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

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

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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

In vitro activity of imipenem/relebactam against non-Morganellaceae Enterobacterales and Pseudomonas aeruginosa in Latin America: SMART 2018‒2020

Carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa are being isolated from patient specimens with increasing frequency in Latin America and worldwide. The current study provides an initial description of the in vitro activity of imipenem/relebactam (IMR) against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa infecting hospitalized patients in Latin America. From 2018 to 2020, 37 clinical laboratories in nine Latin American countries participated in the SMART global surveillance program and contributed 15,466 NME and 3408 P aeruginosa isolates. MICs for IMR and seven comparators were determined using CLSI broth microdilution and interpreted by CLSI M100 (2022) breakpoints. β-lactamase genes were identified in selected isolate subsets. IMR (96.9% susceptible), amikacin (95.9%), meropenem (90.7%), and imipenem (88.7%) were the most active agents against NME. Among piperacillin/tazobactam-nonsusceptible NME (n = 4124), 90.4% of isolates were IMR-susceptible (range by country, 97.2 [Chile] to 67.0% [Guatemala]) and among meropenem-nonsusceptible NME isolates (n = 1433), 74.0% were IMR-susceptible (94.1% [Puerto Rico] to 5.1% [Guatemala]). Overall, 6.3% of all collected NME isolates carried a KPC (metallo-β-lactamase [MBL]-negative), 1.8% an MBL, 0.4% an OXA-48-like carbapenemase (MBL-negative), and 0.1% a GES carbapenemase (MBL-negative). Amikacin (85.2% susceptible) and IMR (80.1%) were the most active agents against P. aeruginosa; only 56.5% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 22.0% (from 23.9% to 45.9%) in piperacillin/tazobactam-nonsusceptible isolates (n = 1031) and by 35.5% (from 5.5% to 41.0%) in meropenem-nonsusceptible isolates (n = 1128). Overall, 7.6% of all collected P. aeruginosa isolates were MBL-positive and 0.7% carried a GES carbapenemase. In conclusion, in 2018‒2020, almost all NME (97%) and most P. aeruginosa (80%) isolates from Latin America were IMR-susceptible. Continued surveillance of the in vitro activities of IMR and comparator agents against Gram-negative pathogens, and monitoring for β-lactamase changes (in particular for increases in MBLs), is warranted

Activity of ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa from patients in the Middle East and Africa – Study for Monitoring Antimicrobial Resistance Trends (SMART) 2017-2020

Objectives: We evaluated the activity of ceftolozane/tazobactam (C/T), and comparators against clinical Pseudomonas aeruginosa isolates collected for the global Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program in ten countries in the Middle East and Africa to augment scarce standardized surveillance data in this region. Methods: Minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institute broth microdilution and interpreted with European Committee on Antimicrobial Susceptibility Testing breakpoints. P. aeruginosa isolates testing with C/T MIC >4 mg/l or imipenem MIC >2 mg/l were screened for β-lactamase genes. Results: C/T was active against 91.4% and 87.0% of P. aeruginosa isolates from the Middle East and Africa, respectively (14-21 and 7-16 percentage points higher than most β-lactam comparators, respectively). Considerable variation in susceptibility was seen across countries, which largely correlated with the observed prevalence of carbapenemases and/or extended-spectrum β-lactamases. Differences across countries were smaller for C/T than for the β-lactam comparators, ranging from 81% C/T-susceptible among isolates from Jordan to 95% for Qatar. Among subsets resistant to meropenem, ceftazidime, or piperacillin/tazobactam, C/T maintained activity against 51-73% of isolates from the Middle East and against 27-54% from Africa (where metallo-β-lactamase and GES carbapenemase rates were higher). Conclusion: Given the desirability of β-lactam use among clinicians, C/T represents an important option in the treatment of infections caused by P. aeruginosa

Genomic epidemiology of global VIM-producing Enterobacteriacea

BACKGROUND : International data on the molecular epidemiology of Enterobacteriaceae with VIM carbapenemases are limited. METHODS : We performed short read (Illumina) WGS on a global collection of 89 VIM-producing clinical Enterobacteriaceae (2008–14). RESULTS : VIM-producing (11 varieties within 21 different integrons) isolates were mostly obtained from Europe. Certain integrons with blaVIM were specific to a country in different species and clonal complexes (CCs) (In87, In624, In916 and In1323), while others had spread globally among various Enterobacteriaceae species (In110 and In1209). Klebsiella pneumoniae was the most common species (n = 45); CC147 from Greece was the most prevalent clone and contained In590-like integrons with four different blaVIMs. Enterobacter cloacae complex was the second most common species and mainly consisted of Enterobacter hormaechei (Enterobacter xiangfangensis, subsp. steigerwaltii and Hoffmann cluster III). CC200 (from Croatia and Turkey), CC114 (Croatia, Greece, Italy and the USA) and CC78 (from Greece, Italy and Spain) containing blaVIM-1 were the most common clones among the E. cloacae complex. CONCLUSIONS : This study highlights the importance of surveillance programmes using the latest molecular techniques in providing insight into the characteristics and global distribution of Enterobacteriaceae with blaVIMs.The John Mung Program from Kyoto University, Japan (Y. M.), a research grant from the Calgary Laboratory Services (no. 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 Numbers U19AI110819 (M. D. A.) and R01AI090155 (to B. K.).https://academic.oup.com/jac2018-08-30hj2017Medical Microbiolog

TRPM8 modulates temperature regulation in a sex-dependent manner without affecting cold-induced bone loss.

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons and is involved in the detection of environmental cold temperatures. TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are both influenced by rodent housing temperature and brown adipose tissue, but it is unknown if TRPM8 is involved in the co-regulation of thermogenesis and bone homeostasis. To address this, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) after a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Dio2 and Cidea compared to WT. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone microarchitecture and marrow adipose tissue. Identifying mechanisms through which cold temperature and BAT influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis