ARGONAUT-I: Activity of cefiderocol (s-649266), a siderophore cephalosporin, against gram-negative bacteria, including carbapenem-resistant nonfermenters and enterobacteriaceae 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 Acinetobacter baumannii complex, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Enterobacteriaceae strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MIC90s against A. baumannii, S. maltophilia, and P. aeruginosa were 1, 0.25, and 0.5 mg/ liter, respectively. Against Enterobacteriaceae, the MIC90 was 1 mg/liter for the group harboring OXA-48-like, 2 mg/liter for the group harboring KPC-3, and 8 mg/liter for the group harboring TEM/SHV ESBL, NDM, and KPC-2

ARGONAUT II study of the in vitro activity of plazomicin against carbapenemase-producing klebsiella pneumoniae

Plazomicin was tested against 697 recently acquired carbapenemresistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of>32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate

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 97.1% for polymyxin B and 92.5% for colistin (7 VM errors, 22.6%). After discrepancy testing, there were 28 colistin resistant isolates by BMD and essential agreement was 94.3% with 4 VM errors (14.3%). Colistin and polymyxin B GNX2F results showed acceptable essential agreement with BMD for MICS without interpretation. Colistin VM errors with EUCAST breakpoints were due to MIC variability in the 2 to 4 μg/mL range that could be addressed by establishing an intermediate category

A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone

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

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

OqxAB, a quinolone and olaquindox efflux pump, is widely distributed among multidrug-resistant Klebsiella pneumoniae isolates of human origin

Use of antibiotics among livestock contributes to the selection and dissemination of multidrug resistant (MDR) bacteria. Olaquindox and carbadox are quinoxaline derivatives with antibacterial properties that prevent dysentery and enhance weight gain in suckling pigs. Resistance to quinoxalines is mediated by the efflux pump OqxAB, which also extrudes antibiotics such as chloramphenicol and fluoroquinolones. The gene encoding this efflux pump, oqxAB, was initially detected within plasmid pOLA52, which was found in Escherichia coli isolated from swine manure. Dissemination of oqxAB has been noted in Salmonella species, and the original genetic reservoir of oqxAB was traced to the chromosome of Klebsiella pneumoniae. Surprisingly, OqxAB has been reported only in clinical isolates of K. pneumoniae from China, South Korea, and Spain

Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agarbased antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae

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, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3

Emergence of resistance to colistin during the treatment of bloodstream infection caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae

We report the emergence of colistin resistance in Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae after 8 days of colistin-based therapy, resulting in relapse of bloodstream infection and death. Disruption of the mgrB 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

Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20–28) of these patients had died. Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. Funding: National Institutes of Health