bluuebunny/crossref_metadata_2025_split huggingface dataset:
620. Sub-MIC Concentrations of Levofloxacin and Delafloxacin Enhance Staphylococcus aureus Biofilm Formation: Significance of Maximizing Exposure
Authors: Bodo Emily C , Daffinee Kathryn E , LaPlante Kerry 
Published: October 2019

Abstract

Background
Fluoroquinolones are utilized in Staphylococcal prosthetic joint infections due to their anti-biofilm activity. When antibiotic dosing is not optimized or antibiotics do not reach the site of infection, additional virulence factors may upregulate. We aimed to determine whether exposure to sub-MIC concentrations of levofloxacin and delafloxacin affect biofilm formation in Staphylococcus aureus.

Methods
This study utilized 50 diverse methicillin-susceptible S. aureus (MSSA) clinical isolates collected between 2004 and 2018. Sources included blood, skin/tissue, bone, and joint fluid. Minimum inhibitory concentrations and minimum bactericidal concentrations were identified according to CLSI. Biofilm assays were conducted as previously described by our program. Biofilm quantification was categorized as strong (OD570 ≥ 2), moderate (OD570 ≥ 1 and < 2), or weak (OD570 < 1). Prevention assays were conducted with the addition of increasing concentrations of delafloxacin or levofloxacin. We evaluated the amount of isolates that demonstrated increased biofilm formation in the presence of sub-MIC concentrations and extent of biofilm enhancement. Percent change was calculated between OD570 of the isolate growth control without antibiotic exposure and peak biofilm OD570 when exposed to the antibiotic.

Results
Of the 50 MSSA isolates, 14 (28%) exhibited moderate/strong formation and 36 (32%) exhibited weak biofilm formation. 52% and 58% of the isolates demonstrated a ≥50% increase in formation when exposed to sub-MIC concentrations of delafloxacin and levofloxacin, respectively. None of the strong biofilm formers demonstrated a ≥50% peak increase in formation when exposed to the antibiotics. Of the isolates that demonstrated a ≥50% peak increase, the average percent change was 267% (±29) with levofloxacin and 258% (±33) with delafloxacin.

Conclusion
Sub-MIC concentrations of delafloxacin and levofloxacin increased biofilm formation in S. aureus isolates that normally exhibit weak or moderate biofilm formation when not in the presence of antibiotics. Maintaining appropriate fluoroquinolone concentrations at the site of action is critical in preventing enhancement of biofilm formation. Further research is needed to identify the mechanism behind this increase.

Disclosures
All authors: No reported disclosures.
621. In vitro Ceftazidime: Avibactam Resistance in Carbapenem-Resistant Enterobacteriaceae Isolates
Authors: Belal Maymonah , Villasis Lori , Diago-Navarro Elizabeth , Motley Michael , Young; Eric Spitzer Allen , Fries Bettina C , Monteforte Melinda 
Published: October 2019

Abstract

Background
Ceftazidime–avibactam (CAZ-AVI) is a new antibiotic with activity against many Carbapenem-resistant Enterobacteriaceae (CRE). Although CAZ-AVI resistance in CRE has been reported, it is not consistently assessed. Our study aimed to assess the prevalence of CAZ-AVI resistance in CRE isolated from patients with and without prior exposure to CAZ-AVI.

Methods
We tested 116 CRE isolates for CAZ-AVI resistance by Kirby–Bauer (KB) disk diffusion susceptibility. Resistant isolates were verified by repeat KB and E-test performed by the Stony Brook Hospital laboratory. The blaKPC gene of resistant strains was amplified by PCR and sequenced. Patient data were used to determine whether patients were colonized or infected, and whether they were exposed to CAZ-AVI.

