bluuebunny/crossref_metadata_2025_split huggingface dataset:
1705. Filamentous Hemagglutinin Polyclonal Antibodies Protect against Multidrug resistant Gram-negative bacteria
Authors: Youssef Eman , Alkhazraji Sondus , Singh Shakti , Gebremariam Teclegiorgis , Ibrahim Ashraf 
Published: December 2022

Abstract

Background
Multidrug-resistant (MDR) Gram-negative bacteria (GNB) are among the major healthcare-associated infections and have high mortality especially in immunocompromised patients. Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) are classified as “critical organism” by CDC. Therefore, new anti-infective therapies are critically needed. Our studies showed that passive immunization using antibodies against Candida Hyr1 peptide#5 are protective in AB pneumonia mouse model and this was attributed to the structure homology between Candida Hyr1 and AB Filamentous hemagglutinin protein B (FhaB). In this study, we identified FhaB epitopes that shared sequence homology with Candida Hyr1 peptide#5. We aim to evaluate antibody-based therapy targeting these epitopes against AB and PA infection.
Designing and evaluating FhaB peptides that share sequence similarity to Hyr1#5
In vivo protection of FhaB antibodies in mouse model on different MDR GNB A) AB B)PA

Methods
Sequence homology was done using BLAST online tool. FhaB peptides and their polyclonal antibodies (pAbs) were commercially produced. Indirect ELISA was done to test recognition FhaB peptides to Hyr1#5 Abs. Binding ability of FhaB pAbs was tested against AB and PA using flow cytometry. The efficacy of pAbs in protecting against AB- or PA-induced pneumonia was studied in immunosuppressed CD1 mice by administering 30 µg of pAbs (i.p.) on Day +1 relative to infection. Survival of mice served as an endpoint.

Results
We identified seven FhaB peptides that shared ∼50% sequence homology with Hyr1#5. These peptides are conserved among many GNB including AB and PA. Two peptides (FhaB#4 & FhaB#5) showed strong binding to Hyr1 Abs in ELISA. The pAbs generated against these two peptides showed ∼90% and 50% binding to AB and PA, respectively. Finally, pAbs targeting FhaB#4 protected mice from lethal dose of both AB and PA with 70% and 40% survival efficacies, respectively (p&lt; 0.05).

Conclusion
We used FhaB to generate protective pAb against MDR AB and PA. Our results warrant the further development of these Ab as novel immunotherapeutics against MDR GNB.

Disclosures
All Authors: No reported disclosures.
1709. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against MDR Enterobacterales and Pseudomonas aeruginosa Collected in Latin America, ATLAS Global Surveillance Program 2018-2020
Authors: Wise Mark , Stone Gregory , Sahm Daniel F 
Published: December 2022

Abstract

Background
Multidrug-resistant (MDR) Gram-negative bacteria are an increasing worldwide problem. Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C, and some class D β-lactamases, enzymes that contribute to MDR. This study examined the in vitro activity of CAZ-AVI and comparators against MDR Enterobacterales and Pseudomonas aeruginosa isolates collected from patients in Latin America.

Methods
9193 non-duplicate Enterobacterales (Ent) and 3225 P. aeruginosa (Psa) isolates from were collected from 36 sites in 10 Latin American countries as part of ATLAS 2018-2020. Antimicrobial susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2022 breakpoints. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin (AMK), aztreonam (ATM), cefepime (FEP), colistin (CST), levofloxacin (LVX), meropenem (MEM), and piperacillin-tazobactam (TZP). Ent isolates testing with meropenem MICs &gt;1 µg/mL and Escherichia coli, Klebsiella pneumoniae, K. oxytoca, K. variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs &gt;1 mg/L were genetically screened for β-lactamases. Psa with meropenem MIC &gt;2 µg/mL were screened in 2018-2019. In 2020, approximately 25% of qualifying Psa were screened.

Results
The activity of CAZ-AVI and comparators against all isolates and the MDR subsets is shown in the table. CAZ-AVI was active against the full collection of Enterobacterales isolates with 96.7% of the population susceptible and an MIC90 value of 1 µg/mL, and maintained considerable activity against the MDR subset, inhibiting 86.5% of the isolates, a value higher than comparator agents. For the full collection of Psa, 86.6% of the isolates were susceptible to CAZ-AVI, again the highest %S among the comparator drugs. Versus the MDR subset of Psa, CAZ-AVI displayed a 45.8% susceptibility rate, approximately 10% higher than the nearest comparator, amikacin.

Conclusion
The in vitro data suggest that CAZ-AVI can be an effective therapeutic for infections caused by MDR Enterobacterales in Latin America. MDR among P. aeruginosa remains challenging, although a significant percentage are inhibited by CAZ-AVI.

Disclosures
All Authors: No reported disclosures.
1710. In Vitro Activity of Cefepime-Taniborbactam and Comparators Against a Global Collection of Carbapenem-Resistant Enterobacterales and Carbapenem-Resistant Pseudomonas aeruginosa With and Without Carbapenemases
Authors: Wise Mark , Hackel Meredith , Sahm Daniel F 
Published: December 2022

Abstract

Background
Carbapenem-resistant Enterobacterales (CRE) and P. aeruginosa (CRPA) present treatment difficulties owing to numerous possible resistance mechanisms, including the carriage of carbapenemases. Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with activity against serine-, and NDM & VIM metallo-β-lactamases (Ambler Classes A, B, C and D). The activity of the investigational combination cefepime-taniborbactam (FTB) and comparator agents was evaluated against a recent global collection of carbapenemase and non-carbapenemase producing CRE and CRPA.

Methods
13,731 Enterobacterales and 4,619 P. aeruginosa isolates collected from 56 countries in 2018-2020 were a part of this study. MICs of cefepime with taniborbactam fixed at 4 µg/mL and comparators were determined according to CLSI guidelines and interpreted using 2022 CLSI breakpoints. CRE and CRPA were defined by resistance to meropenem. Organisms with FTB MIC ≥16 µg/mL were characterized by whole genome sequencing, while those resistant to meropenem were screened for acquired β-lactamase carriage by multiplex PCR followed by Sanger sequencing.

Results
Among the 637 CRE identified, 596 were found to carry a carbapenemase while the remaining 41 did not. For the carbapenemase-positive CRE, 89.8% and 94.5% of isolates were inhibited at ≤8 µg/mL and ≤16 µg/mL FTB, respectively, both values significantly greater than comparators (Table). For carbapenemase-negative CRE, 92.7% of isolates were inhibited at ≤8 µg/mL FTB, and 95.1% were inhibited at ≤16 µg/mL, again higher %s than comparators. Against carbapenemase-negative CRPA (n=703), FTB was the most active agent among the comparators, with 82.6% inhibited at ≤8 µg/mL and 94.9% inhibited at ≤16 µg/mL. Versus CRPA carrying carbapenemases (n=245), 61.9% were inhibited at ≤8 µg/mL FTB and 72.5% were inhibited at ≤16 µg/mL FTB.

Conclusion
FTB displayed substantial in vitro activity against CRE and CRPA regardless of whether they harbored carbapenemases. More isolates of each group were inhibited by FTB at ≤8 µg/mL than were susceptible to all tested β-lactam/β-lactamase inhibitor combinations. These data support the continued development of FTB as a potential new therapeutic antibacterial agent.

Disclosures
All Authors: No reported disclosures.
1717. In Vitro Activity of Aztreonam-Avibactam Against Enterobacterales Isolated from Pediatric and Adult Patients Collected During the ATLAS Global Surveillance Program, 2017-2020
Authors: Estabrook Mark , Arhin Francis , Sahm Daniel F 
Published: December 2022

Abstract

Background
The rapid spread of antimicrobial resistance among clinically isolated Enterobacterales (Eba) continues to threaten 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 drug-resistant isolates of 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 2017-2020 from pediatric and adult patients as part of the ATLAS global surveillance program.

Methods
Non-duplicate clinical Eba isolates were collected from 239 sites in 55 countries in Europe, Latin America, Asia/Pacific (excluding mainland China and India), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2022 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC &gt;1 µg/mL, and 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 were observed for Eba isolates collected from both pediatric and adult patients. Against all Eba isolates, ≤8 µg/ml of ATM-AVI was sufficient to inhibit 99.97% (pediatric) and 99.95% (adult), whereas ATM alone inhibited only 72.0% and 75.9% of these isolates at ≤8 µg/ml, respectively (table). Among isolates that screened positive for an MBL, MIC90 values were 0.25 µg/ml (pediatric) and 0.5 µg/ml (adult). Among MBL-positive isolates, ATM-AVI inhibited 100% (pediatric) and 99.9% (adult) at concentrations ≤8 µg/ml. In contrast, ATM alone only inhibited 19.0% (pediatric) and 25.3% (adult) of isolates carrying MBLs at ≤8 µg/ml.

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

Disclosures
All Authors: No reported disclosures.
1718. In Vitro Activity of Imipenem/Relebactam against Class C β-lactamase-Positive Enterobacterales in the Asia/Pacific Region: SMART 2018-2020
Authors: Lob Sibylle , Estabrook Mark , Chen Wei-Ting , Siddiqui Fakhar , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: December 2022

Abstract

Background
Imipenem/relebactam (IMR) is a combination of imipenem/cilastatin with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. We evaluated the activity of IMR and comparators against AmpC- and extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae as well as against isolates of intrinsic AmpC-producing Enterobacterales species that were collected in 9 countries in Asia/Pacific as part of the global SMART surveillance program.

Methods
In 2018-2020, 48 clinical laboratories in Australia, Hong Kong, Malaysia, New Zealand, Philippines, South Korea, Taiwan, Thailand, and Vietnam each collected up to 250 consecutive, aerobic or facultative, gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2022 CLSI breakpoints. Isolates that were ertapenem- (2018 only), imipenem-, IMR-, or ceftolozane/tazobactam-nonsusceptible were screened by PCR and Sanger sequencing for β-lactamases.

Results
As shown in the table, IMR maintained activity against ≥96% K. pneumoniae and E. coli that carried ampC with or without ESBL as well as against those intrinsic ampC carriers (except S. marcescens, 92.7%) among which no additional β-lactamases other than ESBLs were identified. The addition of relebactam increased the susceptibility to imipenem alone by 8-55 percentage points for K. pneumoniae and E. coli carrying AmpC with or without ESBL. Among intrinsic ampC carriers, the largest increase was seen among K. aerogenes (28 percentage points). Relebactam restored susceptibility to 97.3% of imipenem-nonsusceptible (NS) ampC-positive K. pneumoniae (n=73) and to 95.7%, 98.6%, and 37.7% of imipenem-NS isolates of E. cloacae complex (n=92), K. aerogenes (n=147), and S. marcescens (n=61) that carried no acquired β-lactamases. Among the imipenem-NS S. marcescens isolates, 50.8% tested with an IMR MIC of 2 µg/mL, which would be susceptible according to EUCAST guidelines.

Conclusion
IMR showed strong activity against clinical Enterobacterales isolates that carried either acquired or intrinsic ampC with or without ESBL collected in Asia/Pacific.

Disclosures
Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.
1722. In vivo Activity of Imipenem/XNW4107 Human-Simulated Regimen against Serine Carbapenemase-Producing Acinetobacter baumannii and Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model
Authors: Fratoni Andrew J , Berry Angela , Yuan Haitao , Liu Xiao , Chen Xi , Wu Yuchuan , Nicolau David P , Abdelraouf Kamilia 
Published: December 2022

Abstract

Background
Imipenem (IPM)/XNW4107 is a novel β-lactam/β-lactamase inhibitor with in vitro activity against serine carbapenemase-producing Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales. Herein, we evaluated the in vivo activity of an IPM/XNW4107 human-simulated regimen (HSR) against clinical OXA-23- and OXA-24-producing A. baumannii as well as KPC- and GES-producing P. aeruginosa using a neutropenic murine thigh infection model.

Methods
Seven A. baumannii and 4 P. aeruginosa isolates were included. IPM and IPM/XNW4107 MICs (XNW4107 fixed at 8 mg/L) were tested in triplicate by broth microdilution. One thigh of neutropenic ICR mice (6 mice per group) was inoculated with ∼107 CFU/mL bacterial suspensions. HSR that mimicked the clinical exposures of IPM 500 mg q6h alone or in combination with XNW4107 250 mg q6h each as 1 h infusion were developed in the murine model. In efficacy studies, two hours after inoculation, placebo, IPM 500 mg q6h 1 h infusion HSR, or IPM/XNW4107 500/250 mg q6h 1 h infusion HSR were administered subcutaneously. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls.

