Activity of Cefepime-Zidebactam against Multidrug-Resistant (MDR) Gram-Negative Pathogens

Thomson, Kenneth S.; AbdelGhani, Sameh; Snyder, James W.; Thomson, Gina K.

doi:10.3390/antibiotics8010032

Cited by 46 publications

(34 citation statements)

References 33 publications

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“…In combination with cefepime (which inhibits PBP3), zidebactam adds these PBP2 inhibiting poten cies in E. coli and Klebsiella spp. As expected, the activity against CRPA is mediocre or insufficient (close to or above the clinical breakpoint for cefepime in 50% of the strains, and absent in CRAB 45,46 ). Reduced susceptibil ity to cefepime-zidebactam is mostly associated with MBLs (IMP or VIM) or with combinations of mecha nisms such as the overexpression of MexAB-OprM or MexXY efflux pumps, diminished OprD function and high level AmpC production 46 .…”

Section: Porinsupporting

confidence: 75%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

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| The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. ✉

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Section: Porinsupporting

confidence: 75%

Critical analysis of antibacterial agents in clinical development

Theuretzbacher¹,

et al. 2020

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“…Cefepime-zidebactam at a 1:1 ratio demonstrated antimicrobial activity against 5946 strains of Enterobacteriaceae and 1291 isolates of P. aeruginosa with reported MIC 90 values of 0.12 and 4 μg/mL, respectively [119]. As zidebactam is a β-lactam 'enhancer', the cefepime-zidebactam combination also possesses activity against Enterobacteriaceae producing metallo-β-lactamases and class D oxacillinases and P. aeruginosa with metallo-βlactamases [120][121][122]. Zidebactam, referred to as a bicyclo-acyl hydrazide on the basis of its chemical scaffold, inhibits class A and C β-lactamases and PBP-2 of K. pneumoniae, P. aeruginosa, and A. baumannii [84,[123][124][125].…”

Section: Cefepime-zidebactammentioning

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

100

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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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“…148) While cefepime has antimicrobial activity against A. baumannii, 149) cefepime/zidebactam exhibits better antimicrobial activity against A. baumannii in vitro and in vivo than cefepime alone. 144,150,151) Accordingly, WCK 5222 shows potency for Enterobacteriaceae and P. aeruginosa producing clinically relevant β-lactamases, including ESBL, KPC, AmpC, and MBL. 147,[152][153][154][155] Cefepime/Enmetazobactam (Formerly AAI101) (Fig.…”

Section: Novel β-Lactam/β-lactamase Inhibitors For Mdr Gram-negative mentioning

confidence: 99%

“…144,150,151) Accordingly, WCK 5222 shows potency for Enterobacteriaceae and P. aeruginosa producing clinically relevant β-lactamases, including ESBL, KPC, AmpC, and MBL. 147,[152][153][154][155] Cefepime/Enmetazobactam (Formerly AAI101) (Fig. 4) is a combination of cefepime and a novel β-lactamase inhibitor developed by Allecra that has entered phase III clinical trials for the treatment of cUTIs with QIDP status and Fast Track designation.…”

Section: Novel β-Lactam/β-lactamase Inhibitors For Mdr Gram-negative mentioning

confidence: 99%

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

Otsuka

2020

Chem. Pharm. Bull.

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The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a global problem. Among MDR Gram-negative bacteria, carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii have limited treatment options and present serious threats. Therefore, strong countermeasures must be taken against these bacteria immediately. Accordingly, the focus of this review is on recent advances in the development of promising antibacterial agents against MDR Gram-negative bacteria. These agents include novel tetracyclines, polymyxins, β-lactams, β-lactam/βlactamase inhibitors, aminoglycosides, and peptide mimetics that have been recently approved or have shown promising results in clinical and preclinical development. This review summarizes these potent antibiotics in terms of their development status, mode of action, spectra of activity, and structure-activity relationship. Key words antibiotic; drug candidate; Gram-negative bacteria; carbapenem-resistant 2. Novel Tetracycline-class Antibiotics for MDR Gramnegative Bacteria Tetracycline antibiotics derived from natural products do not contain substituents at the C-7, C-8, and C-9 positions. However, the development of totally synthetic methods to synthesize tetracyclines has made it possible to modify these three positions, 21,22) providing novel and fully synthetic tetracyclines such as XERAVA and TP-6076, developed by Tetraphase Pharmaceuticals Inc. (Fig. 1). The introduction of an electron-withdrawing group at the C-7 position, and substitution at the C-9 position, significantly improved the antimicrobial activity of these synthetic tetracyclines. 23,24) XERAVA (eravacycline, TP-434) 25-27) was the first fully synthetic fluorocycline produced by Michael-Dieckmann reaction. 28) XERAVA was approved by the U.S. Food and Drug Administration (FDA) in August 27, 2018 for the treatment of

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Activity of Cefepime-Zidebactam against Multidrug-Resistant (MDR) Gram-Negative Pathogens

Cited by 46 publications

References 33 publications

Critical analysis of antibacterial agents in clinical development

Critical analysis of antibacterial agents in clinical development

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

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

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