bluuebunny/crossref_metadata_2025_split huggingface dataset:
1281. Longitudinal and Spatial Variation in the Human Microbiome in a Phase 2a Clinical Study of Gepotidacin in Adult Females with Uncomplicated Urinary Tract Infection
Authors: Nuzzo Andrea , Van Horn Stephanie , Traini Christopher , Perry Caroline R , Dumont Etienne , Scangarella-Oman Nicole , Gardiner David , Brown James R 
Published: January 2021

Abstract

Background
Gepotidacin (GSK2140944) is a first in class novel oral triazaacenaphthylene bacterial topoisomerase inhibitor. In this study, we evaluated the potential impact of orally administered gepotidacin on the human microbiome, across three body-sites and at three specific time-points, as an exploratory endpoint in a Phase 2a clinical trial for the treatment of uncomplicated Urinary Tract Infection (uUTI) (ClinicalTrials.gov: NCT03568942).

Methods
Through DNA sequencing of the 16S rRNA variable region 4, we analyzed samples collected with consent from study subjects from the gastrointestinal tract or GIT (stool), pharyngeal cavity (saliva swabs) and vagina (vaginal swabs). Samples were taken at three time points which were pre-dosing (Day 1), end of dosing (Day 5) and follow-up visit (Day 28 ±3 days). A total of 156 samples were collected and 141 samples passed quality control criteria for DNA sequence analyses. Using a rigorous computational work-flow, changes in microbiome diversity and relative abundances of microbial species were quantified.

Results
Time series analyses showed that microbiota alpha diversity dropped, relative to pre-dose, by the end of gepotidacin dosing but trended a return trajectory to original pre-dose levels by the follow-up visit, for all body sites (Figure). However, the character and extent of the microbiota changes varied by location. The relative ordering from least to greatest changes in microbiota diversity of body sites is vaginal, pharyngeal and GIT. We found no statistically significant occurrences of pathogen related taxa, such as Clostridioides or Enterobacterales spp., at the final timepoints.

Conclusion
Since gepotidacin is both orally dosed and elimination includes the biliary route, it was predicted to affect the GIT microbiome, however changes in the distal pharyngeal and vaginal microbiota were also observed. Gepotidacin alteration of the endogenous microbial community appears to be temporary and reversible as microbiota diversity rebounded to near pre-dosing status within a period of several weeks. Our study illustrates how microbiome analyses in antibiotic clinical studies can quantify patterns of microbiota disruption and recovery.

Disclosures
Andrea Nuzzo, PHD, GlaxoSmithKline (Employee) Stephanie Van Horn, B.Sc., GlaxoSmithKline (Employee) Christopher Traini, PHD, GlaxoSmithKline (Employee) Caroline R. Perry, PhD, GlaxoSmithKline (Employee) Etienne Dumont, MD, GlaxoSmithKline (Employee) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) David Gardiner, MD, GlaxoSmithKline (Employee) James R. Brown, PhD, GlaxoSmithKline (Employee)
1287. Pharmacokinetics, Safety, and Tolerability of Nacubactam after Single Coadministration with β-Lactams in Japanese Healthy Subjects
Authors: Asano Masayo , Sato Hiroki , Morita Jun , Ishiwata Kazuya , Kondo Kenichiro 
Published: January 2021

Abstract

Background
A single administration of nacubactam (NAC) with concomitant β-lactams in Japanese healthy subjects was conducted to assess pharmacokinetics (PK), safety, and tolerability of NAC in coadministration with cefepime (FEP), aztreonam (ATM), meropenem (MEM), or piperacillin (PIP).

Methods
The administration period included Period I, Period II, and Period III where NAC alone, concomitant drug alone, NAC and concomitant drug were administered by 1hour-IV infusion in each period. The dose of each drug tested was 2 g of NAC, FEP, ATM, MEM and 4 g of PIP and 8 subjects were administered in each cohort (32 subjects in total).

