bluuebunny/crossref_metadata_2025 huggingface dataset:
2118. Comparative Analysis of Cefiderocol Mono- and Combination Therapy for Multi-Drug Resistant Gram-negative Infections
Authors: Ghali Amer El , Kunz-coyne Ashlan , Lucas Kristen , Tieman Molly , Purdy Andrew , Iturralde Gabriela , Garcia Esther , Holger Dana , Lau Suet-Ping , Xhemali Xhilda , Veve Michael P , Rybak Michael J
Published: November 2023

Background

Multi-drug resistant gram-negative infections are a growing concern, necessitating the development of novel treatments. Cefiderocol (CFDC) is a new siderophore cephalosporin that targets the iron transport mechanism used by many gram-negative pathogens. We aimed to compare the clinical outcomes of CFDC monotherapy and combination therapy in various infection types.

Methods

We performed a retrospective cohort analysis at 5 academic medical centers from May 2022 to April 2023. Patients were included if they were ≥18 years old and received CFDC for ≥48 hours, excluding subsequent courses not separated by ≥90 days. The primary objective was composite clinical success (30-day survival, absence of 30-day infection recurrence and resolution of signs and symptoms), with secondary objectives including individual components of clinical success, on-treatment resistance, 30-day readmission, and adverse reactions. Descriptive statistics and logistic regression were used.

Results

We analyzed 70 patients, with 35 in each treatment group. The cohort was predominantly male (64.3%), had a mean age of 55.5 years (17.6), and 67% were admitted to the Intensive Care Unit. The mean (SD) APACHE II scores were 12.8 (7.5) for monotherapy and 14.9 (6.7) for combination therapy (p=0.22), while the mean (SD) Charlson comorbidity scores were 5.0 (3.6) and 4.5 (3.5) for the respective groups (p=0.61). The most common infection source was respiratory tract (54.3%), with Pseudomonas aeruginosa (55.7%) and Acinetobacter baumannii (25.7%) as the most frequently isolated pathogens. The median (IQR) CFDC mean inhibitory concentration (MIC) was 0.5 µg/mL (0.25-1.0). The 30-day mortality rates for the monotherapy and combination groups were 20% and 28.6%, respectively. There was no significant difference in composite clinical success between the groups (p=0.59).

Conclusion

Our preliminary data suggest that there is no difference in clinical success between CFDC monotherapy and combination therapy with another antibiotic. Further studies are needed to confirm these findings and evaluate the optimal use of CFDC in a variety of clinical settings.

Disclosures

Michael J. Rybak, PharmD, PhD, MPH, Abbvie, Merck, Paratek, Shionogi, Entasis, La Jolla, T2 Biosystems: Advisor/Consultant
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

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 >1 µg/mL, and a randomly sampled subset of approximately 80% of Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC >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

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

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

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

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

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

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

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
2160. Emergence of INDEL Mutations in KPC-2: Insights into Ceftazidime-Avibactam and Imipenem-Relebactam Efficacy
Authors: Brunetti Florencia , Bethel Christopher R , Sanz María Belén , Pasterán Fernando , Gutkind Gabriel , Gomez Sonia , Bonomo Robert A , Power Pablo
Published: November 2023

Background

Enterobacterales producing KPC-2 and KPC-3 β-lactamases (Bla) are a significant clinical threat. Ceftazidime/avibactam (CZA) and imipenem/relebactam (IMI/REL) are successful in the treatment for these infections. Unfortunately, CZA-resistant isolates are emerging as a result of amino acid changes in three “hotspots” in the KPC Bla: Ω-loop region; the 237-243 loop; and the 266-275 loop (Figure 1). Our goal here is to assess the effect of insertion-deletion (INDEL) mutations located in the three hotspots in KPC-2, and their impact on the efficacy of these two drug combinations

Methods

The blaKPC-44 (ins_261_AVYTRAPNKDDKHSE), blaKPC-80 (ins_267_PNK), blaKPC-81 (del_173_I), blaKPC-97 (ins_276_VNSEA), and blaKPC-160 (del_167_LE) genes were amplified by PCR from K. pneumoniae isolates resistant to CZA. The blaKPC-14 (del_242-243_GT) gene was obtained by mutagenesis from the blaKPC-2 gene. Genes were cloned in pMBLe and transformed in E. coli TOP10 for MIC determinations. Immunoblotting with polyclonal anti-KPC-2 antibody was performed in whole-cell preparations. Molecular modeling of KPC variants were obtained by Yasara