Results
Of the 116 CRE isolates from 86 patients (96 encounters), 50% were Klebsiella species, 23.2% were Enterobacter species, 10.3% Escherichia coli and 16.5% other CRE. They were recovered from colonized (37%) and infected (63%) patients of which 18% were treated with CAZ-AVI during their hospitalizations (median duration of therapy, 6 days). Two CRE isolates (1.7%) were found to be resistant on repeated testing. One isolate was K. pneumoniae derived from the sputum of a patient diagnosed with ventilator-associated pneumonia who received 40 days of CAZ-AVI therapy prior to isolation of the resistant isolate (KB diameter 20 mm, MIC > 512 μg/mL by E-Test). Sequencing of the strain’s blaKPC3 gene revealed a previously described Ambler-position D179Y mutation that has been shown to convey resistance. The second CAZ-AVI-resistant K. pneumoniae (KB diameter 19 mm, MIC 64 μg/mL by E-test) was isolated from the urine of a colonized patient naïve to CAZ-AVI therapy. The strain’s blaKPC10 gene had no mutations.

Conclusion
In our strain collection, the rate of resistance to CAZ-AVI remains low <2%. Although we found one mutation (D179Y) previously linked to CAZ-AVI resistance we also discovered one K. pneumoniae isolate with in vitro resistance to CAZ-AVI that did not exhibit any blaKPC mutations conveying CAZ-AVI resistance. Interestingly, this strain was derived from a patient with no prior CAZ-AVI exposure. Whole-genome sequencing will be performed to identify other genes or mutations that may confer resistance.

Disclosures
All authors: No reported disclosures.
623. Antimicrobial Resistance in Non-Typhoidal Salmonella from Retail Poultry Meat by Antibiotic Usage-related Production Claims—Pennsylvania, 2008–2017
Authors: Yin Xin , M’ikanatha Nkuchia M , Dettinger Lisa , Johnston Melinda , Eckroth William , Husband Brigitte , Tait James , Nyirabahizi Epiphanie , Tate Heather 
Published: October 2019

Abstract

Background
Antimicrobial-resistant (AMR) nontyphoidal Salmonella infections are a public health concern. Injudicious use of antimicrobials fuels emergence of resistance. The National Antimicrobial Resistance Monitoring System (NARMS) tracks AMR in Salmonella from humans, animals and foods. There is limited evidence regarding antimicrobial use in food animals and AMR bacteria in retail meat.

Methods
We reviewed antimicrobial susceptibility and whole-genome sequencing data from 320 Salmonella isolated from poultry meat in Pennsylvania as part of NARMS activities. Salmonella strains were isolated from 3,481 samples purchased from randomly selected retail outlets during 2008–2017. Antibiotic usage claims on meat packages were used to compare AMR Salmonella from conventional and antibiotic-free/organic (Abx-free) samples. Genetic mechanisms for AMR were investigated in a subset of isolates.

Results
The prevalence of Salmonella in conventional poultry meat 10.2% (280/2,733) was significantly higher than the prevalence in poultry meat labeled as Abx-free (5.3%, 40/748; P < 0.0001). Salmonella from conventional poultry meat was more likely to be resistant to 3 or more drugs (55.0%, 154/280) compared with poultry meat labeled as Abx-free (27.5%, 11/40; P = 0.0011). Salmonella from conventional poultry exhibited significantly higher resistance to 4 drug classes including β-lactams (P = 0.006) (figure). One hundred isolates from conventional poultry meat and 8 isolates from antibiotic-free/organic samples harbored a gene conferring resistance to the β-lactam class; 24.3% (68/280) of isolates from conventional and 7.5% (3/40) of isolates from Abx-free samples (P = 0.0145) contained the extended-spectrum β-lactamase (ESBL) gene blaCMY-2.

Conclusion
Meat samples from conventionally-raised poultry were more likely to be contaminated with AMR Salmonella strains and have genes that reduce the effectiveness of antimicrobial drugs recommended for treatment of severe infections. Contamination of poultry with AMR Salmonella strains is concerning as is the presence of genes that decrease the power of critical antibiotics such as β-lactams. These findings highlight the importance of judicious use of antibiotics in food-producing animals.

