Success and Challenges Associated with Large Scale Collaborative Surveillance for Carbapenemase Genes in Gram Negative Bacteria

2021 ◽  
Author(s):  
Sanchita Das ◽  
Karen Bush
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Large Scale ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Routine Laboratory ◽  
Significant Morbidity ◽  
Gram Negative ◽  
Surveillance Studies ◽  
The One

The emergence and spread of antimicrobial resistance, especially in Gram negative bacteria has led to significant morbidity and increased cost of healthcare. Large surveillance studies such as the one performed by the Antibiotic Resistance Laboratory Network are immensely valuable in understanding the scope of resistance mechanisms especially among carbapenemase producing Gram negative bacteria. However, the routine laboratory detection of carbapenemases in these bacteria remain challenging and require further optimization.

scholarly journals Investigation of gating in outer membrane porins provides new perspectives on antibiotic resistance mechanisms

2021 ◽  
Author(s):  
Archit Kumar Vasan ◽  
Nandan Haloi ◽  
Rebecca Joy Ulrich ◽  
Mary Elizabeth Metcalf ◽  
Po-Chao Wen ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Outer Membrane ◽  
Large Scale ◽  
Dynamic Equilibrium ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Gram Negative Bacteria ◽  
Bacterial Strains ◽  
Gram Negative ◽  
Scale Motion

AbstractGram-negative bacteria pose a serious public health concern, primarily due to a higher frequency of antibiotic resistance conferred to them as a result of low permeability of their outer membrane (OM). Antibiotics capable of traversing the OM typically permeate through OM porins; thus, understanding the permeation properties of these porins is instrumental to the development of new antibiotics. A common macroscopic feature of many OM porins is their ability to transition between functionally distinct open and closed states that regulate transport properties and rate. To obtain a molecular basis for these processes, we performed tens of microseconds of molecular dynamics simulations of E. coli OM porin, OmpF. We observed that large-scale motion of the internal loop, L3, leads to widening and narrowing of the pore, suggesting its potential role in gating. Furthermore, Markov state analysis revealed multiple energetically stable conformations of L3 corresponding to open and closed states of the porin. Dynamics between these functional states occurs on the time scale of tens of microseconds and are mediated by the movement of highly conserved acidic residues of L3 to form H-bonds with opposing sides of the barrel wall of the pore. To validate our mechanism, we mutated key residues involved in the gating process that alter the H-bond pattern in the open/closed states and performed additional simulations. These mutations shifted the dynamic equilibrium of the pore towards open or closed states. Complementarily, the mutations favoring the open/closed states lead to increased/decreased accumulation of multiple antibiotics in our whole-cell accumulation assays. Notably, porins containing one of the mutations favoring the closed state has previously been found in antibiotic resistant bacterial strains. Overall, our 180 µs of simulation data (wild type and mutants) with concerted experiments suggests that regulation of the dynamic equilibrium between open and closed states of OM porins could be a mechanism by which Gram-negative bacteria acquire antibiotic resistance.

scholarly journals Screening for multi-drug-resistant Gram-negative bacteria: what is effective and justifiable?

2020 ◽  
Vol 38 (S1) ◽  
pp. 72-90 ◽  
Author(s):  
Niels Nijsingh ◽  
Christian Munthe ◽  
Anna Lindblom ◽  
Christina Åhrén
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Large Scale ◽  
Population Level ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Screening Programs ◽  
Scale Population ◽  
Current Screening

AbstractEffectiveness is a key criterion in assessing the justification of antibiotic resistance interventions. Depending on an intervention’s effectiveness, burdens and costs will be more or less justified, which is especially important for large scale population-level interventions with high running costs and pronounced risks to individuals in terms of wellbeing, integrity and autonomy. In this paper, we assess the case of routine hospital screening for multi-drug-resistant Gram-negative bacteria (MDRGN) from this perspective. Utilizing a comparison to screening programs for Methicillin-Resistant Staphylococcus aureus (MRSA) we argue that current screening programmes for MDRGN in low endemic settings should be reconsidered, as its effectiveness is in doubt, while general downsides to screening programs remain. To accomplish justifiable antibiotic stewardship, MDRGN screening should not be viewed as a separate measure, but rather as part of a comprehensive approach. The program should be redesigned to focus on those at risk of developing symptomatic infections with MDRGN rather than merely detecting those colonised.

