scholarly journals Activity of Plazomicin against Enterobacteriaceae Isolates Collected in the United States Including Isolates Carrying Aminoglycoside-Modifying Enzymes Detected by Whole Genome Sequencing

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S377-S377 ◽  
Author(s):  
Mariana Castanheira ◽  
Lalitagauri M Deshpande ◽  
Cory M Hubler ◽  
Rodrigo E Mendes ◽  
Alisa W Serio ◽  
...  
Keyword(s):  
De Novo ◽  
Infection Type ◽  
The United States ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Serious Infections ◽  
Tract Infections ◽  
Encoding Genes ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Plazomicin (PLZ) is a next-generation aminoglycoside (AMG) stable against aminoglycoside-modifying enzymes (AME) that completed Phase 3 studies for complicated urinary tract infections and serious infections due to carbapenem-resistant Enterobacteriaceae (ENT). We evaluated the activity of PLZ and AMGs against ENT collected in US hospitals during 2016. Methods A total of 2,097 ENT were susceptibility (S) tested by CLSI reference broth microdilution methods. E. coli, Klebsiella spp. Enterobacter spp., and P. mirabilis isolates displaying non-S MICs (CLSI criteria) for gentamicin (GEN), amikacin (AMK), and/or tobramycin (TOB) were submitted to WGS, de novo assembly and screening for AME genes. Results Against ENT, PLZ was more active than all 3 clinically available AMGs (Table). PLZ and AMK activities were stable regardless of the infection type; however, differences were observed for GEN and TOB. Bloodstream isolates displayed higher GEN MICs when compared with the other infection sites. TOB activity varied 4-fold, being higher for bloodstream and pneumonia infections and lower for skin/soft tissue and other/unknown specimens. Against 198 isolates carrying 1 or more AME-encoding genes detected among 208 AMG-non-S isolates, the activity of PLZ was 8- to 16-fold greater when compared with the activity of AMK and at least 16-fold higher than the activity of GEN or TOB. Conclusion PLZ was active against ENT isolates from US hospitals regardless of infection type. PLZ displayed activity against isolates carrying AME genes that represent 12.0% of selected species. AME-carrying isolates were considerably more resistant to AMK, GEN, and TOB, highlighting the potential value of PLZ to treat infections caused by these organisms. This project has been funded under BARDA Contract No. HHSO100201000046C. Disclosures M. Castanheira, Achaogen: Research Contractor, Research grant; L. M. Deshpande, Achaogen: Research Contractor, Research grant; C. M. Hubler, Achaogen: Research Contractor, Research grant; R. E. Mendes, Achaogen: Research Contractor, Research grant; A. W. Serio, Achaogen: Employee, Salary; K. M. Krause, Achaogen: Employee, Salary; R. K. Flamm, Achaogen: Research Contractor, Research grant

scholarly journals Antimicrobial Activity of Ceftolozane–Tazobactam Tested against Contemporary (2012–2016) Enterobacteriaceae and Pseudomonas aeruginosa Isolates by US Census Division

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S371-S372
Author(s):  
Dee Shortridge ◽  
Leonard R Duncan ◽  
Michael A Pfaller ◽  
Robert K Flamm
Keyword(s):  
Pseudomonas Aeruginosa ◽  
The United States ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Abdominal Infections ◽  
Us Census ◽  
Phenotype Screen ◽  
Lactamase Inhibitor ◽  
Research Grant

Abstract Background Ceftolozane-tazobactam (C-T) is a combination of a novel antipseudomonal cephalosporin and a well-described β-lactamase inhibitor. C-T was approved by the United States (US) Food and Drug Administration in 2014 for complicated urinary tract infections, including acute pyelonephritis and complicated intra-abdominal infections. C-T is currently in clinical trials for the treatment of nosocomial pneumonia. The Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) monitors C-T resistance to gram-negative (GN) isolates worldwide. In this study, the activities of C-T and comparators vs. GN isolates from each of the 9 US Census divisions were compared. Methods A total of 18,856 Enterobacteriaceae (ENT) and 4,735 Pseudomonas aeruginosa (PSA) isolates were collected from 32 US hospitals in 2012–2016. Isolates were tested for susceptibility (S) to C-T and comparators by CLSI broth microdilution methodology in a central monitoring laboratory. Other antibiotics tested included amikacin (AMK), ceftazidime (CAZ), colistin (COL), meropenem (MER), and piperacillin-tazobactam (TZP). The following resistant phenotypes were analyzed for ENT: carbapenem resistant (CRE); extended-spectrum β-lactamase phenotype screen-positive (ESBL); and ESBL, nonCRE. or PSA, MER-nonsusceptible (NS), TZP-NS, and CAZ-NS isolates were analyzed. CLSI (2017) interpretive criteria were used. Results For all ENT, 94.2% were S to C-T, 91.5% were S to TZP, 98.0% were S to MER, and 98.8% were S to AMK; 1,697 (9.0%) were ESBL, nonCRE and 356 (1.9%) were CRE. For all PSA isolates, 97.4% were S to C-T, 99.3% were S to COL, 96.9% were S to AMK, and 81.2% were S to MER. The % C-T S for each division (DIV) are shown in the table. The % C-T S for ENT ranged from 98.1% (DIV 4) to 87.4% (DIV 2) and % C-T S for ESBL, nonCRE ranged from 93.8% in DIV 4 to 79.8% in DIV 7. For PSA, the % C-T S ranged from 99.6% in DIV 4 to 94.9% in DIV 9. Activity of C-T against PSA NS to MER, CAZ or TZP varied by division and was >80% for all except DIV 9. Conclusion Against PSA, only COL was more active than C-T. C-T demonstrated potent activity against PSA NS to other β-lactams. For ENT, overall activity was good. For both PSA and ENT, C-T varied by DIV. Disclosures D. Shortridge, Merck: Research Contractor, Research grant; L. R. Duncan, Merck: Research Contractor, Research grant; M. A. Pfaller, Merck: Research Contractor, Research grant; R. K. Flamm, Merck: Research Contractor, Research grant

scholarly journals Phylogenetically Diverse Escherichia Coli Strains From Chicken Co-Harbour Multiple Carbapenemase Encoding Genes (blaNDM-blaOXA-blaIMP)

2020 ◽  
Author(s):  
Erkihun Aklilu ◽  
Azian Harun ◽  
Kirnpal Kaur Banga Singh ◽  
Shamsaldeen Ibrahim ◽  
Nor Fadhilah Kamaruzzaman
Keyword(s):  
Public Health ◽  
Phylogenetic Diversity ◽  
Farm Animals ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Resistance Patterns ◽  
Phylogenetic Grouping ◽  
Encoding Genes ◽  
Potential Public Health ◽  
Carbapenem Resistant Enterobacteriaceae

Carbapenem resistant Enterobacteriaceae (CRE) has been public health risk in several countries and recent reports indicate the emergence of CRE in food animals. This study was conducted to investigate the occurrence, resistance patterns, and phylogenetic diversity of CRE E.coli from chicken. Routine bacteriology, PCR detection of E.coli species, multiplex PCR to detect carbapenemase encoding genes and phylogeny of CRE E. coli were conducted. The results show that 24.36 % (19/78) were identified as CRE based on the phenotypic identifications of which 17 were positive for the tested carabanemase genes. The majority, 57.99% (11/19) of the isolates harbored multiple carbapenemase genes. Four isolates harbored all blaNDM blaOXA, blaIMP, five and two different isolates harbored blaNDM and blaOXA, and blaOXA and blaIMP respectively. The Meropenem, Imipenem and Ertapenem MIC values for the isolates ranged from 2g/mL to ≥256g/mL. Phylogenetic grouping showed that the CRE E.coli isolates belonged to five different groups; groups A, B1, C, D and unknown. The detection of carbapenem resistant E.coli in this study shows that CRE is has become an emerging problem in farm animals, particularly, in poultry farms. This also implies the potential public health risks posed by CRE from chicken to the consumers.

scholarly journals 2162. Comparison of Plazomicin Disk Diffusion vs. Gradient Diffusion Susceptibility Testing Results Against Drug-Resistant Clinical Enterobacteriaceae Isolates