Results

All KPC variants demonstrated lower MICs compared to KPC-2 for most β-lactams (carbapenems included), except for CAZ, where variants exhibited up to 8-fold higher MICs. All variant clones showed at least a 3-dilution higher MICs for CZA, except KPC-160. IMI-REL restored susceptibility to KPC-2 and INDEL variants. The Ω−loop variants exhibited lower MICs compared to the other hotspots variants (CZA included). INDEL mutations resulted in decreased levels of protein production, with KPC-81 production being the most affected. In silico models suggest that INDEL mutations have different effects depending on the structural domain affectedTable 1.Minimum Inhibitory Concentrations (μg/mL) of E. coli TOP10F´ recombinant clones

Conclusion

INDEL mutations in the three hotspots of KPC-2 can impair CZA activity, but not affect IMI/REL susceptibility. The differences in MICs among the variants suggest that each hotspot affects the interactions of KPC-2 with CAZ and AVI through different mechanisms. Additionally, INDEL mutations appear to decrease protein stability as Bla production levels are reduced. This work provides relevant information about the changes in the interaction with DBO inhibitors associated with INDEL mutations in KPC-2

Disclosures

Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
2940. Weaving Federal and Private Funding to Achieve Hepatitis C Elimination Goals at Syringe Services Programs in Rural Kentucky
Authors: Van Sickels Nicholas , Soria Jaime , Thornton Alice C , Wilburn Amanda B , Collins Jana
Published: November 2023

Background

Addressing the syndemic of HIV, Hepatitis C (HCV), and Opioid Use Disorder in rural Kentucky requires unique approaches to funding, assessment, and treatment. The Kentucky Income Reinvestment Project (KIRP) leverages Ryan White, CDC, and private funding to provide harm reduction services, including HIV and Hepatitis C testing, across the majority of Kentucky's Syringe Services Programs (SSPs). We sought to compare HCV evaluations between SSPs with KIRP support versus SSPs without KIRP support. Additionally, we describe early results from a pilot study providing direct treatment at the SSP from 2 KIRP-supported counties (Figure 1).

Methods

We performed a cross-sectional review of data reported to Kentucky Department for Public Health from March 2021 to March 2023. OraQuick® HCV rapid antibody tests were used for screening. We compared the number of eligible clients seen and tested for HCV, the seropositivity, and referral rates for treatment. Additionally, we report pilot outcomes from two counties, where patients were treated at the SSP. Study data was managed using the REDCap data capture tool. Chi-squared tests were used to describe statistical differences between groups, with analyses performed using Stata 17 (College Station, TX: Stata Corp LLC).

Results

Over a 24-month period, KIRP sites saw and tested a higher volume and percentage of clients than non-KIRP sites (18.3% versus 4.9%, p< 0.001; see Figure 2). HCV seropositivity was similar between KIRP and non-KIRP sites (31.5% versus 23.2%, p=0.058). HCV treatment referrals were greater at KIRP sites, with 646/654 (98.8%) referred compared to 26/29 (89.7%) referred at non-KIRP sites (p=0.009). Pilot counties received 107 referrals from May 2022 to March 2023. 51/107 were evaluated; nine had negative RNA testing, 17 did not show, and 25 completed one visit. To date, 5 patients achieved SVR, and 5 are undergoing treatment (Figure 3).

Conclusion

Our study demonstrates significantly higher rates of HCV testing, linkage, and referral at KIRP-supported SSPs in Kentucky. Overlaying funding from the Ryan White Care Act with CDC and private entities allows for status neutral assessments for HIV and HCV. Partnerships for direct treatment of HCV at the SSP, especially in more rural areas, are crucial to the HCV elimination strategy.

Disclosures

All Authors: No reported disclosures
2169. A 4-Year Analysis of Antimicrobial Susceptibility to Ceftolozane/Tazobactam in Pseudomonas aeruginosa: How Drug Availability Affects Resistance Rate
Authors: Imeneo Alessandra , Campogiani Laura , Di Lorenzo Andrea , D’Agostini Cartesio , Altieri Anna , Malagnino Vincenzo , Andreoni Massimo , Iannetta Marco , Sarmati Loredana
Published: November 2023

Background

Antibiotic resistance is associated with a fitness cost and reduced bacterial growth that allows susceptible bacteria to outcompete resistant bacteria, if selective pressure from antibiotics is reduced. Ceftolozane/tazobactam (C/T) approved in 2014, was temporarily withdrawn from December 2020 to February 2022: this forced unavailability created the conditions to study how drug discontinuation might influence resistance reversibility.

