bluuebunny/crossref_metadata_2025_split huggingface dataset:
662. Recurrence of Infection and Emergence of Drug Resistance After Treatment with Meropenem/Vaborbactam Compared with Ceftazidime/Avibactam in Carbapenem-Resistant Enterobacteriaceae Infections
Authors: Ackley Renee , Roshdy Danya , Isip Jacqueline , Minor Sarah B, , Elchynski Amanda L , Anderson William E , Capraro Gerald A , Polk Christopher 
Published: October 2019

Abstract

Background
Options for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections were historically limited to antibiotics with limited efficacy and significant toxicities. Ceftazidime/avibactam (CA) and meropenem/vaborbactam (MV) are superior to older regimens; however, a direct comparison of the agents is lacking. This study compared clinical outcomes including recurrence of infection and emergence of drug resistance in patients who received CA vs. MV for CRE infections.

Methods
This was a multicenter, retrospective cohort study of adults with CRE infections who received CA or MV for ≥72 hours from February 2015 to October 2018. Patients with localized urinary tract infection were excluded. The primary endpoint was clinical success (30-day survival, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days in patients with bacteremia, absence of recurrent infection). Secondary endpoints included 30- and 90-day mortality, adverse events (AE), recurrent CRE infection within 90 days, and development of resistance in patients with recurrent infection. We conducted a post hoc subgroup analysis in patients with recurrence to compare development of resistance in those who received CA monotherapy, CA combination therapy, and MV monotherapy.

Results
131 patients were included (CA: 105 patients, MV: 26 patients), 40% had bacteremia. No statistical difference in clinical success was observed between groups (62% vs. 69%, respectively, P = 0.49). Patients in the CA arm received combination therapy more often than patients in the MV arm (61% vs. 15%, P < 0.01). No difference in 30- and 90-day mortality resulted among groups, but numerically higher rates of AE were observed in the CA group (38% vs. 23%, P = 0.17). In patients with recurrent infection, development of resistance occurred more often with CA monotherapy, though not statistically significant (Table 1). One case of MV resistance was observed in a patient who had received 4 prior courses of MV, but this episode was outside of the study period.

Conclusion
Clinical success was similar between the groups despite MV being used more often as monotherapy. Development of resistance and rates of AE were higher in the CA group compared with MV therapy.

Disclosures
All authors: No reported disclosures.
672. Activity of Ibrexafungerp (Formerly SCY-078) Against Candida auris: In vitro, In Vivo, and Clinical Case Studies of Candidemia
Authors: Barat Stephen , Borroto-Esoda Katyna , Ghannoum Mahmoud , Berkow Elizabeth , Angulo David A 
Published: October 2019

Abstract

Background
Candida auris is a growing global threat; a pathogen associated with high mortality (up to 60%), multidrug resistance, the ability to spread from person-to-person and surface-to-person, presenting high risk for outbreaks in healthcare facilities. Ibrexafungerp is a novel IV/oral glucan synthase inhibitor (triterpenoid) antifungal with activity against Candida, Aspergillus, and Pneumocystis spp., in Phase 3 development.

Methods
In vitro studies tested ibrexafungerp against >100 clinical isolates of C. auris. Other in vitro studies evaluated the effects of ibrexafungerp against C. auris biofilms. In vivo activity against C. auris was evaluated using a disseminated murine model and a cutaneous infection guinea pig model. In humans, an ongoing open-label trial of ibrexafungerp for treatment of patients with infections caused by C. auris (the CARES study) has been initiated in the United States and India.

Results
In vitro and in vivo studies demonstrated that ibrexafungerp is active against C. auris, including MDR strains. The MIC mode for ibrexafungerp was 1 μg/mL and the MIC50 and MIC90 were 0.5 and 1 μg/mL, respectively. Many echinocandin-resistant C. auris isolates have shown susceptibility to ibrexafungerp. Furthermore, ibrexafungerp has been shown to reduce biofilm thickness. In animal models of C. auris infection, treatment with ibrexafungerp resulted in improved survival and reduced fungal burden in both the murine model of disseminated infection and the guinea pig model of cutaneous infection as compared with untreated controls. In humans, two patients with difficult to treat C. auris candidemias were enrolled in the CARES study and responded positively to oral ibrexafungerp with eradication of the infection.

Conclusion
These data demonstrate that ibrexafungerp possess potent in vitro and in vivo activity as well as promising clinical activity. Therefore, continued clinical evaluation of ibrexafungerp as an option to treat C. auris infections is warranted.