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S733-S734
Author(s):  
Alexander Lepak ◽  
Alexander Lepak ◽  
Luriane Grajcevci ◽  
Joyce Banach ◽  
Katherine Meyer ◽  
...  
Keyword(s):  
Test Strip ◽  
Disk Diffusion ◽  
Minimal Inhibitory Concentrations ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Gradient Diffusion ◽  
Pearson Coefficient ◽  
Clinical Breakpoints ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Plazomicin, a novel aminoglycoside, is active against carbapenem-resistant Enterobacteriaceae (EB) and is not inhibited by most aminoglycoside modifying enzymes that affect gentamicin and tobramycin. We investigated the activity of plazomicin against resistant EB clinical isolates and compared disk diffusion (DD) vs. gradient diffusion (GD) results. Methods EB isolates that were carbapenem resistant and/or resistant to both gentamicin and tobramycin were retrieved from the UW Health clinical isolate repository. Each isolate was tested against plazomicin using both DD (MAST Group Ltd. Plazomicin disk 30 µg) and GD (Liofilchem Plazomicin MIC Test Strip 0.16–256 µg/mL) methods according to manufacturer instructions and using FDA clinical breakpoints for interpretation. Results 51 isolates were tested: 21 E. coli, 9 P. mirabilis, 7 E. cloacae, 6 K. pneumoniae, 3 K. oxytoca, 3 S. marcescens, 1 K. aerogenes, and 1 C. freundii. Specimen sites included: 29 blood, 8 urine, 8 soft tissue or bone, 5 intra-abdominal, and 1 sputum. Previous phenotypic AST results demonstrated 19 (37%) were CRE, of which 5 were also gentamicin and tobramycin resistant, and 32 (63%) were tobramycin and gentamicin resistant but carbapenem susceptible. Plazomicin zone diameters and minimal inhibitory concentrations (MIC) for all isolates are shown in the figure (data jittered to show frequency). There was a significant correlation between increased MIC and smaller zone diameters (Pearson coefficient −0.443, P = 0.001). However, while all 51 isolates were susceptible by DD breakpoints, only 46 (92%) were susceptible by GD breakpoints. All 5 discordant results were P. mirabilis which had an MIC of 4 µg/mL (intermediate) but zone diameters of 20–21 mm (susceptible). Conclusion Concordance between plazomicin DD and GD susceptibility was only 92%. All 5 discordant results were P. mirabilis. Surveillance studies demonstrate >80% of P. mirabilis have MIC of 2–4 mg/L. Given the DD breakpoint is 16 mm, our data suggest DD was overly active in our sample set. Comparison of DD and GD to reference broth microdilution against a larger set of isolates is warranted to determine which method is optimal; however, our data suggest DD may result in categorical errors for P. mirabilis. Disclosures Alexander Lepak, MD, Paratek Pharmaceuticals: Research Grant; Tetraphase Pharmaceuticals: Research Grant.

scholarly journals Activity of Meropenem-Vaborbactam Against Enterobacteriaceae Isolates Carrying blaKPC Collected Worldwide

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S377-S377 ◽  
Author(s):  
Mariana Castanheira ◽  
Rodrigo E Mendes ◽  
Leonard R Duncan ◽  
Leah N Woosley ◽  
Robert K Flamm
Keyword(s):  
Antimicrobial Agents ◽  
Active Agent ◽  
E Coli ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Wholly Owned Subsidiary ◽  
Us Fda ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Meropenem-vaborbactam (MER-VAB) is a carbapenem-β-lactamase inhibitor combination with enhanced activity against KPC-producing Enterobacteriaceae recently evaluated in a phase 3 clinical trials for cUTIs and infections due to CRE. We analyzed the activity of MER-VAB against 517 isolates carrying blaKPC collected worldwide during 2014–16. Methods Enterobacteriaceae isolates (n = 34,069) from 34 countries were susceptibility (S) tested by reference broth microdilution method for MER-VAB (at fixed 8 µg/mL) and comparators. Carbapenem-resistant Enterobacteriaceae (CRE; CLSI criteria) were submitted to PCR/Sanger sequencing or next-generation sequencing for blaKPC screening. Results A total of 517 (1.5%) carried blaKPC and 6 variants were observed: 293 blaKPC-3, 218 blaKPC-2, 2 blaKPC-4, 2 blaKPC-17, and 1 each of blaKPC-2-like and blaKPC-12. Isolates were mainly K. pneumoniae (437), but also 32 E. cloacae, 13 K. oxytoca, 12 E. coli, 12 S. marcescens, and 4 other species. Isolates carrying blaKPC were detected in 17 countries. The occurrence ranged from <0.1% to 11.3%, being higher in Brazil, Italy (9.3%), Poland (5.6%), and Argentina (5.2%). MER-VAB inhibited 514/517 (99.4%) isolates carrying blaKPC at ≤8 µg/mL and this compound was the most active agent tested against these isolates (MIC50/90, 0.12/1 µg/mL). Three isolates displaying elevated MER-VAB MIC values (>8 µg/mL) co-harbored blaNDM-1 or blaOXA-48-like in addition to blaKPC or had a missense mutation on OmpK35. MER alone (MIC50/90, 32/>32 µg/mL), imipenem (MIC50/90, >8/>8 µg/mL), and doripenem (MIC50/90, >4/>4 µg/mL) were not active against isolates harboring blaKPC. Amikacin (MIC50/90, 16/>32 µg/mL) and gentamicin (MIC50/90, 2/>8) µg/mL inhibited only 54.9% and 57.3% of the isolates (CLSI breakpoint). Colistin (MIC50/90, ≤0.5/>8 µg/mL; 70.4% S/EUCAST breakpoint) and tigecycline (MIC50/90, 0.5/1 µg/mL; 99.4% S/US FDA criteria) were the most active comparators. Conclusion The occurrence of blaKPC is still low overall, but can be as high as 5–10% in a few countries and occur in species other than Klebsiella. KPC-producers are highly resistant to available antimicrobial agents and MER-VAB will be a useful alternative to treat infections caused by these organisms. Disclosures M. Castanheira, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. E. Mendes, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. R. Duncan, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. N. Woosley, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. K. Flamm, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant

scholarly journals Carbapenemase Gene Profiles in Carbapenem-Resistant Enterobacteriaceae—United States, January 2018–August 2019

2020 ◽  
Vol 41 (S1) ◽  
pp. s149-s150
Author(s):  
Jennifer Huang ◽  
Amanda Pettinger ◽  
Katie Bantle ◽  
Amelia Bhatnagar ◽  
Sarah Gilbert ◽  
...  
Keyword(s):  
Public Health ◽  
United States ◽  
Drug Combination ◽  
The United States ◽  
Molecular Testing ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Gene Profiles ◽  
Carbapenemase Gene ◽  
Carbapenem Resistant Enterobacteriaceae

Background: Carbapenem-resistant Enterobacteriaceae (CRE) cause significant morbidity and mortality each year in the United States. Treatment options for these infections are often limited, in part due to carbapenemases, which are mobile β-lactam-hydrolyzing enzymes that confer multidrug resistance in CRE. As part of the CDC’s Containment Strategy for Emerging Resistance, public health laboratories (PHLs) in the CDC Antibiotic Resistance Laboratory Network (AR Lab Network) have worked to characterize clinical isolates of CRE for rapid identification of carbapenemase genes. These data are then used by public health and healthcare partners to promote patient safety by decreasing the spread of resistance. We summarize carbapenemase gene profiles in CRE, by genus and geography, using data collected through the AR Lab Network from January 2018 through August 2019. Methods: CRE isolates were submitted to 55 PHLs, including those of all 50 states, 4 large cities, and Puerto Rico, in accordance with each jurisdiction’s reporting laws. PHLs performed phenotypic and molecular testing on isolates to detect targeted, emerging carbapenemase genes and reported results to submitters. Carbapenemase-positive (CP) isolates were defined as PCR positive for ≥1 carbapenemase gene tested: blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48–LIKE. PHLs submitted results to CDC monthly. Genera other than Enterobacter, Klebsiella, and Escherichia coli are categorized as other genera in this analysis. Data were compiled and analyzed using SAS v 9.4 software. Results: From January 2018 to August 2019, the AR Lab Network tested 25,705 CRE isolates; 8,864 of 25,705 CRE (34%) were CP. Klebsiella spp represented the largest proportion of CP-CRE at 68% (n = 6,063), followed by E. coli (12%, n = 1,052), Enterobacter spp (11%, n = 981), and other genera (9%, n = 768). Figure 1a shows the composition of CP-CRE carbapenemase genes by genus. The most common carbapenemase and genus profiles were blaKPC in Klebsiella (74%; 5,562 of 7,561 blaKPC-positive) blaNDM in E. coli (43%; 372 of 868 blaNDM-positive) blaVIM in Enterobacter spp (35%; 25 of 72 blaVIM-positive), and blaIMP among other genera (90%; 92 of 102 blaIMP-positive). Common CP-CRE genes and genera also varied by geography (Fig. 1b). Conclusions: The AR Lab Network has greatly enhanced our nation’s ability to detect and characterize CP-CRE. Our data provide a snapshot of the organisms and regions where mobile carbapenemase genes are most often detected in CRE. Geographic variation in CP gene profiles provides actionable data to inform local priorities for detection and infection control and provide clinicians with situational awareness of the genes and organisms that are circulating in their region.Funding: NoneDisclosures: In this presentation, the authors discuss the drug combination aztreonam-avibactam and acknowledge that this drug combination is not currently FDA-approved.

