bluuebunny/crossref_metadata_2025 huggingface dataset:
1255. In Vitro Activity of Vancapticin against Methicillin-Resistant Staphylococcus aureus from Periprosthetic Joint Infection
Authors: Cho Hye-Kyung , Karau Melissa J , Greenwood-Quaintance Kerryl E , Hansford Karl A , Cooper Matthew A , Blaskovich Mark A , Patel Robin , Patel Robin
Published: January 2021

Background

The vancapticins are modified vancomycin derivatives developed by adding membrane targeting motifs to the C-terminus of vancomycin. We determined the in vitro activity of a lead vancapticin candidate against periprosthetic joint infection-associated methicillin-resistant Staphylococcus aureus (MRSA) in the planktonic and biofilm states, and the effect of adding 0.002% polysorbate 80 (P-80; Sigma-Aldrich) on vancapticin susceptibility testing.

Methods

Thirty-seven clinical isolates of MRSA collected at Mayo Clinic (Rochester, Minnesota) were studied. Vancapticin minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institutes guidelines. Minimum biofilm bactericidal concentrations (MBBCs) were determined using a pegged lid microtiter plate assay. Vancapticin MIC and MBBC values were assessed with and without P-80. Vancapticin, vancomycin, and dalbavancin biofilm time-kill assays were performed using biofilms formed by 10 MRSA isolates on Teflon coupons.

Results

Vancapticin MICs with and without P-80 ranged from 0.015 to 0.12 μg/mL and 0.25 to 1 μg/mL, respectively. Vancapticin MBBCs with and without P-80 ranged from 0.25 to 4 μg/mL and 1 to 8 μg/mL, respectively. Reductions of biofilm bacterial densities on Teflon coupons after 8 and 24 hours of incubation with vancapticin, vancapticin with P-80, vancomycin, or dalbavancin with P-80 were less than 3-log10 cfu/cm2 for all isolates tested.

Conclusion

Vancapticin has promising in vitro activity against planktonic MRSA and MRSA in a pegged lid biofilm assay, but was not bactericidal against biofilms on Teflon coupons. P-80 decreased vancapticin MICs and MBBCs.

Disclosures

Mark A. Blaskovich, PhD, MAB Consulting (Consultant)The University of Queensland (Employee, Grant/Research Support, Other Financial or Material Support, Inventor on patent) Robin Patel, MD, Accelerate Diagnostics (Grant/Research Support)CD Diagnostics (Grant/Research Support)Contrafect (Grant/Research Support)Curetis (Consultant)GenMark Diagnostics (Consultant)Heraeus Medical (Consultant)Hutchison Biofilm Medical Solutions (Grant/Research Support)Merck (Grant/Research Support)Next Gen Diagnostics (Consultant)PathoQuest (Consultant)Qvella (Consultant)Samsung (Other Financial or Material Support, Dr. Patel has a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued.)Selux Dx (Consultant)Shionogi (Grant/Research Support)Specific Technologies (Consultant)
1264. Assessment of In Vivo Efficacy of CF-296 in addition to Vancomycin (VAN) and Daptomycin (DAP) against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model
Authors: Asempa Tomefa E , DeRosa Nicole A , Cassino Cara , Lehoux Dario , Schuch Raymond , Nicolau David P
Published: January 2021

Background

CF-296 is a novel lysin in pre-clinical development for the treatment of methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections, used in addition to standard of care antibiotics including VAN and DAP. We evaluated the in vivo efficacy of CF-296 alone and in addition to VAN and DAP against S. aureus.

Methods

Eight isolates (1 MSSA and 7 MRSA) were studied. Murine ICR MIC (100% serum) and human MIC (100% serum) for CF-296 ranged from 32-256 mg/L to 0.5-1 mg/L respectively. Broth microdilution MICs for DAP ranged from 0.5-1 mg/L while all isolates exhibited a VAN MIC of 1 mg/L. Neutropenic ICR mice were thigh inoculated with bacterial suspensions (107 CFU/mL). Mice were administered three monotherapy regimens subcutaneously (SC) or intravenously (IV): i) sub-therapeutic VAN, SC (i.e., a dose that yielded bacteria stasis or growth in order to evaluate further bacterial killing), ii) sub-therapeutic DAP, SC, or iii) CF-296 50 mg/kg, IV. Combination of sub-therapeutic VAN or DAP in addition to 5 escalating CF-296 doses ranging from 0.5 to 50 mg/kg were also examined. Control mice were vehicle-dosed. Efficacy was measured as the change in mean thigh bacterial density at 24h relative to 0h controls.