Methods

This is a retrospective observational study, including isolates of P. aeruginosa collected between March 1st 2019 and February 22nd 2023. Isolates collected from swabs (e.g. rectal, skin) or with no C/T susceptibility test were excluded. Antibiotic susceptibility tests were performed with the Vitek-2 assay. Only the first isolate for each patient was included; multiple isolates from the same patient were included if collected at least 5 months apart. Four collection periods were defined (Fig 1). All data were analyzed using JASP.

Results

From the Hospital microbiology laboratory list, 1768 P. aeruginosa isolates were derived, of which 926 isolates fulfilled the inclusion criteria. A significant (p-value < 0.001) reduction of C/T resistance rate was observed when the antibiotic was unavailable, followed by a subsequent increase with its reintroduction (Tab.1). Evaluating phenotypic susceptibility to other antibiotics, production of GES-variants, suggested by resistance to carbapenem and C/T but retained susceptibility to ceftazidime/avibactam, was most likely the predominant resistance mechanism (Tab. 2); a reduction in GES-like isolates, concurrent with decreasing C/T resistance was observed. 19 patients presented a C/T-resistant isolate after a previous susceptible one, but only 4 patients had received a prior C/T treatment (Tab 3).

Conclusion

The temporary unavailability of C/T created the condition to analyze the practical application of the theory of fitness cost to maintain resistance. Our data show a significant reduction of resistance in the absence of the antibiotic, but a subsequent increase with its reintroduction, due to the persistence of resistant isolates. Therefore, continuous monitoring of antibiotic use and evolving resistance is essential.

Disclosures

All Authors: No reported disclosures
2171. Minocycline Susceptibility in Carbapenem-Resistant Acinetobacter baumannii Blood Isolates in South Korea: Role of tetB Gene in Resistance
Authors: Kim Taeeun , Jun Eun Hee , Hong Yoon-Kyoung , Jung Jiwon , Kim Min Jae , Sung Heungsup , Kim Mi-Na , Kim Sung-Han , Choi Sang-Ho , Lee Sang-Oh , Kim Yang Soo , Chong Yong Pil
Published: November 2023

Background

Carbapenem-resistant Acinetobacter baumannii (CRAB) represents a growing global threat with minimal therapeutic options. Minocycline (MIN), a semisynthetic tetracycline derivative, has been suggested as an attractive therapeutic option for CRAB infection. However, the optimal dosing and breakpoint for MIN in treating CRAB infection remain unclear. Furthermore, nonsusceptibility to MIN may occur through the efflux pump, in particular, TetB. As the prevalence of tetB in A. baumannii has increased, so have the MIN minimum inhibitory concentrations (MICs) for A. baumannii strains carrying tetB. Here, we evaluated the MIN susceptibility rate in CRAB clinical strains and the association between tetB carriage and MIN susceptibility.

Methods

Representative CRAB blood isolates were collected from a tertiary care center in South Korea. The Clinical and Laboratory Standards Institute (CLSI) MIN susceptibility breakpoint for A. baumannii was defined as MIC ≤4 mg/L, whereas a new MIN breakpoint of 1 mg/L was suggested based on pharmacokinetic (PK)/pharmacodynamic (PD) studies. For comparison of the impact of the tetB resistance, tigecycline was used. Tigecycline susceptibility breakpoint for Enterobacterales defined by EUCAST was applied (≤0.5 mg/L). TetB carriage was detected by polymerase chain reaction.

Results

Of 160 CRAB isolates, 134 (84%) were susceptible to MIN according to the CLSI criteria, among which 40% (53/134) were PK-PD non-susceptible. The MIN MIC 50/90 was 1/8 mg/L. Seventy-nine (49%) isolates carried tetB. One-third (26/79) of tetB-positive and none of the tetB-negative isolates were CLSI non-susceptible, while 66% of tetB-positive and 33% of tetB-negative isolates were PK-PD non-susceptible. TetB carriage was correlated with a higher MIN MIC than non-tetB carriage (MIC 50/90 2/8 mg/L vs. 1/2 mg/L) (Figure 1). However, no clear correlation was observed between tetB-positivity and tigecycline MIC (Figure 2). Overall, tetB positivity demonstrated 100% sensitivity for MIN CLSI non-susceptibility and 66% sensitivity for PK-PD non-susceptibility.

tetB positivity and MICs of minocycline for carbapenem-resistant A. baumannii. The CLSI susceptibility breakpoint for minocycline is ≤4 mg/L, whereas a new MIN PK-PD breakpoint of 1 mg/L was suggested.