scholarly journals Whole-Genome Sequencing for Molecular Characterization of Carbapenem-Resistant Enterobacteriaceae Causing Lower Urinary Tract Infection among Pediatric Patients

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 972
Author(s):  
Hassan Al Mana ◽  
Sathyavathi Sundararaju ◽  
Clement K. M. Tsui ◽  
Andres Perez-Lopez ◽  
Hadi Yassine ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Antimicrobial Resistance ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Bacterial Species ◽  
Whole Genome ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Carbapenem Resistant Enterobacteriaceae

Antibiotic resistance is a growing public health problem globally, incurring health and cost burdens. The occurrence of antibiotic-resistant bacterial infections has increased significantly over the years. Gram-negative bacteria display the broadest resistance range, with bacterial species expressing extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases. All carbapenem-resistant Enterobacteriaceae (CRE) isolates from pediatric urinary tract infections (UTIs) between October 2015 and November 2019 (n = 30). All isolates underwent antimicrobial resistance phenotypic testing using the Phoenix NMIC/ID-5 panel, and carbapenemase production was confirmed using the NG-Test CARBA 5 assay. Whole-genome sequencing was performed on the CREs. The sequence type was identified using the Achtman multi-locus sequence typing scheme, and antimicrobial resistance markers were identified using ResFinder and the CARD database. The most common pathogens causing CRE UTIs were E. coli (63.3%) and K. pneumoniae (30%). The most common carbapenemases produced were OXA-48-like enzymes (46.6%) and NDM enzymes (40%). Additionally, one E. coli harbored IMP-26, and two K. pneumoniae possessed mutations in ompK37 and/or ompK36. Lastly, one E. coli had a mutation in the marA porin and efflux pump regulator. The findings highlight the difference in CRE epidemiology in the pediatric population compared to Qatar’s adult population, where NDM carbapenemases are more common.

scholarly journals Colistin- and Carbapenem-Resistant Escherichia coli Harboring mcr-1 and bla NDM-5 , Causing a Complicated Urinary Tract Infection in a Patient from the United States: TABLE 1 

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
José R. Mediavilla ◽  
Amee Patrawalla ◽  
Liang Chen ◽  
Kalyan D. Chavda ◽  
Barun Mathema ◽  
...  
Keyword(s):  
United States ◽  
Escherichia Coli ◽  
Urinary Tract ◽  
The United States ◽  
Clinical Samples ◽  
Isolation And Identification ◽  
Gram Negative ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACT Colistin is increasingly used as an antibiotic of last resort for the treatment of carbapenem-resistant Gram-negative infections. The plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China and subsequently reported worldwide, including in the United States. Of particular concern is the spread of mcr-1 into carbapenem-resistant bacteria, thereby creating strains that approach pan-resistance. While several reports of mcr-1 have involved carbapenem-resistant strains, no such isolates have been described in the United States. Here, we report the isolation and identification of an Escherichia coli strain harboring both mcr-1 and carbapenemase gene bla NDM-5 from a urine sample in a patient without recent travel outside the United States. The isolate exhibited resistance to both colistin and carbapenems, but was susceptible to amikacin, aztreonam, gentamicin, nitrofurantoin, tigecycline, and trimethoprim-sulfamethoxazole. The mcr-1 - and bla NDM-5 -harboring plasmids were completely sequenced and shown to be highly similar to plasmids previously reported from China. The strain in this report was first isolated in August 2014, highlighting an earlier presence of mcr-1 within the United States than previously recognized. IMPORTANCE Colistin has become the last line of defense for the treatment of infections caused by Gram-negative bacteria resistant to multiple classes of antibiotics, in particular carbapenem-resistant Enterobacteriaceae (CRE). Resistance to colistin, encoded by the plasmid-borne gene mcr-1 , was first identified in animal and clinical samples from China in November 2015 and has subsequently been reported from numerous other countries. In April 2016, mcr-1 was identified in a carbapenem-susceptible Escherichia coli strain from a clinical sample in the United States, followed by a second report from a carbapenem-susceptible E. coli strain originally isolated in May 2015. We report the isolation and identification of an E. coli strain harboring both colistin ( mcr-1 ) and carbapenem ( bla NDM-5 ) resistance genes, originally isolated in August 2014 from urine of a patient with recurrent urinary tract infections. To our knowledge, this is the first report in the United States of a clinical bacterial isolate with both colistin and carbapenem resistance, highlighting the importance of active surveillance efforts for colistin- and carbapenem-resistant organisms.

