What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

Gentile, Ivan; Maraolo, Alberto Enrico; Borgia, G

doi:10.1080/14787210.2016.1233060

Cited by 20 publications

(12 citation statements)

References 43 publications

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“…baumannii. Ceftolozane is a fifth-generation cephalosporin, recently developed for use in combination with tazobactam (43). The limited isolate results presented here suggest that ceftolozane, partnered with a cyclic boronate, could be an attractive β-lactam/inhibitor combination to pursue in the future.…”

Section: Discussionmentioning

confidence: 99%

Cyclic Boronates Inhibit All Classes of β-Lactamases

Cahill

Cain

Wang

et al. 2017

Antimicrob Agents Chemother

105

158

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ABSTRACTβ-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

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Section: Discussionmentioning

confidence: 99%

Cyclic Boronates Inhibit All Classes of β-Lactamases

Cahill

Cain

Wang

et al. 2017

Antimicrob Agents Chemother

105

158

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“…Meropenem-dirençli izolatlarda etkinliği yok denecek kadar düşük (%1,4-4) bulunmuştur ki bunda en önemli neden antibiyotiğin KPC'ye karşı etkinliğinin olmamasıdır [16] . [6,23] . bulunmuştur.…”

Section: İn Vitro Etkinlikunclassified

“…Seftolozan/tazobaktamın P. aeruginosa ile meydana gelen nozokomiyal pnömonideki etkinliğinin değerlendirildiği çalışmalar devam etmekle birlikte bu çalışmalardaki etkinliği umut verici görülmektedir [23] . Böbrek yetmezliği, malignite, nötropeni ve solid organ nakli vb.…”

Section: İn Vitro Etkinlikunclassified

A Novel β-lactam/β-lactamase inhibitor: Ceftolozane/tazobactam

Şerefhanoğlu¹

2019

mjima

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Seftolozan/tazobaktam yeni kuşak sefalosporin ve β-laktamaz inhibitörü kombinasyonu olan bir antibiyotiktir. On sekiz yaş ve üzerindeki erişkinlerde meydana gelen komplike üriner sistem enfeksiyonları ve metronidazol ile kombine edilerek komplike intraabdominal enfeksiyonların tedavisinde Amerikan Gıda ve İlaç Dairesi onayı almıştır. Başlıca etki spektrumu çoklu ilaç dirençli (ÇİD) Pseudomonas aeruginosa ve diğer aerobik Gram-olumsuz bakterilerdir (GNB). Başlıca karakteristik özellikleri: (1) P. aeruginosa'nın penisilin bağlayan proteinlerine yüksek afinitesi olması, (2) dış membran penetrasyonunun yüksek olması ve bu nedenle efluks pompası aktivitesinden daha az etkilenmesi, (3) AmpC β-laktamaz, primitif β-laktamazlar (TEM-1, TEM-2, SHV-1 ve OXA-1) ve genişlemiş spektrumlu β-laktamaz olumlu bakterilere etkili olmasıdır. Buna karşın, metallo-β-laktamaz ve Klebsiella pneumoniae karbapenemazları enzimleri üreten patojenlere etkisizdir. Seftolozan/tazobaktamın özellikle tedavi seçeneğinin kısıtlı olduğu ÇİD GNB'nin neden olduğu enfeksiyonların tedavisinde faydalı olacağı düşünülmektedir. Bu yazıda, henüz ülkemizde kullanıma girmemiş olan bu antibiyotiğin farmakokinetik özellikleri, antimikrobiyal spektrumu ve güncel çalışmalardaki verileri derlenmiştir. Anahtar Kelimeler: CRE, GSBL, hemodiyaliz, kronik böbrek yetmezliği, komplike intra-abdominal enfeksiyonlar Ceftolozane/tazobactam is a novel generation cephalosporin and β-lactamase inhibitor combination antibiotic. It was approved for the treatment of adults (18 years and older) with complicated intraabdominal infections used in combination with metronidazole and complicated urinary tract infections by the United States Food and Drug Administration. Its primary activity is against multidrug-resistant Pseudomonas aeruginosa and other aerobic Gram-negative bacteria. The main characteristic features of the antibiotic include: (1) a greater affinity for penicillin-binding proteins produced by P. aeruginosa; (2) better outer membrane permeability that displays resistance mechanisms against upregulation of efflux pumps, and (3) effectiveness against pathogens producing AmpC β-lactamases, primitive β-lactamases (TEM-1, TEM-2, SHV-1, and OXA-1), and extended spectrum β-lactamases. However, it is not effective against pathogens producing metallo-β-lactamases and Klebsiella pneumoniae carbapenemases. Ceftolozane/tazobactam is promising for difficult-to-treat infections caused by multidrug-resistant Gram-negative bacteria. Herein, the features of ceftolozane/tazobactam, including its pharmacokinetics, antimicrobial spectrum, and data from recent clinical studies are reviewed.

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“…A relevant issue is to better define its place in therapy: currently, TOL/TAZ has been approved only for complicated urinary tract infections, including pyelonephritis, and for complicated intra-abdominal infections [3]. Differently, physicians need to resort to off-label prescribing, as was the case described by Dr Plant and colleagues [1].…”

Section: Letter To the Editormentioning

confidence: 99%

“…TOL/TAZ belongs to the new wave of beta-lactam /beta-lactamase inhibitor combinations and bases its efficacy against Gram-negative bacteria on ceftolozane's higher stability versus AmpC β-lactamase than the predecessor beta-lactam companions of tazobactam [3].…”

Section: Letter To the Editormentioning

confidence: 99%