Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination.
TL;DR: Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftAZidime alone.
Abstract: Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.
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TL;DR: How basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs is discussed.
Abstract: Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host-pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.
2,251 citations
13 Jun 2018
TL;DR: Understanding more about the mechanisms of resistance should hopefully lead to better treatment options for infective diseases, and development of antimicrobial drugs that can withstand the microorganisms attempts to become resistant.
Abstract: Resistance to antimicrobial agents has become a major source of morbidity and mortality worldwide. When antibiotics were first introduced in the 1900's, it was thought that we had won the war against microorganisms. It was soon discovered however, that the microorganisms were capable of developing resistance to any of the drugs that were used. Apparently most pathogenic microorganisms have the capability of developing resistance to at least some antimicrobial agents. The main mechanisms of resistance are: limiting uptake of a drug, modification of a drug target, inactivation of a drug, and active efflux of a drug. These mechanisms may be native to the microorganisms, or acquired from other microorganisms. Understanding more about these mechanisms should hopefully lead to better treatment options for infective diseases, and development of antimicrobial drugs that can withstand the microorganisms attempts to become resistant.
588 citations
TL;DR: The continued emergence of multi-drug-resistant bacteria is a major public health concern and the identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections.
Abstract: The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (1) and bedaquiline (2), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.
427 citations
TL;DR: It is contended that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new β-lactam:inhibitor combinations and the continuing clinical importance of β- lactams mean that this remains a rewarding research area.
423 citations
TL;DR: This guideline summarizes the current recommendations developed by the SIS task force on the treatment of patients who have IAI regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy.
Abstract: Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the t...
351 citations
Cites background from "Ceftazidime-avibactam: a novel ceph..."
...Ceftazidime-avibactam has activity against KPC-producing strains of Enterobacteriaceae and thus may provide an option for treating patients with HA-IAI because of this organism (Table 10) [276,469]....
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References
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Book•
01 Mar 1989
TL;DR: This updated and expanded edition now offers 297 chapters that cover the basic principles of diagnosis and management, major clinical syndromes, all important pathogenic microbes and the diseases they cause, plus a number of specialised topics useful to the practitioner.
Abstract: This updated and expanded edition now offers 297 chapters that cover the basic principles of diagnosis and management, major clinical syndromes, all important pathogenic microbes and the diseases they cause, plus a number of specialised topics useful to the practitioner. It contains 24 totally-new chapters, offers a whole section on AIDS with seven chapters and a chapter "Microsporidium Disease", which deals with a new disease just discovered because of AIDS. The text is designed for clinical pathologists, microbiologists, virologists, medical scientists, mycologists, allergists, general practitioners and lecturers of medicine.
13,514 citations
"Ceftazidime-avibactam: a novel ceph..." refers background in this paper
...part of the antimicrobial armamentarium for decades [1]....
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...The cephem nucleus is a bicyclic ring system composed of a four-member b-lactam ring fused with a six-member dihydrothiazine ring, with a sulfur atom at position 1, a double-bond between carbon 2 and carbon 3, and a carboxylic acid at position 4 [1, 11]....
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...8 h in patients with normal renal function [1, 87]....
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TL;DR: These enzymes are the major cause of bacterial resistance to b-lactam antibiotics and have been the subject of extensive microbiological, biochemical, and genetic investigations.