scholarly journals 1378. Evaluation of the In vitro Activity of Meropenem-Vaborbactam Against Carbapenem-Resistant Enterobacteriaceae, Including Isolates Resistant to Ceftazidime–Avibactam

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S422-S422
Author(s):  
William R Wilson ◽  
Ellen Kline ◽  
Chelsea Jones ◽  
Kristin Morder ◽  
Cornelius J Clancy ◽  
...  
Keyword(s):  
Premature Stop Codon ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Wild Type ◽  
In Vitro Susceptibility ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Research Grant

Abstract Background Meropenem-vaborbactam (M-V) is a novel antibiotic for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections. Our objective was to determine the in vitro activity of meropenem-vaborbactam against genetically-diverse CRE isolates, including those that have developed resistance to Ceftazidime–Avibactam (C-A). Methods Minimum inhibitory concentrations (MICs) were determined for meropenem (MER), M-V, and C-A by reference broth microdilution (BMD) methods in triplicate. Vaborbactam and avibactam were tested at fixed concentrations of 8 and 4 µg/mL, respectively. Quality control strains were used and within expected ranges. Polymerase chain reaction (PCR) with DNA sequencing was used to detect resistance determinants, including Klebsiella pneumoniae carbapenemase (KPC) subtypes and porin mutations. Results A total of 117 CRE isolates were tested, including K. pneumoniae (Kp; n = 83), E. cloacae (n = 17), E. coli (n = 10), and E. aerogenes (n = 7). Seventy-nine percent harbored blaKPC. KPC subtypes included KPC-2 (n = 32), KPC-3 (n = 41), KPC-3 variants (n = 16), and KPC [not typed] (n = 4, all E. coli). Among 74 K. pneumoniae, 95% had a premature stop codon in ompk35 and ompK36 genotypes included wild type (n = 48), IS5 insertion (n = 13), 135–136 DG duplication (n = 9), and other mutations (n = 4). The median (range) MICs for MER, C-A, and M-V were 8 (0.06 to ≥128), 1 (0.25 to ≥512), and 0.03 (0.015––16), respectively. Corresponding rates of susceptibility were 23, 84, and 98%, respectively. Fifty-three percent and 95% of C-A-resistant isolates were susceptible to MER and M-V, respectively. Among Kp, C-A MICs did not vary by KPC subtype or porin genotype. On the other hand, median M-V MICs were higher among KPC-2 than KPC-3 Kp (0.12 vs. 0.03; P = 0.002), and among Kp with ompK36 porin mutations compared with wild type (0.25 vs. 0.03; P < 0.001). Among Kp with KPC-3 variants (n = 16), the median M-V MIC was 0.03 (0.015––2); 100% were M-V susceptible. Median M-V MICs did not vary by CRE species. Only two isolates were M-V resistant, both were E. cloacae that did not harbor blaKPC. Conclusion M-V demonstrates high rates of in vitro susceptibility against diverse CRE isolates, including those that are resistant to C-A. As this agent is introduced into the clinic, it will be important to identify K. pneumoniae isolates harboring KPC-2 with ompK36 porin mutations that demonstrate higher MICs. Disclosures M. H. Nguyen, Merck: Grant Investigator, Research grant. Astellas: Grant Investigator, Research grant.

scholarly journals Estimating the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in the United States Using Antibiotic Prescription Data

