bluuebunny/crossref_metadata_2025 huggingface dataset:
618. Fluconazole-Resistant Candida albicans Vaginitis with Cross-Resistance to Azoles: A Case Report
Authors: Akdağ Damla , Pullukçu Hüsnü , Yamazhan Tansu , Yesim Metin Dilek , Reşat Sipahi Oğuz , Ener Beyza , Isikgoz Tasbakan Meltem
Published: October 2019

Background

Local and systemic use of azole derivatives are common in the treatment of vulvovaginal candidiasis. However, there are cases unresponsive to these agents. Herein, we present treatment and follow-up of a patient with fluconazole–itraconazole and voriconazole-resistant recurrent vaginal candidiasis.

Methods

A 37-year-old woman with no comorbidity used topical and oral antifungal/antibacterial medications (including fluconazole and itraconazole) in the treatment of recurrent vulvovaginitis, was hospitalized due to continuous complaints. Intense, white-colored, odorless vaginal discharge was observed on physical examination. Urine and vaginal swab samples were taken for mycological and bacteriological culture. Metronidazole (500 mg 3x1 i.v.) and high dose fluconazole (600 mg/day i.v.) were initiated empirically for the possibility of dose-dependent resistant Candida infection, but there was no clinical response.

Results

Candida albicans was isolated in vaginal swab culture, but response to systemic fluconazole treatment for one week was inadequate. Antifungal susceptibility test was performed by microdilution method according to CLSI M27A3 guidelines and MIC values were reported respectively; fluconazole 4 µg/mL (SDD), itraconazole 1 µg/mL (R), posaconazole 0.06 µg/mL (WT), voriconazole 0.25 µg/mL (SDD), anidulafungin ≤ 0.015 µg/mL (S), amphotericin B 0.06 µg/mL (WT). For the resistance mechanism, point mutation in the ERG11 gene and MDR1 and MDR2 from efflux pumps were investigated and only the G464S mutation was detected in the ERG11 gene. Treatment was switched to IV anidulafungin (200 mg on day 1 followed by 100 mg/day). Clinical response was achieved in the patient whose complaints were reduced, and there was no Candida in the repeated vaginal swab culture taken on day 3 of treatment. The patient was discharged after 2 weeks of treatment. She had no recurrence after 2 years follow-up.

Conclusion

It should be kept in mind that resistant strains may be responsible for recurrent and unresponsive vulvovaginal candidiasis cases. Although there is no case report in which anidulafungin is used for treatment and it should be kept in mind that the anidulafungin is also in the treatment as it is summarized.

Disclosures

All authors: No reported disclosures.
634. Incidence of vanC-Mediated Vancomycin-Resistant Enterococcus Bloodstream Infections at Children’s Hospital of Colorado and Implications for Empiric Enterococcal Therapy
Authors: Dodson Daniel S , MacBrayne Christine , Williams Manon , Parker Sarah
Published: October 2019

Background

The most well-known Enterococcal species, E. faecium and E. faecalis, can harbor high-level vancomycin resistance mediated by acquired vanA and vanB operons. However, other Enterococcal species such as E. gallinarum and E. casseliflavus (VCE), harbor intrinsic low-level vancomycin resistance mediated by an intrinsic vanC operon, and the incidence of these pathogens among pediatric patients is not clear. As the antibiotic resistance pattern of VCE is different than E. faecium and E. faecalis, a high prevalence of VCE may have implications for antibiotic therapy. We describe the incidence and susceptibility of VCE bloodstream infections at a large children’s hospital and compare to E. faecalis and E. faecium.

Methods

Positive blood culture results from 2013 to 2018 were obtained from the Children’s Hospital of Colorado data warehouse. All first-time positive cultures for Enterococcus were analyzed for species, susceptibility, and hospital unit location. First-time positive was defined as being at least 2 weeks after any previous positive Enterococcus blood culture. Susceptibilities were categorized by clinical laboratories standards institute (CLSI) guidelines.