Intrinsic, adaptive and acquired antimicrobial resistance in Gram-negative bacteria

2017 ◽  
Vol 61 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Mohsen Arzanlou ◽  
Wern Chern Chai ◽  
Henrietta Venter
Keyword(s):  
Antimicrobial Resistance ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Stress Conditions ◽  
Gram Negative Bacteria ◽  
Mechanisms Of Resistance ◽  
Intrinsic Resistance ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Gram Negative Organisms

Gram-negative bacteria are responsible for a large proportion of antimicrobial-resistant infections in humans and animals. Among this class of bacteria are also some of the most successful environmental organisms. Part of this success is their adaptability to a variety of different niches, their intrinsic resistance to antimicrobial drugs and their ability to rapidly acquire resistance mechanisms. These mechanisms of resistance are not exclusive and the interplay of several mechanisms causes high levels of resistance. In this review, we explore the molecular mechanisms underlying resistance in Gram-negative organisms and how these different mechanisms enable them to survive many different stress conditions.

scholarly journals Making Sense of Antimicrobial Resistance Surveillance: A successful intervention

2018 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Antibiotic Resistance ◽  
Intensive Care ◽  
Antimicrobial Resistance ◽  
Clinical Laboratory ◽  
Gram Negative Bacteria ◽  
Third Generation ◽  
Resistance Development ◽  
Antibiotic Policy ◽  
Gram Negative ◽  
High Level

Background: The intensive care units are epicenters for the emergence of antibiotic resistant Gram-negative bacteria because of the high use of antibiotics, prolonged hospital stay, reduced patient immunity, use of medical devices, and the frequent contact between healthcare workers and patients. Surveillance of bacterial resistance is the key element to understand the size of the problem, drive interventions, and measures the effect of these measures. Several reports have linked the use of third generation cephalosporins with β-lactam resistance in gram-negative bacteria. Several strategies were introduced by the Antibiotic Stewardship Programs to reduce antibiotic resistance but the efficacies of these interventions are not well studied. Methods: The Microbiology Laboratory of Hamad Medical Corporation (HMC) monitors antimicrobial resistance by continuous surveillance using the National Committee for Clinical Laboratory Standards (NCCLS) - currently Clinical Laboratory Standards Institute interpretive criteria. Surveillance data were released annually and shared with clinicians and policy makers for review of the antibiotic policy and the antibiotic formulary. Results: Surveillance data in 2001 showed high level β-lactam antibiotics resistance and high level production of extended spectrum β-lactamases (ESBL) among gram-negative bacteria. As a result, the Hospital Antibiotic Policy Committee decided to withdraw ceftazidime a third –generation cephalosporin known to be a strong inducer of ESBL, from the hospital formulary. Subsequent resistance surveillance over the following three years in the Medical Intensive Care unit (MICU) demonstrated a gradual drop in the resistance of Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; the commonest isolated gram negative bacteria from MICU), not only to third and fourth generation cephalosporins, but also to Piperacillin – Tazobactam in spite of the increased use of the later drug in the MICU. Discussion and conclusion: Antibiotic resistance is an increasing global problem. Surveillance studies are needed to monitor resistance development, to guide local empirical therapy, and to implement timely and adequate countermeasures. Since resistance development is an evolutionary process, constant surveillance is necessary to gain insight into the problem in a timely fashion. Several measures were taken including antibiotic cycling, antibiotic rotation and restriction. Restriction of the use of Ceftazidime resulted in a significant drop in the resistance of the common Gram-negative bacteria to the betalactam antibiotics. The sustainability and efficacy of these measures need to be monitored over time.

scholarly journals Predictive comparative antibiotic resistance (AMR) profiles of rhizobacteria genes using CARD: a bioinformatics approach

2020 ◽  
Author(s):  
Adeoti Olatunde Micheal ◽  
Oni Abosede Catherine ◽  
Adeoye Kafilat Adenike ◽  
Adeoti Oluwole Adeola ◽  
Adeoye Basirat Adedamola ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Large Scale ◽  
Paenibacillus Polymyxa ◽  
Plant Growth Promoting Rhizobacteria ◽  
Gene Families ◽  
Resistance Mechanisms ◽  
Antibiotics Resistance ◽  
Bioinformatics Tool ◽  
Pathogenic Genes

Members of the Plant Growth Promoting Rhizobacteria (PGPR) have been severally implicated as excellent growth enhancers, yield promoters as well as bio-fertilizers. A study on antibiotics surveillance of PGPR is urgently needed as caution towards its continued usage in Bio-science and Agro-allied. Antimicrobial resistance has become a great concern in agriculture and public health. The detection and characterization of antimicrobial resistance move from targeted culture and enzyme-based reaction to high-throughput metagenomics; acceptable resources for the analysis of large-scale information area unit as an expected rescue. The excellent bioinformatics tool newly curated for Antibiotic Resistance information (CARD; https://card.mcmaster.ca) could be a curated hub and resource-providing-referenced server for deoxyribonucleic acid and protein sequences as well as detection models on the molecular radar for antimicrobial resistance. This study employed CARD as pathogenomics repertoires for high-quality reference information on retrieving antibiotics resistance information on twenty-two carefully-selected members of Rhizobacter from NCBI. NCBI and CARD on-line platform were employed in polishing of antiobitics resistance info of selected PGPR genera such as Leguminosarum, Azotobacter, Azospirillum, Erwinia, Mesorhizobium, Flavobacterium Paenibacillus Polymyxa, Bacilli mycoides, B. subtilis, and Burkholderia pseudomallei among others. The data generated showed evidence that these rhizobacteria could be resistant to certain drug classes under a different Antimicrobial Resistance (AMR) Gene families using different phyto-pathogenic genes (ARO terms) using different resistance mechanisms. This distinctive platform provides bioinformatics tool that bridges antibiotic resistance considerations, which could be a fallback for policies in healthcare, agriculture and the environment.

