bluuebunny/crossref_metadata_2025_split huggingface dataset:
AAI101, a Novel β-Lactamase Inhibitor: Microbiological and Enzymatic Profiling
Authors: Papp-Wallace Krisztina M , Bethel Christopher R , Barnes Melissa D , Rutter Joseph D , Taracila Magdalena A , Bajaksouzian Saralee , Jacobs Michael R , Bonomo Robert A 
Published: October 2017

Abstract

Background
AAI101 is a novel β-lactamase inhibitor (BLI), active against ESBLs and other β-lactamases. AAI101 combined with cefepime (FEP) is in Phase 2 clinical trials. The objective of this study was to determine differences between AAI101 and tazobactam in their inhibition of selected β-lactamases of clinical relevance.

Methods
Isogenic E. coli strains expressing single clinically relevant β-lactamases were tested for susceptibility (broth microdilution MIC) to FEP, FEP/AAI101 and piperacillin-tazobactam (P/T). Periplasmic β-lactamase extracts from selected strains then were used to determine IC50s for AAI101 and for tazobactam. β-Lactamases with low IC50s for AAI101 were purified, and steady-state inactivation kinetics determined for AAI101 and for tazobactam.

Results
AAI101 restored activity of FEP against E. coli strains producing defined β-lactamases, and FEP/AAI101 was more potent than P/T (Table).

Conclusion
Addition of AAI101 enhances cefepime activity vs. a selected array of β-lactamases expressed in E. coli in an isogenic Background. The inhibitory kinetics of β-lactamases by AAI101 compared with those of tazobactam indicate different mechanisms of β-lactamase inhibition.

Disclosures
K. M. Papp-Wallace, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Merck: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant M. R. Jacobs, Allecra: Grant Investigator, Research grant Roche: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant; R. A. Bonomo, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Wockhardt: Grant Investigator, Research grant Merck: Grant Investigator, Research grant Roche: Grant Investigator, Research grant GSK: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant
In Vitro Activity of Cefiderocol against Multi-Drug Resistant Carbapenemase-Producing Gram-Negative Pathogens
Authors: Boyd Sandra , Anderson Karen , Albrecht Valerie , Campbell Davina , Karlsson Maria S , Rasheed J Kamile 
Published: October 2017

Abstract

Background
Few options remain for treatment of infections caused by multi-drug resistant (MDR), carbapenemase-producing gram-negative pathogens. Cefiderocol (CFDC; Shionogi & Co. Ltd), is a novel parenteral siderophore cephalosporin that enters the bacterial cell through the iron–siderophore uptake system. Here we report on the in vitro activity of CFDC against a set of well-characterized MDR gram-negative isolates collected by the Centers for Disease Control and Prevention.

Methods
Minimum inhibitory concentrations (MIC) values for CFDC in iron-depleted cation-adjusted Mueller Hinton broth were determined using reference broth microdilution. Study isolates (n = 315) included Enterobacteriaceae (59%), Pseudomonas aeruginosa (19%), Acinetobacter baumannii (17%), Stenotrophomonas maltophilia (4%), and Burkholderia cepacia complex (1%). Of these, 229 (73%) were carbapenemase-producers including Ambler Class A- (37%), Class B- (29%) and Class D- type (29%) enzymes. The remaining isolates included 51 β-lactam-resistant isolates that were non-carbapenemase-producers, and 35 β-lactam-susceptible isolates. Results were interpreted using suggested CFDC breakpoints of Sensitive ≤4 μg/mL and Resistant ≥16 μg/mL.

Results
The majority of the isolates (90.8%) were categorized as CFDC susceptible; the percentage of isolates with a CFDC MIC ≤4 μg/mL among Enterobacteriaceae, P. aeruginosa, and A. baumannii was 87.5%, 100%, and 89%, respectively. Percentage of isolates with a CFDC MIC ≤4 μg/mL that harbored a carbapenemase of the Class A-, Class B-, and Class D-type was 91.8%, 74.8%, 98.0%, respectively. By applying suggested breakpoints, 12 isolates were categorized as intermediate and 17 as resistant. The resistant isolates included 11 NDM-, 2 OXA-23- and 4 KPC-positive organisms.

Conclusion
Cefiderocol showed potent activity against MDR gram-negative pathogens including Class A, B, and D carbapenemase-producing isolates. Of note, all P. aeruginosa, including Class B metallo-β-lactamase producers, were susceptible to CFDC.

Disclosures
All authors: No reported disclosures.
Activity of Ceftolozane/tazobactam (C/T) and Ceftazidime/avibactam (CZA) against Extended-spectrum Β-lactamase (ESBL)-producing Enterobacteriaceae and Multidrug-resistant (MDR) Pseudomonas aeruginosa Isolates
Authors: Hirsch Elizabeth B , Zucchi Paola , Cheung Nicole , Krevolin Kyle , Emery Christopher , Bias Tiffany 
Published: October 2017

Abstract

Background
Antibiotic resistance among Gram-negative bacterial pathogens is a serious public health threat underscored by a diminishing antibiotic development pipeline. This study evaluated the in vitro activity of two new β-lactam/β-lactamase inhibitors, C/T and CZA, against the problematic pathogens ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.

Methods
A convenience sample of 74 ESBL-producing Enterobacteriaceae and 32 MDR P. aeruginosa clinical isolates (1 per patient episode), collected between 2012 and 2017 from 2 academic medical centers in Boston and Philadelphia, was used. MDR was defined as non-susceptibility to ≥1 agent in at least 3 antibiotic classes. Phenotypic confirmation of ESBL isolates was conducted via double disk testing. MICs were determined by broth microdilution in at least duplicate, on separate days, as recommended by CLSI. Klebsiella pneumoniae ATCC 700603 was used as a quality control strain with each experiment. Interpretive criteria for C/T per CLSI were: ≤2 (susceptible) / 4 (intermediate) / ≥8 (resistant) mg/L (Enterobacteriaceae) and ≤4 (susceptible) / 8 (intermediate) / ≥16 (resistant) mg/L (P. aeruginosa). Interpretive criteria for CZA per FDA were: ≤8 (susceptible) / ≥16 mg/L (resistant) (all organisms).

Results
Culture sites for the total isolate collection consisted of urine (n = 62), sputum (n = 30), wounds (n = 9), blood (n = 3), and bone (n = 2). ESBL-producing Enterobacteriaceae included Escherichia coli (n = 60), Klebsiella spp. (n = 12), Enterobacter cloacae (n = 1), and Citrobacter freundii (n = 1). ESBL Enterobacteriaceae isolates were 97.3% and 100% susceptible to C/T and CZA, respectively. The corresponding MIC50/90 values were 0.5/2 mg/L for C/T and 0.25/0.5 mg/L for CZA. MDR P. aeruginosa isolates were 90.6% and 96.9% susceptible to C/T and CZA, respectively. The corresponding MIC50/90 values were 1/4 mg/L for C/T and 2/8 mg/L for CZA.

Conclusion
C/T and CZA, two recently approved β-lactam/β-lactamase inhibitor combinations, maintained reliable activity against a collection of 106 MDR isolates from 2 geographically diverse medical centers.

Disclosures
E. B. Hirsch, Merck: Grant Investigator, Research grant The Medicines Company: Speaker’s Bureau, Speaker honorarium; T. Bias, Merck: Grant Investigator, Research grant The Medicines Company: Speaker’s Bureau, Speaker honorarium
Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from United States (US) Medical Centers (2013–2016)
Authors: Sader Helio S , Castanheira Mariana , Shortridge Dee , Mendes Rodrigo E , Flamm Robert K 
Published: October 2017

Abstract

Background
The in vitro activity of ceftazidime-avibactam (CAZ-AVI) and many comparator agents were tested against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 P. aeruginosa isolates.

Methods
Isolates were consecutively collected from 94 US hospitals in 2013–2016 and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Enterobacteriaceae strains with elevated CAZ-AVI MIC values (≥16 μg/mL) were evaluated for the presence of genes encoding extended-spectrum β-lactamases, KPC, NDM, and transferable AmpC enzymes.

Results
CAZ-AVI inhibited &gt;99.9% of all Enterobacteriaceae at the susceptible (S) breakpoint of ≤8 μg/mL and was active against multidrug-resistant (MDR; n = 2,953; MIC50/90, 0.25/1 μg/mL; 99.2%S, extensively drug-resistant (XDR; n = 448; MIC50/90, 0.5/2 μg/mL; 97.8%S), and carbapenem-resistant isolates (CRE; n = 513; MIC50/90, 0.5/2 μg/mL; 97.5%S). Only 82.2% of MDR Enterobacteriaceae and 64.2% of ceftriaxone-nonsusceptible (NS) Klebsiella pneumoniae (n = 1,063) were meropenem-S. Among Enterobacter cloacae (n = 3,740; 22.2% ceftazidime-NS), 99.8% of isolates, including 99.3% of ceftazidime-NS isolates, were CAZ-AVI-S. Only 22 of 36,380 Enterobacteriaceae (0.06%) isolates were CAZ-AVI-NS, including 8 MBL-producers (0.02%) and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. CAZ-AVI showed potent activity against P. aeruginosa (n = 7,868; MIC50/90, 2/4 μg/mL; 97.1% S), including meropenem-NS (n = 1,471; MIC50/90, 4/16 μg/mL; 87.2%S) and MDR (n = 1,562; MIC50/90, 4/16 μg/mL; 86.5%S) isolates, and inhibited 71.8% of isolates NS to meropenem, piperacillin-tazobactam, and ceftazidime (n = 628).

Conclusion
CAZ-AVI demonstrated potent activity against a large US collection (n = 44,248) of contemporary gram-negative bacilli, including organisms resistant to most currently available agents, such as CRE and meropenem-NS P. aeruginosa.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research grant; M. Castanheira, Allergan: Research Contractor, Research grant; D. Shortridge, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant
Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents Tested against Contemporary (2016) Clinical Enterobacteriaceae Isolates
Authors: Sader Helio S , Mendes Rodrigo E , Shortridge Dee , Flamm Robert K , Castanheira Mariana 
Published: October 2017

Abstract

Background
Avibactam (AVI) is a non-β-lactam β-lactamase (BL) inhibitor that inhibits Ambler class A, C, and some class D enzymes (eg, ESBL, KPC, and AmpC), and aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBL).

Methods
A total of 10,451 Enterobacteriaceae(ENT) consecutively collected from 84 United States (US) medical centers and 250 carbapenem-resistant ENT (CRE) collected from 38 centers in 25 other countries (ex-US) were tested for susceptibility (S) by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). CRE strains were screened for the presence of carbapenemase (CBP)-encoding genes using whole genome sequencing analysis.

Results
All ENT isolates from US (MIC50/90, ≤0.03/0.12 μg/mL), except for 1 Escherichia coli strain with an ATM-AVI MIC of 8 μg/mL, and all ex-US CRE isolates (MIC50/90, 0.25/0.5 μg/mL) were inhibited at ATM-AVI MIC of ≤4 µg/mL (CLSI S breakpoint for ATM). Among US isolates, ATM-AVI was also very active against CRE (n = 120; MIC50/90, 0.12/0.5 μg/mL; highest MIC, 4 μg/mL), multidrug-resistant (MDR; n = 876; MIC50/90, 0.06/0.25 μg/mL), extensively drug-resistant (XDR; n = 111; MIC50/90, 0.12/0.5 μg/mL), pan-drug resistant (n = 2; MICs ≤0.03 and 0.12 μg/mL), and ceftazidime-non-S Enterobacter cloacae (MIC50/90, 0.25/1 μg/mL) isolates. Meropenem was very active against US ENT overall (MIC50/90, 0.03/0.06 μg/mL; 98.8%S per CLSI), but showed limited activity against MDR (86.2%S) and XDR (30.6%S) isolates. Amikacin and colistin were active against 74.2% and 81.7% of US CRE, 93.4% and 58.3% US MDR, 65.8% and 57.7% of US XDR, and 58.0% and 79.2% of ex-US CRE isolates, respectively. A total of 106 CBPs were detected in 106 US CRE isolates, including 102 KPC-like, 2 SME-4, 1 NDM-1, and 1 IMP-27. Also, 248 CBPs were identified on 241 ex-US CRE isolates, including 124 KPC-like, 64 OXA-like, 50 NDM-like, 7 VIM-1, 2 IMP-4, and 1 SME-4. All CRE isolates, including all CBP-producing ENT (US and ex-US), were inhibited at ATM-AVI MIC of ≤4 μg/mL.

