Does broad-spectrum  -lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria?

Nordmann, Patrice; Poirel, Laurent; Toleman, Mark A.; Walsh, Timothy R.

doi:10.1093/jac/dkq520

Cited by 273 publications

(235 citation statements)

References 23 publications

Supporting

Mentioning

207

Contrasting

Unclassified

Order By: Relevance

“…In health-care settings, multi-drug resistance in gram negative infections has severely restricted therapeutic options, and sometimes no effective drugs are available to treat life-threatening infections [7]. The isolation of NDM 1 strain in India which produces metallo-beta-lactamases capable of degrading carbepenems indicates the extent of this growing problem [8]. Our data show high prevalence of ESBL producing Escherichia coli and Klebsiella species.…”

Section: Discussionmentioning

confidence: 75%

A multi centre laboratory study of Gram negative bacterial blood stream infections in Sri Lanka

Chandrasiri

Elwitigala²,

Nanayakkara³

et al. 2013

Ceylon Med. J.

View full text Add to dashboard Cite

Introduction Data on causative agents and antibiotic susceptibility patterns of blood stream infections in Sri Lanka is scarce. Information on trends of antibiotic resistance is necessary for the prescribers to treat patients effectively and policy makers to develop policies and guidelines.Objectives To lay the foundation for a national data base on antimicrobial resistance in Sri Lanka.Methods A prospective study was carried out in seven hospitals to study the Gram negative aetiological agents and their susceptibility patterns in patients suspected of having bacteraemia. We reviewed 817 patients with clinically significant blood cultures including both adults and children.Results Data were complete for analysis in 733 Gram negative isolates only. Of the 733 isolates, 488 were from adults (> 12 years), 109 were from children (1-12 years) and 136 were from infants (<1 year). Intensive care units represented 18.4% of the isolates (123 adult patients and 27 paediatric patients). The highest number of isolates (33.7%) was from patients with septicaemia of unknown origin. Enteric fever, pyelonephritis and respiratory tract infections accounted for 20% of the isolates. Bacteraemia with underline malignancies were responsible for 24.5% of infections. Salmonella paratyphi A was the commonest cause of enteric fever in adults with 92% resistance to ciprofloxacin. The prevalence of extended spectrum beta lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae was high in this study population.Conclusions It is essential to introduce multidisciplinary interventions to reduce the inappropriate use of antibiotics to increase the lifespan of precious antibiotics. Introduction of a National antibiotic policy with strict implementation and a well-planned stewardship programme is essential to control antimicrobial resistance in our country.

show abstract

Section: Discussionmentioning

confidence: 75%

A multi centre laboratory study of Gram negative bacterial blood stream infections in Sri Lanka

Chandrasiri

Elwitigala²,

Nanayakkara³

et al. 2013

Ceylon Med. J.

View full text Add to dashboard Cite

show abstract

“…In particular, some Gram-negative pathogens have accumulated enough resistance mechanisms to render them virtually untreatable by modern antibacterial chemotherapy (1,2). A mainstay for treatment of Gram-negative infections is the β-lactam classes of drugs.…”

mentioning

confidence: 99%

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Ehmann

Jahić

Ross

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

453

450

View full text Add to dashboard Cite

Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising Gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the offrate for deacylation. The deacylation off-rate was 0.045 min −1 , which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.antibacterial | drug discovery | enzymology T here is an urgent need for new antibacterial agents that are active against drug-resistant bacteria. In particular, some Gram-negative pathogens have accumulated enough resistance mechanisms to render them virtually untreatable by modern antibacterial chemotherapy (1, 2). A mainstay for treatment of Gram-negative infections is the β-lactam classes of drugs. The most common form of resistance to β-lactam antibiotics is the expression of various β-lactamase enzymes capable of hydrolyzing the β-lactam ring of β-lactam drugs, rendering them ineffective. As new β-lactams have been introduced into clinical use, a changing landscape of β-lactamases has been selected and disseminated. Presently, over 1,000 β-lactamases have been documented comprising several structural classes and a wide range of substrate promiscuities and catalytic efficiencies (3, 4).In efforts to restore the efficacy of β-lactam antibiotics, β-lactamases have also been targeted with a variety of inhibitors (5, 6). The three inhibitors approved for clinical use are clavulanic acid, tazobactam, and sulbactam, all of which contain a β-lactam core. A challenge for the development of broad-spectrum β-lactamase inhibitors is the mechanistic diversity in β-lactamase enzymes, with the largest distinction being between the enzyme classes that use a serine residue as the nucleophilic species and the metallo-β-lactamases, which directly activate water for hydrolysis (7). A shared mechanistic feature of the marketed β-lactam-based inhibitors is their reaction with the serine enzymes to form a covalent acylenzyme intermediate. On ring opening, the acyl-enzyme intermediate can undergo additional rearrangements or be released through hydrolysis to regenerate the active β-lactamase enzyme (8). Originally designed to combat class A serine β-lactamase enzymes such as TEM-1, the clinical use of β-lactam-based inhibitors has been diminished by the emergence of enzymes against which they are ineffective. Despite intense investigation by pharmaceutical companies, no new β-lactamas...

show abstract

“…(Kumarasamy et al, 2010;Nordmann et al, 2011;Richter et al, 2011). This gene has been identified in strains that possess other resistance mechanisms contributing to their multidrug resistance patterns, because these bacteria have often been referred to in the news media as "superbugs" because infections caused by them are difficult to treat successfully (Raghvendra et al, 2011).…”

Section: The Resistance Crisis: Increasing Need For New Antimicrobialsmentioning

confidence: 99%

“…Most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections (Health Protection Agency [HPA], 2009a,b). It has been recently extensively reported from the United Kingdom, India and Pakistan and, albeit to a lesser extent, from a number of other countries worldwide (Nordmann et al, 2011). The emergence of multiresistant pathogenic microorganisms, increased use of immunosuppressive therapies, and the association with HIV co-infection, represent a serious public health problem with high mortality and morbidity rates, such as Cryptococcus, Cryptosporidium and Leishmania (Abu-Raddad et al, 2006;Pukkila-Worley & Mylonakis, 2008;Rivas et al, 2009;Vaara, 2009).…”

Section: The Resistance Crisis: Increasing Need For New Antimicrobialsmentioning

confidence: 99%

“…Until then, many efforts have been carried out in order to use the AMPs in the development of new infection-fighting drugs applicable to new treatments of nosocomial infections and multidrug-resistant infections (Amiche et al, 2000), due to the skill of the AMPs to kill multidrug resistant strains of microorganism by a mechanism unlikely to induce antibioticresistance. The development of new antimicrobials based on AMPs hold promises to medicine at the end of the classical antibiotic age by the emergence of the multidrugresistant microorganisms (Alanis, 2005;Arias & Murray, 2009;Nordmann et al, 2011). Even with the expected advantages in the use of AMPs as new antimicrobials for the postantibiotic age, several impediments to therapeutic peptides arise.…”

Section: Peptide Antibiotics: Nanotechnological Approaches Against Sumentioning

confidence: 99%

See 1 more Smart Citation

Anuran Amphibians: A Huge and Threatened Factory of a Variety of Active Peptides with Potential Nanobiotechnological Applications in the Face of Amphibian Decline

Calderon¹,

Stábeli²

2011

Changing Diversity in Changing Environment

View full text Add to dashboard Cite

Does broad-spectrum -lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria?

Cited by 273 publications

References 23 publications

A multi centre laboratory study of Gram negative bacterial blood stream infections in Sri Lanka

A multi centre laboratory study of Gram negative bacterial blood stream infections in Sri Lanka

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Anuran Amphibians: A Huge and Threatened Factory of a Variety of Active Peptides with Potential Nanobiotechnological Applications in the Face of Amphibian Decline

Contact Info

Product

Resources

About