bluuebunny/crossref_metadata_2025_split huggingface dataset:
1700. Efficacy and Safety in Subjects with Renal Impairment in Contezolid and Contezolid Acefosamil Phase 2 and Phase 3 Skin Infection Clinical Trials
Authors: Fang Edward , Yang Huahui , Yuan Hong 
Published: December 2022

Abstract

Background
Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). Contezolid acefosamil (CZA; MRX-4) is an intravenous (IV) double prodrug of CZD. Nonclinical and initial clinical data indicate CZA and CZD may cause less myelosuppression, particularly with longer duration therapy, and with reduced risk of monoamine oxidase inhibition compared with linezolid (LZD). In 3 CZD Phase 2 (Ph2) and Phase 3 (Ph3) skin infection trials and 1 CZA Ph2 acute bacterial skin and skin structure infection (ABSSSI) study, primary efficacy and overall safety outcomes were comparable to LZD, and the most common treatment emergent adverse events (TEAEs) were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD and CZA. In June 2021, CZD was approved in China for complicated skin and soft tissue infections (cSSTI). Sequential therapy with CZA IV followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and ABSSSI clinical trials. Because patients with diabetes commonly have diminished kidney function, efficacy and safety outcomes in subjects with renal impairment were evaluated in completed Ph2 and Ph3 CZD and CZA studies.

Methods
In 4 CZD and CZA Ph2 and Ph3 skin infection trials, subjects were included with estimated creatinine clearance (CLcr) of 60 to &lt; 90 mL/min (mild impairment) and 30 to &lt; 60 mL/min (moderate impairment); no dose adjustments were made for renal function status. Primary efficacy outcomes and occurrence of TEAEs were evaluated for CZD and CZA subjects with no (CLcr ≥90 mL/min), mild, and moderate renal impairment.

Results
Primary efficacy outcomes and occurrence of TEAEs for CZD and CZA subjects with mild or moderate renal impairment were similar to that of subjects with no impairment in 4 skin infection trials.

Conclusion
In 4 completed Ph2 and Ph3 skin infection clinical trials, subjects who received CZD or CZA with mild and moderate renal impairment appeared to have primary efficacy and safety outcomes similar to subjects with no impairment, supporting current Ph3 global DFI and ABSSSI studies which will enroll subjects with reduced kidney function.

Disclosures
Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1701. Pharmacokinetics in Subjects with Renal Impairment in a Contezolid Complicated Skin and Soft Tissue Infection Phase 3 Clinical Trial
Authors: Fang Edward , Yang Huahui , Yuan Hong 
Published: December 2022

Abstract

Background
Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). In a Phase 3 (Ph3) complicated skin and soft tissue infections (cSSTI) clinical trial (MRX-I-06), 719 subjects were randomized to either CZD 800 mg PO q12h or linezolid (LZD) 600 mg PO q12h with a treatment duration of 7-14 days in both groups. CZD was demonstrated to be noninferior to LZD for the primary efficacy outcome, and overall safety assessments were comparable to LZD. The most common treatment emergent adverse events (TEAEs) in both the CZD and LZD groups were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD. In June 2021, CZD was approved in China for cSSTI. Sequential therapy with intravenous contezolid acefosamil (CZA; double prodrug of CZD) followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and acute bacterial skin and skin structure infection (ABSSSI) clinical trials. Because patients with diabetes commonly have diminished kidney function, pharmacokinetics (PK) in renally impaired subjects were evaluated in MRX-I-06.

Methods
In MRX-I-06, subjects enrolled included those with estimated creatinine clearance (CLcr) of 60 to &lt; 90 mL/min (mild impairment) and 30 to &lt; 60 mL/min (moderate impairment); no dose adjustments were made for renal status. In a subset of the CZD group, PK was evaluated for subjects with no (CLcr ≥90 mL/min), mild, and moderate renal impairment.

Results
The CZD PK subset had 63 subjects, of which 19 had renal impairment (18 mild, 1 moderate). CZD subjects with CLcr above and below 90 mL/min had similar PK values, and CLcr was not a significant covariate (below are means ± SD). There was no indication that the variability in CL/F or in AUC was larger due to renal impairment, and the average AUC and Cmax were comparable between subjects with renal impairment and those with normal renal function.

Conclusion
In a Ph3 cSSTI clinical trial, PK in renally impaired subjects who received CZD appeared similar to those without dysfunction, supporting current Ph3 global DFI and ABSSSI studies with CZD and CZA which will enroll subjects with reduced kidney function.

Disclosures
Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1706. IgM Monoclonal Antibodies Targeting Peptidoglycan May Provide Therapeutic Strategies against Antimicrobial Resistant Bacteria
Authors: Kroscher Kellie , Rikhi Nimisha , Muema Kevin , Schuman Richard F , Assiaw-Dufu Aba , Sei Clara J , Fischer Gerald W 
Published: December 2022

Abstract

Background
Antimicrobial resistance (AMR) poses a substantial global threat to human health and development. In addition to death and disability, the cost of AMR to the global economy is significant. Prolonged illness results in longer hospital stays and the need for more expensive medicines and financial challenges for those impacted. Therapeutics such as monoclonal antibodies (mAbs) may offer prevention and control measures against microbial infections without the use of antibiotics. In this study, we developed human antibodies (serum and mAbs) against components of staphylococcus aureus (SA) and Mycobacterium tuberculosis (MTB) and evaluated their capabilities.

Methods
Humanized DRAGA mice were immunized with 20μg of a combination vaccine comprised of Ultrapure peptidoglycan (PGN, derived from SA) and TB Pep01 peptide (targeting MTB HSP16.3), formulated with AddaVax™ adjuvant. Serum antibody responses to PGN, TB Pep01, and various whole bacteria were analyzed using ELISA. Mice with high antisera titers was selected for hybridoma production. Hybridomas were screened for binding to PGN, TB Pep01, and whole bacteria using ELISA and high producing clones were selected for monoclonal antibody development.

Results
Early and enhanced serum IgM responses to PGN were observed by Day-21, while IgG responses to PGN were detected at Day-35. Antisera binding to TB Pep01 was demonstrated, albeit lower than PGN. In addition, antisera recognition of whole bacteria was shown. Hybridoma clones (IgM) targeting PGN were identified for monoclonal antibody production.

Conclusion
Hybridomas developed in humanized DRAGA mice immunized with PGN and TBPep01 bound to the immunogens and showed broad recognition of various microbes. Ongoing studies to evaluate mAb functional activity against various microbes to include mycobacteria and staphylococci are in progress. IgM mAbs that recognize and whole bacteria, and opsonize and kill multiple bacterial strains, may provide an effective antimicrobial strategy for treatment of drug resistant bacterial infections.

Disclosures
All Authors: No reported disclosures.
1714. In Vitro Activity of Tebipenem Against Clinically Significant Gram-Positive Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat Z , Rosenblatt Joel , Hachem Ray Y , Chaftari Anne-Marie , Raad Issam I 
Published: December 2022

Abstract

Background
Carbapenems represent the most potent and broad-spectrum β-lactams and are minimally affected by most β-lactamase enzymes. however, all carbapenems currently in use including meropenem and ertapenem, are parenterally administered. Tebipenem pivoxil (TBPM-PI-HBr) is a new broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. It is the only oral carbapenem and could be an alternative to intravenous injection carbapenem antibiotic therapy. This study aimed to evaluate the in vitro activity of tebipenem, a novel oral carbapenem, against recent gram-positive clinical isolates from cancer patients.

Methods
We tested 300 gram-positive isolates are recently isolated (2019-2021) from our cancer patients, collected from blood cultures against tebipenem and comparators. Clinical and laboratory Standards Instituted (CLSI) approved broth microdilution method was used with appropriate ATCC controls. MIC50, MIC90, MIC ranges and percent of susceptibility calculations were made using FDA breakpoints when available. There is no tebipenem susceptibility breakpoint for gram-positive isolates currently.
MIC90 and MICs range of tebipenem and comparators against 300 gram-positive isolates from cancer patients

Results
MIC90 and range of tebipenem and comparators are shown in table(1). Tebipenem gave the lowest MIC90 and MIC ranges against most gram-positive isolates including Bacillus species, Corynebacterium species, Enterococcus faecalis, Micrococcus species, MSSA S.aureus, Staphylococcus lugdunensis. β-hemolytic Streptococcus, Streptococcus pneumonie, Viridans group streptococci, and Rothia species. The comparative potency of tebipenem vs meropenem as a carbapenem in this study showed that, tebipenem MIC values were generally lower at least 2-4 fold.

