bluuebunny/crossref_metadata_2025_split huggingface dataset:
2119. In Vitro Activity of Aztreonam-Avibactam Against Enterobacterales Isolated from Pediatric and Adult Patients Collected During the ATLAS Global Surveillance Program, 2017-2021
Authors: Estabrook Mark , Arhin Francis , Sahm Daniel F 
Published: November 2023

Abstract

Background
The spread of antimicrobial resistance among clinically isolated Enterobacterales (Eba) threatens public health. Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs) and avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases. ATM-AVI is being developed for use against infections caused by drug-resistant Eba, especially those co-producing MBLs and other β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Eba collected in 2017-2021 from pediatric and adult patients as part of the ATLAS global surveillance program.

Methods
84428 non-duplicate Eba isolates were collected from patients in 255 medical centers in 56 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC &gt;1 µg/mL, and a randomly sampled subset of approximately 80% of Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC &gt;1 µg/mL.

Results
MIC90 values for ATM-AVI of 0.12 µg/ml (pediatric isolates) and 0.25 µg/ml (adult isolates) were observed. Against all Eba isolates, ≤8 µg/ml of ATM-AVI was sufficient to inhibit 99.9% of both pediatric and adult isolates, whereas only 68.0% (pediatric) and 71.9% (adult) of these isolates were susceptible to ATM alone (table). Among isolates that screened positive for an MBL, MIC90 values for ATM-AVI were 0.5 µg/ml (pediatric) and 1 µg/ml (adult) and ATM-AVI inhibited 100% (pediatric) and 99.1% (adult) at concentrations ≤8 µg/ml. In contrast, only 16.1% (pediatric) and 17.9% (adult) of MBL-positive isolates were susceptible to ATM alone.

Conclusion
Based on MIC90 values, ATM-AVI demonstrated potent in vitro activity against Eba isolated both from pediatric and adult patients. Avibactam’s ability to potentiate ATM against MBL-positive isolates warrants its continued development.

Disclosures
Mark Estabrook, PhD, Pfizer Inc.: Honoraria Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2904. Use Of Biofire® Joint Infection Filmarray for the Microbiological Diagnosis of Acute Hematogenous Septic Arthritis in Children
Authors: Boast Alison , Gonis Gena , Gauci Melisa , Velagapudi Sunitha , Harris Peter C , Johnson Michael B , Curtis Nigel , Daley Andrew J , Gwee Amanda 
Published: November 2023

Abstract

Background
Making a microbiological diagnosis in paediatric joint infections is challenging due to the high proportion of fastidious pathogens, in particular Kingella kingae. The Biofire® Joint Infection (JI) Panel allows the rapid molecular diagnosis of a wide spectrum of organisms implicated in pediatric acute haematogenous septic arthritis.

Methods
This study was done in children enrolled in the BEST trial (NCT04538053), a non-inferiority trial comparing entirely oral to intravenous antibiotic treatment of acute bone and joint infections. When sufficient synovial fluid was available after routine tests, the Biofire JI panel was done in parallel with culture. As the assay was used prior to Therapeutic Goods Administration registration as an in vitro diagnostic device, it was not released to clinicians.

Results
Overall, 16 joint fluid samples from 16 children with a median age of 2.3 (range 1 to 13.3) years were included. All children had pleocytosis on microscopy. Standard bacterial culture and Biofire JI panel had concordant results in nine children – K. kingae (3), Streptococcus pyogenes (1), Staphylococcus aureus (1), and negative (4). In six samples, a pathogen was identified by Biofire when culture was negative (4 K. kingae, 1 Streptococcus pneumoniae, 1 S. aureus). One child cultured S. aureus that was not detected by Biofire.

Conclusion
Biofire JI panel improved the microbiological diagnostic yield from synovial fluid samples from children with septic arthritis. Larger studies are required to determine the influence on clinical practice.

