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

Grupper, Mordechai; Stainton, Sean M.; Nicolau, David P.; Kuti, Joseph L.

doi:10.1128/aac.00144-19

Cited by 10 publications

(10 citation statements)

References 23 publications

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“…It should be noted, however, that exposure requirements exceeding 100% fT > MIC in specific isolates were absent from the majority of these studies. While pharmacokinetic variability among mice in these studies can account for some of this variability, differences within individual isolates still contribute to varying pharmacodynamic thresholds, as demonstrated in in vitro chemostat experiments where drug exposure can be quantified in each individual model (Grupper et al, 2019). As a result, some have suggested that the variability in thresholds observed should be accounted for alongside pharmacokinetic variability and natural MIC variation when conducting Monte Carlo simulations to guide optimal dosing and susceptibility breakpoints (Soon et al, 2013).…”

Section: Summary Of Pharmacodynamic Thresholds From Pre-clinical Muri...mentioning

confidence: 99%

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

Berry

Kuti

2022

Front. Pharmacol.

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Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%fT > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of fT > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the fT > MIC should exceed approximately 40–70% fT > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

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Section: Summary Of Pharmacodynamic Thresholds From Pre-clinical Muri...mentioning

confidence: 99%

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

Berry

Kuti

2022

Front. Pharmacol.

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“…In studies that explored different PK/PD indices for BLI, the fraction of the dosing interval that the free drug concentration is above a threshold concentration ( fT >CT ) was identified as the best PK/PD index for tazobactam, 50–53 , 57 avibactam 40 , 44 , 54 , 55 and clavulanic acid. 38 , 46 Consistent with this, Louie et al 47 demonstrated that fT >CT adequately describes the exposure–response relationship for avibactam. The PD portion of the PK/PD index of these BLIs, due to lack of intrinsic antibacterial activity, is usually represented by a C T for inhibition instead of MIC.…”

Section: Resultsmentioning

confidence: 75%

“…A total of 23 studies were included in this systematic review. 38–60 From these, 11 studies used in vitro infection models, 39 , 43 , 44 , 46–48 , 52 , 56–59 7 studies used in vivo infection models, 38 , 40 , 49–51 , 53 , 60 and 2 studies used both in vitro and in vivo infection models 45 , 54 to evaluate the optimal concentration of BLI necessary to protect the companion BL antibiotic. Three of the studies were based on in silico methods, using mathematical modelling to determine the outcome of interest.…”

Section: Resultsmentioning

confidence: 99%

What are the optimal pharmacokinetic/pharmacodynamic targets for β-lactamase inhibitors? A systematic review

Assefa,

Roberts,

Mohammed

et al. 2024

Journal of Antimicrobial Chemotherapy

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Background Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For β-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of β-lactam/β-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. Objectives This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with β-lactam antibiotics. Methods Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. Results Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0–24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion β-lactam antibiotics, type of bacteria and β-lactamase enzyme gene transcription levels. Conclusions The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

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“…Ceftibuten-clavulanate was the most active oral agent tested against a world-wide collection of 5,568 isolates of Enterobacteriaceae from 2017 [146,147]. Moreover, the pharmacodynamics of ceftibuten-clavulanate were evaluated in an in vitro chemostat model and a murine thigh infection model using ESBL-producing Enterobacteriaceae [148,149]. Unfortunately, in April 2019, Achaogen filed for bankruptcy, so the future of ceftibutenclavulanate is unclear.…”

Section: Ceftibuten-clavulanatementioning

confidence: 99%

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

Papp-Wallace

2019

Expert Opinion on Pharmacotherapy

107

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Introduction: Antimicrobial resistance in Gram-negative pathogens is a significant threat to global health. β-Lactams (BL) are one of the safest and most-prescribed classes of antibiotics on the market today. The acquisition of β-lactamases, especially those which hydrolyze carbapenems, is eroding the efficacy of BLs for the treatment of serious infections. During the past decade, significant advances were made in the development of novel BL-β-lactamase inhibitor (BLI) combinations to target β-lactamasemediated resistant Gram-negatives. Areas covered: The latest progress in 20 different approved, developing, and preclinical BL-BLI combinations to target serine β-lactamases produced by Gram-negatives are reviewed based on primary literature, conference abstracts (when available), and US clinical trial searches within the last 5 years. The majority of the compounds that are discussed are being evaluated as part of a BL-BLI combination. Expert opinion: The current trajectory in BLI development is promising; however, a significant challenge resides in the selection of an appropriate BL partner as well as the development of resistance linked to the BL partner. In addition, dosing regimens for these BL-BLI combinations need to be critically evaluated. A revolution in bacterial diagnostics is essential to aid clinicians in the appropriate selection of novel BL-BLI combinations for the treatment of serious infections.

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

Cited by 10 publications

References 23 publications

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

What are the optimal pharmacokinetic/pharmacodynamic targets for β-lactamase inhibitors? A systematic review

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

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