Disclosures
All authors: No reported disclosures.
675. Efficacy of Human-Simulated Bronchopulmonary Exposures of Cefepime and Zidebactam (WCK 5222) Against Multidrug-Resistant (MDR) Pseudomonas aeruginosa (PSA) in a Neutropenic Murine Pneumonia Model
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P 
Published: October 2019

Abstract

Background
WCK 5222 combines cefepime (FEP) with zidebactam (ZID), a bicycloacyl hydrazide β-lactam enhancer which binds PBP2 in PSA and inhibits class A and C β-lactamases. The in vivo efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR PSA, a recalcitrant pneumonia-causing pathogen with few treatment options, was investigated in a neutropenic murine pneumonia model.

Methods
Thirteen clinical isolates of MDR PSA with FEP MIC ≥64 mg/L were studied in neutropenic CD-1 mice. FEP, ZID, and WCK 5222 MICs were measured by broth microdilution in triplicate. For in vivo experiments, lungs were intranasally inoculated with 107–108 CFU/mL bacterial suspensions. Human-simulated regimens (HSR) of FEP and ZID alone and in combination which achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g FEP/1 g ZID as a 1 hour infusion at steady state were developed. For each regimen, groups of 6 mice were dosed subcutaneously 2 hours after inoculation for 24 hours, then sacrificed. Vehicle-dosed control mice were sacrificed at the start (0 hour) and end (24 hours) of the dosing period. Lungs were aseptically harvested and bacterial CFU/lungs were determined.

Results
FEP MIC was >64 mg/L for all isolates, while ZID and WCK 5222 MICs ranged from 4–512 and 4–32 mg/L, respectively. Mean bacterial growth for all isolates at 0 hour was 6.68 log10 CFU/lungs. Mean changes ± SD in bacterial density at 24 hours compared with 0 hour controls for 12 isolates with WCK5222 MIC ≤16 mg/L were 2.08 ± 1.09, 1.09 ± 0.98, −0.92 ± 1.45, and −2.13 ± 0.75, for control, FEP, ZID, and WCK5222, respectively. Against these isolates, ZID yielded >1 log10 CFU/lungs reduction in 7/12, while activity was enhanced with WCK5222, producing >1 log10 CFU/lungs reduction in 11/12 and >2 log10 CFU/lungs reduction in 9/12. All isolates showed growth or stasis on FEP.

Conclusion
Human-simulated bronchopulmonary exposures of WCK5222 is effective against MDR PSA at MIC up to 16 mg/L in a neutropenic murine model. These data support the clinical development of WCK5222 for the treatment of pseudomonal lung infections, but further studies of PSA with high WCK5222 MIC are necessary to delineate the susceptibility breakpoint.

Disclosures
All authors: No reported disclosures.
677. Activity of Novel β-Lactamase Inhibitor QPX7728 Combined with β-Lactam Agents When Tested Against Carbapenem-Resistant Enterobacteriaceae (CRE) Isolates
Authors: Castanheira Mariana , Lindley Jill , Huynh Holly , Mendes Rodrigo E , Lomovskaya Olga 
Published: October 2019

Abstract

Background
CREs have been described worldwide and these isolates are often multidrug resistant with few therapeutic options remaining active against them. New β-lactam (BL)/β-lactamase inhibitor (BLI) combinations recently approved are active against KPC and some OXA-48 producers, but not against isolates producing metallo-β-lactamases (MBLs). We evaluated the activity of QPX7728 (QPX), a novel BLI paired with various BLs against a collection of CRE isolates characterized for the presence of carbapenemases.

Methods
A total of 508 CRE clinical isolates were susceptibility (S) tested by reference broth microdilution methods against meropenem (MER), tebipenem (TEB), cefepime (FEP), ceftolozane (TOL), and ertapenem (ETP), and meropenem (MEM) combined with QPX at fixed 2, 4, and 8 mg/L. Agents were provided by Qpex Biopharma except for FEP, ETP, and MEM. Carbapenemases were detected using PCR/sequencing or whole-genome sequencing.

Results
All BLs had limited activity against CRE isolates (MIC50/90, ≥32/ >32 mg/L) and QPX lowered the MIC for all agents (figure). Against 157 isolates carrying serine-carbapenemase (SCarb) genes (153 KPC-producers), MEM or ETP plus QPX at fixed 4 or 8 mg/L displayed MIC50 at ≤ 0.03 mg/L and MIC90 ranging from 0.12 to 0.5 mg/L. QPX lowered the FEP or TOL MIC50 to ≤ 0.25 mg/L and MIC90 to 0.25, 0.5 or 1 mg/L depending on the BLI concentration. Over 98.0% of the 150 isolates harboring OXA-48-like genes were inhibited by FEP, TOL, ETP or MEM plus QPX at ≤2 mg/L. Similarly, MEM, FEP, TOL and ETP + QPX inhibited >98.0% of the 51 CREs that did not carry carbapenemases at ≤2 mg/L when using a higher BLI concentration. The activity of FEP (MIC50/90, 0.06/1 mg/L), ETP (MIC50/90, 0.03/4 mg/L), and MEM (MIC50/90, ≤ 0.015/2 mg/L) was mostly restored when 8 mg/L of QPX was combined with these agents and tested against 150 MBL-producing isolates.

Conclusion
QPX restored the activity of several BLs when tested against 508 CRE isolates that include 157 harboring SCarb, 150 OXA-48-like-producers, and 150 MBL-producing isolates. Further development of this BLI with inhibitory activity against all carbapenemase types seems warranted.

Disclosures
All authors: No reported disclosures.
690. Activity of a Novel Polymyxin Analog, QPX9003, Tested Against Resistant Gram-Negative Pathogens, Including Carbapenem-Resistant Acinetobacter, Enterobacterales, and Pseudomonas
Authors: Castanheira Mariana , Lindley Jill , Huynh Holly , Mendes Rodrigo E , Lomovskaya Olga 
Published: October 2019

Abstract

Background
Multidrug resistance (MDR) among Gram-negative (GN) organisms and the limited active therapeutic options against these pathogens are matters of worldwide concern. Polymyxins are cationic peptides that act on the bacterial cell membrane and have good activity against GN organisms, including MDR strains. We evaluated the activity of QPX9003, a novel polymyxin analog with an improved safety profile over current polymyxins, against a large collection of resistant GN isolates collected worldwide.

Methods
Susceptibility testing was performed by reference microbroth dilution against 2,518 GN organisms for QPX9003, colistin (COL), levofloxacin, tigecycline, gentamicin, amikacin, meropenem, cefepime, piperacillin–tazobactam, and ceftazidime–avibactam. Isolates included 1,000 Pseudomonas aeruginosa (PSA) enriched for MDR, 503 carbapenem-resistant Acinetobacter baumannii (CRAB), and 1,105 Enterobacterales (ENT).

Results
QPX9003 had potent activity against PSA isolates enriched for resistance against β-lactam/β-lactamase inhibitor combinations and was 4-fold more potent than COL (MIC50/90, 0.25/0.25 mg/L vs. MIC50/90 of 1/1 mg/L). QPX9003 was also more potent than COL against the panel of CRAB with MIC50/90 of 0.125/1 mg/L and 0.5/4 for QPX9003 and COL, respectively. QPX9003 had a modal MIC of 0.06 mg/L against a large collection of ENT isolates resistant to cephalosporins and/or carbapenems (MIC50/90, 0.06/16 mg/L). QPX9003 activity was identical against 508 carbapenem-resistant Enterobacterales (CRE; MIC50/90, 0.06/16 mg/L) isolates and 511 Klebsiella pneumoniae isolates (MIC50/90, 0.06/16 mg/L) in this collection. Escherichia coli isolates were considerably more sensitive to QPX9003 (MIC50/90, 0.06/0.12 mg/L) compared with K. pneumoniae isolates. Activity of QPX9003 and COL was similar against ENT. Other comparator agents had limited activity against PSA, CRAB, and CRE isolates.

Conclusion
QPX9003 had activity against this collection of highly resistant GN isolates and was particularly active against the PSA and CRAB isolates. QPX9003 is a promising new-generation polymyxin agent.

Disclosures
All authors: No reported disclosures.
691. Activity of TNP-2092 Against Biofilms Formed by Prosthetic Joint Infection-Associated Staphylococci
Authors: Fisher Cody , Schmidt-Malan Suzannah , Yuan Ying , He Shijie , Ma Zhenkun , Patel Robin , Patel Robin 
Published: October 2019

Abstract

Background
Infection occurs in ~1–2% of prosthetic joint replacement surgeries, with staphylococci being the most common cause. TNP-2092 is an investigational drug composed of rifamycin and quinolizinone pharmacophores conjugated via a stable linker. Here, we determined TNP-2092’s in vitro activity against biofilms formed by staphylococci associated with prosthetic joint infection and compared activity to that of ciprofloxacin and rifampin alone and in combination, as well as to daptomycin and vancomycin.

Methods
A total of 80 staphylococcal isolates (40 Staphylococcus aureus and 40 Staphylococcus epidermidis) were studied. Planktonic state minimum inhibitory concentrations (MICs) of TNP-2092, ciprofloxacin, rifampin, ciprofloxacin + fixed concentration (1 mg/mL) rifampin, daptomycin and vancomycin were determined following CLSI guidelines. Tween-80（0.002%）was added to TNP-2092 to prevent drug binding to plastic plates. Minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm bactericidal concentration (MBBCs) were determined as follows. Bacteria were grown in TSB to logarithmic phase and adjusted to a turbidity of 0.5 McFarland; 150 µL aliquots were transferred to individual wells of 96-well flat-bottom plates and the plates covered with 96-pegged lids. Plates were incubated on a shaker for 5 hours at 37℃. Pegged lids were rinsed using 200 µL PBS/well and placed into a microtiter plate containing serial 2-fold drug dilutions in CAMHB Plates were incubated for 20–24 hours at 37°C and MBICs read by visual turbidity. Pegged lids were rinsed with PBS and placed into plates filled with 200 µL CAMHB/well and incubated for 20–24 hours at 37°C after which MBBCs were determined by assessing visual turbidity.

Results
Results shown in the table.

Conclusion
TNP-2092 has promising in vitro activity against prosthetic joint infection-associated staphylococcal biofilms.

Disclosures
Robin Patel, MD, ASM and IDSA: Other Financial or Material Support, Travel reimbursement, editor’s stipends; CD Diagnostics, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, ContraFect, TenNor Therapeutics Limited, Shionogi: Grant/Research Support; Curetis, Specific Technologies, NextGen Diagnostics, PathoQuest, Qvella: Consultant; NBME, Up-to-Date, the Infectious Diseases Board Review Course: Honorarium recipient, Other Financial or Material Support; 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: Other Financial or Material Support, Patents.
707. QPX9003: Pharmacology of a Novel Polymyxin in Mice and Rats
Authors: Sabet Mojgan , Tarazi Ziad , Parkinson Jonathan , Roberts Kade , Thompson Philip , Nation Roger , Velkov Tony , Hecker Scott , Lomovskaya Olga , Dudley Michael , Li Jian , Grifith David 
Published: October 2019

Abstract

Background
Currently available polymyxins are limited by toxicity and poor efficacy at tolerated doses. We have developed a new series of polymyxin derivatives with improved safety profiles and in vitro potency against major MDR bacteria. The following describes studies on the in vivo antimicrobial activity and toxicity of QPX9003 in mice and rats.

Methods
Mouse studies. The minimum lethal dose (MLD by IV bolus) and nephrotoxicity (6 IP doses administered 2 hours apart) of QPX9003 and polymyxin B (PMB) were determined in Swiss mice. For the neutropenic mouse thigh infection using A. baumannii, Swiss mice were infected with ~106 CFU/thigh. Doses were administered IP at various intervals starting 2-hour post-infection and continued over 24 hours. Rat studies. For the rat lung infection model, Sprague-Dawley rats were infected with ~107 CFU/lung. QPX9003 and PMB were administered IV every 4 hours starting 2 hours post-infection and continued over 24 hours. Bacteria. For both infection models, animals were infected with A. baumannii AB1016 (QPX9003 MIC of 0.5 mg/L and PMB MIC of 1.0 mg/L). Untreated control groups were sacrificed at the start of treatment and both untreated and treated groups were sacrificed 24 hours after the start of treatment, infected tissues harvested, homogenized, and plated to determine colony counts.

Results
QPX9003 had reduced acute toxicity and nephrotoxicity compared with PMB in mice. QPX9003 showed better bacterial killing of A. baumannii than PMB at similar plasma exposures in both the mouse thigh model (−0.41 vs. +0.83 log CFU/thigh) and rat lung infection model (−1.10 vs. +1.44 log CFU/lung).

Conclusion
QPX9003 was less acutely toxic, less nephrotoxic, and was more efficacious in mouse and rat infection models compared with PMB. QPX9003 is a promising new polymyxin. (This work was supported in part by federal funds from the National Institutes of Allergy and Infectious Diseases [R01AI098771], and the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under OTA number HHSO100201600026C).

Disclosures
All authors: No reported disclosures.
712. Activity of Exebacase (CF-301) Against Methicillin-Resistant Staphylococcus aureus (MRSA) Biofilms on Orthopedic Kirschner Wires
Authors: Karau Melissa J , Schmidt-Malan Suzannah , Mandrekar Jayawant , Lehoux Dario , Schuch Raymond , Cassino Cara , Patel Robin 
Published: October 2019

Abstract

Background
Orthopedic foreign body-associated infection can be difficult to treat due to the formation of biofilms protecting microorganisms from both antimicrobials and the immune system. Exebacase (EXE) is a phage-derived lysin which acts as a direct lytic agent by hydrolyzing the peptidoglycan cell wall of Staphylococcus aureus. In this study, the activity of EXE was evaluated in comparison to daptomycin against MRSA biofilms on orthopedic Kirschner wires (K-wires).

Methods
MRSA strain IDRL-6169 was studied; it has a MIC of 0.5 µg/mL for both daptomycin (DAP) and EXE. Biofilms were formed in 1 mL of 106 cfu/mL tryptic soy broth on 0.5x0.1 mm threaded stainless steel K-wires for 10 hours, after which the wires were removed from the media and placed into 0.04 mL of either DAP or EXE at 0 (vehicle only), 0.098, 0.98, or 9.8 mg/mL. DAP+EXE was also tested, each at 0.098 mg/mL. Bacteria were quantified after 0, 2, 4, 8, and 12 hours of incubation at 37ºC. Testing was performed in triplicate. Results were reported as log10 cfu/K-wire reduction relative to vehicle alone. A 3-log10 cfu/K-wire reduction was considered bactericidal. P-values were calculated using Kruskal–Wallis.

Results
The bacterial burden of vehicle alone ranged from 5.49- to 6.33-log10 cfu/K-wire at all time points. Bacterial reductions for each treatment compared with carrier solution are shown in the table. DAP showed no bactericidal activity. EXE showed bactericidal activity at all concentrations at all time points studied except 0.098 mg/mL at 8 hours. There was no significant difference between EXE at 0.098 and 0.98 mg/mL at any time point but EXE at 9.8 mg/mL did show superiority over the lower concentrations. DAP+EXE 0.098 mg/mL was bactericidal at all time points.

Conclusion
EXE showed a rapid effect against MRSA biofilms on orthopedic K-wires apparent within the first 2 hours of exposure and was more active than daptomycin alone at the same concentrations.

Disclosures
All authors: No reported disclosures.
727. Potency of the β-Lactamase Inhibitor QPX7728 Is Minimally Affected by KPC Mutations that Reduce Potency of Ceftazidime–Avibactam
Authors: Lomovskaya Olga , Nelson Kirk J , Rubio-Aparicio Debora 
Published: October 2019

Abstract

Background
In the United States, carbapenem-resistant Enterobacteriaceae (CRE) are mainly represented by KPC-producing strains and ceftazidime–avibactam (C/A) is increasingly used to treat infections caused by KPC-producers. C/A resistant (C/A-R) mutants with mutations in blaKPC can be isolated in vitro and were reported in patients treated with C/A. QPX7728 (QPX) is a new ultra-broad-spectrum β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with a potent activity against serine and metallo-β-lactamases. QPX in combination with meropenem (MER), M/Q, or cefepime (FEP), F/Q, has potent activity against all types of CRE (KPC, MBLs and OXA-48). The objective of these studies was to evaluate the activity of QPX in combination with various antibiotics against KPC-producing strains with C/A-R due to mutations in blaKPC.

Methods
Ten strains of KPC-producing Klebsiella pneumoniae with C/A MIC varied from 0.5 µg/mL to 8 µg/mL were used in resistance studies using C/A at 2x–8x the MIC (with avibactam [AVI] fixed at 4 µg/mL). Mutations in blaKPC were identified by sequence analysis. Ceftazidime (CAZ), MER and FEP MIC alone and with AVI and QPX (both BLIs at 4 µg/mL) were determined using the reference broth microdilution method. Five C/A-R clinical isolates with mutations in blaKPC were also included in the panel.

Results
Mutations in blaKPC that result in C/A resistance were selected in all strains. Mutants had 4- to 64-fold (16-fold average) increase in C/A MIC that varied from 16 to 128 μg/mL. In contrast, there was a 2-fold increase for CAZ-QPX MICs (MICs between ≤0.125 to 2 μg/mL. Similarly, there was no more than 2-fold increase in MER/QPX and FEP/QPX MICs, and the majority of mutants did not have an increase in MER/QPX or FEP/QPX MICs (MICs varied from ≤0.125 to 1 µg/mL). For five clinical C/A-R isolates, C/A, M/Q and F/Q MIC varied from 16 to ≥128 μg/mL, ≤0.125 to 4 μg/mL, and ≤0.125 to 2 μg/mL, respectively.

Conclusion
These data indicate that KPC mutations that affect the potency of C/A have minimal effect on the potency of QPX7728 combinations with either CAZ, MER or FEP indicating the potential differences in binding sites for these inhibitors in KPC. Further studies of QPX combinations are in progress.

Disclosures
All authors: No reported disclosures.