scholarly journals Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-negative (ESKAPEE) Bacteria

2019 ◽  
Author(s):  
Akif Reza ◽  
J. Mark Sutton ◽  
Khondaker Miraz Rahman
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Protein Structures ◽  
Underlying Mechanism ◽  
Resistance Mechanisms ◽  
Healthcare Provision ◽  
Gram Negative ◽  
Environmental Threats ◽  
Efflux Pump Inhibitors

Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens, in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

scholarly journals Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 229 ◽  
Author(s):  
Akif Reza ◽  
J. Mark Sutton ◽  
Khondaker Miraz Rahman
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Protein Structures ◽  
Underlying Mechanism ◽  
Resistance Mechanisms ◽  
Healthcare Provision ◽  
Gram Negative ◽  
Environmental Threats ◽  
Efflux Pump Inhibitors

Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens (Enterococcus faecium., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli), in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

scholarly journals Fluoroquinolone Metalloantibiotics to Bypass Antimicrobial Resistance Mechanisms: Decreased Permeation through Porins

Membranes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 3
Author(s):  
Mariana Ferreira ◽  
Carla F. Sousa ◽  
Paula Gameiro
Keyword(s):  
Antimicrobial Resistance ◽  
Membrane Permeability ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Specific Association ◽  
Location Association

Fluoroquinolones (FQs) are broad-spectrum antibiotics largely used in the clinical practice against Gram-negative and some Gram-positive bacteria. Nevertheless, bacteria have developed several antimicrobial resistance mechanisms against such class of antibiotics. Ternary complexes of FQs, copper(II) and phenanthroline, known as metalloantibiotics, arise in an attempt to counteract an antibiotic resistance mechanism related to low membrane permeability. These metalloantibiotics seem to use an alternative influx route, independent of porins. The translocation pathways of five FQs and its metalloantibiotics were studied through biophysical experiments, allowing us to infer about the role of OmpF porin in the influx. The FQ-OmpF interaction was assessed in mimetic membrane systems differing on the lipidic composition, disclosing no interference of the lipidic composition. The drug-porin interaction revealed similar values for the association constants of FQs and metalloantibiotics with native OmpF. Therefore, OmpF mutants and specific quenchers were used to study the location-association relationship, comparing a free FQ and its metalloantibiotic. The free FQ revealed a specific association, with preference for residues on the centre of OmpF, while the metalloantibiotic showed a random interaction. Thereby, metalloantibiotics may be an alternative to pure FQs, being able to overcome some antimicrobial resistance mechanism of Gram-negative bacteria related to decreased membrane permeability.

scholarly journals Proanthocyanidin Interferes with Intrinsic Antibiotic Resistance Mechanisms of Gram‐Negative Bacteria

2019 ◽  
Vol 6 (15) ◽  
pp. 1802333 ◽  
Author(s):  
Vimal B. Maisuria ◽  
Mira Okshevsky ◽  
Eric Déziel ◽  
Nathalie Tufenkji
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Gram Negative

scholarly journals Epidemiology and Mechanisms of Resistance of Extensively Drug Resistant Gram-Negative Bacteria

Antibiotics ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 37 ◽  
Author(s):  
Emily M. Eichenberger ◽  
Joshua T. Thaden
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Mechanisms ◽  
Individual Treatment ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Mechanisms Of Resistance ◽  
Gram Negative ◽  
Treatment Practices ◽  
Extensively Drug Resistant ◽  
Global Epidemiology

Antibiotic resistance has increased markedly in gram-negative bacteria over the last two decades, and in many cases has been associated with increased mortality and healthcare costs. The adoption of genotyping and next generation whole genome sequencing of large sets of clinical bacterial isolates has greatly expanded our understanding of how antibiotic resistance develops and transmits among bacteria and between patients. Diverse mechanisms of resistance, including antibiotic degradation, antibiotic target modification, and modulation of permeability through the bacterial membrane have been demonstrated. These fundamental insights into the mechanisms of gram-negative antibiotic resistance have influenced the development of novel antibiotics and treatment practices in highly resistant infections. Here, we review the mechanisms and global epidemiology of antibiotic resistance in some of the most clinically important resistance phenotypes, including carbapenem resistant Enterobacteriaceae, extensively drug resistant (XDR) Pseudomonas aeruginosa, and XDR Acinetobacter baumannii. Understanding the resistance mechanisms and epidemiology of these pathogens is critical for the development of novel antibacterials and for individual treatment decisions, which often involve alternatives to β-lactam antibiotics.

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