Results
Plasma NAC concentrations and NAC urinary excretion rate after coadministration with each concomitant drug were similar to those of administration of NAC alone. The PK parameter of NAC showed the similar value both after administration of NAC alone and after concomitant administration with each concomitant drug. Based on these findings, it was confirmed that coadministration of NAC with FEP, ATM, MEM or PIP did not affect the PK of NAC.
Plasma concentrations and urinary excretion rate of FEP, ATM, MEM or PIP after coadministration of each concomitant drug with NAC were similar to those of administration of each concomitant drug alone. The PK parameter of each β-lactam tested showed the similar value both after administration of β-lactam alone and after concomitant administration with NAC. Based on these finding, it was confirmed that coadministration of each concomitant drug with NAC did not affect the PK of FEP, ATM, MEM and PIP.
As for the safety, there was no serious adverse event, all of TEAEs reported were mild in severity and judged to be “not related”.

Conclusion
It was confirmed that single coadministration of NAC with FEP, ATM, MEM, or PIP did not affect the both PKs of NAC and β-lactams, and was safe and well-tolerated in Japanese healthy subjects.

Disclosures
Masayo Asano, BS, Meiji Seika Pharma Co., Ltd. (Employee) Hiroki Sato, BS, Meiji Seika Pharma Co., Ltd. (Employee) Jun Morita, PhD, Meiji Seika Pharma Co., Ltd. (Employee) Kazuya Ishiwata, MS, Meiji Seika Pharma Co., Ltd. (Employee) Kenichiro Kondo, PhD, Meiji Seika Pharma Co., Ltd. (Employee)
1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections
Authors: Talley Angela , Thurston Archie , Moore Grayson , Satterfield Myriah M , Manyak Erika L , Kumar Vipul , Stokes Suzanne , Dane Aaron , Melnick David 
Published: January 2021

Abstract

Background
SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers.

Methods
This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis.

Results
A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14.

Conclusion
Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned.

Disclosures
Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)
1289. Pravibismane is a Potent, Broad Spectrum Anti-Infective Small Molecule that Rapidly Disrupts Bacterial Bioenergetics and Halts Bacterial Growth
Authors: Baker Brett 
Published: January 2021

Abstract

Background
The rise in resistance to existing antimicrobials has prompted a need for the development of novel antibiotics. Microbion has identified a novel compound, pravibismane, with potent broad spectrum anti-infective and anti-biofilm activity.

Methods
Here we used a variety of assays, including Bacterial Cytological Profiling (BCP), to analyze pravibismane in E.coli to gain insight into its likely mechanism of action (MOA). The BCP profile of pravibismane suggested it rapidly shut down cell growth, potentially by turning off cellular gene or protein expression. This was confirmed using a plasmid based GFP induction assay in E.coli tolC that showed pravibismane strongly reduced expression of GFP. The kinetics, reversibility and MOA of pravibismane was further characterized by using time-lapse microscopy, wash out experiments and measurements of both membrane potential and relative intracellular ATP levels.

Results
We found that pravibismane acts rapidly (within 30 mins) to completely halt cell growth rather than causing immediate cell lysis such as that observed with non-specific cell damaging agents bleach or detergent. Inhibitor wash out experiments in which cells were exposed to pravibismane for 2 hours, washed to remove the compound, and then observed using time-lapse microscopy revealed that the effect of pravibismane is reversible and that cells recovered 8-12 hrs after removing the compound. Wash out experiments with an E.coli tolC strain carrying a plasmid with an IPTG inducible GFP demonstrated that transcription and translation ultimately resumed in most cells after washout. The bioenergetics of the membrane was measured using DiBAC 4(5), a membrane potential sensitive dye which can enter depolarized cells, which revealed that pravibismane caused depolarization of the membrane within 30 mins of exposure in a concentration dependent manner. Finally, a luciferase assay determined pravibismane reduced ATP levels (resulting in decreased luminescence) within 15 mins of exposure in a concentration dependent manner unlike antibiotic controls that had modest or no effect on luminescence.

Conclusion
Our results suggest that pravibismane acts rapidly to disrupt cellular bioenergetics, resulting in the immediate cessation of cell growth and protein expression.

Disclosures
Brett Baker, M.Sc., D.C., Microbion Corporation (Board Member, Employee)
1293. Sulbactam-durlobactam is active against recent, multi-drug resistant Acinetobacter baumannii clinical isolates from the Middle East
Authors: Miller Alita , McLeod Sarah , Moussa Samir , Hackel Meredith 
Published: January 2021

Abstract

Background
The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of &gt;3600 isolates from 2012-2017, the MIC90 of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region.

Methods
190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available.

Results
This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC90 from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of &gt; 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes.

Conclusion
SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections.

Disclosures
Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)
1294. A survey on Vancomycin and Beta Lactams usage in critical care settings in Makkah, Kingdom of Saudi Arabia
Authors: Hanif Abdul-Hasseb , Radwan Rozan , Baghdadi Rehab Adnan , Faidah Hani Saleh 
Published: January 2021

Abstract

Background
Drug pharmacokinetics/pharmacodynamics (pk/PD) play a vital role in the dose optimization of antimicrobials to maintain targeted effective plasma concentration. Pharmacokinetics parameters e.g., Volume of distribution, clearance, half-life are highly variable in Critically ill patients, therefore require a patient-specific approach to maximize antimicrobials’ clinical effectiveness.
The percentage of the dosing interval to ensure free plasma concentration more then MIC is an evidence-based approach to achieve pharmacodynamic targets among critically ill patients. Therefore, using Extended and continuous infusions of Vancomycin and Beta lactams will optimize therapy by promising more time for free plasma concentration above MIC in treatment.

Methods
A self-administered survey was distributed during morning meeting to intensivists to record their attitude and practice towards Vancomycin and Beta lactams usage in intensive care units. The regional institutional review board approved the study of the ministry of health, Makkah, Saudi Arabia.

Results
The response rate was 95 %, as the survey was distributed electronically before the dose optimization workshop conducted at each hospital. The majority (72.5 %) of the intensivists were using only extended infusion for Meropenem in practice. Interestingly, none of the hospitals was familiar with the pk/PD target for vancomycin dosing. Further, most of the intensivists (65 %) were unfamiliar with continuous/extended infusion strategy for Vancomycin in their practice. The majority of them were using traditional trough level target by utilizing standard dosing.

Conclusion
This survey concludes the requirement of a dose optimization policy for beta-lactam and vancomycin in critical settings by utilizing extended/continuous infusion.

Disclosures
All Authors: No reported disclosures
103. Empiric Antibiotic Susceptibility Using a Traditional vs. Syndromic Antibiogram-Implications for Antimicrobial Stewardship Programs
Authors: Klinker Kenneth , Bauer Karri A , DeRyke C Andrew , Hidayat Levita K 
Published: January 2021

Abstract

Background
A primary tenet of antimicrobial stewardship programs (ASPs) is to establish empiric antibiotic treatment recommendations. While traditional antibiograms are useful, intrinsic variability in susceptibility exists when stratifying by source and/or location. In contrast, a syndromic antibiogram displays the likelihood of adequate coverage for a specific infection syndrome, considering the weighted incidence of pathogens causing that syndrome. The aim of the study was to compare antibiotic susceptibilities using a traditional versus syndromic antibiogram.

Methods
Between 2016–2019, 20 US institutions per year submitted up to 250 consecutive targeted gram-negative pathogens from hospitalized patients as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART). MICs were determined by broth microdilution and interpreted using 2020 CLSI breakpoints, except for imipenem/relebactam (I/R) for which FDA breakpoints were used. The traditional antibiogram included the 3 most common Gram-negative pathogens from all sources and represented critical organisms considered for empiric antibiotic coverage; the syndromic antibiogram included the 3 most commonly isolated Gram-negative pathogens from a respiratory source based on patient location.

Results
17,561 Gram-negative isolates, including 6,654 lower respiratory isolates were evaluated. The top 3 most common Gram-negative organisms included: E. coli (n=6095, 44%), Klebsiella spp. (n=4097, 30%), P. aeruginosa (n=3649, 26%). Cumulative susceptibilities were comparable using a traditional vs. syndromic antibiogram (Figure 1); however, cefepime (FEP), piperacillin/tazobactam (TZP), and meropenem (MEM) susceptibilities were 5 – 8% lower when stratified by patient location (Figure 2) and ≥10% for P. aeruginosa (Figure 3). Ceftolozane/tazobactam (C/T) and I/R demonstrated ≥90% susceptibility regardless of respiratory source or patient location.
Figure 1. Cumulative susceptibility of E. coli, Klebsiella spp, and P. aeruginosa for traditional vs. syndromic antibiogram

Figure 2. Syndromic antibiogram evaluating cumulative susceptibility of E. coli (n = 637), Klebsiella spp. (n = 1190) and P. aeruginosa (n = 1997) respiratory isolates stratified by patient location

Figure 3. Syndromic antibiogram evaluating susceptibility of P. aeruginosa (n = 1997) respiratory isolates stratified by patient location

Conclusion
Our analysis demonstrated that susceptibilities were lower for first-line agents when stratified by ICU and P. aeruginosa. ASPs should consider syndromic antibiograms based on source and patient location to optimize empiric antibiotic therapy recommendations.

Disclosures
Kenneth Klinker, PharmD, Merck & Co, Inc (Employee) Karri A. Bauer, PharmD, Merck Research Laboratories (Employee) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Levita K. Hidayat, PharmD BCIDP, Merck & Co (Employee)
1297. In-Vitro Antibacterial Activities of Cefiderocol (S-649266) Alone and With the Addition of Beta-Lactamase Inhibitors Against Multidrug-resistant Acinetobacter baumannii
Authors: Abdul-Mutakabbir Jacinda C , Nguyen Logan , Maassen Philip , Stamper Kyle , Kebriaei Razieh , Lev Katherine , Morrisette Taylor , Kaye Keith S , Rybak Michael J 
Published: January 2021

Abstract

Background
Multidrug-resistant (MDR) infections caused by Acinetobacter baumannii continue to pose a serious public health threat. Cefiderocol (CFDC) is a new parental siderophore cephalosporin that has displayed potent activity against Gram-negative bacteria, more specifically non-fermenting Gram-negative bacilli, including A. baumannii. Although uncommon, elevated minimum inhibitory concentrations (MICs) to CFDC have been reported, when tested against A. baumannii isolates, in-vitro. The addition of beta-lactamase inhibitors has been shown to be successful in decreasing elevated CFDC MICs. The evaluation of sulbactam (SUL), tazobactam (TAZO), or clavulanic acid (CLAV) in addition to CFDC against A. baumannii isolates with elevated CFDC MICs, has yet to be reported. The objective of this study was to evaluate the activity of several beta-lactamase inhibitors in combination with CFDC against A. baumannii strains with high CFDC MICs.

Methods
One hundred and fifty carbapenem-resistant A. baumannii strains were selected from the Anti-infective Research Laboratory. MIC susceptibility testing was performed for all of the strains via broth microdilution (BMD). Seven strains that exhibited elevated CFDC MICs,16-32 mg/L, were assessed via BMD, with the addition of the following beta-lactamase inhibitors: TAZO, SUL, AVI, and CLAV to CFDC. All in-vitro testing for CFDC was completed with the use of iron-depleted cation-adjusted Mueller-Hinton broth to ensure the induction of bacterial iron transporters per manufacturer standards.

Results
A decline in elevated CFDC MIC values was observed in six of the seven A. baumannii strains, with the addition of each beta-lactamase inhibitor. AVI showed the most potent activity when added to CFDC, with an average 28- fold reduction in MIC values observed. SUL and CLAV produced similar fold reductions in the MIC values with an average 20-fold reduction observed with the addition of either agent to FDC. The addition of TAZO to CFDC also presented with a decline in MIC values, with an average 7-fold-reduction observed.
Cefiderocol (CFDC) strains with MICs of 16-32 mg/l plus Beta-Lactamase Inhibitors

Conclusion
The addition of several beta-lactamase inhibitors to CFDC has shown promise in decreasing elevated CFDC MICs. Further research is warranted to determine the role of BLIs on CFDC activity.

Disclosures
Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)