The role of the plasmid-mediated fluoroquinolone resistance genes as resistance mechanisms in pediatric infections due to Enterobacterales.

Introduction: Fluoroquinolones (FQs) are not commonly prescribed in children, yet the increasing incidence of multidrug-resistant (MDR) Enterobacterales (Ent) infections in this population often reveals FQ resistance. We sought to define the role of FQ resistance in the epidemiology of MDR Ent in children, with an overall goal to devise treatment and prevention strategies.

Methods: A case-control study of children (0-18 years) at three Chicago hospitals was performed.

Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits -Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum.

Class C -derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen . Many ADC variants have emerged, and characterization of their structural and functional differences is essential. Equally as important is the development of compounds that inhibit all prevalent ADCs despite these differences.

Sulfonamidoboronic Acids as "Cross-Class" Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in .

is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to -lactams. One of the most important mechanisms is the production of -lactamase enzymes capable of hydrolyzing -lactam antibiotics.

Multidrug-Resistant Gram-Negative Bacteria in Burn Patients.

Patients with burn injuries are at high risk for infectious complications, and infections are the most common cause of death after the first 72 h of hospitalization. Hospital-acquired infections caused by multidrug resistant (MDR) Gram-negative bacteria (GNB) in this population are concerning. Here, we evaluated carriage with MDR GNB in patients in a large tertiary-care burn intensive care unit.

Risk Factors for and Mechanisms of listin esistance Among nterobacterales: Getting at the CORE of the Issue.

Background: Despite the recent emergence of plasmid-mediated colistin resistance, the epidemiology and mechanisms of colistin-resistant Enterobacterales (CORE) infections remain poorly understood.

Methods: A case-case-control study was conducted utilizing routine clinical isolates obtained at a single tertiary health system in Ann Arbor, Michigan. Patients with CORE isolates from January 1, 2016, to March 31, 2017, were matched 1:1 with patients with colistin-susceptible Enterobacterales (COSE) and uninfected controls.

A Multicentered Study of the Clinical and Molecular Epidemiology of TEM- and SHV-type Extended-Spectrum Beta-Lactamase Producing Enterobacterales Infections in Children.

Background: Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales-(Ent) infections are increasing in pediatrics. Before CTX-M ESBL emerged, the most common infection-associated ESBL genes were TEM and SHV-type ESBLs. We sought to define the current epidemiology of Ent infections in children due to blaTEM and blaSHV (TEM-SHV-Ent).

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, , are reported along with the finding that is resistant to hydrolysis by all four classes of β-lactamases.

Cryo-electron Microscopy Structure of the Acinetobacter baumannii 70S Ribosome and Implications for New Antibiotic Development.

Antimicrobial resistance is a major health threat as it limits treatment options for infection. At the forefront of this serious issue is , a Gram-negative opportunistic pathogen that exhibits the remarkable ability to resist antibiotics through multiple mechanisms. As bacterial ribosomes represent a target for multiple distinct classes of existing antimicrobial agents, we here use single-particle cryo-electron microscopy (cryo-EM) to elucidate five different structural states of the ribosome, including the 70S, 50S, and 30S forms.

Identification of four patients with colistin-resistant Escherichia coli containing the mobile colistin resistance mcr-1 gene from a single health system in Michigan.

Clinical Enterobacteriacae isolates with a colistin minimum inhibitory concentration (MIC) ≥4 mg/L from a United States hospital were screened for the mcr-1 gene using real-time polymerase chain reaction (RT-PCR) and confirmed by whole-genome sequencing. Four colistin-resistant Escherichia coli isolates contained mcr-1. Two isolates belonged to the same sequence type (ST-632).

The Clinical and Molecular Epidemiology of CTX-M-9 Group Producing Enterobacteriaceae Infections in Children.

Introduction: The pandemic of extended-spectrum beta-lactamase-(ESBL)-producing Enterobacteriaceae (Ent) is strongly linked to the dissemination of CTX-M-type-ESBL-Ent. We sought to define the epidemiology of infections in children due to an emerging resistance type, CTX-M-9-group-producing-Ent (CTX-M-9-grp-Ent).

Methods: A retrospective matched case-control analysis of children with CTX-M-9-grp-Ent infections who received medical care at three Chicago area hospitals was performed.

