A Kinetic Study on the Interaction Between Tazobactam (A Penicillanic Acid Sulphone Derivative) and Active-Site Serine B-Lactamases

Perilli, Mariagrazia; Franceschini, Nicola; Bonfiglio, Giovanni; Segatore, Bernardetta; Stefani, Stefania; Nicoletti, Giuseppe; Pérez, Miguel Ángel González; Bianchi, Ciro; Zollo, Alessandro; Amicosante, Gianfranco

doi:10.1080/14756369909030337

Cited by 4 publications

(4 citation statements)

References 13 publications

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“…Therefore, a %fTϾMIC of 30% (of an 8-h dosing interval) for an MIC of 4 g/ml (the Clinical and Laboratory Standards Institute susceptibility breakpoint for P. aeruginosa [14]) can be assumed to be a suitable PK/PD target for ceftolozane, based on existing regulatory PK/PD guidance for the development of antibacterial treatments for potentially life-threatening infections (15). Tazobactam is a competitive, essentially irreversible inhibitor of specific serine ␤-lactamases, including common ESBLs (16)(17)(18)(19). Since tazobactam does not have intrinsic antibacterial activity, an MIC cannot be determined.…”

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confidence: 99%

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Larson

Patel

Willavize

et al. 2019

Antimicrob Agents Chemother

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Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum ␤-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to Ͻ18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of Ն50 ml/min/1.73 m 2 only): for children Ն12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children Ͻ12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

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confidence: 99%

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Larson

Patel

Willavize

et al. 2019

Antimicrob Agents Chemother

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“…Kinetic study showed that tazobactam is an efficient suicide inhibitor of β-lactamase produced of P. aeruginosa (Livermore et al, 1992;Perilli et al, 1999). The principal β-lactam resistance mechanism in P. aeruginosa in Italy seems principally due to combination of β-lactamase production and impermeability (Bonfiglio et al, 1998b).…”

Section: Discussionmentioning

confidence: 99%

“…It is widely accepted that β-lactamases function cooperatively with outer membrane impermeability to protect the Gram-negative cells from the antibacterial actions of β-lactam drugs (Livermore, 1988;Nikaido, 1989). Tazobactam is an excellent suicide β-lactamase-inhibitor (Livermore et al, 1992;Perilli et al, 1999). Piperacillin in association to tazobactam showed a very good activity against P. aeruginosa resistant strains isolated in intensive care units (Bonfiglio et al, 1998a).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of polyethylenimine plus piperacillin/tazobactam on clinicalPseudomonas aeruginosa isolates resistant to piperacillin/tazobactam

Bonfiglio

2006

Ann. Microbiol.

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We investigated the in vitro susceptibility of piperacillin/tazobactam in association with polyethylenimine (PEI), a synthetic polycation polymer, against 24 clinical isolates of Psedomonas aeruginosa resistant to piperacillin/tazobactam. The strains were isolated from patients with respiratory tract infections. MIC of piperacillin/tazobactam was determined by agar dilution method in accordance with NCCLS methodology. An inoculum of 10 4 CFU/spot with or without PEI (250 nM final concentration) was used. Killing curves were performed for 3 piperacillin/tazobactam resistant strains chosen for their different range of MIC values to piperacillin/tazobactam (128, 256 and 512 mg/L, respectively). Analyses were performed in duplicate using a concentration of antibiotic of 16 mg/L. The addition of PEI (250 nM) increased the susceptibility of piperacillin/tazobactam (from 8 to 32 folds) in all the strains tested. Moreover, in all the strains tested piperacillin/tazobactam in association with PEI showed a bactericidal activity before 6 h. Intrinsic resistance of P. aeruginosa affects susceptibility to penicillins and is believed to entail broad spectrum impermeability. Different theories suggest that some degree of structure or organization exists in the periplasm of P. aeruginosa and that this modulates both the level of intrinsic, impermeability-determined resistance expressed by a strain and the efficiency with which the β-lactamase can contact and destroy the incoming β-lactamase molecules. The explanation of this behaviour could be that PEI determines an increased permeability of the outer membrane of P. aeruginosa; tazobactam inhibits β-lactamase allowing the antibacterial activity of piperacillin. In conclusion our data suggest that PEI can be expected to act as a vehicle for experimental drug delivery into cells, and as a potentiating agent for antibacterial agents that are normally excluded by Gram-negative bacteria.

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“…Concomitant with immense interests in the novel inhibitor discovery are the demands for efficient approaches for screening and characterizing a vast array of potential candidates that comes from nature or is generated from structure‐guided in‐parallel synthesis. Conventional approaches for identifying the potential drug candidates are microbial susceptibility testing and β‐lactamase inhibition assay . These methods determine the minimal inhibitory concentration (MIC) and inhibition constants (IC 50 or K i ) of the candidates respectively, thus providing indices for the drug potency.…”

Section: Introductionmentioning

confidence: 99%

A fluorescein‐labeled AmpC β‐lactamase allows rapid characterization of β‐lactamase inhibitors by real‐time fluorescence monitoring of the β‐lactamase‐inhibitor interactions

Tsang

Chan

Liu

et al. 2015

Biotechnology Journal

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Rapid emergence of class C β-lactamases has urged an immediate need for developing class C β-lactamase specific inhibitors for effective clinical treatment. To facilitate the development of effective class C β-lactamase inhibitors, we propose a new approach for a rapid analysis of the interaction of AmpC β-lactamase and its inhibitors using our recently developed V211Cf fluorescent β-lactamase biosensor during drug screening. Since the fluorescein of V211Cf can report the local environment change in the active site of AmpC β-lactamase, fluorescence responses of V211Cf toward its substrates/inhibitors can provide real-time traces of the dynamic change of the interaction of the β-lactamase with its substrates/inhibitors. In this study, we found that V211Cf displayed distinct fluorescence signal patterns toward different kinds of inhibitors (including clavulanic acid, sulbactam, tazobactam and 2-thiopheneboronic acid) due to the differences in their interactions with β-lactamase. V211Cf not only enables a high throughput screening for inhibitors but can also provide a rapid preliminary indication on the inhibitor's potency and stability to β-lactamase's hydrolytic action as well as how the inhibitors interact with the target enzyme, thereby speeding up the drug discovery and development cycle of class C β-lactamase inhibitors.

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A Kinetic Study on the Interaction Between Tazobactam (A Penicillanic Acid Sulphone Derivative) and Active-Site Serine B-Lactamases

Cited by 4 publications

References 13 publications

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Synergistic effect of polyethylenimine plus piperacillin/tazobactam on clinicalPseudomonas aeruginosa isolates resistant to piperacillin/tazobactam

A fluorescein‐labeled AmpC β‐lactamase allows rapid characterization of β‐lactamase inhibitors by real‐time fluorescence monitoring of the β‐lactamase‐inhibitor interactions

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