In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria

Livermore, David M.; Mushtaq, Shazad; Warner, Marina; Vickers, Anna; Woodford, Neil

doi:10.1093/jac/dkw593

Cited by 116 publications

(92 citation statements)

References 17 publications

(20 reference statements)

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“…Avibactam targets class A and C b-lactamases,i ncluding ESBLs,A mpC,a nd Klebsiella pneumoniae carbapenemase (KPC). [304,305] Thecombination with the approved b-lactam antibiotic cefepime enables treatment of carbapenem-resistant A. baumannii, Enterobacteriaceae,a nd metallo-carbapenemase-harboring P. aeruginosa. [292,301] Four DBO-based compounds are currently in development and differ from avibactam by substitution at the amide at position 2( Figure 21).…”

Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

“…[302,303] Zidebactam, a3 -piperidinylcarbonyl hydrazide from Wockhardt is in phase Ii nc ombination with cefepime and targets class Aand C b-lactamases.Remarkably for aBLI, the compound also inhibits PBP2 of Gram-negative pathogens and thereby shows antibacterial properties against some Enterobacteriaceae and P. aeruginosa. [304,305] Thecombination with the approved b-lactam antibiotic cefepime enables treatment of carbapenem-resistant A. baumannii, Enterobacteriaceae,a nd metallo-carbapenemase-harboring P. aeruginosa. Nacubactam, a2 -aminoethoxyamine from Roche in phase I, inhibits class Aa nd C b-lactamases.…”

Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

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Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

Section: B-lactamase Inhibitors (Blis)mentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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“…Additionally, the loss of outer membrane porins (OMPs) further contributes to the varied resistance mechanisms harbored by this pathogen (9,10). Clinically available ␤-lactamase inhibitors (BLIs), such as clavulanic acid, tazobactam, sulbactam, avibactam, and vaborbactam (formerly RPX-7009), have no inhibitory activity against MBL enzymes (11)(12)(13). Therefore, newer therapeutic approaches that can tackle diverse ␤-lactam-impacting resistance mechanisms, including MBLs expressed in K. pneumoniae, are warranted.…”

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confidence: 99%

In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

Moyá

Barceló

Cabot

et al. 2019

Antimicrob Agents Chemother

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Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as ␤-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity for cefepime and aztreonam against metallo-␤-lactamase (MBL)-producing strains in vitro and in vivo. Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (IC 50 s) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical K. pneumoniae isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C ␤-lactamases) to assess the in vitro enhancer effect of BCH compounds in conjunction with ␤-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. The MICs of BLEs were Ͼ64 g/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to Ͼ3 log 10 kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE-␤-lactam combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the ␤-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display in vitro and in vivo BLE effects against multidrug-resistant (MDR) K. pneumoniae clinical isolates producing MBLs.

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“…In den vergangenen Jahren wurden zwei neuartige BLI-Klassen zugelassen, die sich von den klassischen b-Lactam-Antibiotika in ihrer Struktur deutlich unterscheiden:A vibactam und Va borbactam. [304,305] In Kombination mit dem b-Lactam-AntibiotikumC efepim ermçglicht es die Be-handlung vom Carpapenem-resistenten A. baumannii, Enterobacteriaceae und Metallo-carbapenemase-enthaltenden P. aeruginosa. Avibactam inhibiert b-Lactamasen der Klassen Aund C, inklusive ESBLs,A mpC und der Carbapenemase aus K. pneumoniae (KPC).…”

Section: B-lactamase-inhibitoren (Blis)unclassified

“…[302,303] Zidebactam, ein 3-Piperidinylcarbonylhydrazid von Wockhardt, ist in Kombination mit Cefepime in Phase Iu nd inhibiert b-Lactamasen der Klassen Au nd C. Bemerkenswert füreinen BLI, hemmt diese Verbindung auch PBP2 der Gram-negativen Pathogene und besitzt dadurch antibakterielle Eigenschaften gegenüber einigen Enterobacteriaceae und P. aeruginosa. [304,305] In Kombination mit dem b-Lactam-AntibiotikumC efepim ermçglicht es die Be-handlung vom Carpapenem-resistenten A. baumannii, Enterobacteriaceae und Metallo-carbapenemase-enthaltenden P. aeruginosa. Nacubactam, ein 2-Aminoethoxyamin von Roche in Phase I, hemmt b-Lactamasen der Klassen Au nd C. [306,307] Es bindet außerdem an PBP2 und zeigt deshalb antibakterielle Wirkung,welche allerdings schwächer ist als bei Zidebactam.…”

Section: Aufsätzeunclassified

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

et al. 2018

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Die öffentliche Wahrnehmung von Antibiotika als verlässliche Arzneimittel veränderte sich drastisch, als Meldungen über “multiresistente Super‐Erreger” die Nachrichten aufrüttelten. Während die Ursachen für die bakterielle Resistenzentwicklung schnell erkannt wurden, befindet sich die Forschung zur Wiedergewinnung von Antibiotika als effektive Arzneistoffe immer noch am Anfang. Dieser Aufsatz umfasst zahlreiche Aspekte des Entwicklungsprozesses neuer Antibiotika, von der Grundlagenforschung bis zum fertigen Medikament. Er bietet einen interdisziplinären Überblick über Methoden zur Identifizierung neuer Antibiotika und erörtert Strategien, um ihren molekularen Wirkmechanismus aufzuklären. Die Darstellung ausgewählter Antibiotika, die kürzlich mithilfe dieser Plattformen entdeckt wurden, verdeutlicht die Effizienz der Ansätze und hebt vielversprechende klinische Kandidaten mit therapeutischem Potential hervor. Zusätzlich wird das Konzept von Molekülen erörtert, die Krankheitserreger “entwaffnen”, indem sie Schlüsselpunkte der Virulenz adressieren. Der Aufsatz schließt mit einer kritischen Beurteilung jener antibakteriellen Wirkstoffe, die sich derzeit in klinischer Entwicklung befinden. Insgesamt soll dieser Aufsatz ausgewählte, innovative antibakterielle Ansätze verknüpfen, um interdisziplinäre Partnerschaften zwischen Chemikern aus der akademischen und industriellen Forschung anzuregen.

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In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria

Cited by 116 publications

References 17 publications

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

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