Disclosures
All Authors: No reported disclosures
2132. Surveillance of Eravacycline Against Enterobacterales and Non-Fermenter Clinical Isolates, Including Resistant Isolates, Collected Worldwide from Multiple Infection Sites During 2021
Authors: Hawser Stephen , Kothari Nimmi , Monti Federica , Hodges Tony , Zappas Kristie 
Published: November 2023

Abstract

Background
Eravacycline is a fully synthetic, fluorocycline approved for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age in Europe, Singapore, Hong Kong, mainland China, the US, and the UK. The purpose of this study was to monitor the in vitro activity of eravacycline against 2,942 Gram-negative clinical isolates, including multidrug-resistant (MDR) isolates, collected worldwide in 2021.

Methods
As part of a worldwide surveillance study, a total of 2,942 Gram-negative isolates were collected during 2021 from various infections including IAI, body fluids, respiratory and other sources. Of the 2,942 isolates, 654, 1263, and 1025 were from Asia/Pacific, Europe, and North America, respectively. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined with FDA or CLSI breakpoints.

Results
Summary MIC data for tested antimicrobials are shown in the Table. Susceptibility to eravacycline for Enterobacterales was 93.9%, 85.7%, 90.0%, and 96.8% for all isolates, MDR Enterobacterales, ESBL-positive, and ESBL-negative isolates, respectively. Although there are no clinical breakpoints for Acinetobacter baumannii or Stenotrophomonas maltophilia, eravacycline exhibited promising activity against these species with MIC50 / MIC90 of 0.5 & 1 and 1 & 2 µg/ml, respectively.

Conclusion
Eravacycline exhibited sustained high susceptibility against multiple Enterobacterales species, including MDR and ESBL-positive isolates. While breakpoints are not defined for A. baumannii or S. maltophilia, eravacycline demonstrated promising activity against these species. These results suggest that, following several years of clinical use, susceptibility to eravacycline remains high.

Disclosures
Stephen Hawser, PhD, Allecra: study funding|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Nimmi Kothari, PhD, Allecra: Allecra (study funding)|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Federica Monti, PhD, Allecra: Study funded|Innoviva Specialty Therapeutics, Inc.: Honoraria Tony Hodges, MD, La Jolla Pharmaceutical Company: Employee|La Jolla Pharmaceutical Company: Stocks/Bonds Kristie Zappas, PhD, La Jolla Pharmaceutical Company: employee|La Jolla Pharmaceutical Company: Stocks/Bonds
2133. Surveillance of Eravacycline Against Gram-positive Clinical Pathogens, Including Resistant Isolates, Collected Worldwide From Multiple Infection Sites During 2021
Authors: Hawser Stephen , Kothari Nimmi , Monti Federica , Hodges Tony , Zappas Kristie 
Published: November 2023

Abstract

Background
Eravacycline is a fully synthetic, fluorocycline approved for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age in Europe, Singapore, Hong Kong, mainland China, the US, and the UK. Previous surveillance studies of eravacycline have demonstrated potent in vitro activity against specific Gram-positive pathogens. The purpose of this study was to further monitor the in vitro activity of eravacycline against Staphylococcus aureus (including methicillin-resistant S. aureus, MRSA), Enterococcus spp. (including vancomycin-resistant Enterococcus, VRE) and Streptococcus spp.

Methods
A total of 1,557 clinical isolates were collected worldwide during 2021 from multiple infection sources, including bodily fluids, gastrointestinal, genitourinary, and respiratory. Of the 1,557 isolates, 316, 649, and 592 were from Asia/Pacific, Europe, and North America, respectively. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. For comparative purposes, antibiotic susceptibility for eravacycline and tigecycline was determined with both FDA and EUCAST breakpoints, where available.

Results
Summary MIC data for eravacycline and tigecycline, as a selected comparator, are shown in the Table. Susceptibility to eravacycline in all Gram-positive pathogens was greater than 90% for most species/phenotypes though was notably higher when EUCAST breakpoints were applied to the analysis.

