Carbapenem Resistance in Gram-Negative Bacilli: Mechanisms and Challenges

2020 ◽  
pp. 33-52
Author(s):  
Sarita Mohapatra ◽  
Arti Kapil
Keyword(s):  
Carbapenem Resistance ◽  
Gram Negative

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

scholarly journals Utilization of Vector Autoregressive and Linear Transfer Models to Follow Up the Antibiotic Resistance Spiral in Gram-negative Bacteria From Cephalosporin Consumption to Colistin Resistance

2018 ◽  
Vol 69 (8) ◽  
pp. 1410-1421 ◽  
Author(s):  
Hajnalka Tóth ◽  
Adina Fésűs ◽  
Orsolya Kungler-Gorácz ◽  
Bence Balázs ◽  
László Majoros ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Carbapenem Resistance ◽  
Gram Negative Bacteria ◽  
Vicious Cycle ◽  
Var Models ◽  
Gram Negative ◽  
Vector Autoregressive ◽  
E Coli ◽  
Cephalosporin Resistance ◽  
Klebsiella Spp

Abstract Background Increasing antibiotic resistance may reciprocally affect consumption and lead to use of broader-spectrum alternatives; a vicious cycle that may gradually limit therapeutic options. Our aim in this study was to demonstrate this vicious cycle in gram-negative bacteria and show the utility of vector autoregressive (VAR) models for time-series analysis in explanatory and dependent roles simultaneously. Methods Monthly drug consumption data in defined daily doses per 100 bed-days and incidence densities of gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter baumannii) resistant to cephalosporins or to carbapenems were analyzed using VAR models. These were compared to linear transfer models used earlier. Results In case of all gram-negative bacteria, cephalosporin consumption led to increasing cephalosporin resistance, which provoked carbapenem use and consequent carbapenem resistance and finally increased colistin consumption, exemplifying the vicious cycle. Different species were involved in different ways. For example, cephalosporin-resistant Klebsiella spp. provoked carbapenem use less than E. coli, and the association between carbapenem resistance of P. aeruginosa and colistin use was weaker than that of A. baumannii. Colistin use led to decreased carbapenem use and decreased carbapenem resistance of P. aeruginosa but not of A. baumannii. Conclusions VAR models allow analysis of consumption and resistance series in a bidirectional manner. The reconstructed resistance spiral involved cephalosporin use augmenting cephalosporin resistance primarily in E. coli. This led to increased carbapenem use, provoking spread of carbapenem-resistant A. baumannii and consequent colistin use. Emergence of panresistance is fueled by such antibiotic-resistance spirals.

scholarly journals Prevalence of Carbapenem Resistance among Gram-Negative Bacteria in a Tertiary Care Hospital in North-East India

2014 ◽  
Vol 13 (12) ◽  
pp. 56-60 ◽  
Author(s):  
Dr. Ph. Henkhoneng Mate ◽  
◽  
Dr. Kh Sulochana Devi ◽  
Dr. Ksh Mamta Devi ◽  
Dr. San Damrolien ◽  
...  
Keyword(s):  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Carbapenem Resistance ◽  
Gram Negative Bacteria ◽  
Care Hospital ◽  
Gram Negative ◽  
North East India ◽  
North East

scholarly journals An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

2020 ◽  
Vol 9 (9) ◽  
pp. 1454
Author(s):  
Hari P. Nepal ◽  
Rama Paudel
Keyword(s):  
Bacterial Infections ◽  
Carbapenem Resistance ◽  
Therapeutic Options ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
Carbapenem Resistant ◽  
The World

Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.

scholarly journals Rapid Detection of Imipenem Resistance in Gram-Negative Bacteria Using Tabletop Scanning Electron Microscopy: A Preliminary Evaluation

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriel Haddad ◽  
Anthony Fontanini ◽  
Sara Bellali ◽  
Tatsuki Takakura ◽  
Yusuke Ominami ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Morphological Changes ◽  
Carbapenem Resistance ◽  
Preliminary Evaluation ◽  
Gram Negative Bacteria ◽  
Blind Test ◽  
Gram Negative ◽  
Length Width ◽  
Imipenem Resistance ◽  
Scanning Electron

Background: Enabling faster Antimicrobial Susceptibility Testing (AST) is critical, especially to detect antibiotic resistance, to provide rapid and appropriate therapy and to improve clinical outcomes. Although several standard and automated culture-based methods are available and widely used, these techniques take between 18 and 24 h to provide robust results. Faster techniques are needed to reduce the delay between test and results.Methods: Here we present a high throughput AST method using a new generation of tabletop scanning electron microscope, to evaluate bacterial ultra-structural modifications associated with susceptibilities to imipenem as a proof of concept. A total of 71 reference and clinical strains of Gram-negative bacteria were used to evaluate susceptibility toward imipenem after 30, 60, and 90 min of incubation. The length, width and electron density of bacteria were measured and compared between imipenem susceptible and resistant strains.Results: We correlated the presence of these morphological changes to the bacterial susceptibility and their absence to the bacterial resistance (e.g., Pseudomonas aeruginosa length without [2.24 ± 0.61 μm] and with [2.50 ± 0.68 μm] imipenem after 30 min [p = 3.032E-15]; Escherichia coli width without [0.92 ± 0.07 μm] and with [1.28 ± 0.19 μm] imipenem after 60 min [p = 1.242E-103]). We validated our method by a blind test on a series of 58 clinical isolates where all strains were correctly classified as susceptible or resistant toward imipenem.Conclusion: This method could be a potential tool for rapidly identifying carbapenem-resistance in Enterobacterales in clinical microbiology laboratories in <2 h, allowing the empirical treatment of patients to be rapidly adjusted.

scholarly journals Genome-Wide Identification of Carbapenem-Resistant Gram- Negative Bacterial (CR-GNB) Isolates Retrieved From Hospitalized Patients in Bihar, India

2021 ◽  
Author(s):  
Namrata Kumari ◽  
Mukesh Kumar ◽  
Amit Katiyar ◽  
Abhay Kumar ◽  
Pallavi Priya ◽  
...  
Keyword(s):  
Resistance Genes ◽  
Carbapenem Resistance ◽  
Cross Sectional Study ◽  
Clinical Isolates ◽  
Cross Sectional ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Genome Wide ◽  
Synergy Test ◽  
Global Threat

Abstract Carbapenemase-producing clinical isolates are becoming more common over the world, posing a severe public health danger, particularly in developing nations like India. Carbapenem-resistant Gram-negative bacterial (CR-GNB) infection has become a fast-expending global threat with limited antibiotic choice and significant mortality. The aim of this study was to highlight the carbapenem-resistance among clinical isolates of hospital admitted patients in Bihar, India. A cross-sectional study was conducted with 101 clinical isolates of E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa. All GNB isolates were tested for their antimicrobial susceptibility using double disc synergy test / modified hodge test (DDST/MHT) and subsequently confirmed carbapenemase-producing isolates were evaluated for carbapenem-resistance genes using whole-genome sequencing (genotypically) method. The overall percentage of carbapenem-resistance among GNB was (17/101) 16.83%. The AMR analysis demonstrates a significantly high prevalence of blaCTX−M followed by blaSHV, blaTEM, blaOXA and blaNDM β-lactams carbapenem-resistance genes among clinical isolates of GNB. Co-occurrence of carbapenemase-encoding genes with blaNDM was found in 70.6% of carbapenemase-producing isolates. Our study highlights the mechanism of carbapenem-resistance to curb the overwhelming threat posed by emergence of drug-resistance in India.

scholarly journals Using Molecular Diagnostics to Develop Therapeutic Strategies for Carbapenem-Resistant Gram-Negative Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Fred C. Tenover
Keyword(s):  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Therapeutic Strategies ◽  
Beta Lactam ◽  
Gram Negative ◽  
Molecular Tests ◽  
Negative Results ◽  
Carbapenem Resistant ◽  
Class B ◽  
Global Threat