Results

Of 240 positive isolates, 7% were ampicillin susceptible and vancomycin nonsusceptible (resistant or intermediate), vs. 6% that were ampicillin resistant and vancomycin susceptible. An additional 3% of isolates were not susceptible to either antibiotic; all of these were E. faecium. VCE accounted for 12% of our isolates while E. faecalis and E. faecium accounted for 66% and 16%, respectively. All VCE were susceptible to ampicillin, but 52% were nonsusceptible to vancomycin. VCE incidence, ampicillin resistance, and vancomycin nonsusceptibility were most prevalent in our hematology, oncology, and bone marrow transplant (BMT) units.

Conclusion

At our institution, an as yet unspeciated Enterococcus is equally likely to be ampicillin susceptible and vancomycin nonsusceptible as ampicillin resistant and vancomycin susceptible. This is driven by a significant incidence of VCE, especially on our hematology, oncology, and BMT units. Therefore, vancomycin may not provide adequate empiric Enterococcal coverage on these units, and the addition of ampicillin will be recommended.

Disclosures

All authors: No reported disclosures.
661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)
Authors: Emu Brinda , DeJesus Edwin , Berhe Mezgebe , Leider Jason , Creticos Catherine , Weinheimer Steve , Cohen Zvi
Published: October 2019

Background

Ibalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study.

The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients.

Methods

Major eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0.

Results

Cohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels <50 copies/mL. Of 17 patients with a VL assessment at Week 48, 8 (47%) achieved <50 copies/mL. Seven patients did not have a Week 48 endpoint because they withdrew from the study to receive commercial IBA. At both time points, the median change in VL from Baseline was -2.6 log10 copies/mL. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (24%), headache (21%), and nausea, cough, rash, and fatigue (16% each). No injection site reactions related to IBA were reported. Most events were mild; 9 patients reported Grade ≥3 TEAEs. Two events were fatal (sepsis and cardiac arrest); neither related to IBA. One event of immune reconstitution inflammatory syndrome was reported and considered possibly related to IBA.

Conclusion

Results from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA.

Disclosures

All authors: No reported disclosures.
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

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

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

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

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

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

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

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

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

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.
751. Study on Daptomycin Prescription Suitability as a First Step Towards an Antimicrobial Stewardship Program
Authors: Sánchez Sebastián García , Moreno Félix Jesús García , de Vega Esther Chamorro , Minero Maricela Valerio , González Carmen Guadalupe Rodríguez , Galar Alicia , Samperio María Olmedo , Machado Marina , Pedromingo Miguel , García-Paredes Patricia Muñoz , Bouza Emilio , Sáez María Sanjurjo
Published: October 2019

Background

Daptomycin use has increased since its approval and has often extended to indications not included in the summary of product characteristics with highly variable dosing. Our objective was to assess daptomycin real use in an institution with Pharmacy and ID consultation available and to explore the need for establish specific Daptomycin stewardship.

Methods

Observational, retrospective study including all patients treated with daptomycin during 2017 in a tertiary hospital. Clinical variables were collected in a pre-established protocol including demographics, comorbidities, infection type, microbiological results, adverse events (AE), outcomes, and treatment adequacy (selection, dosage, microbiological adjustment and duration). Daptomycin prescription is not restricted at our institution. The dosages were considered adequate according to clinical guidelines.

Results

Overall 176 patients (62% men, median age: 70years) started treatment with daptomycin, 58% of them on empirical bases. Main uses were: skin and soft-tissue infections (37.5%), fever without obvious source (17.6%) and osteoarticular infection (12.5%). Sixty-three patients (35.8%) had concomitant bacteremia. An etiologic diagnosis was reached in 89.2% patients and S.aureuswas the most frequently isolated microorganism (n = 58, and 10 MRSA), followed by CoNS (n = 35). Overall, 77.7% of patients evolved satisfactorily. Five patients discontinued treatment due to AE (urticaria, cholestasis, increased CPK and rhabdomyolysis). Infection-related mortality was 7.4%. Daptomycin was correctly selected in 94.3% patients, length of therapy was adequate in 87.4%. However, only 47.1% of patients received adequate dosage (underdosing in 27.8%) and in 9.8% of patients, the treatment was not adjusted according to microbiological results. The prevalence of daptomycin use was 3.7 patients/1,000 admissions.