Conclusion
ATM-AVI demonstrated potent in vitro activity against a large collection of contemporary (2016) ENT isolated from patients in US hospitals and CRE isolates collected worldwide, including NDM, KPC, OXA, VIM, and SME producers.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; D. Shortridge, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant; M. Castanheira, Allergan: Research Contractor, Research grant
Activity of Plazomicin against Enterobacteriaceae Isolates Collected in the United States Including Isolates Carrying Aminoglycoside-Modifying Enzymes Detected by Whole Genome Sequencing
Authors: Castanheira Mariana , Deshpande Lalitagauri M , Hubler Cory M , Mendes Rodrigo E , Serio Alisa W , Krause Kevin M , Flamm Robert K 
Published: October 2017

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
Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Tested against Enterobacteriaceae and Pseudomonas aeruginosa from United States (US) Medical Centers Stratified by Infection Type (2015–2016)
Authors: Sader Helio S , Castanheira Mariana , Duncan Leonard R , Flamm Robert K 
Published: October 2017

Abstract

Background
We evaluated and compared the in vitro activities of ceftazidime-avibactam (CAZ-AVI) and comparators against of Enterobacteriaceae (ENT) and P. aeruginosa (PSA) from various infection types.

Methods
23,440 isolates composed of 19,249 ENT and 4,191 PSA were consecutively collected from 85 US hospitals and tested for susceptibility (S) by broth microdilution methods in a central monitoring laboratory (JMI Laboratories). The antimicrobial S and frequency of key resistance (R) phenotypes, such as multidrug-R (MDR) and extensively drug-R (XDR) among others, were assessed and stratified by these infection types: bloodstream (BSI; 3,434 isolates; 14.7%), pneumonia (6,439; 27.5%), skin/skin structure (SSSI; 4,134; 17.6%), intra-abdominal (IAI; 951; 4.1%), urinary tract (UTI; 7,873; 33.6%), and others combined (609; 2.6%).

Results
CAZ-AVI was active against 99.9% to 100.0% of ENT and 97.0% (pneumonia) to 99.4% (UTI) of PSA isolates. S rates were consistently lower among ENT from pneumonia compared with other infection types for β-lactams such as CAZ (82.3% vs. 87.1–90.8%), piperacillin-tazobactam (P-T; 87.5% vs. 90.2–95.6%) and meropenem (MEM; 96.8% vs. 98.4–99.4%). S to gentamicin (GEN) was also generally lower among isolates from pneumonia, whereas S to levofloxacin (LEV) and colistin (COL) were lowest among BSI and SSSI isolates, respectively. The occurrence of MDR, XDR, and carbapenem-resistant ENT (CRE) phenotypes were markedly higher among isolates from patients with pneumonia compared with other infection types (Table). Among PSA, S rates for CAZ, P-T, and GEN were lowest among isolates from pneumonia, whereas S to MEM was similar among isolates from BSI, pneumonia, and IAI (77.3–77.9%), and S to LEV was markedly lower among UTI isolates (67.1%). The frequency of PSA isolates with MDR and XDR phenotypes, as well as non-S to CAZ, MER, and P-T, were also highest among isolates from patients with pneumonia (Table).

Conclusion
Antimicrobial S rates were generally lower among ENT and PSA isolates from patients with pneumonia compared with other infections. CAZ-AVI was highly active against a large collection of contemporary ENT and PSA isolates from US hospitals (2015–2016), including MDR and XDR organisms, regardless of the infection type.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research grant; M. Castanheira, Allergan: Research Contractor, Research grant; L. R. Duncan, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant
In Vitro and In Vivo Activity of Single and Dual Antimicrobial Agents Against KPC-producing Klebsiella pneumoniae
Authors: Moussavi Farzad , Nath Sarath , Abraham Daniel , Landman David , Quale John 
Published: October 2017

Abstract

Background
Options for treatment of infections due to KPC-producing K. pneumoniae are limited, and combination therapy is often recommended. In this report, the in vitro and in vivo activity of potential therapeutic agents and combinations was assessed against four KPC-producing K. pneumoniae isolates.

Methods
Using clinically-relevant concentrations, time-kill experiments and the Galleria mellonella model of infection were used to examine the activity of polymyxin B, ceftazidime-avibactam, meropenem, rifampin, and amikacin alone and in combination. Four isolates of KPC-producing K. pneumoniae were studied, including two isolates that were resistant to polymyxin B and had ceftazidime-avibactam MICs of 8 µg/mL. The other two K. pneumoniae isolates were susceptible to polymyxin B and had lower MICs of ceftazidime-avibactam.

Results
Two isolates that were resistant to polymyxin B and with ceftazidime-avibactam MICs of 8 µg/mL were also resistant to amikacin and meropenem. When ceftazidime-avibactam was combined with either amikacin or meropenem, synergy was observed in vitro, and these combinations were associated with improved survival with the in vivo model. The other two K. pneumoniae isolates were susceptible to polymyxin B and had lower MICs of ceftazidime-avibactam. At concentrations four times the MIC, ceftazidime-avibactam had bactericidal activity in vitro; at one fourth the MIC, synergy was observed when combined with meropenem. Improved survival rates were observed with therapy with ceftazidime-avibactam, particularly when combined with a second agent for one isolate. In the in vivo model, polymyxin B with or without rifampin or meropenem, was ineffective against polymyxin B resistant strains.

Conclusion
Pending clinical studies, combining ceftazidime-avibactam with another agent (e.g., a carbapenem) should be encouraged when treating serious infections due to these pathogens, especially for isolates with ceftazidime-avibactam MICs near the susceptibility breakpoint.

Disclosures
All authors: No reported disclosures.
Socioeconomic Status Factors Associated with Increased Incidence of Community-Associated Clostridium difficile Infection
Authors: Skrobarcek Kimberly , Mu Yi , Winston Lisa G , Brousseau Geoff , Lyons Carol , Farley Monica , Perlmutter Rebecca , Holzbauer Stacy , Phipps Erin C , Dumyati Ghinwa , Beldavs Zintars G , Kainer Marion , Guh Alice 
Published: October 2017

Abstract

Background
Traditionally a hospital-acquired pathogen, Clostridium difficile is increasingly recognized as an important cause of diarrhea in community settings. Health disparities in C. difficileinfection (CDI) have been reported, but little is known about the social determinants of health that influence community-associated (CA) CDI incidence. We sought to identify socioeconomic status (SES) factors associated with increased CA-CDI incidence.

Methods
Population-based CDI surveillance is conducted in 35 U.S. counties through the Centers for Disease Control and Prevention’s Emerging Infections Program. A CA-CDI case is defined as a positive C. difficile stool specimen collected as an outpatient or within three days of hospitalization in a person aged ≥ 1 year who did not have a positive test in the prior 8 weeks or an overnight stay in a healthcare facility in the prior 12 weeks. ArcGIS software was used to geocode 2014–2015 CA-CDI case addresses to a 2010 census tract (CT). Incidence rate was calculated using 2010 Census population denominators. CT-level SES factors were obtained from the 2011–2015 American Community Survey 5-year estimates and divided into deciles. To account for CT-level clustering effects, separate generalized linear mixed models with negative binomial distribution were used to evaluate the association between each SES factor and CA-CDI incidence, adjusted by age, sex and race.

Results
Of 9686 CA-CDI cases, 9417 (97%) had addresses geocoded to a CT; of these, 62% were female, 82% were white, and 35% were aged ≥65 years. Annual CA-CDI incidence was 42.9 per 100,000 persons. After adjusting for age, sex and race, CT-level SES factors significantly associated with increased CA-CDI incidence included living under the poverty level (rate ratio [RR] 1.12; 95% confidence interval [CI] 1.09–1.53), crowding in homes (RR 1.11; 95% CI 1.01–1.21), low education (RR 1.11; 95% CI 1.07–1.15), low income (RR 1.15; 95% CI 1.12–1.17), having public health insurance (RR 1.21; 95% CI 1.18–1.24), receiving public assistance income (RR 1.69; 95% CI 1.55–1.84), and unemployment (RR 1.14; 95% CI 1.07–1.22).

Conclusion
Areas with lower SES have modestly increased CA-CDI incidence. Understanding the mechanisms by which SES factors impact CA-CDI incidence could help guide prevention efforts in these higher-risk areas.

Disclosures
All authors: No reported disclosures.