Conclusion
Eravacycline demonstrated sustained high susceptibility rates against clinically important Gram-positive pathogens, including resistant isolates. Importantly, no CLSI breakpoint exists to date for eravacycline, though the use of EUCAST breakpoints showed higher susceptibilities compared with the use of FDA breakpoints. Harmonization of clinical breakpoints for eravacycline would be desirable.

Disclosures
Stephen Hawser, PhD, Allecra: study funding|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Nimmi Kothari, PhD, Allecra: Allecra (study funding)|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Federica Monti, PhD, Allecra: Study funded|Innoviva Specialty Therapeutics, Inc.: Honoraria Tony Hodges, MD, La Jolla Pharmaceutical Company: Employee|La Jolla Pharmaceutical Company: Stocks/Bonds Kristie Zappas, PhD, La Jolla Pharmaceutical Company: employee|La Jolla Pharmaceutical Company: Stocks/Bonds
2137. Real World Experience with Eravacycline for the Treatment of Infections Caused by Carbapenem-Resistant Acinetobacter baumannii
Authors: Lim Andy , Guo Yi , McSweeney Terrence D 
Published: November 2023

Abstract

Background
Carbapenem-resistant Acinetobacter baumannii (CRAB) are considered an urgent public health threat responsible for causing severe infections with high associated mortality. CRAB isolates are often resistant to several antibiotic classes thereby limiting treatment options. Eravacycline is a novel tetracycline antibiotic with potent in vitro activity against CRAB. Per the recent Infectious Diseases Society of America (IDSA) Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections, clinical data are limited for eravacycline use for CRAB infections. The purpose of this study was to evaluate clinical outcomes of patients treated with eravacycline for CRAB infections at Montefiore Medical Center.

Methods
This was a retrospective chart review of patients 18 years of age and older who received eravacycline for at least 72 hours for the treatment of an infection due to CRAB between January 1, 2019 to February 28, 2023. Patients were excluded if they had a urinary tract infection. Patient demographics, risk factors, type/source of infection, clinical outcomes, etc. were collected.

Results
Eighteen patients received eravacycline for the treatment of non-urinary CRAB infections (Table 1). Ventilator-associated pneumonia was the predominant infection, representing 14/18 (78%) cases. High rates of antibiotic non-susceptibility were demonstrated in all cases. Median eravacycline minimum inhibitory concentration (MIC) was 1 mg/L, with a range of 0.19 – 6 mg/L. Median duration of eravacycline therapy was 7 days. Overall, the clinical success rate was 33% (6/18). Four patients (22%) experienced progression or worsening of symptoms that required a change in antibiotics. Of 11 evaluable patients, three patients (27%) had a recurrent infection caused by CRAB within 30 days of completion of eravacycline therapy. All-cause 30-day mortality was 56% (10/18), with six deaths (33%) attributed to CRAB infection.

Conclusion
CRAB infections pose a significant challenge in the healthcare setting and are associated with high mortality rates. Eravacycline remains a last resort option for these difficult to treat infections. Further study is warranted for eravacycline use for CRAB infections.

Disclosures
All Authors: No reported disclosures
2147. Design of a Ligand-Targeted Immunotherapy for Treatment of Influenza Virus Infections
Authors: Shahriar Imrul , Campbell Charity L , Kanduluru Ananda K , Srinivasarao Madduri , Low Philip S 
Published: November 2023

Abstract

Background
Nearly 10% of world’s population is affected by influenza virus infections and more than 26 million Americans were infected during the 2022-2023 flu season, with 290,000-640,000 patients requiring hospitalization. While flu vaccines are widely available, they were only 36% effective during the 2021-2022 season. Standard-of-care (SOC) drugs such as Tamiflu and Xofluza are only effective when taken in the early stages of infection requiring novel flu drugs for treating later stages of infection.
Schematics of the mechanism of action of EV21

