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In Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

ABSTRACT: A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the ?-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-?-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (?59% free time above the CTB-CLA MIC) against ESBL-producing Escherichia coli and Klebsiella pneumoniae (CTB-CLA MICs of 0.25/0.125 to 1/0.5??g/ml) using the in vitro chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (fT>threshold) to be the best pharmacodynamic index (R ² = 0.85) compared with the free area under the curve (AUC)/threshold ratio (R ² = 0.62) and free maximum concentration/threshold ratio (R ² = 0.37). For E. coli isolates, stasis and 1-log₁₀ CFU reductions were achieved at 30.9 and 47.9% fT>CTB concentrations of the 2:1 CTB-CLA MIC (fT>MIC here), respectively. For K. pneumoniae isolates, stasis and 1-log₁₀ CFU reductions were achieved at 51.9 and 92.0% fT>MIC, respectively. These data inform exposure requirements for CLA combined with CTB for optimizing pharmacodynamics against Enterobacteriaceae and should be useful in designing dosage regimens for this combination antibiotic.

SUBMITTER: Grupper M

PROVIDER: S-EPMC6591603 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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In Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

Grupper Mordechai M Stainton Sean M SM Nicolau David P DP Kuti Joseph L JL

Antimicrobial agents and chemotherapy 20190624 7

A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the β-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-β-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (∼59% free time above the CTB-CLA MIC) against ESBL-producing Escherichia coli and Klebsiella ...[more]

PMID: 31061148

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Project description:The intrinsic L1 metallo- and L2 serine-β-lactamases in Stenotrophomonas maltophilia make it naturally multidrug resistant and difficult to treat. There is a need to identify novel treatment strategies for this pathogen, especially against isolates resistant to first-line agents. Aztreonam in combination with avibactam has demonstrated potential, although data on other aztreonam-β-lactamase inhibitor (BLI) combinations are lacking. Additionally, molecular mechanisms for reduced susceptibility to these combinations have not been explored. The objectives of this study were to evaluate and compare the in vitro activities and to understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia A panel of 47 clinical S. maltophilia strains nonsusceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution, and 6 isolates were then evaluated in time-kill analyses. Three isolates with various aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase PCR. Avibactam restored aztreonam susceptibility in 98% of aztreonam-resistant isolates, compared to 61, 71, and 15% with clavulanate, relebactam, and vaborbactam, respectively. The addition of avibactam to aztreonam resulted in a ≥2-log10-CFU/ml decrease at 24 h versus aztreonam alone against 5/6 isolates compared to 1/6 with clavulanate, 4/6 with relebactam, and 2/6 with vaborbactam. Molecular analyses revealed that decreased susceptibility to aztreonam-avibactam was associated with increased expression of genes encoding L1 and L2, as well as the efflux pump (smeABC). Aztreonam-avibactam is the most promising BLI-combination against multidrug-resistant S. maltophilia Decreased susceptibility may be due to the combination of overexpressed β-lactamases and efflux pumps. Further studies evaluating this combination against S. maltophilia are warranted.

Dataset Information

In Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

Publications

<i>In Vitro</i> Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

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