Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

Murano, Keiko; Yamanaka, Toshio; Toda, Ayako; Ohki, Hidenori; Okuda, Shinya; Kawabata, Kazushige; Hatano, Kazuo; Takeda, Shinobu; Akamatsu, Hisashi; Itoh, Kenji; Misumi, Keiji; Inoue, Satoshi; Takagi, Tatsuya

doi:10.1016/j.bmc.2007.11.074

Cited by 39 publications

(24 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ceftolozane has features of ceftazidime but has a bulkier side chain, which prevents cleavage by AmpC beta-lactamases [65], enhancing activity against P. aeruginosa. The combination also appears to have activity against non-CRE ESBL-producing Enterobacteriaceae [66, 67].…”

Section: Contemporary Treatment Strategies For Gram-negative Vapmentioning

confidence: 99%

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Rhodes

Cruce

O’Donnell

et al. 2018

Curr Infect Dis Rep

View full text Add to dashboard Cite

Rapid identification technologies and phenotypic methods, new therapeutic strategies, and novel treatment paradigms have evolved in an attempt to improve treatment outcomes for VAP; however, clinical data supporting alternative treatment strategies and adjunctive therapies remain sparse. Importantly, new classes of antimicrobials, novel virulence factor inhibitors, and beta-lactam/beta-lactamase inhibitor combinations are currently in development. Conscientious stewardship of new and emerging therapeutic agents will be needed to ensure they remain effective well into the future.

show abstract

Section: Contemporary Treatment Strategies For Gram-negative Vapmentioning

confidence: 99%

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Rhodes

Cruce

O’Donnell

et al. 2018

Curr Infect Dis Rep

View full text Add to dashboard Cite

show abstract

“…The substitution of a pyrazole side chain on the 3‐position of the cephem ring improves the outer membrane permeability of ceftolozane and grants stability against some AmpC β‐lactamases, leading to improved activity against P. aeruginosa . Tazobactam, a known β‐lactamase inhibitor, is added to improve the spectrum of activity against ESBL‐producing Enterobacteriaceae and some anaerobes (Figure ) . The combination of ceftolozane/tazobactam is also known as CXA‐201.…”

Section: Chemistry Structure and Functionmentioning

confidence: 99%

Ceftolozane/Tazobactam: A Novel Cephalosporin/β‐Lactamase Inhibitor Combination

2015

View full text Add to dashboard Cite

Ceftolozane/tazobactam is a novel antipseudomonal β-lactam/β-lactamase inhibitor combination that is currently approved by the United States Food and Drug Administration for the treatment of complicated intraabdominal infections (cIAI) and complicated urinary tract infections (cUTI). It exhibits bactericidal properties through inhibition of bacterial cell wall biosynthesis, which is mediated through penicillin-binding proteins (PBPs). Ceftolozane is a potent PBP3 inhibitor and has a higher affinity for PBP1b compared with other β-lactam agents. Ceftolozane/tazobactam differs from other cephalosporins due to its increased activity against some AmpC β-lactamases and Pseudomonas aeruginosa. The addition of tazobactam provides enhanced activity against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and certain anaerobic organisms. Population pharmacokinetic studies for ceftolozane and ceftolozane/tazobactam are best described by a two-compartment model with zero-order input and linear elimination. Similar to other cephalosporins, the best pharmacodynamic property to predict efficacy for ceftolozane/tazobactam is a concentration that remains above the minimum inhibitory concentration (MIC) for 40-50% of the dosing interval. For Enterobacteriaceae and P. aeruginosa strains, the time above the MIC (T > MIC) needed to produce bactericidal activity was much less with ceftolozane than other cephalosporins, with T > MIC requirements of approximately 30%. For currently approved indications, the dose of ceftolozane/tazobactam is 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) intravenously every 8 hours given as a 1-hour infusion. Ceftolozane has low plasma protein binding (20%) and is predominantly excreted unchanged in the urine (≥ 92%). Dosage adjustments are required for moderate-to-severe renal impairment and in patients receiving hemodialysis. Based on data from clinical trials, adverse effects due to ceftolozane/tazobactam do not differ considerably from other cephalosporins, with the most common being nausea, diarrhea, headache, and pyrexia. Ceftolozane/tazobactam is a promising new agent for the treatment of cIAI and cUTI, including those caused by multidrug-resistant gram-negative organisms.

show abstract

“…24 At the 3-position, the bulky, substituted pyrazole ring prevents hydrolysis of the β-lactam ring by steric hindrance and confers some stability to AmpC β-lactamases commonly seen in P. aeruginosa. 25, 26 Unlike ceftaroline and ceftobiprole, the 3-position substituent of ceftolozane does not appear to improve the drug's affinity for PBP2a, which explains the compounds lack of activity against MRSA, and the drug has low overall affinity for PBP4, similar to ceftazidime, which explains it's very weak induction of AmpC expression. 27 However, the ceftolozane has particularly strong affinity for PBP3, at least 2-fold higher than ceftazidime, which explains its potent P. aeruginosa activity.…”

Section: Discussionmentioning

confidence: 99%

Recent advances in the rational design and optimization of antibacterial agents

et al. 2016

View full text Add to dashboard Cite

This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents. The discussion of the agents focuses on the rational design strategies employed and the synthetic medicinal chemistry and structure-based design techniques utilized by the scientists involved in the discoveries, including such methods as ligand- and structure-based strategies, structure-activity relationship (SAR) expansion strategies, and novel synthetic organic chemistry methods. As such, the discussion is limited to small-molecule therapeutics that have confirmed macromolecular targets and encompasses only a fraction of all antibacterial agents recently approved or in late-stage clinical trials. The antibacterial agents selected have been recently approved for use on the U.S. or European markets or have shown promising results in phase 2 or phase 3 U.S. clinical trials.

show abstract

Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

Cited by 39 publications

References 21 publications

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia

Ceftolozane/Tazobactam: A Novel Cephalosporin/β‐Lactamase Inhibitor Combination

Recent advances in the rational design and optimization of antibacterial agents

Contact Info

Product

Resources

About