title: In vivo comparison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms.
abstract: CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.
authors: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors: Catharine C
authors: CC
authors: Bulik
authors: Pamela R
authors: PR
authors: Tessier
authors: Rebecca A
authors: RA
authors: Keel
authors: Christina A
authors: CA
authors: Sutherland
authors: David P
authors: DP
authors: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002511:Cephalosporins / Q000008:administration & dosage / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004338:Drug Combinations; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010641:Phenotype; D010878:Piperacillin / Q000008:administration & dosage / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D000078142:Tazobactam; D013848:Thigh / Q000382:microbiology*; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004338:Drug Combinations; D000077725:Piperacillin, Tazobactam Drug Combination; C519491:ceftolozane; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam; D010878:Piperacillin