Figure2.

tetB positivity and MICs of tigecycline for carbapenem-resistant A. baumannii. The tigecycline susceptibility breakpoint for Enterobacterales defined by EUCAST was applied (≤0.5 mg/L).

Conclusion

In our study, 49% CRAB isolates carried tetB gene. Our findings suggest that the lack of tetB is not a reliable marker of MIN PK-PD susceptibility. Therefore, further clinical data on MIN usage is necessary.

Disclosures

All Authors: No reported disclosures
2175. Emergence of Dual-Carbapenemase Producing Enterobacterales in Chile After the COVID-19 Pandemic
Authors: Villamil Aura , Rodas Paula I , Quesille-Villalobos Ana M , Martinez Jose R W , Alcalde-Rico Manuel , Quiroz Valeria E , Rivas Lina M , Riquelme María P , Solar Camila , Rafael Araos , Dias Lorena , Garcia Patricia , Munita José M
Published: November 2023

Background

Carbapenem-resistant Enterobacterales (CRE) are a major public health threat, largely due to the presence of carbapenemases, which are globally disseminated in mobile genetic elements. The emergence of CRE carrying multiple carbapenemases has been reported in several countries, particularly after the COVID-19 pandemic. In this study, we report the emergence of dual-producing CRE (DP-CRE) in Chile and provide a phenotipic and genomic characterization using whole-genome sequencing (WGS).

Methods

We evaluated the presence of carbapenemase in a total of 1367 CRE isolates recovered from invasive infections in 11 healthcare centers since 2018. Among them, 9 DP-CRE were detected and included in this report. Antimicrobial susceptibility was tested by broth microdilution and disk diffusion methods (CLSI, 2023), while blaKPC, blaVIM, blaIMP and blaNDM genes were detected by PCR. WGS was carried out using short and long reads (Illumina and Oxford Nanopore) and hybrid assemblies were performed.

Results

All 9 DP-CRE identified were recovered between November 2021 and June 2022 from 3 healthcare centers of a single city. In terms of species, 6 were identified as E. coli, one isolate of K. pneumoniae, one K. oxytoca and one C. freundii. All DP-CRE identified carried the combination of blaKPC and blaNDM. Genomic analyses confirmed all but one isolate carried blaKPC-2 and blaNDM-7. The remaining genome belonged to a K. pneumoniae that harboured blaKPC-3 and blaNDM-7. All 9 isolates exhibited resistance to all β-lactams, including carbapenems, aztreonam (ATM), cephalosporins and β-lactam/β-lactamase inhibators. Cefiderocol (FDC) was the only compound active against all the isolates. Also, all the DP-CRE became susceptible to ATM when combined with ceftazidime/avibactam (CZA). Hybrid assemblies revealed that blaKPC and blaNDM were harboured on independent plasmids (∼58,900 bp and ∼41,100 bp, respectively) as shown in Figure 1.

Conclusion

To the best of our knowledge, this is the first report of the emergence of DP-CRE in Chile after COVID-19 pandemic. Our results highlight the relevance of active surveillance of multidrug-resistance pathogens. FDC and CZA/ATM were the only compounds that remained active in vitro against these pathogens.

Disclosures

All Authors: No reported disclosures
2176. Cardiolipin Synthases Play Redundant Roles And Are Required for Membrane Remodeling in Daptomycin Resistant Enterococcus faecalis
Authors: Nguyen April , Tran Truc , Panesso Diana , Hood Kara S , Polamraju Vinathi , Zhang Rutan , Khan Ayesha , Miller William R , Mileykovskaya Eugenia , Shamoo Yousif , Xu Libin , Vitrac Heidi , Arias Cesar A
Published: November 2023

Background

Daptomycin (DAP) is a lipopeptide antibiotic targeting anionic phospholipids (APLs) at the division septum. Resistance to DAP (DAP-R) in E. faecalis (Efs) has been associated with activation of the LiaFSR response and redistribution of APL microdomains through the effector protein LiaX. We also identified a novel transmembrane protein (designated LiaY) as essential for changes in APL microdomains which contain cardiolipin (CL). Efs encodes two CL synthase genes, cls1 and cls2. While changes in Cls1 are associated with DAP-R, their link to the LiaFSR system remains unclear. We aim to establish the roles of Cls in DAP-R to provide insights into membrane remodeling associated with DAP-R.