Methods
Herein we report a targeted therapy (EV21) with a dual mechanism of action that elicits a host immune response to infections. Because neuraminidase is expressed on both the viral envelope and infected host cell surface, we repurposed the neuraminidase inhibitor zanamivir for use as the targeting ligand. We linked zanamivir to two distinct haptens that bind to two different naturally occurring antibodies in humans. Once recruited, these antibodies recruit the innate immune system to kill both virus and virus-infected cells. Preclinical in vitro and in vivo experiments were performed to evaluate the efficacy, safety, and pharmacokinetics of EV21.

Results
When tested in BALB/c mice supplemented with physiological levels of human IgG (IVIG) and infected with 10xLD50 of influenza A virus (H1N1, A/Puerto Rico/8/1934), EV21 elicited excellent antiviral activity. A single dose of our EV21 showed much better activity in late-stage infections than daily doses of the SOC drugs. Also, EV21 caused a significantly faster reduction of viral titer in the lungs of infected mice. Although EV21 exerts its antiviral effect by engaging the innate immune system, it did not give rise to any local or systemic cytokine storm while protecting mice from virus-induced cytokine release syndrome. Moreover, EV21 demonstrated excellent safety, pharmacokinetics, and metabolic stability making it a promising clinical candidate.

Conclusion
Our zanamivir-targeted dual hapten immunotherapy (EV21) has the potential to treat both early and late-stage influenza infections more effectively and rapidly than SOC drugs. Further testing in more clinically relevant ferret models and against multiple influenza strains, however, will be necessary to confirm the above benefits.

Disclosures
Imrul Shahriar, PhD Candidate, Eradivir Inc.: Ownership Interest|Eradivir Inc.: Stocks/Bonds Charity L. Campbell, n/a, Eradivir Inc.: Salary Ananda K. Kanduluru, PhD, Eradivir Inc.: Salary|Eradivir Inc.: Ownership Interest|Eradivir Inc.: Stocks/Bonds Madduri Srinivasarao, PhD, Eradivir Inc.: Ownership Interest|Eradivir Inc.: Stocks/Bonds Philip S. Low, PhD, Eradivir Inc.: Board Member|Eradivir Inc.: Ownership Interest|Eradivir Inc.: Stocks/Bonds
2152. Activity of Imipenem/Relebactam Against Carbapenem-Resistant Non-Morganellaceae Enterobacterales (NME) in the United States – SMART 2019-2021
Authors: Lob Sibylle , Wise Mark G , Bauer Karri , Siddiqui Fakhar , Hilbert David W , Esterly John , DeRyke C Andrew , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: November 2023

Abstract

Background
Antimicrobial resistance has been increasing among gram-negative pathogens. Carbapenem resistance is especially concerning, as carbapenems are a mainstay of therapy for resistant infections. KPC production is the most common cause of carbapenem resistance in the US, but it can also be mediated by mechanisms such as porin loss or efflux. Imipenem/relebactam (IMI/REL) combines imipenem/cilastatin with relebactam, an inhibitor of class A and C β-lactamases. IMI/REL’s spectrum of activity makes it a therapeutic option for infections with carbapenemase producers and isolates resistant due to other mechanisms. We evaluated the activity of IMI/REL and comparators against carbapenem-resistant (CR) non-Morganellaceae Enterobacterales (NME) isolates collected from patients in the US as part of the SMART surveillance program.

Methods
In 2019-2021, 24 US clinical labs collected up to 250 consecutive, aerobic or facultative, gram-negative pathogens from various infection sources. Susceptibility was determined with CLSI broth microdilution and 2023 breakpoints. CR was defined as meropenem-nonsusceptible (NS). Only NME were analyzed because no CLSI breakpoint exists for IMI/REL against Morganellaceae. IMI-, IMI/REL-, and/or C/T-NS isolates were screened for β-lactamase genes.