Results
Isolates were IPM resistant (MICs 16 - &gt; 64 mg/L). IPM/XNW4107 A. baumannii and P. aeruginosa MIC ranges were 1-16 and 1- 8 mg/L, respectively. Across all examined isolates, 0 h mean ± SD bacterial burden was 5.86 ± 0.32 log10 CFU/thigh. The 24 h increase in bacterial burden was 2.68 ± 0.91 log10 CFU/thigh in the sham controls. IPM HSR monotherapy groups showed mean increase in bacterial burden of 2.34 ± 0.95 log10 CFU/thigh. Bacterial kill with IPM/XNW4107 500/250 mg q6h 1 h infusion HSR ranged from -0.46 ± 1.69 to -3.77 ± 0.15 and -2.33 ± 0.25 to -3.76 ± 0.57 among A. baumannii and P. aeruginosa isolates, respectively. IPM/XNW4107 500/250 mg q6h 1 h infusion HSR produced &gt; 1-log kill against 6/7 examined A. baumannii with the exception of A. baumannii 160 (IPM/XNW4107 MIC 16 mg/L) and 4/4 P. aeruginosa as well as &gt; 2-log kill against 4/7 A. baumannii and 4/4 P. aeruginosa.

Conclusion
IPM/XNW4107 500/250 mg q6h 1 h infusion HSR showed potent in vivo activity against serine carbapenemase-producing A. baumannii and P. aeruginosa. These data support the consideration of IPM/XNW4107 for the treatment of serious infections due to these organisms in clinical trials.

Disclosures
Haitao Yuan, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xiao Liu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xi Chen, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Yuchuan Wu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds David P. Nicolau, PharmD, Shionogi: Grant/Research Support Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support.
1726. Patterns of Isavuconazole Use for Invasive Fungal Infections
Authors: Gow-Lee Vanessa , Chesdachai Supavit , Gile Jennifer , Akhiyat Nadia , Harris Courtney E , Abu Saleh Omar M 
Published: December 2022

Abstract

Background
Isavuconazole (ISA) is a relatively recent triazole antifungal with several attractive qualities and so increased clinical experience and data on the use of ISA are desirable. However, the data on the pattern of ISA use in invasive fungal infections (IFI) is limited.

Methods
We conducted a retrospective study of patients with probable or proven IFI treated with ISA at Mayo Clinic from 1/1/2015 to 4/1/2020 to examine temporal trends and characteristics of ISA use.

Results
The use of ISA rose over this period, from 4 cases in 2015 to 42 cases in 2019. Of 131 patients identified, ISA was used as the initial antifungal in 15 (11.5%) patients and as the secondary agent in 116 (88.5%) patients. The most cited reasons for choosing ISA as first-line therapy were drug-drug interactions (5, 33%) and baseline QTc prolongation (3, 20%). In cases of ISA used as a secondary agent, the reasons for transitioning to ISA were QTc prolongation (22, 19%), followed by judged failure of the primary therapy (20, 17%), drug-drug interactions (12, 10%), and various toxicities with the first agent. ISA was discontinued early in 81 (62%) patients. Common reasons for early discontinuation were patient death or comfort care (27, 33%), intolerance (18, 22%), failure of therapy (17, 21%), cost or access (6, 7%), drug-drug interaction (3, 4%), issues with absorption or drug delivery (3, 4%), and microbe susceptibility (1, 1%). ISA was judged successful and used as definitive treatment in the remaining 50 (38%) patients. About 30 patients took &gt;1 year of ISA, and no major adverse effects from long-term therapy were noted.

Conclusion
Although ISA is approved for pulmonary aspergillosis and mucormycosis, we found that few patients were treated with ISA as either primary or salvage therapy. In cases where it was used, shortening the QTc and fewer drug-drug interactions were its most attractive qualities. Although it is a newer azole, the morbidity common with other antifungals should prompt more studies on ISA’s efficacy to increase clinicians’ confidence in this option.