Results

Relative to starting inoculum (5.71 ± 0.27 at 0h), bacterial density in controls increased by +2.49 ± 0.98 log10 CFU/thigh across all 8 strains. On average, VAN, DAP, and CF-296 monotherapy resulted in +0.90 ± 1.21, +1.47 ± 0.80, and +0.87 ± 1.39 log10 CFU/thigh bacteria growth, respectively. In addition to VAN, escalating CF-296 exposures (0.5 – 50 mg/kg) resulted in an augmented dose-response, ranging from bacterial reduction of -0.26 ± 1.10 (with addition of CF-296 0.5 mg/kg) to -1.01 ± 0.41 log10 CFU/thigh (with addition of CF-296 50 mg/kg). Similarly, escalating CF-296 exposures in addition to DAP resulted in an augmented dose-response, ranging from bacterial density of +0.80 ± 1.19 to -0.72 ± 0.59 log10 CFU/thigh.

Conclusion

Compared with 24h control, VAN, DAP, and CF-296 alone displayed modest CFU reduction while CF-296 synergized with VAN and DAP to cause further bacterial killing highlighting a potential role for CF-296 adjunctive therapy against MSSA and MRSA isolates.

Disclosures

Cara Cassino, MD, ContraFect Corporation (Employee)ContraFect Corporation (Employee) Dario Lehoux, PhD, ContraFect Corporation (Consultant) Raymond Schuch, PhD, ContraFect Corporation (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
1268. Dalbavancin for the Treatment of Infections due to Staphylococcus aureus
Authors: Streifel Amber C , Sukerman Ellie , Sikka Monica , Makadia Jina , Lewis James , Luke Strnad
Published: January 2021

Background

Dalbavancin is a lipoglycopeptide antibiotic active against gram-positive organisms. Its extended half-life allows for weekly dosing that can last 4 to 6 weeks with 2 doses. Although approved for treating skin and soft tissue infections, use for more complicated infections is appealing, particularly when daily intravenous antibiotics are impractical. S aureus is the most common cause of complex infections for which dalbavancin is considered at our institution, so we sought to better understand its use.

Methods

We conducted a retrospective study to describe dalbavancin use at our institution for infections caused by Staphylococcus aureus. We identified all patients ≥18 years who received ≥1 dose of dalbavancin. Infectious disease faculty reviewed charts for clinical characteristics and outcomes of the infections.

Results

Fifty-two patients with S. aureus infections (60% MRSA) were treated with at least a partial course of dalbavancin. Twenty-seven (52%) had a history of IV drug use (IDU) and the most common infections were bone and joint infection in 51% and bacteremia in 40% (Table 1). The most common dosing regimen was 1500 mg x 1 in 55% or 1500 mg weekly x 2 in 25% (Table 2). The most common reasons for use of dalbavancin were history of IDU in 48% and lack of a safe home environment in 21%. Suppressive oral antibiotics for the primary infection were prescribed to 3 patients after completing dalbavancin (2 received for other indications). Clinical outcomes include 15% of patients lost to follow-up, readmission due to infection recurrence or dalbavancin adverse effects in 12%, and overall infection recurrence or relapse by day 90 in 31% (Table 3). There were no severe dalbavancin-related adverse drug events.

Table 1. Patient and Disease Characteristics

Table 2. Dalbavancin Use Characteristics

Table 3. Clinical Endpoints

Conclusion

While our results suggest dalbavancin is well tolerated, questions about relapse rates in the treatment of complicated S. aureus infections remain. Further research is needed to evaluate clinical outcomes for dalbavancin compared to standard of care antibiotics and to better elucidate whether relapses were related to true antibiotic failure versus other complexities of the S. aureus infections.

Disclosures

All Authors: No reported disclosures
1270. Early Real-world Evidence in the Use of Eravacycline for the Management of Draconian Infections
Authors: Carr Amy , El Ghali Amer , Kaur Parminder , Minor Sarah B , Casapao Anthony M
Published: January 2021

Background

Eravacycline (ERV) is a next-generation tetracycline approved for complicated intra-abdominal infections (cIAI) with in-vitro activity to multidrug-resistant organisms such as carbapenem resistant Enterobacteriaceae, extended spectrum beta-lactamase, and carbapenem-resistant Acinetobacter baumannii (CRAB). The purpose of this study was to identify the utility of ERV in clinical practice.

Methods

Retrospective case series was conducted on patients at AdventHealth that received at least two doses of ERV. Primary endpoint for the study was clinical success while on ERV, meeting none of the following criteria: changing therapy, mortality, or lack of improvement from sign/symptoms.

Results

Of 23 patients, 74% were males with a mean age of 55 ±18 years and mean body weight of 79 ±27 kg. Mean APACHE II and Charleson scores were 20 (±11) and 6 (±4), respectively. 91% received ERV for an off-label indication or organism. Infection types were respiratory (44%), cIAI (35%), skin (9%), and other (13%). All patients had positive cultures, while 61% were treated as a polymicrobial infection and 17% had bacteremia. Microorganisms included A. xylosoxidans, S. maltophilia, CRAB, and K pneumoniae. 48% had ERV susceptibilities from .06-4 mcg/mL, including two MIC ≥32mcg/mL for S. maltophilia. 70% were given another antibiotic prior to ERV with a median duration of 5 (1-35) days. Median duration of ERV was 8 (3-30) days. 83% percent received ERV in combination with another antibiotic. During treatment, 26% had a Child-Pugh Class C at baseline and 30% had elevated liver function tests. No adverse drug reactions were reported. Upon discharge, 35% continued ERV. Clinical success was observed in 57% (12/21) of patients. Clinical outcome by infection type is summarized in Figure 1. Of 9 cases of clinical failure, 14% were changed to alternative, 19% died while on ERV, and 10% failed to resolve signs/symptoms. Two cases of M. abscessus infections had insufficient follow-up to assess clinical outcome.

Figure 1. Eravacycline Clinical Outcome by Infection Type

Conclusion

Initial real-world experience with ERV differs significantly from the trials regarding severity of illness, types of infection, and clinical outcomes. Further evaluation is necessary for using ERV as combination therapy and in off-label indications.

Disclosures

All Authors: No reported disclosures
1273. Efficacy of Cefiderocol against carbapenem-resistant A. baumannii and P. aeruginosa in ventilator-associated pneumonia mouse model
Authors: Ota Kenji , Kaku Norihito , Uno Naoki , Sakamoto Kei , Kosai Kosuke , Hasegawa Hiroo , Miyazaki Taiga , Izumikawa Koichi , Mukae Hiroshi , Yanagihara Katsunori
Published: January 2021

Background

Cefiderocol (CFDC) is a novel cephalosporin with siderophore structure, characterized by transportation through siderophore receptor on outer membrane of Gram-negative bacteria and structural stability against beta-lactamase. The antimicrobial activity against multidrug resistant bacteria is demonstrated in vitro and in vivo. In this study, we aimed to elucidate the in vivo efficacy of CFDC using ventilator-associated pneumonia (VAP) mouse model.

Methods

The minimum inhibitory concentration (MIC) of CFDC and meropenem (MEPM) against the test Acinetobacter baumannii (Ab) and Pseudomonas aeruginosa (Pa) isolates were measured by broth microdilution assay. Iron depleted medium was used for CFDC. For VAP mouse models, neutropenia was induced by cyclophosphamide intraperitoneal administration, followed by intubation of sterile tube in the trachea and inoculation of bacterial suspension. PK analysis were performed in infected mice, in order to determine treatment regimens to achieve targeted time above MIC (TAM) of free concentrations in plasma. Treatment was initiated 3 hours post infection and continued up to 120 h for survival analysis. To investigate the bactericidal effect, the mice were sacrificed to count bacterial load in the lung at 48 h and 24 h for VAP-Ab and Pa, respectively.

Results

MICs(mg/L) of CFDC and MEPM against Ab were 0.5 and 128, and Pa were 0.008 and 16, respectively. The treatment regimens to achieve target MIC were shown in Table 1. In order to assess dose dependency of CFDC, required doses to achieve TAM of 70%, 90%, and 100% were calculated. These doses used in the studies were achievable in human for CFDC, but not for MEPM due to high MICs of the test strains. In treatment study for VAP-Ab, bactericidal effect was achieved at TAM > 70% in CFDC groups, as well as TAM 30% in MEPM group. In VAP-Pa, bactericidal effect was observed at TAM > 90% in CFDC groups, as well as TAM 30% in MEPM group.

Table 1.Treatment regimen and free TAM against VAP-Ab and Pa

Figure 1. Bacterial load in the lungs of VAP-Ab and Pa

Conclusion

The efficacy of CFDC against VAP-Ab and Pa were demonstrated in this study. Although 90% free TAM was required for bactericidal effect, CFDC was shown to be effective against carbapenem-resistant Gram-negative pathogens at the recommended clinical dosing regimen.

Disclosures

Katsunori Yanagihara, MD, PhD, Shionogi & Co.,Ltd. (Grant/Research Support)
1274. Evaluating the Activity of SPR719, a Novel Aminobenzimidazole, against Nontuberculous Mycobacteria
Authors: Murray Beverly , Hall Danielle , Cotroneo Nicole S , Critchley Ian , Pucci Michael , Stokes Suzanne , Pillar Chris
Published: January 2021

Background

Pulmonary infections caused by Nontuberculous Mycobacteria (NTM) are increasing in prevalence and are associated with high mortality and morbidity. Members of the Mycobacterium avium complex (MAC; primarily M. avium and M. intracellulare) and M. abscessus are most commonly associated with NTM pulmonary disease. Treatment options are limited and new agents with potent activity are needed. In this study, the activity of SPR719, a novel aminobenzimidazole, against NTM is reported.

MIC range and MIC50/90 summary table

Methods

The susceptibility of 58 non-consecutive, non-duplicate clinical NTM isolates was determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) standard M24. Isolates included 20 rapidly-growing mycobacteria (10 M. abscessus/chelonae Group, 6 M. fortuitum Group, and 4 M. mucogenicum Group) and 38 slow-growing mycobacteria (28 MAC and 10 M. kansasii). SPR719 and comparators clarithromycin (CLA), amikacin (AMK), moxifloxacin (MXF), rifabutin (RFB), minocycline (MIN), and imipenem (IPM) were evaluated. Minimum bactericidal concentrations (MBC) for SPR719, CLA, and AMK were determined in accordance with CLSI M26.

Results

The activity of SPR719 and comparators by MIC range and MIC50/90 (µg/mL) is summarized in the accompanying table. SPR719 activity was not affected by resistance to CLA, AMK, or MXF. MBC:MIC ratios for SPR719 and CLA were typically >8 which indicates a bacteriostatic mode of action; AMK MBC:MIC ratios were typically ≤ 4 indicative of bactericidal activity.

Conclusion

SPR719 had potent activity by both MIC50/90 and MIC range across the evaluated NTM species. The SPR719 activity against clinically relevant MAC and M. abcessus/chelonae Group isolates was comparable or superior to the evaluated comparators, and SPR719 was active against isolates resistant to currently utilized agents. These results highlight the potential of SPR719 in the treatment of NTM pulmonary disease.

Disclosures

Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Michael Pucci, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder)
1275. Evaluation of in vitro activity of manogepix against multidrug-resistant and pan-resistant Candida auris from the New York Outbreak
Authors: Zhu Yan Chun , Kilburn Shannon N , Kapoor Mili , Chaturvedi Sudha , Shaw Karen J , Chaturvedi Vishnu
Published: January 2021

Background

An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. NY C. auris isolates demonstrate resistance to fluconazole and variable resistance to other antifungals. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is in clinical development for the treatment of invasive fungal infections.

Methods

We evaluated the susceptibility of 200 NY C. auris isolates (2017-2020) to MGX and 10 comparators. Testing was performed using TREK frozen broth microdilution panels for FLC, VRC, ITC, ISA, POS, AFG, CAS, and MFG. MGX MICs were evaluated (CLSI M27-A3 guidelines) using a 50% reduction in fungal growth endpoint at 24 h. MICs were determined by ETEST® at 24 h for AMB and FLC. We defined pan-resistant C. auris as isolates with in vitro resistance to two or more azoles, all echinocandins, and AMB. The epidemiological cutoff values (ECVs, ECOFFs) for MGX were estimated using the Microsoft Excel spreadsheet calculator ECOFFinder.

Results

MGX demonstrated lower MICs than comparators (MIC50 and MIC90 0.03 mg/L; range 0.004-0.06 mg/L). MGX was 8-32-fold more active that the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than AMB. No differences were found in the MGX or comparators’ MIC50, MIC90, or GEOMEAN values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. The MGX epidemiological cutoff value (ECV, 99% cutoff) was 0.06 mg/L.

Conclusion

MGX MICs were low against C. auris isolates including those with variable patterns of resistance to AMB, azoles, and echinocandins. In addition, MGX retained potent activity against six pan-resistant isolates. These data support the continued clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

Disclosures

Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Vishnu Chaturvedi, PhD, Amplyx (Grant/Research Support)
101. Diagnostic Utility of a Multiplex PCR Meningitis/Encephalitis Panel and Impact on Antibiotic Use
Authors: Vanood Aimen , Hospodar Alexandra , Carpenter Christopher F
Published: January 2021

Background

The detection and identification of meningitis and encephalitis pathogens from CSF via traditional microbiologic methods may take several hours to days. The BioFire FilmArray Meningitis/Encephalitis Panel (BioFire), approved by the FDA in 2015, can detect 14 different pathogens within one hour, providing a faster time to diagnosis of a broad range of pathogens. The purpose of this study was to examine the impact of BioFire on length of hospital stay and duration of antibiotic use.

Methods

We conducted a retrospective chart review of patients diagnosed meningitis/encephalitis between 2015 and 2019 at 3 Beaumont Health (BH) hospitals. BioFire was adopted by BH midyear in 2017, allowing for analysis of cohorts over comparable periods before and after the introduction of the panel. Data collected and analyzed included biodemographics, comorbidities, presenting signs and symptoms, CSF analysis results, pathogens, days of antibiotic therapy, length of stay, and mortality.

Results

A total of 161 patients diagnosed with meningitis and/or encephalitis were reviewed, including 59 who underwent testing via BioFire. Of the 161 patients, 68 had a pathogen identified, 50 via traditional methods (6 bacterial and 44 viral) and 18 via BioFire (3 bacterial and 15 viral). West Nile Virus accounted for 17 of the viral infections diagnosed via traditional methods. The mean duration of antibiotic use after the assays resulted was not significantly different between patients with bacterial infections diagnosed by traditional methods or BioFire (11.2 vs 13.0 days, p=0.82) or for those with viral infections (0.1 vs 0 days, p=0.3). The median length of stay was also not significantly different between the two cohorts for patients with bacterial infections (21.7 vs 15.0 days, p = 0.36) or viral infections (6.2 vs. 10.0 days, p = 0.10).

Conclusion

While utilization of the BioFire panel yielded a faster diagnostic result, we have no evidence to demonstrate that it contributes to a significant reduction in duration of antibiotic use or length of stay.

Disclosures

All Authors: No reported disclosures
1280. In-Vitro Activity of Cefiderocol, Imipenem/Relebactam, & Ceftazidime/Avibactam in Ceftolozane/Tazobactam Resistant Strains of Multidrug Resistant Pseudomonas aeruginosa
Authors: Navas Daniel , Charles Angela , Carr Amy , Alexander Jose
Published: January 2021

Background

The activity of imipenem/relebactam (I/R), ceftazidime/avibactam (CZA) and cefiderocol (FDC) were evaluated against clinical isolates of multidrug resistant (MDR) strains of P. aeruginosa which was resistant to ceftolozane/tazobactam (C/T). The recent increase of MDR P. aeruginosa strains isolated from clinical samples has prompted research and development of new antimicrobials that can withstand its multiple resistance mechanisms. C/T is an effective option for treatment of MDR P. aeruginosa in our facility with only 10% of resistance in MDR strains, but the emergence of resistance may occur due to the presence of a carbapenemase gene or an ampC mutation.

Methods

Antimicrobial susceptibility testing for C/T Etest® (bioMérieux, Inc.) were performed on all MDR strains initially screened by the VITEK2® (bioMérieux, Inc.). 10% (n=20) of all MDR isolates were resistant to C/T by the CLSI 2019 breakpoints. These resistant isolates were tested for presence of a carbapenemase gene using the GeneXpert CARBA-R (Cepheid®) PCR and against CZA Etest® (bioMérieux, Inc.) I/R gradient strips (Liofilchem®) and FDC broth microdilution (Thermo Scientific™ Sensititre™).

Results

A total of 20 clinical isolates of MDR P. aeruginosa resistant to C/T were tested following standardized CLSI protocols and techniques. All 20 isolates were screened for the presence of a carbapenemase gene (blaVIM, blaNDM, blaKPC, blaOXA-48, blaIMP). A blaVIM gene was detected in 6 (30%) out of 20 isolates. FDC demonstrated the greatest activity with 85% (n=17) of susceptible isolates (CLSI MIC <4µg/dL). CZA (CLSI MIC <8µg/dL) and I/R (FDA MIC <2µg/dL) showed 15% (n=3) and 10% (n=2) of susceptible isolates respectively. FDC was active against all 6 blaVIM isolates, where all 6 strains were resistant to CZA and I/R as expected. 3 isolates tested non-susceptible against FDC; additional characterization was not performed at this time.

Conclusion

Based on these results, FDC demonstrated the greatest in-vitro activity against C/T resistant strains of MDR P. aeruginosa. FDC also demonstrated activity against all 6 MDR P. aeruginosa carrying blaVIM gene. FDC is a strong option to consider on MDR P. aeruginosa strains based on a resistance testing algorithm and a cost/effective protocol.

Disclosures

All Authors: No reported disclosures
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

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

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

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

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

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 >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 > 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

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

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

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)
1301. Breakthrough Invasive Fungal Infections based on CYP2C19 Levels in Patients Who were on Voriconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) undergoing Induction Chemotherapy
Authors: Singam Hareesh v , Pasikhova Yanina , Quilitz Rod , Greene John N , Baluch Aliyah
Published: January 2021

Background

Voriconazole (Vori) is often used for prophylactic anti-fungal therapy in induction chemotherapy for Acute Myeloid Leukemia (AML) patients due to predictable absorption and an extended spectrum antifungal activity. Vori is metabolized predominately by CYP2C19 to metabolites with less antifungal activity. There has been a great interest in understanding CYP2C19 as it significantly affects drug metabolism and pharmacokinetics of numerous drugs including voriconazole.

Approximately 39% of patients are genetically predicted to be CYP2C19 ultra-rapid or rapid metabolizers and thus are at an increased risk of breakthrough fungal infection. This study assesses the incidence of breakthrough invasive fungal infections (bIFI) at Moffitt Cancer Center based on CYP2C19 activity. bIFI is defined as new fungal infection while on vori, leading to treatment with liposomal amphotericin B, echinocandin, and/or different triazole.

Methods

This is a single-center retrospective analysis of patients who underwent induction chemotherapy for newly diagnosed AML and received voriconazole as the primary antifungal prophylaxis between July 2017 and June 2019. The patients enrolled were over 18 years old and did not have a history of stem cell transplant or solid organ transplant, Human Immunodeficiency Virus, relapsed AML or received systematic antifungal therapy 30 days prior. CYP2C19 were checked for each of the patients between July 2017 to June 2019 who were undergoing induction chemotherapy for newly diagnosed AML. It was checked within one week of admission. The patients were categorized as rapid metabolizers, intermediate metabolizers, normal metabolizers, and unknown CYP2C19.

Results

There was an incidence of 20.2% (18/89) bIFI in patients who were on Vori in this study. Of these patients with bIFI infections, 15.7% (3/19) of patients were rapid metabolizers, 14.7% (5/34) were normal metabolizers, 28.5% (4/14) were intermediate metabolizers and 0% (0/3) were poor metabolizers. There were 31% (6/19) breakthrough infections in patients with unknown CYP2C19 characteristics.

Conclusion

There is no significant statistical difference (p=0.6) among CYP2C19 categories with respect to breakthrough of invasive fungal infections at Moffitt Cancer Center between July 2017 - June 2019.

Disclosures

Rod Quilitz, Pharm D., Astellas (Advisor or Review Panel member)