Abstract: A classification scheme for b-lactamases based on functional characteristics is presented. Three major groups of enzymes are defined by their substrate and inhibitor profiles: group 1 cephalosporinases that are not well inhibited by clavulanic acid; group 2 penicillinases, cephalosporinases, and broadspectrum b-lactamases that are generally inhibited by active site-directed b-lactamase inhibitors; and the group 3 metallob-lactamases that hydrolyze penicillins, cephalosporins, and carbapenems and that are poorly inhibited by almost all b-lactam-containing molecules. Functional characteristics have been correlated with molecular structure in a dendrogram for those enzymes with known amino acid sequences. b-Lactamases (EC 3.5.2.6) have been designated by the Nomenclature Committee of the International Union of Biochemistry as ‘‘enzymes hydrolysing amides, amidines and other CON bonds . . . separated on the basis of the substrate: . . . cyclic amides’’ (323). These enzymes are the major cause of bacterial resistance to b-lactam antibiotics and have been the subject of extensive microbiological, biochemical, and genetic investigations. Investigators have described more than 190 unique bacterial proteins with the ability to interact with the variety of b-lactam-containing molecules that can serve as sub-
2,563 citations
"Ceftazidime-avibactam: a novel ceph..." refers background in this paper
...As new b-lactams and b-lactamase inhibitors have been introduced, selective pressure on clinical species expressing b-lactamases has driven their evolution such that for any given b-lactam, a b-lactamase now exists that is capable of inactivating it [28, 29]....
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...A second system that classifies the b-lactamases by spectrum of activity and resistance to b-lactamase inhibitors was described by Bush and colleagues [28, 29], though the molecular (Ambler) classification system is referred to in this paper....
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TL;DR: The functional classification scheme updated herein is based on the 1995 proposal and includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrums β-lactamases and serine carbapenemases; and group 3 metallo-β-lacticamases.
Abstract: Two classification schemes for β-lactamases are currently in use. The molecular classification is based on the amino acid sequence and divides β-lactamases into class A, C, and D enzymes which utilize serine for β-lactam hydrolysis and class B metalloenzymes which require divalent zinc ions for substrate hydrolysis. The functional classification scheme updated herein is based on the 1995 proposal by Bush et al. (K. Bush, G. A. Jacoby, and A. A. Medeiros, Antimicrob. Agents Chemother. 39:1211-1233, 1995). It takes into account substrate and inhibitor profiles in an attempt to group the enzymes in ways that can be correlated with their phenotype in clinical isolates. Major groupings generally correlate with the more broadly based molecular classification. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrum β-lactamases and serine carbapenemases; and group 3 metallo-β-lactamases. Several new subgroups of each of the major groups are described, based on specific attributes of individual enzymes. A list of attributes is also suggested for the description of a new β-lactamase, including the requisite microbiological properties, substrate and inhibitor profiles, and molecular sequence data that provide an adequate characterization for a new β-lactam-hydrolyzing enzyme.
1,878 citations
TL;DR: In several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions, and the different models for the architecture are discussed with respect to structural and physical parameters.
Abstract: The peptidoglycan (murein) sacculus is a unique and essential structural element in the cell wall of most bacteria. Made of glycan strands cross-linked by short peptides, the sacculus forms a closed, bag-shaped structure surrounding the cytoplasmic membrane. There is a high diversity in the composition and sequence of the peptides in the peptidoglycan from different species. Furthermore, in several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions. Limited number of biophysical data on the thickness, elasticity and porosity of peptidoglycan are available. The different models for the architecture of peptidoglycan are discussed with respect to structural and physical parameters.
1,876 citations
TL;DR: In this article, it was shown that the β-lactamases have a polyphyletic origin and all the enzymes of currently known amino acid sequence belong to one homology group, called class A enzymes.
Abstract: The beta-lactamases are widely distributed in both Gram-positive and Gram-negative bacteria. They all inactivate penicillins and cephalosporins by opening the beta-lactam ring. Many varieties of the enzyme can be distinguished on the basis of their catalytic and molecular properties, but only amino acid sequence determination gives information upon which a molecular phylogeny can be based. The present evidence suggests that the beta-lactamases have a polyphyletic origin. All the beta-lactamases of currently known amino acid sequence belong to one homology group, here called class A enzymes. Class B consists of the mechanistically distinct Bacillus cereus beta-lactamase II, which preliminary partial sequence analysis suggests to be structurally unrelated to the class A enzymes. It is predicted that sequence analysis will show that further classes will need to be created to account for particular beta-lactamases of distinctive molecular and mechanistic properties.
1,624 citations