The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant .

In the Consortium on Resistance Against Carbapenems in and other (CRACKLE), trimethoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMP-SMX. Development of resistance further limits the use of TMP-SMX in CRE infections.

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and with Defined Extended-Spectrum β-Lactamases and Carbapenemases.

The activity of the siderophore cephalosporin cefiderocol is targeted against carbapenem-resistant Gram-negative bacteria. In this study, the activity of cefiderocol against characterized carbapenem-resistant complex, , , and strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MICs against , , and were 1, 0.

Community Origins and Regional Differences Highlight Risk of Plasmid-mediated Fluoroquinolone Resistant Enterobacteriaceae Infections in Children.

Background: Fluoroquinolones are uncommonly prescribed in children, yet pediatric multidrug resistant (MDR) enterobacteriaceae (Ent) infections often reveal fluoroquinolone resistance (FQR). We sought to define the molecular epidemiology of FQR and MDR-Ent in children.

Methods: A case-control analysis of children with MDR-Ent infections at 3 Chicago hospitals was performed.

: Defining the Role of Efflux Pumps in Resistance to Antimicrobial Therapy, Surface Motility, and Biofilm Formation.

is a member of the (ACB) complex. Increasingly, reports are emerging of the pathogenic profile and multidrug resistance (MDR) phenotype of this species. To define novel therapies to overcome resistance, we queried the role of the major efflux pumps in strain M2 on antimicrobial susceptibility profiles.

Emergence of Resistance to Colistin During the Treatment of Bloodstream Infection Caused by Carbapenemase-Producing .

We report the emergence of colistin resistance in carbapenemase (KPC)-producing after 8 days of colistin-based therapy, resulting in relapse of bloodstream infection and death. Disruption of the gene by insertion of a mobile genetic element was found to be the mechanism, which was replicated in vitro after exposure to subinhibitory concentrations of colistin and meropenem.

Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using β-Lactamase Inhibitors and β-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.

Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria.

Evaluation of Sensititre Broth Microdilution Plate for determining the susceptibility of carbapenem-resistant Klebsiella pneumoniae to polymyxins.

Colistin and polymyxin B MICs were determined for 106 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) isolates using Sensititre Research Use Only GNX2F plates (Thermo Fisher) and compared to CLSI broth macrodilution (BMD) as the reference method. For colistin, EUCAST breakpoints were applied and testing of isolates with very major (VM) errors was repeated in duplicate by both methods to determine a majority result. Essential agreement (MIC ± one dilution) of GNX2F with the reference method was 97.

"Double carbapenem" and oral fosfomycin for the treatment of complicated urinary tract infections caused by bla -harboring Enterobacteriaceae in kidney transplantation.

Infections with carbapenemase-producing carbapenem-resistant Enterobacteriaceae represent an emergent problem worldwide. Treatment of infections caused by New Delhi metallo-beta-lactamase (NDM)-harboring Enterobacteriaceae is particularly challenging as it frequently involves the use of nephrotoxic agents, which is problematic in kidney transplant recipients and non-renal transplant patients with marginal kidney function. We present two cases of urinary tract infections caused by NDM-harboring Enterobacteriaceae successfully treated with a combination of "double carbapenem" and oral fosfomycin.

A Prospective Observational Study of the Epidemiology, Management, and Outcomes of Skin and Soft Tissue Infections Due to Carbapenem-Resistant .

Background: This study was performed to characterize the epidemiology, management, and outcomes of skin and soft tissue infection (SSTI) and colonization due to carbapenem-resistant (CRE).

Methods: Patients from the Consortium on Resistance Against Carbapenem in and Other (CRACKLE-1) from December 24, 2011 to October 1, 2014 with wound cultures positive for CRE were included in the study. Predictors of surgical intervention were analyzed.

Nosocomial Outbreak of Extensively Drug-Resistant Acinetobacter baumannii Isolates Containing Carried on a Plasmid.

Carbapenem antibiotics are among the mainstays for treating infections caused by , especially in the Northwest United States, where carbapenem-resistant remains relatively rare. However, between June 2012 and October 2014, an outbreak of carbapenem-resistant occurred in 16 patients from five health care facilities in the state of Oregon. All isolates were defined as extensively drug resistant.