Conclusion

Daptomycin is often prescribed empirically, using nonadequate dosages and duration of therapy needs also an improvement. The follow-up of patients treated with daptomycin should be considered a priority intervention within an Antimicrobial Stewardship Program.

Disclosures

All authors: No reported disclosures.
770. Multimodal Sepsis Performance Improvement Initiative Improves Early and Appropriate Treatment, Reduces Sepsis-related Readmissions, and Reduces Overall Mortality
Authors: Yohannes Seife
Published: October 2019

Background

CMS has implemented the SEP-1 Core Measure, which mandates that hospitals implement sepsis quality improvement initiatives. At our hospital, a 900-bed tertiary hospital, a sepsis performance improvement initiative was implemented in April 2016. In this study, we analyzed patient outcomes before and after these interventions.

Methods

We studied coding data in patients with a diagnosis of Sepsis reported to CMS using a third-party performance improvement database between October, 2015 and July, 2017. The interventions included a hospital-wide education campaign about sepsis; a 24–7 electronic warning system (EWS) using SIRS criteria; a rapid response nursing team that monitors the EWS; a 24–7 mid-level provider team; a database to monitor compliance and timely treatment; and education in sepsis documentation and coding. We performed a before and after analysis of patient outcomes.

Results

A total of 4,102 patients were diagnosed with sepsis during the study period. 861 (21%) were diagnosed during the pre-intervention period and 3,241 (80%) were diagnosed in the post-intervention period. The overall incidence of sepsis, severe sepsis, and septic shock were 59%, 13%, and 28% consecutively. Regression analysis showed age, admission through the ED, and severity of illness as independent risk factors for increased mortality. Adjusted for these risk factors, the incidence of severe sepsis and septic was reduced by 5.3% and 6.9% in the post-intervention period, while the incidence of simple sepsis increased by 12%. In the post-intervention period, compliance with all 6 CMS mandated sepsis bundle interventions improved from 11% to 37% (P = 0.01); hospital length of stay was reduced by 1.8 days (P = 0.05); length of stay above predicted was less by 1.5 days (P = 0.05); re-admission rate was reduced by 1.6% (P = 0.05); and death from any sepsis diagnosis was reduced 4.5% (P = 0.01). Based on an average of 2000 sepsis cases at our hospital, this amounted to 90 lives saved per year. Death from severe sepsis and septic shock both were also reduced by 5% (P = 0.01) and 6.5% (P = 0.01).

Conclusion

A multi-modal sepsis performance improvement initiative reduced the incidence of severe sepsis and septic shock, reduced hospital length of stay, reduced readmission rates, and reduced all-cause mortality.

Disclosures

All authors: No reported disclosures.
997. Practical partnering of Antibiotic Stewardship and Allergy to address referrals to Penicillin allergy debunking clinic at a VA Medical Center
Authors: Sheth Dipa , Adenew Ayne , Charya Raghava , Santelices Judy , Liappis Angelike P
Published: October 2019

Background

The majority of Penicillin (PCN) allergies can be “debunked.” During acute medical care, opportunities to refer for formal evaluation are often overlooked, hampered by medication-interactions and lack of time and resources for bedside testing. Frequently, inpatients are not referred for PCN debunking evaluations (PCN-DE). Antimicrobial Stewardship Teams (ASTs) who partner with Allergy Clinical Teams (ACTs) can work collaboratively to target those who would benefit from de-labeling and are unlikely to otherwise be referred for formal evaluation.

Methods

The DCVAMC is an urban 240 bed 1a complexity acute and LTC teaching hospital with both on-site AST and well-established ACT. β-lactam allergy was tracked by the AST in inpatient, outpatient and long-term care setting utilizing a clinical surveillance system (TheraDoc, DSS Inc.) and allergy education was incorporated into prospective auditing rounds. PCN-DE involved face-face visit with an Allergist and careful history, chart/medication review. Option for skin testing (Pre-Pen, ALK Abello) with/without oral challenge performed at the discretion of ACT. EMR was altered to reflect results.

Results

We collaborated to develop a PCN-DE outpatient Allergy Clinic on the hospital campus. 2,564 designed β-lactam allergy alerts were identified as part of routine AST workflow prior to the initiation of the clinic in October 2017. Referrals resulted from AST prospective audits, consults to ACT and by surveillance of historical allergy history among acute and LTC admissions. Providers, including trainees, were engaged through education and encouraged to place outpatient referrals at the time of discharge or upon follow-up. ACT evaluated patients in groups of 2–3/session, roughly one clinic/month. Mean age of patients tested 56.3y (24–80y) with 35% >65yo; to date, (19/26) 73% have been successfully de-labeled

Conclusion

The success in de-labeling after formal evaluation is well established. Developing working relationships with allergists and encouraging providers to recognize often overlooked opportunities to refer to existing or newly established clinics is easily adopted by ASTs. In conjunction with screening, targeted education and referral to PCN-DE as a part of routine stewardship workflow has practical and immediate benefits.

Disclosures

All authors: No reported disclosures.
1046. Evaluating the outcomes of embedding Antimicrobial Stewardship order sets in the General Medicine Admission Electronic Order Set: A Retrospective Study
Authors: Chan April , Kapur Ajay , Langford Bradley , Downing Mark
Published: October 2019

Background

The use of facility-specific guidelines and clinical decision-making tools are recommended by a number of organizations to improve the appropriateness of empiric antimicrobial prescribing; however, how to increase usage is not clear. We evaluated the impact of embedding antimicrobial stewardship (AS) electronic order sets (EOS) into the general medicine admission EOS in the context of an established AS program.

Methods

The standalone EOS for community-acquired pneumonia (CAP), urinary tract infection (UTI) and cellulitis were reviewed and simplified to only include the antibiotic section prior to embedding. The intervention was introduced on March 30, 2017 with pre-intervention period defined as January 1, 2016 to March 29, 2017 and post-intervention period as of March 30, 2017 to June 30, 2018. The primary outcome was the change in usage of embedded AS EOS compared with the corresponding standalone EOS using counts. In addition, other standalone AS EOS (i.e., Clostridioides difficile infection (CDI), etc) were used as a control. The secondary outcomes were the change in antibiotic usage de-emphasized in embedded EOS (i.e., ceftriaxone, ciprofloxacin, clindamycin, moxifloxacin) and predicted prescribing shifts to antibiotics in the embedded EOS (i.e., amoxicillin-clavulanate, azithromycin and sulfamethoxazole-trimethoprim) using Days of Therapy (DOT)/1000 patient-days (PD). Paired t-test was used to compare antibiotic usage pre- and post-intervention.

Results

The usage of standalone EOS remained similar pre- and post-intervention except for a 16-fold increased usage of CDI EOS. There were large increases in uptake of the embedded EOS compared with the standalone EOS: 11-fold () increase for CAP, 47-fold () increase for UTI and 24-fold () increase for cellulitis. In addition, there was a statistically significant decrease in ciprofloxacin (mean 16.6 DOT/1000-PD vs. 13.6 DOT/1000-PD, P = 0.026) and moxifloxacin usage (mean 9.3 DOT/1000-PD vs. 5.2 DOT/1000-PD) during the study time period.

Conclusion

Our study showed that simplifying AS EOS and embedding these into a more commonly used EOS is associated with a significant increase in EOS usage and uptake of AS recommended empiric antibiotics with a decrease in fluoroquinolone usage.

Disclosures

All authors: No reported disclosures.
1048. A Randomized Controlled Trial of an Electronic Tool for Empiric Antibiotic Prescription: Results from the ANti-infective Stewardship using the WISCA tool in the Electronic Medical Record (AnSWER) Study
Authors: Ridgway Jessica , Shah Nirav , Ellen Acree Mary , Semel Jeffrey , Datta Avisek , Singh Kamaljit , Peterson Lance
Published: October 2019

Background

The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) is a computer-based, clinical tool for improving initial antibiotic selection in the management of pneumonia, cellulitis, urinary tract infection (UTI) and intraabdominal infection (IAB). WISCA predicts the likelihood that an antibiotic regimen will be active against the expected organisms causing the infection for each of these syndromes.

