ESBL-producing Enterobacteriaceae has become a major multidrug-resistant pathogen in the last two decades, especially in the community settings. The multifactorial nature of its expansion poses a major challenge in the efforts to control them.
Synopsis Carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a major threat to modern medicine. Commonly used antibiotics are generally inactive against CRE. Therefore, timely detection of CRE in the clinical laboratory is of paramount importance. Among CRE, those producing carbapenem-hydrolyzing β-lactamase enzymes (carbapenemase-producing Enterobacteriaceae; CPE) are particularly of concern since they tend to spread among patients, and treatment of active infection is difficult. The carbapenemase groups most commonly encountered include KPC, NDM and OXA-48, with KPC overrepresented in the United States. Various phenotypic and genetic tests have been proposed and validated for rapid detection of CPE. Phenotypic tests detect carbapenemase activity either by inhibiting their activity with specific inhibitors of carbapenemases, or by detecting hydrolysis of carbapenems by carbapenemases. Genetic tests mostly depend on nucleic acid detection and amplification. Treatment options for CRE infections are limited and typically include combinations of polymyxins, tigecycline, aminoglycosides, or carbapenems, but newer agents with activity against CRE and better safety profiles are starting to become available and will likely emerge as the preferred therapy for the treatment of CRE infections in the near future.
BackgroundLimited treatment options are available for patients infected with multidrug (MDR)- or pan-drug (PDR)-resistant bacterial pathogens, resulting in infections that can persist for weeks or months. In order to better understand transmission and evolutionary dynamics of MDR Acinetobacter baumannii (Ab) during long-term infection, we analyzed genomes from a series of isolates from individual patients at isolate-specific, patient-specific, and population levels.MethodsWhole genome analysis of longitudinal isolates (range 2-10 isolates per patient spanning 0-829 days) from 40 patients included detection of single-nucleotide variants (SNVs), insertion sequence (IS) mapping, and gene content changes.ResultsPhylogenetic analysis revealed that a significant fraction of apparently persistent infections are in fact due to re-infection with new strains. SNVs primarily resulted in protein coding changes, and IS events primarily interrupted genes or were in an orientation such that the adjacent gene would be over-expressed. Mutations acquired during infection were over-represented in transcriptional regulators, notably pmrAB and adeRS, which can mediate resistance to the last line therapies colistin and tigecycline, respectively, as well as transporters, surface structures, and iron acquisition genes.ConclusionsMost SNVs and IS events were isolate-specific indicating these mutations did not become fixed on the time scale investigated, yet over-representation of independent mutations in some genes or functional categories suggests that they are under selective pressure. Genome analysis at the population-level suggests that gene transfer including recombination also contributes to Ab evolutionary dynamics. These findings provide important insight into the transmission dynamics of Ab and the identification of patients with repeat infections has implications for infection control programs targeted to this pathogen.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0279-y) contains supplementary material, which is available to authorized users.
Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of 'serious' by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients. Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants. Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient's PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.
We report 2 independent patients from whom carbapenem and ceftazidime-avibactam–resistant Enterobacter cloacae complex strains were identified. The ceftazidime-avibactam resistance was attributed to a 2–amino acid deletion in the R2 loop of AmpC β-lactamase, which concurrently caused resistance to cefepime and reduced susceptibility to cefiderocol, a novel siderophore cephalosporin.
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