fr-264205 and Escherichia-coli-Infections

We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single β-lactamase enzyme and that clinical isolates typically produce multiple β-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r(2) values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r(2) value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized β-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E

Topics: Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Computer Simulation; Drug Administration Schedule; Drug Combinations; Drug Dosage Calculations; Escherichia coli; Escherichia coli Infections; Gene Expression; Half-Life; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Models, Statistical; Penicillanic Acid; Plasmids; Tazobactam

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.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillanic Acid; Phenotype; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thigh

CXA-101, a novel cephalosporin with good antipseudomonal activity, was evaluated against a consecutive and polyclonal collection of extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli (n = 149) and Klebsiella pneumoniae (n = 20), mainly CTX-M-15- (69%) or CTX-M-14 producing (22%). A total of 41% of the E. coli isolates belonged to the international clone O25b-ST131. Broth microdilution versus CXA-101, CXA-tazobactam 4 and 8 mg/L (CXA-201), ceftazidime-tazobactam (CAT), ceftazidime-clavulanate (CAC), piperacillin-tazobactam (TZP), amoxicillin-clavulanate (ACL), ampicillin-sulbactam (ASU), and other comparators was performed, using EUCAST methodology and breakpoints. Susceptibility to CXA-201 was 96% (tazobactam 8 mg/L, tentative breakpoint S ≤ 1 mg/L), CAT 93%, CAC 95%, ACL 24%, ASU 2%, TZP 58%, ciprofloxacin 25%, levofloxacin 30%, gentamicin 54%, tobramycin 34%, amikacin 90%, and tigecycline 98%. Ninety-four percent of the TZP-resistant and all ACL-resistant isolates were CXA-201 susceptible. CXA-201 has good in vitro activity against ESBL-producing Enterobacteriaceae and might be a future therapeutic option for infections caused by TZP- and ACL-resistant isolates.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; beta-Lactamases; Cephalosporins; Escherichia coli; Escherichia coli Infections; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Typing; Penicillanic Acid; Tazobactam