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.

Fig 1

(a) Free-concentration–time profiles of piperacillin-tazobactam at 4.5 g q6h in healthy human volunteers versus mice. (b) Free-concentration–time profiles of CXA-101 at 1,000 mg q8h in healthy human volunteers versus mice. (c) Free-concentration–time profiles of CXA-101–tazobactam (2:1) at 1,000/500 mg q8h in healthy human volunteers versus mice. Each value represents the mean ± standard deviation of 6 infected mice.

Fig 2

Comparative efficacies of human simulated piperacillin-tazobactam (black bars), CXA-101 (light-gray bars), and CXA-tazobactam (dark-gray bars) against a distribution of P. aeruginosa, presented as mean ± standard deviation. Statistical significance (SS) between antimicrobial agents is denoted as follows: * indicates SS between piperacillin-tazobactam and CXA-101–tazobactam, δ indicates SS between piperacillin-tazobactam and CXA-101, and ψ indicates SS between CXA-101 and CXA-101–tazobactam.

Fig 3

Comparative efficacies of human simulated piperacillin-tazobactam (black bars), CXA-101 (light-gray bars), and CXA-tazobactam (dark-gray bars) against a distribution of ESBL-positive and ESBL-negative K. pneumoniae isolates, presented as mean ± standard deviation. SS between antimicrobial agents is denoted as follows: * indicates SS between piperacillin-tazobactam and CXA-101–tazobactam, δ indicates SS between piperacillin-tazobactam and CXA-101, and ψ indicates SS between CXA-101 and CXA-101–tazobactam. +, positive; −, negative.

Fig 4

Comparative efficacies of human simulated piperacillin-tazobactam (black bars), CXA-101 (light-gray bars), and CXA-tazobactam (dark-gray bars) against a distribution of ESBL-positive and ESBL-negative E. coli isolates, presented as mean ± standard deviation. SS between antimicrobial agents is denoted as follows: * indicates SS between piperacillin-tazobactam and CXA-101–tazobactam, δ indicates SS between piperacillin-tazobactam and CXA-101, and ψ indicates SS between CXA-101 and CXA-101–tazobactam. +, positive; −, negative.