2019 ◽  
Vol 6 (8) ◽  
Author(s):  
Cornelius J Clancy ◽  
Brian A Potoski ◽  
Deanna Buehrle ◽  
M Hong Nguyen
Keyword(s):  
United States ◽  
Online Survey ◽  
Antibiotic Use ◽  
The United States ◽  
New Drugs ◽  
Prescription Data ◽  
First Line ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Polymyxins (colistin, polymyxin B) have been first-line antibiotics against carbapenem-resistant Enterobacteriaceae (CRE) infections. New anti-CRE antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) improve outcomes in CRE-infected patients and reduce toxicity compared with polymyxins. It is unclear how widely polymyxins and newer agents are used to treat CRE infections. Methods We conducted an online survey of US hospital-based pharmacists to determine antibiotic positioning against CRE infections. Numbers of all infections and CRE infections treated with different antibiotics in the United States were determined using IQVIA prescription data and Driving Re-investment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) estimates of CRE infections. Results Ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin were positioned as first-line agents against CRE pneumonia, bacteremia, intra-abdominal infections, and urinary tract infections at 87%, 90%, 83%, and 56% of surveyed US hospitals, respectively. From February 2018 to January 2019, an estimated 9437 and 7941 CRE infections were treated with an intravenous polymyxin or new agent, respectively; these figures represented ~28% (range, 19%–50%) and ~23% (range, 16%–42%) of CRE infections in the United States. Use of ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin exceeded that of intravenous polymyxins against CRE infections as of December 2018. Currently, the new drugs are estimated to treat 35% (23% to 62%) of CRE infections in which they were expected to be first-line agents. Conclusions New anti-CRE agents recently surpassed intravenous polymyxins as treatment for CRE infections, but use is less than expected from their positioning at US hospitals. Research on behavioral and economic factors that impact use of new antibiotics is needed, as are financial “pull” incentives that promote an economically viable marketplace.

scholarly journals 1278. Impact of Different Breakpoint Criteria on the Susceptibility Rates of Enterobacterales resistant Subsets to the Aminoglycosides

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S654-S655
Author(s):  
Helio S Sader ◽  
S J Ryan Arends ◽  
Jaideep Gogtay ◽  
Cecilia G Carvalhaes ◽  
Mariana Castanheira
Keyword(s):  
The United States ◽  
Multidrug Resistant ◽  
Chemical Diversity ◽  
Asia Pacific ◽  
Medical Centers ◽  
Carbapenem Resistant ◽  
Us Fda ◽  
Tract Infections ◽  
Center Research ◽  
Research Grant

Abstract Background Plazomicin (PLZ) is an aminoglycoside recently approved by the United States (US) Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections, including pyelonephritis. We evaluated the susceptibility (S) rates of PLZ, amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) by applying current breakpoints published by different organizations. Methods A total of 9,303 Enterobacterales (ENT) isolates (1/patient) were collected in 2018-2019 from medical centers located in the US (n=3,899; 33 centers), Europe (n=3,782; 39 centers in 19 nations), Asia-Pacific (n=795; 13 centers in 7 nations [2018 only]), and Latin America (n=827; 10 centers in 6 nations [2018 only]). PLZ and comparator agents were S tested by reference broth microdilution methods at a central laboratory. Breakpoints for the following organizations were applied when available: CLSI, EUCAST, USCAST, and US FDA. Results PLZ was active against 95.5% and 98.0% of isolates as per US FDA (≤2 mg/L) and USCAST (≤4 mg/L) criteria, respectively. S rates as per US FDA and USCAST criteria were 97.4% and 90.2% for AMK, 86.4% and 85.6% for GEN, and 83.8% and 81.1% for TOB, respectively (Table). CLSI and US FDA breakpoints were identical for these three older aminoglycosides, and EUCAST breakpoints were identical for GEN and TOB and one doubling dilution higher for AMK when compared with USCAST. Per US FDA criteria, carbapenem-resistant ENT (CRE) S rates to PLZ and AMK were 71.5% and 58.3%, respectively. Differences in S rates between PLZ and AMK were higher when applying USCAST for resistant subsets, such as CRE (72.2% versus 38.5%, respectively), ESBL-phenotype (92.7% versus 72.4%, respectively), and multidrug-resistant isolates (n=1,348; 88.6% versus 59.6%, respectively). GEN and TOB exhibited limited activity against ENT resistant subsets. Conclusion PLZ retained potent activity against ENT, including resistant subsets. The discrepancies among the S rates for aminoglycosides were greater when applying breakpoints generated using the same stringent contemporary methods applied to determine PLZ breakpoints. Table 1 Disclosures Helio S. Sader, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support) S. J. Ryan Arends, PhD, Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support) Jaideep Gogtay, n/a, Cipla Ltd. (Employee) Cecilia G. Carvalhaes, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Pfizer (Research Grant or Support) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support)

Sign in / Sign up

Export Citation Format

Share Document