Conclusion
Our data demonstrate that oral tebipenem has promising activity against clinically significant bacterial pathogens isolated from cancer patients and it has compatible activity to that of meropenem as a carbapenem in this study. Further clinical evolution for oral carbapenem treatment of bacterial infections is warranted.

Disclosures
All Authors: No reported disclosures.
1716. In Vitro Drug-Drug Interaction Evaluation of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor
Authors: Shafiee Afshin , Wong Bradley K , Chanda Sanjay 
Published: December 2022

Abstract

Background
Epetraborole (EBO) is a boron-containing oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. EBO is being developed for the treatment of Mycobacterium avium complex lung disease patients and will be used in combination with other drugs. Therefore, EBO and its major circulating metabolite M3 were evaluated in a comprehensive drug-drug interactions (DDI) risk assessment.

Methods
Stability of EBO was evaluated in human liver microsomes, hepatocytes and recombinant CYP enzymes. The inhibitory potential of EBO (0.03-100 μM) and M3 (1-1000 μM) on cytochrome P450 (CYP) activities was assessed using human hepatic microsomes. The CYP induction potential of EBO (25-200 μM), M3 was evaluated and compared to prototypical inducers in human hepatocytes (three donors) and mRNA. Fold increase in mRNA expression was utilized to investigate the CYP induction potential of EBO (0.3-100 µM) and M3 (1-250 µM). Stably transfected cell lines that expressed individual transporters were used to determine whether EBO or M3 were substrates or inhibitors for these proteins.

Results
In vitro studies with microsomes, hepatocytes and recombinant cytochrome P450 (CYP) enzymes indicated that EBO was a poor substrate for major CYP enzymes; drug interactions with epetraborole as victim are considered unlikely. Neither EBO nor its major metabolite M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. Half maximal inhibitory concentration (IC50) values for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 were &gt;100 µM. EBO was not an inducer of CYP1A2 mRNA in human hepatocytes from three donors, while it was a weak inducer of CYP2B6 and CYP3A4. No induction of mRNA was observed in human hepatocytes at concentrations relevant to planned clinical doses. EBO is unlikely to be a substrate for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 and MATE2K. EBO was an in vitro substrate for OCT2, a transporter involved in active renal secretion. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters.

Conclusion
At clinically relevant concentrations of EBO and its major circulating metabolite M3, there is a low risk of victim or perpetrator DDI.

Disclosures
Afshin Shafiee, PhD, AN2 Therapeutics: Stocks/Bonds Bradley K. Wong, PhD, AN2 Therapeutics: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds.
1719. In Vitro Activity of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected from Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2017-2020
Authors: Estabrook Mark , Stone Gregory , Sahm Daniel F 
Published: December 2022

Abstract

Background
Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The use of ceftazidime (CAZ) with AVI is approved for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales (Eba) and Pseudomonas aeruginosa (Pae) isolated from the blood of infected patients as part of the ATLAS surveillance program in 2017-2020.

Methods
A total of 67326 Eba and 23051 Pae non-duplicate clinically significant isolates, including 14216 Eba and 3002 Pae isolated from bloodstream infections, were collected in 56 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes. Only 25% of MEM-NS Pae collected in 2020 were screened.

Results
Of all isolates collected, 97.3% Eba and 90.4% Pae were susceptible to CAZ-AVI (MIC90 values of 0.5 and 8 µg/ml, respectively), more than any comparator tested (table). This was true of blood isolates as well, with 96.9% (Eba) and 90.4% (Pae) isolates susceptible to CAZ-AVI. CAZ-AVI was active against 89.9% of Eba collected from blood that were CAZ-nonsusceptible (NS), more than the comparators tested. While this was not true of CAZ-NS Pae blood isolates (52.9% susceptible to CAZ-AVI), the next most active comparator, amikacin, was active against only 3.9 percentage points more isolates. More MEM-NS isolates that screened negative for MBLs were susceptible to CAZ-AVI than any comparator tested (97.8% of Eba and 80.1% of Pae).

Conclusion
CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by Eba and Pae, except those carrying MBLs.

Disclosures
All Authors: No reported disclosures.
1725. National Surveillance of Gram-negative Bacteria in Qatar, the Study for Monitoring of Antimicrobial Resistance Trends (SMART): from 2017 to 2019
Authors: Sid Ahmed Mazen A , Saleh Thoraya M , Albirair Mohamed , Dousa Khalid M , Arisgado Lolita C , Al Maslamani Muna A , Khal Abdul Latif Al , Ibrahim Emad B , Hadi Hamad Abdel 
Published: December 2022

Abstract

Background
Monitoring Antimicrobial Resistance Trends (SMART) is a global study for the surveillance of antimicrobial resistance (AMR) in Gram-negative bacteria (GNB) from different regions around the World including Gulf countries. To evaluate prevalence and trends in AMR in GNB from clinical specimens including microbiological and genomic characteristics as well as examine Antimicrobial Susceptibility Tests (AST) for existing and novel antimicrobials.

Methods
A prospective study was conducted on clinical specimens from Hamad Medical Corporation, Qatar, between 2017 and 2019 according to the SMART protocol that covers community as well as hospital-associated infections reported to secondary care. Consecutive GNB were included from different sites including lower respiratory and urinary tracts, intrabdominal, and bloodstream infections.

Results
Over the three years study period, 895 isolates were studied from the specified sites comprising 38 GNB with four key pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Meropenem resistance was 3.6% for E. coli and 9.3% for K. pneumoniae while imipenem/relebactam resistance was 3% compared to 8% respectively. The overall ceftolozane/tazobactam resistance for E. coli was 9% (25/281) compared to 13% (34/257) for K. pneumoniae while resistance for ceftazidime/avibactam was 2% (3/137) and 4% (5/117) respectively. Genomic characteristics of 70 Enterobacterales including 48 carbapenem-resistant, revealed the prevalence of β-lactamase from all classes dominated by blaCXM-15 while carbapenem resistance revealed a paucity of blaKPC and supremacy of blaOXA-48 like and blaNDM resistance genes (Table 1). Table 1.The frequency of different β-lactamase genes among 48 Carbapenem Resistant Enterobacterales (ERSs) isolates collect from Qatar between 2017 - 2019.*Intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs)

Conclusion
Surveillance of GNB from Qatar showed the prevalence of key pathogens similar to the rest of the world but demonstrated significant resistance to existing and novel antimicrobials, particularly for K. pneumoniae with different underlying resistance mechanisms.

Disclosures
All Authors: No reported disclosures.
1732. Single Center Dalbavancin Experience: A cost saving surprise in people with substance use disorder
Authors: Nakagami Peter , Morita Kazumi , Schultz Sara K , Rodriguez Leah 
Published: December 2022

Abstract

Background
Dalbavancin is a lipoglycopeptide antibiotic that has efficacy in the treatment of skin/soft tissue infections secondary to Gram-positive organisms. Given its long half-life, there has been increasing use for other indications including osteomyelitis, joint infections, and bacteremia. Our goal was to evaluate the indications for usage in our health system, characteristics of the patients receiving dalbavancin, and outcomes with recurrence of infection and cost to the health system.

Methods
A retrospective chart review was conducted reviewing all patients who were ordered dalbavancin in the Temple health system between Nov 1, 2019 to Mar 31, 2021. Charts were reviewed in Epic with data collection in REDCap.

Results
34 orders for dalbavancin use were reviewed, representing 33 unique patients with 31 instances of dalbavancin administered. The majority of patients were male (79%) and had substance use disorder (88%). 97% of patients had formal ID consult. The majority of the patients were recommended dalbavancin due to concerns for adherence to prolonged oral regimens (17) or difficulties with SNF placement (19). The most common indications were bone and joint infections (16, 5 of which involved prosthesis) and bacteremia (9). 94% of patient received effective antibiotics prior to dalbavancin, with a median of 4 days. 75% of patients received their full prescribed course of dalbavancin. Only 1 adverse event was reported (itching and skin sloughing). At the time of writing, 12/23 (52%) of patients who were more than 90 days from a completed dalbavacin course returned for treatment for an infection at the same site within 90 days. Cost savings estimated from the alternate planned antibiotics and facility stay were calculated out to $1.47 million and 445 total hospital days were averted.

Conclusion
Our results show that dalbavancin use at our institution had minimal adverse reactions and were used to treat infections beyond skin/soft tissue infections in a population of predominantly people with substance use disorder.
Our early experience with this drug uncovered potentially significant cost savings with dalbavancin due to avoided hospital days.

Disclosures
All Authors: No reported disclosures.
1737. Xeruborbactam (QPX) Potentiates the Activity of β-Lactam (BL) Antibiotics Against a Diverse Group of Highly Drug-Resistant Enterobacterales (ENT)
Authors: Newbrough Anthony , Fleres Giuseppe , Hao Binghua , Chen Liang , Shields Ryan K , Clancy Cornelius J , Nguyen Minh-Hong 
Published: December 2022

Abstract

Background
Antibiotic resistant ENT are a growing threat worldwide. QPX is an ultra-broad-spectrum β-lactamase inhibitor (BLI) with potent inhibition of classes A and D, and many metallo-β-lactamases, which has potential to fill the void of currently available BL-BLIs.

Methods
We evaluated QPX (fixed concentration of 8 µg/mL) in combination with meropenem (MEM), cefepime (FEP) and aztreonam (ATM) against a diverse group of ENT clinical isolates selected from a worldwide repository. Antibiotic resistance determinants were assessed by mining whole-genome sequencing data generated using Illumina MiSeq.

Results
Klebsiella spp, Enterobacter spp, and Escherichia coli were most common among the 90 isolates tested (Fig. 1). 71% (64) produced carbapenemases (Fig. 2): 3 isolates produced both class A and B carbapenemases. 11% of isolates harbored mutations in ompK 36/ompC genes. 57% (51) were resistant to MEM, 31% to imipenem-relebactam, 17% (15) to ceftazidime-avibactam (CZA), and 9% to MEM-vaborbactam (MVB). ENT-resistant to CZA were due to production of class B, D or KPC-3 variants, or ompC mutation in a K. aerogenes isolate. ENT-resistant to MVB were due to class B or D enzymes, or class A with ompK36 or ompC mutations. MIC distributions of BL with or without QPX against all isolates tested are presented in Fig. 3. Addition of QPX to MEM, FEP and AMT reduced MIC50s and MIC90s of these agents (Fig. 3; p&lt; 0.0001). Of note, addition of QPX reduced MEM MICs more than did vaborbactam (median 533- versus 24-fold; p=0.0006). QPX reduced MICs of MEM, FEP and ATM to levels below respective breakpoints for non-susceptibility (Fig. 3). MIC distribution of ENT isolates stratified by the types of carbapenemases are presented in Fig. 4. QPX potentiated activity of MEM, FEP or ATM against ENT, regardless of whether they produced class A, B or D carbapenemases.

Conclusion
QPX enhanced activity of MEM, FEP and ATM against carbapenemase-producing or other carbapenem-resistant ENT (CRE), regardless of species or other resistance determinants. Most remarkably, QPX rendered each BL equally active against CRE. The expanded spectrum of QPX against class B and D carbapenemases addresses a major unmet need against CRE.

Disclosures
Cornelius J. Clancy, MD, receives research funding paid to his institution from Astellas and Merck: Grant/Research Support|serves as an advisory Board member for Astellas, Cidara, and Scynexis, served on the advisory board for Merck, Qpex Biopharma, and Shionogi: Advisor/Consultant|Venatorx and Needham & Associates: Advisor/Consultant.