Results
Among 9524 collected NME isolates, 100 (1.0%) were CR. Among the most common species, CR rates ranged from 0.2% for E. coli to 2.1% for K. pneumoniae and E. cloacae. Of the 100 CR NME isolates, 90 were molecularly characterized: Two-thirds carried carbapenemases, almost all KPC; 13% carried only ESBL or AmpC, and in 20%, no acquired β-lactamases were detected (Figure 1). IMI/REL maintained activity against 76% of all CR NME, ≥50 percentage points higher than the comparator β-lactams and levofloxacin (Figure 2). IMI/REL inhibited 94% of 52 KPC-positive, 0 of 8 MBL- or OXA-48-like-positive, and 73% of 30 carbapenemase-negative CR NME isolates.

Conclusion
Carbapenem resistance among clinical NME isolates collected in the US was largely due to carbapenemases, predominantly KPC while MBL or OXA-48-like were rare. IMI/REL represents an important therapy option for infections with CR NME that are KPC-positive or carbapenemase-negative.

Disclosures
Sibylle Lob, MD, Merck & Co., Inc.: Honoraria Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck & Co Inc.: Employee Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2155. Low prevalence of OXA-48-like carbapenemases and susceptibility to imipenem/relebactam among carbapenem-resistant non-Morganellaceae Enterobacterales isolates from Latin America – SMART 2018-2021
Authors: Lob Sibylle , Wise Mark G , Siddiqui Fakhar , Polis Thales , DeRyke C Andrew , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: November 2023

Abstract

Background
Imipenem/relebactam (IMI/REL) is a combination of imipenem/cilastatin with relebactam, an inhibitor of class A and C β-lactamases. IMI/REL is not active against metallo-β-lactamases (MBLs) or OXA-48-like carbapenemases. Using non-Morganellaceae Enterobacterales (NME) isolates collected in 9 countries in Latin America as part of the SMART surveillance program, we evaluated the proportion of carbapenemases among carbapenem-resistant (CR) isolates as well as the activity of IMI/REL against all and CR isolates.

Methods
In 2018-2021, 44 clinical labs in Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Panama, and Puerto Rico each collected up to 250 consecutive, gram-negative pathogens per year from patients with bloodstream, intraabdominal, respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with CLSI breakpoints. Isolates that were imipenem-, IMI/REL-, or ceftolozane/tazobactam-nonsusceptible were screened for β-lactamases. Carbapenem-resistance was defined as nonsusceptibility (I+R) to meropenem.

Results
Susceptibility to IMI/REL among all collected NME isolates from Latin America was 96.5%, ranging from 90% (Guatemala) to 99% (Puerto Rico) (Figure 1). Among CR isolates, IMI/REL-susceptibility was 72.0% overall, ranging from 4% (Guatemala) to 95% (Puerto Rico). Carbapenem-resistance among NME isolates collected in Latin America was mostly attributable to carriage of MBLs or KPCs, while OXA-48-like and GES carbapenemases were rare (Figure 2). Lower IMI/REL-susceptibility of CR NME from Guatemala, Mexico, and Panama correlated with higher MBL rates among CR NME (37-93%), while IMI/REL activity against CR NME in countries with high KPC rates (≥80% in Argentina, Brazil, Colombia, Ecuador, and Puerto Rico) remained high (73-95% susceptible). Rates of isolates carrying OXA-48-like carbapenemases among CR NME were low everywhere (≤2% in all countries except Mexico [14%]).

Conclusion
IMI/REL showed strong activity against carbapenem-resistant NME isolates collected in most countries in Latin America. Susceptibility was only reduced in countries with higher MBL rates, while OXA-48-like carbapenemases were detected rarely.

Disclosures
Sibylle Lob, MD, Merck & Co., Inc.: Honoraria Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck & Co Inc.: Employee Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation