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Helio S Sader - One of the best experts on this subject based on the ideXlab platform.

  • wck 5222 Cefepime zidebactam antimicrobial activity tested against gram negative organisms producing clinically relevant β lactamases
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Helio S Sader, Robert K Flamm, Ronald N Jones, Paul R Rhomberg, Mariana Castanheira
    Abstract:

    Background Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives To evaluate the in vitro activities of Cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types. Methods β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against Cefepime/zidebactam, Cefepime and zidebactam. Results Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

  • wck 5222 Cefepime zidebactam antimicrobial activity against clinical isolates of gram negative bacteria collected worldwide in 2015
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Ronald N Jones, Michael D Huband, Robert K Flamm
    Abstract:

    WCK 5222 consists of Cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of Cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (5, 946), Pseudomonas aeruginosa (1, 291) and Acinetobacter spp. (639) from the United States (2, 919), Europe (3, 004), Asia-Pacific (1, 370) and Latin America (583). The isolates were susceptibility tested by reference broth microdilution method against Cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC 50/90 , ≤0.03/0.12 [1:1] and 0.06/0.25 μg/mL [2:1]; 99.9% inhibited at ≤4 [1:1] and ≤8 μg/mL [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC 50/90 , ≤0.03-0.06/≤0.03-0.5 μg/mL [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC 50/90 , 1/4 μg/mL; 99.3% inhibited at ≤8 μg/mL [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/mL (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC 50/90 values of 1/4 μg/mL and 99.5% of isolates inhibited at ≤8 μg/mL (1:1). Cefepime-zidebactam 1:1 ratio MIC values were generally 2-fold lower than those for 2:1 ratio (MIC 50/90 , 2/8 μg/mL) and zidebactam alone (MIC 50/90 , 4/8 μg/mL). Against Acinetobacter spp., Cefepime-zidebactam at 1:1 and 2:1 ratios (MIC 50/90 , 16/32 μg/mL for both) were 4-fold more active than Cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support clinical development of WCK 5222 for the treatment of Gram-negative infections, including those caused by multidrug-resistant isolates.

  • antimicrobial activity of high proportion Cefepime tazobactam wck 4282 against a large number of gram negative isolates collected worldwide in 2014
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Rodrigo E Mendes, Robert K Flamm, Ronald N Jones
    Abstract:

    Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to Cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 μg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 μg/ml) and Cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 μg/ml. The activity of Cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by Cefepime-tazobactam at ≤8/8 μg/ml. The prevalence of the extended-spectrum β-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 μg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 μg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 μg/ml). The activity of Cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 and ≤16/8 μg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, Cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the Cefepime-tazobactam combination.

  • potency and spectrum trends for Cefepime tested against 65746 clinical bacterial isolates collected in north american medical centers results from the sentry antimicrobial surveillance program 1998 2003
    Diagnostic Microbiology and Infectious Disease, 2005
    Co-Authors: Helio S Sader, Thomas R Fritsche, Ronald N Jones
    Abstract:

    Abstract We evaluated the antimicrobial spectrum and potency of Cefepime and selected comparators agents against clinical bacterial strains collected in North America over a 6-year period (1998–2003). Isolates were consecutively collected from bloodstream (44%), respiratory tract (41%), urinary tract (6%), and skin/soft tissue (5%) infections in 48 medical centers. Isolates were susceptibility tested by reference broth microdilution methods in a central laboratory. Oxacillin-resistant staphylococci and enterococci were excluded from the analysis. Imipenem (MIC 90 = 1 μg/mL, 99.9% susceptible) was the most active compound tested against Enterobacteriaceae (22860 isolates tested) followed by Cefepime (MIC 90 = 0.25 μg/mL, 99.5% susceptible) > amikacin (99.4% susceptible) > ceftriaxone (95.6% susceptible) > aztreonam (95.1% susceptible). Among comparators, the lowest susceptibility rate for Enterobacteriaceae was observed with ciprofloxacin (92.8% susceptible). Imipenem was also the most active compound against ESBL-producing Klebsiella spp. and Escherichia coli (99.3% and 100% susceptible, respectively), followed by amikacin (81.4% and 97.2% susceptible, respectively) and Cefepime (92.5% and 93.8% susceptible, respectively). Cefepime activity against Pseudomonas aeruginosa (85.2% susceptible) was similar to that of imipenem (86.9% susceptible). Against oxacillin-susceptible Staphylococcus aureus , Cefepime (MIC 90 = 4 μg/mL, 100.0% susceptible) was 4-fold more active than ceftazidime (MIC 90 = 16 μg/mL, 86.4% susceptible) and showed a higher susceptibility rate than ciprofloxacin (93.2% susceptible). Cefepime was the most active compound tested against Streptococcus pneumoniae (MIC 90 = 1 μg/mL, 97.4% susceptible), ranked after gatifloxacin and levofloxacin (99.2% susceptible). The activity of Cefepime remained stable during the study period evaluated with the susceptibility rates varying from 99.3% to 99.8% among the Enterobacteriaceae and 84.4% to 88.4% among P. aeruginosa isolates. In summary, Cefepime has retained broad activity and spectrum against Enterobacteriaceae, P. aeruginosa , and Gram-positive cocci (except oxacillin-resistant staphylococci and enterococci) isolated from North American medical centers in the 1998–2003 period. Continued resistance surveillance is critical to monitor the effectiveness of widely used parenteral antimicrobial agents such as Cefepime.

Ronald N Jones - One of the best experts on this subject based on the ideXlab platform.

  • wck 5222 Cefepime zidebactam antimicrobial activity tested against gram negative organisms producing clinically relevant β lactamases
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Helio S Sader, Robert K Flamm, Ronald N Jones, Paul R Rhomberg, Mariana Castanheira
    Abstract:

    Background Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives To evaluate the in vitro activities of Cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types. Methods β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against Cefepime/zidebactam, Cefepime and zidebactam. Results Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

  • wck 5222 Cefepime zidebactam antimicrobial activity against clinical isolates of gram negative bacteria collected worldwide in 2015
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Ronald N Jones, Michael D Huband, Robert K Flamm
    Abstract:

    WCK 5222 consists of Cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of Cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (5, 946), Pseudomonas aeruginosa (1, 291) and Acinetobacter spp. (639) from the United States (2, 919), Europe (3, 004), Asia-Pacific (1, 370) and Latin America (583). The isolates were susceptibility tested by reference broth microdilution method against Cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC 50/90 , ≤0.03/0.12 [1:1] and 0.06/0.25 μg/mL [2:1]; 99.9% inhibited at ≤4 [1:1] and ≤8 μg/mL [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC 50/90 , ≤0.03-0.06/≤0.03-0.5 μg/mL [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC 50/90 , 1/4 μg/mL; 99.3% inhibited at ≤8 μg/mL [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/mL (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC 50/90 values of 1/4 μg/mL and 99.5% of isolates inhibited at ≤8 μg/mL (1:1). Cefepime-zidebactam 1:1 ratio MIC values were generally 2-fold lower than those for 2:1 ratio (MIC 50/90 , 2/8 μg/mL) and zidebactam alone (MIC 50/90 , 4/8 μg/mL). Against Acinetobacter spp., Cefepime-zidebactam at 1:1 and 2:1 ratios (MIC 50/90 , 16/32 μg/mL for both) were 4-fold more active than Cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support clinical development of WCK 5222 for the treatment of Gram-negative infections, including those caused by multidrug-resistant isolates.

  • antimicrobial activity of high proportion Cefepime tazobactam wck 4282 against a large number of gram negative isolates collected worldwide in 2014
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Rodrigo E Mendes, Robert K Flamm, Ronald N Jones
    Abstract:

    Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to Cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 μg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 μg/ml) and Cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 μg/ml. The activity of Cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by Cefepime-tazobactam at ≤8/8 μg/ml. The prevalence of the extended-spectrum β-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 μg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 μg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 μg/ml). The activity of Cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 and ≤16/8 μg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, Cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the Cefepime-tazobactam combination.

  • potency and spectrum trends for Cefepime tested against 65746 clinical bacterial isolates collected in north american medical centers results from the sentry antimicrobial surveillance program 1998 2003
    Diagnostic Microbiology and Infectious Disease, 2005
    Co-Authors: Helio S Sader, Thomas R Fritsche, Ronald N Jones
    Abstract:

    Abstract We evaluated the antimicrobial spectrum and potency of Cefepime and selected comparators agents against clinical bacterial strains collected in North America over a 6-year period (1998–2003). Isolates were consecutively collected from bloodstream (44%), respiratory tract (41%), urinary tract (6%), and skin/soft tissue (5%) infections in 48 medical centers. Isolates were susceptibility tested by reference broth microdilution methods in a central laboratory. Oxacillin-resistant staphylococci and enterococci were excluded from the analysis. Imipenem (MIC 90 = 1 μg/mL, 99.9% susceptible) was the most active compound tested against Enterobacteriaceae (22860 isolates tested) followed by Cefepime (MIC 90 = 0.25 μg/mL, 99.5% susceptible) > amikacin (99.4% susceptible) > ceftriaxone (95.6% susceptible) > aztreonam (95.1% susceptible). Among comparators, the lowest susceptibility rate for Enterobacteriaceae was observed with ciprofloxacin (92.8% susceptible). Imipenem was also the most active compound against ESBL-producing Klebsiella spp. and Escherichia coli (99.3% and 100% susceptible, respectively), followed by amikacin (81.4% and 97.2% susceptible, respectively) and Cefepime (92.5% and 93.8% susceptible, respectively). Cefepime activity against Pseudomonas aeruginosa (85.2% susceptible) was similar to that of imipenem (86.9% susceptible). Against oxacillin-susceptible Staphylococcus aureus , Cefepime (MIC 90 = 4 μg/mL, 100.0% susceptible) was 4-fold more active than ceftazidime (MIC 90 = 16 μg/mL, 86.4% susceptible) and showed a higher susceptibility rate than ciprofloxacin (93.2% susceptible). Cefepime was the most active compound tested against Streptococcus pneumoniae (MIC 90 = 1 μg/mL, 97.4% susceptible), ranked after gatifloxacin and levofloxacin (99.2% susceptible). The activity of Cefepime remained stable during the study period evaluated with the susceptibility rates varying from 99.3% to 99.8% among the Enterobacteriaceae and 84.4% to 88.4% among P. aeruginosa isolates. In summary, Cefepime has retained broad activity and spectrum against Enterobacteriaceae, P. aeruginosa , and Gram-positive cocci (except oxacillin-resistant staphylococci and enterococci) isolated from North American medical centers in the 1998–2003 period. Continued resistance surveillance is critical to monitor the effectiveness of widely used parenteral antimicrobial agents such as Cefepime.

Robert K Flamm - One of the best experts on this subject based on the ideXlab platform.

  • wck 5222 Cefepime zidebactam antimicrobial activity tested against gram negative organisms producing clinically relevant β lactamases
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Helio S Sader, Robert K Flamm, Ronald N Jones, Paul R Rhomberg, Mariana Castanheira
    Abstract:

    Background Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives To evaluate the in vitro activities of Cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types. Methods β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against Cefepime/zidebactam, Cefepime and zidebactam. Results Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

  • wck 5222 Cefepime zidebactam antimicrobial activity against clinical isolates of gram negative bacteria collected worldwide in 2015
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Ronald N Jones, Michael D Huband, Robert K Flamm
    Abstract:

    WCK 5222 consists of Cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of Cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (5, 946), Pseudomonas aeruginosa (1, 291) and Acinetobacter spp. (639) from the United States (2, 919), Europe (3, 004), Asia-Pacific (1, 370) and Latin America (583). The isolates were susceptibility tested by reference broth microdilution method against Cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC 50/90 , ≤0.03/0.12 [1:1] and 0.06/0.25 μg/mL [2:1]; 99.9% inhibited at ≤4 [1:1] and ≤8 μg/mL [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC 50/90 , ≤0.03-0.06/≤0.03-0.5 μg/mL [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC 50/90 , 1/4 μg/mL; 99.3% inhibited at ≤8 μg/mL [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/mL (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC 50/90 values of 1/4 μg/mL and 99.5% of isolates inhibited at ≤8 μg/mL (1:1). Cefepime-zidebactam 1:1 ratio MIC values were generally 2-fold lower than those for 2:1 ratio (MIC 50/90 , 2/8 μg/mL) and zidebactam alone (MIC 50/90 , 4/8 μg/mL). Against Acinetobacter spp., Cefepime-zidebactam at 1:1 and 2:1 ratios (MIC 50/90 , 16/32 μg/mL for both) were 4-fold more active than Cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support clinical development of WCK 5222 for the treatment of Gram-negative infections, including those caused by multidrug-resistant isolates.

  • antimicrobial activity of high proportion Cefepime tazobactam wck 4282 against a large number of gram negative isolates collected worldwide in 2014
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Rodrigo E Mendes, Robert K Flamm, Ronald N Jones
    Abstract:

    Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to Cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 μg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 μg/ml) and Cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 μg/ml. The activity of Cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by Cefepime-tazobactam at ≤8/8 μg/ml. The prevalence of the extended-spectrum β-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 μg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 μg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 μg/ml). The activity of Cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 and ≤16/8 μg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, Cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the Cefepime-tazobactam combination.

Mariana Castanheira - One of the best experts on this subject based on the ideXlab platform.

  • wck 5222 Cefepime zidebactam antimicrobial activity tested against gram negative organisms producing clinically relevant β lactamases
    Journal of Antimicrobial Chemotherapy, 2017
    Co-Authors: Helio S Sader, Robert K Flamm, Ronald N Jones, Paul R Rhomberg, Mariana Castanheira
    Abstract:

    Background Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections. Objectives To evaluate the in vitro activities of Cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types. Methods β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against Cefepime/zidebactam, Cefepime and zidebactam. Results Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)]. Conclusions Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

  • wck 5222 Cefepime zidebactam antimicrobial activity against clinical isolates of gram negative bacteria collected worldwide in 2015
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Ronald N Jones, Michael D Huband, Robert K Flamm
    Abstract:

    WCK 5222 consists of Cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of Cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (5, 946), Pseudomonas aeruginosa (1, 291) and Acinetobacter spp. (639) from the United States (2, 919), Europe (3, 004), Asia-Pacific (1, 370) and Latin America (583). The isolates were susceptibility tested by reference broth microdilution method against Cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC 50/90 , ≤0.03/0.12 [1:1] and 0.06/0.25 μg/mL [2:1]; 99.9% inhibited at ≤4 [1:1] and ≤8 μg/mL [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC 50/90 , ≤0.03-0.06/≤0.03-0.5 μg/mL [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC 50/90 , 1/4 μg/mL; 99.3% inhibited at ≤8 μg/mL [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/mL (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC 50/90 values of 1/4 μg/mL and 99.5% of isolates inhibited at ≤8 μg/mL (1:1). Cefepime-zidebactam 1:1 ratio MIC values were generally 2-fold lower than those for 2:1 ratio (MIC 50/90 , 2/8 μg/mL) and zidebactam alone (MIC 50/90 , 4/8 μg/mL). Against Acinetobacter spp., Cefepime-zidebactam at 1:1 and 2:1 ratios (MIC 50/90 , 16/32 μg/mL for both) were 4-fold more active than Cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support clinical development of WCK 5222 for the treatment of Gram-negative infections, including those caused by multidrug-resistant isolates.

  • antimicrobial activity of high proportion Cefepime tazobactam wck 4282 against a large number of gram negative isolates collected worldwide in 2014
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Helio S Sader, Mariana Castanheira, Rodrigo E Mendes, Robert K Flamm, Ronald N Jones
    Abstract:

    Cefepime-tazobactam (WCK 4282) is currently under clinical development for use at a dosage of 2 g/2 g every 8 h. A total of 7,981 isolates were collected from 146 medical centers (39 countries) in 2014 as a part of the SENTRY Antimicrobial Surveillance Program, and their susceptibilities to Cefepime-tazobactam (with tazobactam at fixed concentrations of 4 and 8 μg/ml) were tested by a reference broth microdilution method. Isolates were mainly from patients with pneumonia (29.5%) and bloodstream infections (26.9%). Cefepime-tazobactam (with tazobactam at a fixed concentration of 8 μg/ml) and Cefepime inhibited 96.9 and 87.9% of Enterobacteriaceae strains at ≤8 μg/ml. The activity of Cefepime-tazobactam against Enterobacteriaceae strains was comparable to that of meropenem (96.7% of isolates were susceptible) and greater than that of piperacillin-tazobactam (87.7% susceptible). All Enterobacteriaceae species from the United States except Klebsiella pneumoniae had >99.0% of isolates inhibited by Cefepime-tazobactam at ≤8/8 μg/ml. The prevalence of the extended-spectrum β-lactamase (ESBL)-screening-positive phenotype was the highest among Escherichia coli isolates in China (66.3%) and among K. pneumoniae isolates (58.0%) in Latin America. Cefepime-tazobactam at ≤8/8 μg/ml inhibited 98.7 and 71.3% of ESBL-screening-positive phenotype E. coli strains and K. pneumoniae strains, respectively. Meropenem showed limited activity against ESBL-screening-positive phenotype K. pneumoniae strains (69.6% susceptible). Cefepime-tazobactam was active against Enterobacter spp. (MIC50 and MIC90, 0.06 and 0.5 μg/ml, respectively), including ceftazidime-nonsusceptible isolates (96.1% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 μg/ml). The activity of Cefepime-tazobactam against Pseudomonas aeruginosa (82.4 and 91.6% of isolates were inhibited by Cefepime-tazobactam at ≤8/8 and ≤16/8 μg/ml, respectively) was comparable to that of meropenem and piperacillin-tazobactam (79.2% susceptible). In summary, Cefepime-tazobactam was highly active against P. aeruginosa and Enterobacteriaceae strains, including ESBL-screening-positive phenotype E. coli strains and ceftazidime-nonsusceptible Enterobacter spp. These results support the further clinical development of the Cefepime-tazobactam combination.

Alejandro A Rabinstein - One of the best experts on this subject based on the ideXlab platform.

  • Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy
    Critical Care, 2013
    Co-Authors: Jennifer E Fugate, Ejaaz A Kalimullah, Sara E Hocker, Sarah L Clark, Eelco Fm Wijdicks, Alejandro A Rabinstein
    Abstract:

    Introduction Cefepime, a broad spectrum antibiotic, is commonly prescribed in intensive care units (ICU) and may be an overlooked cause of neurologic symptoms such as encephalopathy, myoclonus, seizures, and coma. We aimed to characterize Cefepime neurotoxicity in the ICU. Methods We performed a retrospective study of adult ICU patients treated with intravenous Cefepime for at least 3 days between January 1, 2009 and December 31, 2011. The primary outcome was the development of Cefepime neurotoxicity, with the likelihood of causality ascribed via a modified Delphi method. Results This study included 100 patients. The mean age was 65.8 years (± 12.7 years). The median daily average dose of Cefepime was 2.5 (IQR 2.0 to 3.5) grams. The median treatment duration was 6 (IQR 4 to 10) days. Renal failure in any form was present in 84 patients. Chronic kidney disease affected 40 patients, and 77 had acute kidney injury. Cefepime neurotoxicity occurred in 15 patients. Of these, seven were considered definite cases, three probable, and five possible. Neurotoxic symptoms included impaired consciousness (n = 13), myoclonus (n = 11), disorientation (n = 6), and nonconvulsive status epilepticus (n = 1). The dose of Cefepime was appropriately adjusted for renal clearance in 64 patients (75.3%) without Cefepime neurotoxicity and four patients (28.6%) with neurotoxicity ( P  = 0.001). Chronic kidney disease was present in 30 patients (35.3%) without neurotoxicity and in 10 (66.7%) of those with neurotoxicity ( P  = 0.04). Conclusions Critically ill patients with chronic kidney disease are particularly susceptible to Cefepime neurotoxicity. Myoclonus and impaired consciousness are the predominant clinical manifestations. Neurotoxic symptoms occur more often when the Cefepime dose is not adjusted for renal function, but can still occur despite those modifications.

  • Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy
    Critical Care, 2013
    Co-Authors: Jennifer E Fugate, Ejaaz A Kalimullah, Sara E Hocker, Sarah L Clark, Eelco Fm Wijdicks, Alejandro A Rabinstein
    Abstract:

    Cefepime, a broad spectrum antibiotic, is commonly prescribed in intensive care units (ICU) and may be an overlooked cause of neurologic symptoms such as encephalopathy, myoclonus, seizures, and coma. We aimed to characterize Cefepime neurotoxicity in the ICU. We performed a retrospective study of adult ICU patients treated with intravenous Cefepime for at least 3 days between January 1, 2009 and December 31, 2011. The primary outcome was the development of Cefepime neurotoxicity, with the likelihood of causality ascribed via a modified Delphi method. This study included 100 patients. The mean age was 65.8 years (± 12.7 years). The median daily average dose of Cefepime was 2.5 (IQR 2.0 to 3.5) grams. The median treatment duration was 6 (IQR 4 to 10) days. Renal failure in any form was present in 84 patients. Chronic kidney disease affected 40 patients, and 77 had acute kidney injury. Cefepime neurotoxicity occurred in 15 patients. Of these, seven were considered definite cases, three probable, and five possible. Neurotoxic symptoms included impaired consciousness (n = 13), myoclonus (n = 11), disorientation (n = 6), and nonconvulsive status epilepticus (n = 1). The dose of Cefepime was appropriately adjusted for renal clearance in 64 patients (75.3%) without Cefepime neurotoxicity and four patients (28.6%) with neurotoxicity (P = 0.001). Chronic kidney disease was present in 30 patients (35.3%) without neurotoxicity and in 10 (66.7%) of those with neurotoxicity (P = 0.04). Critically ill patients with chronic kidney disease are particularly susceptible to Cefepime neurotoxicity. Myoclonus and impaired consciousness are the predominant clinical manifestations. Neurotoxic symptoms occur more often when the Cefepime dose is not adjusted for renal function, but can still occur despite those modifications.