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New strategies and structural considerations in development of therapeutics for carbapenem-resistant Enterobacteriaceae.

ABSTRACT: Antimicrobial resistance poses a significant threat to our ability to treat infections. Especially concerning is the emergence of carbapenem-resistant Enterobacteriaceae (CRE). In the new 2019 United States Centers for Disease Control and Prevention Antibiotic Resistance Report, CRE remain in the most urgent antimicrobial resistance threat category. There is good reason for this concerning designation. In particular, the combination of several resistance elements in CRE can make these pathogens untreatable or effectively untreatable with our current armamentarium of anti-infective agents. This article reviews recently approved agents with activity against CRE and a range of modalities in the pipeline, from early academic investigation to those in clinical trials, with a focus on structural aspects of new antibiotics. Another article in this series addresses the need to incentive pharmaceutical companies to invest in CRE antimicrobial development and to encourage hospitals to make these agents available in their formularies. This article will also consider the need for change in requirements for antimicrobial susceptibility testing implementation in clinical laboratories to address practical roadblocks that impede our efforts to provide even existing CRE antibiotics to our patients.

SUBMITTER: Brennan-Krohn T

PROVIDER: S-EPMC7293954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Carbapenem Resistant Enterobacteriaceae

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Cost Utility of Competing Strategies to Prevent Endoscopic Transmission of Carbapenem-Resistant Enterobacteriaceae.

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| S-EPMC4721926 | biostudies-literature

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Carbapenem-Resistant Enterobacteriaceae Infections in Children.

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Considerations About Antimicrobial Stewardship in Settings with Epidemic Extended-Spectrum β-Lactamase-Producing or Carbapenem-Resistant Enterobacteriaceae.

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The rapid spread of carbapenem-resistant Enterobacteriaceae.

Project description:Carbapenems, our one-time silver bullet for multidrug resistant bacterial infections, are now threatened by widespread dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Successful expansion of Enterobacteriaceae clonal groups and frequent horizontal gene transfer of carbapenemase expressing plasmids are causing increasing carbapenem resistance. Recent advances in genetic and phenotypic detection facilitate global surveillance of CRE diversity and prevalence. In particular, whole genome sequencing enabled efficient tracking, annotation, and study of genetic elements colocalized with carbapenemase genes on chromosomes and on plasmids. Improved characterization helps detail the co-occurrence of other antibiotic resistance genes in CRE isolates and helps identify pan-drug resistance mechanisms. The novel β-lactamase inhibitor, avibactam, combined with ceftazidime or aztreonam, is a promising CRE treatment compared to current colistin or tigecycline regimens. To halt increasing CRE-associated morbidity and mortality, we must continue quality, cooperative monitoring and urgently investigate novel treatments.

| S-EPMC5140036 | biostudies-literature

Evaluation of Resistance Mechanisms in Carbapenem-Resistant Enterobacteriaceae.

Project description:Background:Carbapenem-resistant Enterobacteriaceae (CRE) is a major concern leading to morbidity and mortality in the world. CRE often is becoming a cause of therapeutic failure in both hospital and community-acquired infections. Aim:This study aimed to investigate the resistance mechanisms of CRE by phenotypic and molecular methods. Materials and Methods:Sixty CRE (50 Klebsiella pneumoniae, 6 Escherichia coli, and 4 Enterobacter spp.) were isolated from October 2018 to June 2019. Antimicrobial susceptibility testing was carried out using phenotypic methods. The carbapenem resistance mechanisms including efflux pump hyperexpression, AmpC overproduction, carbapenemase genes, and deficiency in OmpK35 and OmpK36 were determined by phenotypic and molecular methods, respectively. Results:Sixty CRE (50 Klebsiella pneumoniae, 6 Escherichia coli, and 4 Enterobacter spp.) were isolated from October 2018 to June 2019. Amikacin was found to be the most effective drug against CRE isolates. All isolates were resistant to imipenem and meropenem by the micro-broth dilution. AmpC overproduction was observed in all Enterobacter spp. and three K. pneumoniae isolates. No efflux pump activity was found. Carba NP test and Modified Hodge Test could find carbapenemase in 59 (98%) isolates and 57 (95%) isolates, respectively. The most common carbapenemase gene was bla OXA-48-like (72.8%) followed by bla NDM (50.8%), bla IMP (18.6%), bla VIM (11.8%), and bla KPC (6.7%). The ompK35 and ompK36 genes were not detected in 10 and 7 K. pneumoniae isolates, respectively. Conclusion:The amikacin is considered as a very efficient antibiotic for the treatment of CRE isolates in our region. Carbapenemase production and overproduction of AmpC are the main carbapenem resistance mechanisms in CRE isolates. Finally, Carba NP ?test is a rapid and reliable test for early detection of carbapenemase-producing isolates.

| S-EPMC7229782 | biostudies-literature

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