Methods

qRT-PCR was used to study cls expression. Membrane lipid content was analyzed using hydrophilic interaction chromatography-mass spectrometry. Mutants were characterized by DAP minimum inhibitory concentration (MIC) using E-test and localization of APL microdomains with 10-N-nonyl-acridine orange. The bacterial two hybrid system was used to evaluate protein interaction. Fluorescence microscopy evaluated protein co-localization.

Results

cls1 was upregulated in DAP-R Efs OG117ΔliaX. Deletion of either cls caused upregulation of the remaining cls gene. Development of DAP-R altered membrane lipid content, namely, an increase in CL and a shift towards species with longer fatty acid chains and higher degree of unsaturation. Upon deletion of both cls, CL content was eliminated, peripheral APL microdomains were abolished, and a decrease in the DAP MIC was observed. LiaY interacted with Cls1, but not Cls2 using the two-hybrid system. The interaction was confirmed with fluorescence microscopy showing co-localization of LiaY and Cls1 at the septum and away from the septum in DAP-S and DAP-R strains, respectively. LiaY and Cls1 were also individually co-localized to APL microdomains.

Conclusion

While Cls1 is predominantly associated with DAP-R, we show a functional redundancy between Cls1 and Cls2 in both membrane homeostasis and in DAP-R. Cls1 interacts with LiaY, which bridges the resistance mechanism with membrane adaptation, ultimately leading to altered localization of APL microdomains that divert DAP away from the division septum.

Disclosures

William R. Miller, M.D., Merck: Grant/Research Support|UpToDate: Honoraria
2178. Resistance to Cefepime/Taniborbactam in NDM-1 -Are We Losing the Battle against MDROs?
Authors: Ono Daisuke , Mojica Maria F , Bethel Christopher R , Ishii Yoshikazu , Moreno Diego , Vila Alejandro J , Bonomo Robert A
Published: November 2023

Background

Taniborbactam (TAN; Fig 1) is a novel cyclic boronate that inhibits Serine- and some Metallo-β-Lactamases like NDM and VIM. The combination cefepime (FEP)/ TAN has just completed a Phase III clinical trial. Notably, resistance mechanisms of FEP/TAN have already been described, such as the one provided by NDM-9 (Glu152Lys; PMID:36796395). The crystal structure of the NDM-1:TAN complex revealed that Lys224 anchors TAN by forming two hydrogen bonds (PMID:31454231). We previously showed that the Arg228Leu substitution in VIM-24, the homologous residue of Lys224 in VIM-2, improves the activity towards ceftazidime (CAZ) and FEP (PMID:25915520 ). Therefore, we hypothesized that substitutions at position 224 in NDM-1 could also have a similar effect and potentially confer FEP/TAN resistance.

Methods

NDM-1 clones containing all 19 amino acid variants at position 224 were synthesized (Genscript, NJ) and used to transform E. coli DH10B. Minimal inhibitory concentrations (MICs) were determined using the CLSI-approved agar dilution method. NDM-1 and Lys224Ile were further studied by steady-state kinetics, inhibitor analysis, and dockings.

Results

Compared to NDM-1, all but the Lys224Ile variant display lower MICs for FEP, CAZ, and imipenem (IMI) and higher MICs for FEP/TAN. Contrary, resistance to FEP and CAZ conferred by the Lys224Ile variant was similar to that by NDM-1. However, TAN did not alter MIC for FEP (Table 1). Kinetic assays confirmed differences in the catalytic efficiency of NDM-1 and the Lys224Ile variant to FEP and IMI, respectively (Table 2). Likewise, the IC50 of TAN for NDM-1 (0.01 µM) was significantly lower than for the Lys224Ile variant (0.14 µM) (Table 2). Lastly, docking simulations revealed that the Lys224Ile substitution results in the loss of the anchoring H-bonds and yields an unproductive binding of TAN (Fig 2-a, b).

Conclusion

Resistance to CEF/TAN arises from the Lys224Ile substitution in NDM-1. This finding, in addition to the occurrence of NDM-9 (Glu152Lys), may portend vulnerabilities in this novel β-lactam/β-lactamase inhibitor combination by single amino acid changes even before clinical release. Further attention should be focused on exploring the impact of other amino acid substitutions on susceptibility to CEF/TAN to anticipate clinical failure.