Disclosures
All Authors: No reported disclosures.
1728. Real world experience with cefiderocol for multi drug resistant gram negative bacterial infection in a tertiary hospital
Authors: Rondain Patricia Isabella , Ramdeen Sheena , Norman Sarah J 
Published: December 2022

Abstract

Background
Increasing rates of antibiotic resistance has emerged as one of the top concerns in health care. New resistance mechanisms such as carbapenemase production present a challenge in treating common infections. Novel antibiotics are being developed to tackle these pathogens, and one of the newest drugs in this arsenal is cefiderocol, a siderophore cephalosporin. Real-world data regarding the clinical use and outcomes of cefiderocol is limited.

Methods
A single-center, retrospective chart review was completed from July 2020 to March 2022 and included adult patients who received at least one dose of cefiderocol. Patient baseline characteristics were obtained along with other variables related to the primary infection. The primary outcome was clinical failure defined as 30 day mortality following cefiderocol administration. Secondary outcomes were development of resistance to cefiderocol, clearance of bacteremia, adverse drug reactions, and hospital length of stay.

Results
Cefiderocol was dispensed in 22 unique patient encounters. It was most often used to treat respiratory tract (45.4%, 10/22) and cardiac device infections (40.9%, 9/22). Most infections were polymicrobial, however, the most common organisms isolated were Pseudomonas aeruginosa and Klebsiella pneumoniae. The clinical failure rate was 22.7% (5/22). One patient developed resistance to cefiderocol throughout the hospitalization. Eight patients were treated for bacteremia, and 87.5% (7/8) demonstrated microbiological cure. Minimal side effects were observed in this cohort; two patients developed diarrhea, and one of whom had confirmed C. difficile colitis. The median length of stay was 24 days.

Conclusion
This cohort of patients demonstrated that cefiderocol can be used in a variety of multidrug resistant infections including bacteremia. Although limited by a small sample size, this study demonstrated a low prevalence of resistance. These results are promising in the ongoing and emerging issue of antibiotic resistance, and larger studies are needed to determine true efficacy and place in therapy for cefiderocol.

Disclosures
All Authors: No reported disclosures.
1729. Real-world Experience with Ceftazidime-avibactam Compared with Ceftolozane-tazobactam on Clinical Outcomes in Pseudomonas aeruginosa Infections
Authors: Golia Austin , Guo Yi , Chang Mei H , McSweeney Terrence D , Lee Philip J , Bao Hongkai 
Published: December 2022

Abstract

Background
The 2022 IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-negative Infections recommends the use of a novel beta-lactam/beta-lactamase inhibitor, such as ceftolozane-tazobactam (C/T) or ceftazidime-avibactam (C/A), as first-line for treatment of resistant Pseudomonas aeruginosa infections. C/T is often preferred for these infections due to a narrower spectrum and lower cost. However, from December 2020 to January 2022, a global shortage of C/T resulted in widespread adoption of C/A as an alternative. While in vitro susceptibilities support the use of C/A for P. aeruginosa, real-world experience comparing clinical outcomes to C/T is limited.

Methods
This multicenter, retrospective analysis was conducted at an urban, academic healthcare system in the Bronx, NY. Between January 2018 and December 2020, admitted adult patients who received C/A or C/T to treat P. aeruginosa infections were included. Patients were excluded if in vitro resistance to either drug was demonstrated or if susceptibility was missing. The primary outcome was clinical success, defined as resolution of signs and symptoms of infection, by end of treatment. Secondary outcomes included 30-day mortality, resistance to study drug after therapy, modification of therapy, 14-day microbiological failure, 90-day infection recurrence, and length of stay.

Results
A total of 46 patients received C/A and 56 patients received C/T to treat P. aeruginosa infections. Most baseline characteristics were similar between the two arms, though more patients were critically ill in the C/A arm (Table 1). Clinical success was similar between C/A and C/T patients (72% vs. 63%, p=0.33). No significant differences between arms were identified for secondary outcomes (Table 2). Development of drug resistance within 90 days of treatment occurred more frequently in the C/A arm, approaching significance. On multivariate regression analysis, vasopressor use at the time of study drug initiation was the only variable associated with reduced clinical success.

Conclusion
C/A may be an effective alternative treatment for multidrug-resistant P. aeruginosa infections with close monitoring for development of resistance. Larger comparative studies are needed to confirm these findings.

Disclosures
Yi Guo, PharmD, BCIDP, Merck: Grant/Research Support.