bluuebunny/crossref_metadata_2025_split huggingface dataset:
2130. Safety and Pharmacokinetics of SPR206 in Subjects with Varying Degrees of Renal Impairment
Authors: Bruss Jon , Bader Justin C , Hamed Kamal 
Published: November 2023

Abstract

Background
SPR206 is a novel polymyxin derivative with potent in vitro activity against susceptible and multidrug-resistant strains of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species. In nonclinical studies, SPR206 had similar or greater activity than polymyxin B with an improved safety profile.

Methods
We evaluated the safety, tolerability, and pharmacokinetics (PK) of SPR206 in healthy subjects with normal renal function and subjects with various degrees of renal impairment (RI) or end-stage renal disease (ESRD) on hemodialysis (HD). All subjects except those with ESRD on HD received a single 100 mg dose of SPR206 as a 1-hour intravenous (IV) infusion. Subjects with ESRD on HD received a 100 mg IV dose within 2 hours after HD on Day 1 (Period 1) and 1 hour before HD on Day 5 (Period 2).

Results
Among 37 subjects, no deaths, treatment-related serious adverse events (AEs), or discontinuations due to AEs were reported. Paresthesias were the most common treatment-related AEs. Systemic exposure to SPR206 increased as RI worsened, with mean AUC
0-last of 39% to 239% greater with mild to severe RI vs. healthy subjects (Figure). Renal clearance (CL) decreased (1.2 L/h to 0.13 L/h) with decreasing renal function, and plasma CL was 29% to 76% lower with RI vs. healthy subjects. In subjects with ESRD on HD, mean AUC0-last was 372% greater and mean CL was 87% lower in Period 1 (nondialyzed) vs. healthy subjects. In Period 2 (dialyzed), AUC0-last was 131% greater and CL was 75% lower vs. healthy subjects. In subjects with ESRD on HD, SPR206 systemic exposure (AUC0-last) decreased by 51% and CL increased by 92% during dialyzed vs. nondialyzed conditions. AUC was negatively correlated and CL positively correlated with estimated glomerular filtration rate (eGFR) (p&lt; 0.0001). SPR206 was mostly excreted in urine within 12 hours in healthy subjects and subjects with mild RI, but excretion was slower in subjects with moderate and severe RI. HD was effective in removing SPR206 from the circulation.

Conclusion
In summary, SPR206 appeared to be safe and well tolerated in subjects with varying degrees of RI including those with ESRD on HD. These results will inform dose adjustments in future studies for patients with various degrees of RI including those with ESRD on HD.

Disclosures
Jon Bruss, M.D., Spero Therapeutics, Inc.: employee Justin C. Bader, PharmD, Spero Therapeutics, Inc.: former employee Kamal Hamed, MD, MPH, Spero Therapeutics, Inc.: current employee
2142. The use of Pseudomonas aeruginosa Phage PASA16 for non resolving infections
Authors: Onallah Hadil , Hazan Ronen , Nir-Paz Ran 
Published: November 2023

Abstract

Background
A growing number of compassionate phage therapy use cases reported in the last decade, with only a limited number of clinical trials conducted and very few unsuccessful clinical trials reported. However, the limited understanding of individual clinical cases and lack of successful published clinical trials provides little evidence on the role of phages in refractory infections. Our objective was to bridge between single cases to early clinical trials and to describe the compassionate use of a single same phage - PASA16 - in sixteen patients with non-resolving Pseudomonas aeruginosa infections.

Methods
We have collected all cases in which PASA16 was used and summarized clinical microbiology data, administration protocol, clinical data and outcome. In all instances involving intravenous phage administration (14 out of 16 cases), PASA16 phage was manufactured and provided pro-bono by Adaptive Phage Therapeutics.

Results
PASA16 was administered either IV, locally to infection site or by topical use to 16 patients, with data available for 15 patients, mainly for osteoarticular and foreign device associated infections. Few minor side effects were noted including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 (86%). Two clinical failures were reported.

Conclusion
PASA16 with antibiotics was found to be relatively successful in patients who have failed previously in traditional approaches. Minimal successful duration of phage therapy was 8 days with once to twice a day administration. Such pre-phase 1 cohorts can outline the potential clinical protocols to be used and facilitate the design of future clinical trials.

Disclosures
Ran Nir-Paz, MD, Adaptive phage theraputics: Supplied the phage product for this study|BiomX: Advisor/Consultant|Technophage: Grant/Research Support
2144. A Phase 1, Multicenter, Open-Label, Parallel-Group Study to Assess the Safety and Pharmacokinetics (PK) of Oral Epetraborole Tablets in Adult Subjects with Varying Degrees of Renal Function
Authors: Patel Gina , Canas George C , Cruz Kimberly , Marbury Thomas C , Gotfried Mark , Chan Wallace (Boon Chun) , Duchin Kenneth , Maier Gary , Chanda Sanjay , Kammerer Linda , Long Jennifer , Moore Stephanie , O’Shea Kevin , Shafiee Afshin , Smith Alex , Eckburg Paul B 
Published: November 2023

Abstract

Background
Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is in clinical development for treatment-refractory MAC lung disease. The objective of the study was to evaluate EBO PK in adult subjects with varying degrees of renal impairment (RI) including end stage renal disease (ESRD) with intermittent hemodialysis (IHD).

Methods
Open-label, single-dose EBO 500 mg PO was given to subjects in 5 cohorts: normal renal function, mild, moderate, and severe RI, and ESRD-IHD (Table); ESRD subjects received a second 500 mg dose on Day 5 approximately 1 hour before receiving IHD. EBO and its inactive major metabolite (M3) concentrations in plasma, urine and dialysate were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods and compared among cohorts using analysis of variance (ANOVA). Standard clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed.

Results
40 subjects were enrolled (8/cohort). Subjects with RI did not exhibit quantitatively distinct EBO plasma PK profiles compared to those with normal renal function; AUC mean ratios were 110-140% in subjects with RI, and the mean ratios of maximum observed concentration (Cmax ) values did not exceed 116% (Table). The elimination half-life (t1/2) increased slightly from 9.3 to 11.0 h in ESRD subjects, and clearance decreased by about 30%. Renal elimination was not a major route of excretion (∼15% of dose over 72 h) for EBO, with mean renal clearance ranging from 4.24 L/h to 1.04 L/h. Metabolite M3 AUC increased 4-fold in subjects with severe RI, and t1/2 increased from 20 to 32 h. EBO was well tolerated; 7 subjects (17.5%) experienced at least 1 TEAE (11 events), all mild in severity except 1 moderately-severe TEAE of worsening anemia. There were no severe or serious TEAEs.

Conclusion
Minimal increases in plasma EBO exposures and similar t1/2 values were observed in subjects with varying degrees of RI, including ESRD-IHD. Single 500 mg doses of EBO were well tolerated in each RI cohort. Overall, these data suggest that no dose adjustment of EBO is needed in subjects with any degree of RI.

Disclosures
All Authors: No reported disclosures
2148. In vitro Potency of a Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Against Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium abscessus
Authors: Shoen Carolyn M , DeStefano Michelle S , Wang Wen , Cynamon Michael H 
Published: November 2023

Abstract

Background
The family of Mycobacteriaceae contains hundreds of species, some causing diseases in humans. The most well-known is Mycobacterium tuberculosis (Mtb), the causative agent for tuberculosis. Approximately 2 billion people are infected with M. tuberculosis. Drug-resistant strains of M. tuberculosis have emerged in the last 30 years, making the development of newer, effective drugs important. Non-tuberculous mycobacteria (NTM) cause difficult to treat infections. M. abscessus (Mabs) and M. avium (MAC) fall within this category. Drug-resistance and/or drug tolerance is a serious hurdle in trying to control NTM infections. The goal of this study was to evaluate the in vitro activity of a novel leucyl-tRNA synthetase inhibitor, MRX-6038, against Mtb, MAC, and Mabs.

Methods
MRX-6038, epetroborole (EBO), and GSK656 (GSK) was provided by MicuRx Pharmaceutical Co., Ltd. Clarithromycin (CLR) and isoniazid (INH) were purchased from Biosyth Ltd and Sigma-Aldrich Chemical Company, respectively. Stock solutions were dissolved in 100% DMSO and frozen at -20oC until used. Drugs were serially diluted in cation adjusted Mueller-Hinton broth (CAMHB) (Mabs), CAMHB with 5% OADC (MAC), and 7H9 Broth with 10% OADC (Mtb) in microtiter plates for MIC evaluation in duplicate. Wells were inoculated with ∼ 1.25 x 105 CFU/ml of bacteria. Plates were incubated for 4-5 (Mabs), 7 (MAC), or 14 (Mtb) days at 37oC in ambient air. The MIC is defined as the lowest concentration of drug that yielded no visible turbidity.

Results
The MIC50 and MIC90 (µg/ml) of the MAC isolates against CLR, EBO, and MRX-6038 were 1 and 4, 1 and 8, and 1 and 8, respectively. The MIC50 and MIC90 of the Mabs isolates against CLR, EBO, and MRX-6038 were 8 and 16, 0.125 and 0.25, and 0.25 and 0.25, respectively. The MIC50 and MIC90 of the Mtb isolates against INH, GSK, and MRX-6038 were 1 and 8, 0.06 and 0.06, and 0.5 and 1, respectively. Many of the Mtb isolates used were known to be MDR strains.

Conclusion
The in vitro activity of MRX-6038 was quite promising against Mabs, MAC, and Mtb. Based on work by others, MRX-6038 has shown encouraging in vivo activity against Mabs in mice. The next steps will be to determine the in vivo activity against both MAC and Mtb infection in mice.

Disclosures
Wen Wang, PhD, MicuRx Pharmaceuticals: Employee of
2153. Addition of Relebactam Increases Susceptibility to Imipenem Alone against Class C β-lactamase-Positive Enterobacterales: Asia/Pacific SMART 2019-2021
Authors: Lob Sibylle , Wise Mark G , Chen Wei-Ting , Siddiqui Fakhar , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: November 2023

Abstract

Background
Imipenem/relebactam (IMI/REL) 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 IMI/REL 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 2019-2021, 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 2023 CLSI breakpoints. Isolates that were imipenem-, IMI/REL-, or ceftolozane/tazobactam-nonsusceptible (NS) were screened for β-lactamases.

Results
IMI/REL maintained activity against ≥96% of K. pneumoniae and E. coli that carried ampC with or without ESBL, and the addition of relebactam increased the susceptibility to imipenem alone by 13-54 percentage points among these isolates (Table). IMI/REL maintained activity against ≥92% of intrinsic ampC carriers, and the largest increase by addition of relebactam to imipenem alone was seen among K. aerogenes (25 percentage points). For imipenem-NS isolates, relebactam restored susceptibility to 98.3% of imipenem-NS ampC-positive K. pneumoniae (n=58), and to 96.8%, 97.3%, and 29.5% of imipenem-NS Enterobacter spp. (n=125), K. aerogenes (n=147), and S. marcescens (n=61) that carried no acquired β-lactamases, respectively.

Conclusion
IMI/REL showed strong activity against clinical Enterobacterales isolates that carried either acquired or intrinsic ampC with or without ESBL collected in Asia/Pacific. The addition of relebactam increased susceptibility to imipenem alone by up to 54 percentage points.

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
2158. An outbreak of carbapenem-resistant Acinetobacter baumannii at a tertiary hospital in Ethiopia
Authors: Adbaru Mulatu G , Gudina Esayas K , Kroidl Arne , Wieser Andreas 
Published: November 2023

Abstract

Background
Since there are no effective alternative treatments, health professionals in resource-constrained countries struggle to treat infections caused by microorganisms those are resistant to carbapenem antibiotics. The purpose of this study was to determine the magnitude of carbapenem-resistant Acinetobacter baumannii isolated from patients with surgical site infection.

Methods
A cross-sectional study was conducted among patients who underwent surgical procedures at Jimma Medical Center. Two wound swab samples were collected from patients who had clinical evidence of surgical site infection (SSI) and processed at JMC microbiology laboratory. All A. baumannii species were confirmed by MALDI TOF MS and the carbapenem-resistant isolates were further characterized using PCR.

Results
Of 1205 participants enrolled in the study, more than one-fourth (312) of them showed clinical evidence of SSI. A couple of wound swabs were collected from 83.3% (260) of the patients who had SSI for microbiological analysis. Of those, 72%, (189/260) were culture positive with 252 isolates and 36 different bacterial species. Acinetobacter baumannii, (20.2%; 51) were the second most frequent bacteria and showed the highest resistance to carbapenem antibiotics. The PCR analysis revealed blaOXA-51 60.8% (31/51) was the predominant carbapenemase-encoding gene followed by blaNDM 23.5% (12/51), and blaVIM, blaOXA-23, and blaOXA-58 (15.7%; 8 each) genes. About 37.3% (19) of the strains were co-harboring two or more resistance-encoding genes for carbapenem antibiotics.

Conclusion
It is concluded that A. baumannii is one of the predominant bacteria causing SSIs. The resistance genes blaOXA-51 and blaNDM-1 were highly prevalent in the strains. In light of this finding, it is recommended that current antimicrobial resistance surveillance programs and infection prevention practice and control measures should be re-evaluated.

Disclosures
All Authors: No reported disclosures
2164. Resistome patterns associated with vancomycin non-susceptibility in clinical Clostridioides difficile isolates
Authors: Eubank Taryn A , Gonzales-Luna Anne J , Hanson Blake M , Treangen Todd , Earl Ashlee , Garey Kevin W 
Published: November 2023

Abstract

Background
Clostridioides difficile exhibits phenotypic resistance to multiple classes of antibiotics. Associated antibiotic resistance genes (ARGs) are commonly transferred via mobile genetic elements, which often carry distinct ARG groupings. Increases in vancomycin non-susceptible C. difficile have been reported and understanding associated trends in ARG co-carriage are critical for strain transmission dynamics. Here we aimed to determine C. difficile resistome patterns associated with vancomycin non-susceptibility (NS).

Methods
Whole genome sequencing (WGS) was performed (Illumina NextSeq 500) on C. difficile isolated from adult patients hospitalized with C. difficile infection in two health systems (14 hospitals) in the Houston Area between 2016–18. Isolates were ribotyped by fluorescent PCR and susceptibility tested by agar dilution in accordance with CLSI standards. Vancomycin NS was defined by minimum inhibitory concentrations (MICs) &gt; 2 mg/L. Genome assembly and analysis was completed through The Bacterial and Viral Bioinformatics Resource Center (BV-BRC) web resources.

Results
Overall, 36% (13/36) of the cohort was vancomycin NS. The most common ribotypes were F106 (n=13), F027 (n=10), and F014-020 (n=7). Median ARG abundance was 46 (IQR 45 – 49) and included genes encoding targeted and non-specific (i.e., encoding ABC transporters or efflux pumps) resistance. Specific antibiotics/classes targeted by identified ARGs included aminoglycosides, daptomycin, diaminopyrimidines, fluoroquinolones, fosfomycin, glycopeptides, isoniazid, lincosamides, macrolides, nitroimidazoles, oxazolidinones, rifamycins, streptogramins, and sulfonamides. Median ARG abundance did not differ between vancomycin NS (46.5 genes) and susceptible (46 genes) isolates and no differences in ARG patterns were observed. ARG abundance and patterns were similar amongst ribotypes.

Conclusion
C. difficile vancomycin non-susceptibility did not correlate with increased ARG abundance or any distinct ARG patterns. Future studies investigating interactions and implications of the C. difficile resistome on the microbiome and host are warranted.

Disclosures
Anne J. Gonzales-Luna, PharmD, BCIDP, Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Personal Fees|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|Ferring: Advisor/Consultant|Paratek: Grant/Research Support
2170. It takes two to tango: ß-lactam/ß-lactamase inhibitor combinations targeting metallo-ß-lactamase (MBL)- producing Klebsiella pneumoniae.
Authors: Kaur Jan Naseer , Klem Jack F , Singh Navaldeep , Holden Patricia N , Cha Raymond , Chen Liang , Kreiswirth Barry N , Smith Nicholas M , Tsuji Brian T 
Published: November 2023

Abstract

Background
The emergence of pan drug resistant (PDR) gram-negatives co-producing NDM-1 and CTX-M-15 calls for devising more efficient biocidal regimens. Also, understanding the salient transcriptomic and phenotypic changes that contribute to persistence which aid in pathogen survival is critical to therapeutic preparation in the clinical setting.

Methods
A 10-day hollow fiber infection model (HFIM) was utilized to simulate humanized β-lactam regimens involving imipenem (IMI) 1g q8h, aztreonam (ATM) 2g q8h, and ceftazidime/avibactam (CAZ/AVI) 2g/500mg alone and in 3-drug combination regimens against a PDR Klebsiella pneumonia isolate co-harboring blaNDM-1 and blaCMY-6, blaCTX-M-15 and blaSHV-2. Static time kills were performed to investigate the interplay between IMI and ATM. At 2h post drug exposure, total RNA was analyzed by qRT-PCR for the expression of pertinent genes. Glutaraldehyde-fixed samples were imaged using fluorescence and scanning electron microscopy.

Results
In HFIM, IMI contributed synergistically to the antimicrobial action as the average bacterial concentration between 30-120h was 2.1 log10 CFU/mL lower in ATM + CAZ/AVI + IMI than in ATM + CAZ/AVI (2.44 log10 CFU/mL vs. 4.54 log10 CFU/mL, respectively). Adding IMI to ATM+ CAZ/AVI also resulted in an enhanced post-antibiotic effect. Although ATM + IMI reduced bacterial counts by ≥4 log10 CFU/mL in 6h time kill assays, regrowth to the system carrying capacity of ∼8.5 log10 CFU/mL by 24h in all arms rendered these drugs ineffective. By 2h of treatment, ATM alone resulted in long filamentous cells whereas IMI resulted in significant populations of spheroplasts. ATM+IMI caused blebbing in the center of elongating filaments followed by a burst in spheroplast formation. qRT-PCR showed upregulation of spheroplast protein Y (spy) and penicillin binding proteins (pbp1, pbp2, pbp3) for all combinations involving IMI. However, pbp1, pbp3 and spy remained unchanged and pbp2 levels were downregulated by &gt;25% in ATM monotherapy.

Conclusion
Overall, this PDR clinical isolate persisted in the presence of ATM + CAZ/AVI. The addition of IMI to target PBP2 in β-lactam combinations maximally suppressed the emergence of filamentous persisters and may be a promising strategy to prepare for increasing rates of gram-negative resistance.

Disclosures
All Authors: No reported disclosures
2182. Expression of the MadR regulon in Enterococcus faecalis OG117 is influenced by the presence of the LiaS Histidine Kinase of the LiaFSR pathway
Authors: Rizvi Samie A , Gomez Villegas Sara I , Panesso Diana , Arias Cesar A , Miller William R 
Published: November 2023

Abstract

Background
The MadRS pathway is a two-component signaling (TCS) system which mediates resistance to antimicrobial peptides (AP) and AP-like antibiotics in E. faecalis (Fig. 1). The system is composed of a transmembrane histindine-kinase, MadS, which is responsible for the phosphorylation of the transcriptional response regulator, MadR. This leads to increased expression of the madR regulon, containing madG, madL, and dltA, which provide resistance against APs and AP-like antibiotics. Interestingly, deletion of madS does not result in loss of expression of madG, suggesting an alternative mechanism of phosphorylation of MadR independent of MadS. We hypothesize that LiaS, of the LiaFSR pathway, may phosphorylate MadR in the presence of APs and AP-like antibiotics.Figure 1.MadRS initiates a regulatory response to defend against antimicrobial peptides.
In the presences of APs, the MadS Histidine Kinase phosphorylates the MadR response regulator, leading to transcription of downstream genes madAB, madEFG, madLM and the dlt operon.

Methods
Wild type (WT) E. faecalis OG117, OG117FΔmadS, and OG117ΔliaSΔmadS were grown to mid-exponential phase in tryptic soy broth. Each strain was grown either with or without ½ of the minimum inhibitory concentration (MIC) of bacitracin (BAC), an inducer of the MadRS system. RNA was isolated, and expression of madG was evaluated by qRT-PCR relative to the control strain, OG117, without bacitracin exposure. Values were normalized to the gyrB “housekeeping” gene. Fold-change was calculated using the Pfaffl method. Differences in gene expression were determined using two-way ANOVA with Tukey’s test for multiple comparisons.

Results
Both the control strain, OG117, and the OG117ΔmadS mutant exhibited a BAC MIC of 32 mg/L. The BAC MIC for OG117ΔliaSΔmadS decreased to 2 mg/L. In the presence of BAC exposure, OG117ΔmadS had a statistically significant increase in madG expression (p&lt; 0.001) as compared to OG117ΔmadS without BAC exposure (Fig. 2). In contrast, OG117ΔliaSΔmadS displayed no significant change in madG expression when exposed to bacitracin (Fig 2).Figure 2.Gene expression of madG in OG117, madS, and liaSmadS knockout strains.

Conclusion
In the absence of a functional MadS histidine-kinase there is still transcriptional upregulation of madG. This effect is reversed with the deletion of both LiaS and MadS. This suggests that the LiaS histidine-kinase may lead to MadR dependent activation of the MadRS pathway in E. faecalis OG117.

Disclosures
William R. Miller, M.D., Merck: Grant/Research Support|UpToDate: Honoraria