Disclosures

Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
2179. Clinical Characteristics And Outcomes of Peritoneal Dialysis-Related Peritonitis Infection by Ampc β-lactamase-producing Enterobacterales
Authors: Navarro Alberto Ordinola , Salazar-Leal Jazmín Itzayana , Luis Bruno Ali Lopez
Published: November 2023

Background

Peritonitis is one of the most significant complications in patients undergoing peritoneal dialysis (PD). Even when appropriately treated, approximately 20% of all episodes are refractory to treatment. Enterobacteriaceae represent about 10% of cases of peritonitis associated with PD, gram-negative organisms that have inducible beta-lactamase genes known as AmpC are usually more severe clinically and are associated with worse outcomes, including an increased risk of hospitalization and death.

Methods

A retrospective case series in Centro Médico Nacional 20 de Noviembre in Mexico from 2020-2022. We included hospitalized patients diagnosed with peritonitis who met the following criteria: Cloudy peritoneal effluent, Abdominal pain, white-cell counts higher than 100/μL with at least 50% polymorphonuclear cells and culture of peritoneal effluent with the isolation of AmpC β-lactamase-producing Enterobacterales Identified by Vitek 2 and corroborated by phenotypic tests.

Results

30 episodes of peritonitis associated with PD by AmpC enterobacterales were identified. Clinical characteristics are summarized in Table1. Their resistance profiles are reported in Table2. Two patients had refractory peritonitis, 3 changed modality to hemodialysis, 2 had repeat peritonitis at 90 days due to Serratia marcescens and required removal. Four patients had a new episode of peritonitis due to another organism, and two died secondary to septic shock Table3. Notably, this infection may be related to poor hygiene conditions and poor techniques in replacing peritoneal fluid bags since we found that 71% of our patients acquired the infection at their homes. We found that 58% of patients treated with at least two antibiotics occupying 2 routes of administration (intravenous/intraperitoneal) had a good response.

Table 2

Table3

Conclusion

AmpC peritonitis can lead to refractoriness, loss of the catheter, change to hemodialysis and even death, which in our particular context, dual antibiotic therapy may be sufficient; however, removing the catheter improves the response to treatment and decreases refractory peritonitis. The relationship to complications by these agents are high (50% in this study), so aggressive management is necessary for better outcomes in case of isolation.

Disclosures

All Authors: No reported disclosures
2184. Clinical and Molecular Epidemiology of Carbapenem-Resistant Gram-Negative Bacilli in a Los Angeles Tertiary Medical Center
Authors: Sanchez John Michael , Contreras Deisy , Morgan Margie Ann
Published: November 2023

Background

Multidrug-resistant gram-negative bacilli are a significant public health threat, associated with 2.2 million deaths worldwide. Of particular importance is the rise of carbapenem-resistant gram-negative bacilli (CRGNB) given the limited options for treatment. The 30-day mortality associated with carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and carbapenem-resistant Acinetobacter baumannii ranges from 16 to 24%. In recognition of the substantial danger of these organisms, the World Health Organization has designated three CRGNB as Critical Priority pathogens.

Methods

Based on culture data and antimicrobial susceptibility testing, patients with CRGNB at Cedars-Sinai Medical Center from December 2022 to April 2023 were identified. Clinical data including patient demographics, prior carbapenem use, isolation of additional antibiotic-resistant organisms, subsequent antibiotic therapy, and mortality were compared among CRGNB.

Results

Of over 65 isolates, the largest proportion of isolates were cultured from pulmonary sources (44%), followed by urine (34%), skin (12%), blood (6%), and abdominal sources (4%). The most prevalent CRGNB isolated were Pseudomonas aeruginosa (65%), Escherichia coli (13%), and Klebsiella pneumoniae (7%). A majority of patients with CRGNB had prior documented carbapenem use (74%) and 71% of CRGNB were associated with at least one other antibiotic resistant organism. Cefiderocol was used to treat 12% of cases. However, 24% of CRGNB were not treated with antibiotics, often with the rationale that the isolate was likely a colonizing strain. The mortality rate among patients with CRGNB during our observation period was 18%.

Conclusion

CRGNB are emerging pathogens associated with prior carbapenem use and result in significant mortality. Subsets of organisms from our dataset will be further studied for relatedness using Fourier-Transform infrared spectroscopy and whole genome sequencing.

Disclosures

All Authors: No reported disclosures