Infections caused by multidrug-resistant Gram-negative organisms have become a global threat. Such infections can be very difficult to treat, especially when they are caused by carbapenemase-producing organisms (CPO). Since infections caused by CPO tend to have worse outcomes than non-CPO infections, it is important to identify the type of carbapenemase present in the isolate or at least the Ambler Class (i.e., A, B, or D), to optimize therapy. Many of the newer beta-lactam/beta-lactamase inhibitor combinations are not active against organisms carrying Class B metallo-enzymes, so differentiating organisms with Class A or D carbapenemases from those with Class B enzymes rapidly is critical. Using molecular tests to detect and differentiate carbapenem-resistance genes (CRG) in bacterial isolates provides fast and actionable results, but utilization of these tests globally appears to be low. Detecting CRG directly in positive blood culture bottles or in syndromic panels coupled with bacterial identification are helpful when results are positive, however, even negative results can provide guidance for anti-infective therapy for key organism-drug combinations when linked to local epidemiology. This perspective will focus on the reluctance of laboratories to use molecular tests as aids to developing therapeutic strategies for infections caused by carbapenem-resistant organisms and how to overcome that reluctance.

Occurrence of Non-Fermenting Gram-Negative Bacilli and Their In Vitro Susceptibility Pattern by Vitek 2 at a Tertiary Care Teaching Hospital – An Observational Study

2021 ◽  
Vol 8 (8) ◽  
pp. 429-434
Author(s):  
Atit Dineshchandra Shah ◽  
Urvashi Natubhai Limbachia ◽  
Bhavin K. Prajapati ◽  
Lata Patel ◽  
Dharati Tusharbhai Shah ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Antimicrobial Susceptibility ◽  
Susceptibility Testing ◽  
Tertiary Care ◽  
Carbapenem Resistance ◽  
Antimicrobial Susceptibility Testing ◽  
Clinical Samples ◽  
Gram Negative ◽  
Vitek 2

BACKGROUND Non fermenting gram-negative bacilli (NFGNB) are a group of heterogenous, aerobic and non-sporing saprophytic bacteria, found as commensals in humans and other animals primarily causing opportunistic healthcare-associated infections. They are innately resistant to many antibiotics and are known to acquire resistance by various mechanisms. They pose a particular difficulty for the healthcare community because multidrug resistance is common and increasing among them and a number of strains have now been identified that exhibit pan drug resistance. This study was conducted to isolate and identify various non-fermenter gram negative bacilli (NFGNB), to study their antibiotic sensitivity pattern and their clinical significance from various clinical samples. METHODS A study was undertaken from March 2019 to February 2020 to isolate NFGNB from various clinical samples received for culture and sensitivity in the department of microbiology in a tertiary care hospital, Ahmedabad. Non lactose fermenting colonies on MacConkey agar plates were further processed by Vitek 2 to identify them and to study their antimicrobial susceptibility testing (AST). RESULTS A total of 2010 NFGNB were isolated from various clinical samples and their AST was evaluated by Vitek 2. Pseudomonas aeruginosa (52.7 %) and Acinetobacter baumannii (36.5 %) were the most common NFGNB isolated. Carbapenem resistance was 93 % for Acinetobacter species and 61 % for Pseudomonas species. CONCLUSIONS Accurate and rapid identification and antimicrobial susceptibility testing of NFGNB help in early initiation of appropriate antimicrobial therapy and proper management of patients thereby help in reducing emergence of MDR strains of NFGNB, mortality and overall hospital stay. KEYWORDS NFGNB – Non-Fermenting Gram-Negative Bacilli, Multidrug Resistance, Pan Drug Resistance, Carbapenem Resistance

Determination of carbapenemase genes in clinical isolates using Cepheid Xpert Carba-R

2021 ◽  
pp. 16-19
Author(s):  
N. I. Gabrielyan ◽  
V. G. Kormilitsyna ◽  
V. K. Zaletaeva ◽  
A. V. Krotevich ◽  
I. A. Miloserdov ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Infection Control ◽  
Resistance Genes ◽  
Carbapenem Resistance ◽  
Critical Issue ◽  
Sensitivity Study ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant

Detection of carbapenem resistance genes is a critical issue for hospitals due to possible recommendations for infection control and targeted therapy. The Cepheid Xpert instrument, a Carba-R test for the detection and differentiation of five common carbapenemase genes, was tested from September 2020 to February 2021. As part of the approbation, 20 tests were provided. This review presents the results of the approbation of a relatively regular sensitivity study on Siemens WalkAway‑96 plus. Cepheid Xpert Carba-R analysis has been shown to be an accurate and fast tool for detecting colonization by carbapenem-resistant gram-negative bacteria, which can help limit the spread of these organisms in hospitals.

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