem resistant enterobacterales with varying intrinsic and acquired resistance mechanisms
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Kirk Nelson, Debora Rubioaparicio, Michael N. Dudley, Dongxu Sun, Olga LomovskayaAbstract:QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of Meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 μg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to Meropenem (MIC ≥ 4 μg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of Meropenem against CRE, with the Meropenem MIC90 decreasing from >64 μg/ml to 0.5 μg/ml for QPX7728 (8 μg/ml). QPX7728 significantly increased the potency of Meropenem against CRE with multiple resistance mechanisms; the reduction in the Meropenem MIC90 with QPX7728 (8 μg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, Meropenem with QPX7728 was the most potent beta-lactam-BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of Meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus Meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 μg/ml of Meropenem with QPX7728 at 8 μg/ml or lower. The combination of QPX7728 with Meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.
