Global molecular epidemiology of IMP-producing Enterobacteriaceae

International data on the molecular epidemiology of Enterobacteriaceae with IMP carbapenemases are lacking. We performed short read (Illumina) whole genomic sequencing on a global collection of 38 IMP-producing clinical Enterobacteriaceae (2008-14). IMP-producing Enterobacteriaceae (7 varieties within 11 class 1 integrons) were mainly present in South Pacific and Asia. Specific blaIMP containing integrons (In809 with blaIMP-4, In722 with blaIMP-6, In687 with blaIMP-14) were circulating among different bacteria in countries such as Australia, Japan and Thailand. In1312 with blaIMP-1 was present in K. pneumoniae from Japan and C. freundii from Brazil. Klebsiella pneumoniae (n=22) was the most common species; clonal complex (CC) 14 from the Philippines and Japan was the most common clone and contained In1310 with blaIMP-26 and In1321 with blaIMP-6. Enterobacter cloacae complex (n=9) consisted of E. hormaechei and E. cloacae cluster III. CC78 (from Taiwan) containing In73 with blaIMP-8, was the most common clone among E. cloacae complex. This study highlights the importance of surveillance programs using the latest molecular techniques in providing insight into the characteristics and global distribution of Enterobacteriaceae with blaIMPs.This work was supported by the John Mung Program from Kyoto University, Japan (Y.M.), a research grant from the Calgary Laboratory Services (#10015169; J.D.D.P) and federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under Award Number U19AI110819 (MDA).http://aac.asm.org2017-10-30hb2017Medical Microbiolog

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Catheter-Related Bacteremia due to Streptomyces in a Patient Receiving Holistic Infusions

Streptomyces species are rare causes of invasive infection in humans. We report the first documented case of a catheter-associated bacteremia due to Streptomyces. The most likely source of infection was unlicensed, injectable holistic preparations that the patient had received. We review reported cases of invasive infections caused by Streptomyces and comment on the potential infectious complications of parenteral holistic treatments

Enfumafungin Derivative MK-3118 Shows IncreasedIn VitroPotency against Clinical Echinocandin-Resistant Candida Species and Aspergillus Species Isolates

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Caspofungin Susceptibility in Aspergillus and Non-Aspergillus Molds: Inhibition of Glucan Synthase and Reduction of β-d-1,3 Glucan Levels in Culture

Caspofungin inhibits synthesis of β-d-1,3 glucan, essential to cell walls in Candida and Aspergillus spp., but activity against less common molds is largely uncharacterized. We demonstrate that caspofungin inhibits β-d-1,3 glucan synthesis and reduces in vitro growth of clinical isolates from the genera Alternaria, Curvularia, Scedosporium, Acremonium, Bipolaris, and Trichoderma

Antimicrobial stewardship and antibiograms: importance of moving beyond traditional antibiograms

The rapid evolution of resistance, particularly among Gram-negative bacteria, requires appropriate identification of patients at risk followed by administration of appropriate empiric antibiotic therapy. A primary tenet of antimicrobial stewardship programs (ASPs) is the establishment of empiric antibiotic recommendations for commonly encountered infections. An important tool in providing empiric antibiotic therapy recommendations is the use of an antibiogram. While the majority of institutions use a traditional antibiogram, ASPs have an opportunity to enhance antibiogram data. The authors provide the rationale for why ASPs should implement alternative antibiograms, and the importance of incorporating an antibiogram into clinical decision support systems with the goal of providing effective empiric antibiotic therapy

Acquisition of Resistant Bowel Flora during a Double-Blind Randomized Clinical Trial of Ertapenem versus Piperacillin-Tazobactam Therapy for Intraabdominal Infections

Bowel colonization with resistant bacteria can develop in patients receiving broad-spectrum antimicrobial therapy. We compared the impact of two antimicrobial regimens often used to treat intraabdominal infections on susceptibility patterns of bowel flora at the end of therapy. In a double-blind clinical trial, adults with complicated intraabdominal infection requiring surgery were randomized to receive piperacillin-tazobactam (3.375 g every 6 h) or ertapenem (1 g once a day) for 4 to 14 days. Rectal swabs were obtained at baseline and at the end of study therapy to determine the acquisition rates of Enterobacteriaceae resistant to the study drug, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli or Klebsiella species, Pseudomonas aeruginosa resistant to imipenem or piperacillin-tazobactam, and vancomycin-resistant Enterococcus faecalis or Enterococcus faecium. Treated patients were assessable for the acquisition of resistant bacteria if appropriate specimens were obtained at both time points. Enterobacteriaceae resistant to the treatment received were acquired during study therapy by 8/122 assessable piperacillin-tazobactam recipients (6.6%) compared to 0/122 assessable ertapenem recipients (P = 0.007). Neither ESBL-producing E. coli or Klebsiella species nor P. aeruginosa resistant to piperacillin-tazobactam was isolated from patients in either treatment group. Imipenem-resistant P. aeruginosa was acquired by two of the ertapenem recipients (1.6%) versus zero of the piperacillin-tazobactam recipients (P = 0.50). Vancomycin-resistant enterococci were acquired during therapy by 8/125 assessable ertapenem recipients (6.4%) versus 2/123 assessable piperacillin-tazobactam recipients (1.6%; P = 0.10). In this study, the acquisition of resistant Enterobacteriaceae occurred significantly more often in patients treated with piperacillin-tazobactam than in those treated with ertapenem

Genomic Epidemiology of Global Carbapenemase-Producing Enterobacter spp., 2008–2014

We performed whole-genome sequencing on 170 clinical carbapenemase-producing Enterobacter spp. isolates collected globally during 2008–2014. The most common carbapenemase was VIM, followed by New Delhi metallo-β-lactamase (NDM), Klebsiella pneumoniae carbapenemase, oxacillin 48, and IMP. The isolates were of predominantly 2 species (E. xiangfangensis and E. hormaechei subsp. steigerwaltii) and 4 global clones (sequence type [ST] 114, ST93, ST90, and ST78) with different clades within ST114 and ST90. Particular genetic structures surrounding carbapenemase genes were circulating locally in various institutions within the same or between different STs in Greece, Guatemala, Italy, Spain, Serbia, and Vietnam. We found a common NDM genetic structure (NDM-GE-U.S.), previously described on pNDM-U.S. from Klebsiella pneumoniae ATCC BAA-214, in 14 different clones obtained from 6 countries spanning 4 continents. Our study highlights the importance of surveillance programs using whole-genome sequencing in providing insight into the molecular epidemiology of carbapenemase-producing Enterobacter spp