Methods

We performed a crossover randomized controlled trial of the WISCA tool between July 1, 2015 and June 30, 2018 at 4 hospitals. WISCA suggests an empiric antibiotic regimen based on individual patients’ comorbidities, severity of illness, allergy profile, history of multidrug-resistant organisms (MDRO), and prior antibiotics. Within 24 hours of admission an ID physician-reviewed patient charts to determine whether one of the clinical syndromes was present. At intervention hospitals, patients’ providers were notified when a change in empiric therapy was suggested or antibiotics were recommended to be stopped (if no bacterial infection was present). Outcomes included readmission, mortality, C. difficile infection (CDI), MDRO infection, length of stay (LOS), and cost of antibiotics.

Results

10,202 patients enrolled in the study with 4,451 (57% female, mean age 72) in the intervention arm and 5,751 (55% female, mean age 71) in the control arm. There were no significant differences in clinical outcomes for any of the syndromes. Among 2,146 patients determined to have no bacterial infection, WISCA intervention resulted in lower antibiotic cost during the hospital stay ($714.46 vs. $927.56, P < 0.01). When providers accepted the recommendation to stop antibiotics, there were fewer antibiotic days (mean 296 antibiotic days/1000 patient-days vs. mean 378 antibiotic days/1000 patient-days, P = 0.038) and no significant difference in mortality or readmission rates. No bacterial infection patients also experienced a nearly 3-fold lower rate of CDI vs. patients with infection (0.8% vs. 2.3%, P < 0.001).

Conclusion

Although the use of the WISCA tool was not associated with a reduction in mortality, readmissions, or LOS, intervention to stop antibiotics for those with no bacterial infection was associated with reduced antibiotic use and cost savings.

Disclosures

All authors: No reported disclosures.
1065. Keeping Score: Utilizing a Prioritization Tool to Create Multidisciplinary Antimicrobial Stewardship Documentation
Authors: Mediwala Krutika N , Raux Brian R , Philip Acshah , Parks Amanda , Dixon Terry , Gnann John W
Published: October 2019

Background

A multidisciplinary approach using pre-authorization and/or prospective audit and feedback combined with institutional guidelines, personnel education, and intervention monitoring is essential for successful antimicrobial stewardship programs (ASP). Assessing the impact of ASPs can be process-based and/or outcome-based. Electronic medical record-based clinical decision support (CDS) tools can be used to prioritize stewardship interventions.

Methods

The Medical University of South Carolina (MUSC) transitioned from Theradoc® to Epic® for ASP surveillance and data collection in 2018. The ASP team developed a scoring algorithm with integral rules to identify and analyze inpatients who might require ASP interventions. The dynamic list captures and scores patients based on key infection-related data and prioritizes interventions. Additionally, we created a smart form flowsheet to streamline stewardship efforts for use by physicians and pharmacists. Accuracy of event capture was assessed during the buildout and via daily comparisons between Theradoc® and Epic®. Our goals are to optimize the treatment of potentially fatal infections (e.g., bacteremia) and delay emerging resistance.

Results

Our ASP module utilizes a scoring algorithm to identify and prioritize patients with positive blood or central nervous system cultures, other positive critical diagnostic tests, and high-risk antimicrobial use. Additional rules identify “bug-drug” mismatches, multiple positive cultures, and de-escalation opportunities. For example, the rules assign a high priority to patients with positive blood cultures and no prescribed antibiotics, but a lower priority score to restricted antimicrobial orders. We created a smart form flowsheet to document microorganism, presumed source, anti-infective use, ASP intervention, and acceptance of recommendations, allowing for multidisciplinary documentation outside of Epic® I-vents. Finally, we created a Reporting Workbench report which allows for monthly compilation and analysis of ASP interventions.

Conclusion

The MUSC Epic® ASP platform build showcases a CDS system that allows for streamlined, multidisciplinary communication, documentation, and analysis of outcomes.

Disclosures

All authors: No reported disclosures.