Disclosures
All authors: No reported disclosures.
625. Genomic Epidemiology of Carbapenem-Resistant Enterobacteriaceae from Colombia: A Prospective Multicenter Study
Authors: Reyes Jinnethe , Diaz Lorena , Carvajal Lina P , Rios Rafael , Millan Lina V , Echeverri Aura M , Hernandez Angie K , Vargas Sandra , Salcedo Soraya , Marin Adriana , Mora Laura , Ordonez Diaz Karen M , Cristancho Quintero Edilberto , Valderrama Sandra , Elena Ariza Beatriz , Cortes Gloria , Rojas Laura J , Chambers Henry F , Fowler Vance G , Kreiswirth Barry , Virginia Villegas Maria , Bonomo Robert A , Hanson Blake , van Duin David , Arias Cesar A 
Published: October 2019

Abstract

Background
Carbapenem-resistant Enterobacteriaceae (CRE) is a serious public health threat. A major epidemic of carbapenemase-producing Klebsiella pneumoniae has occurred in Colombia through complex mechanisms of blaKPC dissemination. In the framework of a prospective, observational cohort study (CRACKLE-2), we aimed to characterize the genomic epidemiology of CRE circulating in Colombia.

Methods
We performed whole-genome sequencing of 52 isolates collected from the same number of patients (July 2017–April 2018) in 5 Colombian hospitals. Species confirmation and sequence type were determined using Strain Seeker and MLST database. Resistance genes were detected using ResFinder and CARD databases. Phylogenetic reconstruction included additional 108 isolates of carbapenem-resistant K. pneumoniae from a previous study.

Results
K. pneumoniae (36%), Escherichia coli (17%), and Enterobacter cloacae complex(17%) were the most frequent species. Genes conferring resistance to carbapenems were detected in 93% of isolates. blaKPC-2/3,blaNDM-1 andblaVIM-2/24 were identified in 81%, 15%, and 5% of isolates, respectively. Phylogenetic reconstructions of K. pneumoniae showed that clonal group 258 (CG258) were the predominant genetic lineage (Figure 1). Among CG258, ST11 was the most common comprising ca. 26% of isolates. Of note, ST11 had been extremely rare in previous surveillance studies in Colombia. The non-CG258 were from 9 different STs and exhibited high genomic diversity. Among E. coli isolates 33% belonged to the high-risk clone ST131 harboring blaKPC-2 and we detected both blaKPC-2 and blaVIM-24 in 1 E. coli ST131 isolate. ST510 E. cloacae complex harboring blaKPC-2 was the most common (44%) lineage.

Conclusion
K. pneumoniae and E. coli are the most frequent CRE isolated from patients in Colombian hospitals. Dissemination of blaKPC through horizontal gene transfer to several species of Enterobacteriaceae continues to be a common mechanism of spread. Although KPC continues to be the most common carbapenemase, a rise in high-risk clonal lineages harboring metallo-carbapenemases, in particular NDM-1 is worrisome. Our results indicate emergence of virulent genetic lineages of K. pneumoniae ST11 and E. coli ST131 carrying carbapenemases in Colombia.

Disclosures
All authors: No reported disclosures.
687. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Acinetobacter spp.
Authors: Goldberg Joel , Bethel Christopher , Hujer Andrea M , Hujer Kristine , Marshall Steven , Papp-Wallace Krisztina M , Perez Federico , Spencer Elizabeth , Hoyer Denton , Plummer Mark , Bonomo Robert A 
Published: October 2019

Abstract

Background
Acinetobacter spp. resistant to common antibiotics have become a worrying cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (figure) which facilitates transport to the periplasm are being developed which show promise against Gram-negative organisms including Acinetobacter spp.

Methods
YU253911, an example of this new class of antibacterials, was characterized in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a collection of 200 previously described (whole-genome sequencing) Acinetobacter isolates including 98 carbapenem-resistant A. baumannii strains. YU253911’s antimicrobial activity was also evaluated in combination with complementary PBP agents and β-lactamase inhibitors by MIC and disc diffusion testing. All studies were performed according to current Clinical and Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Breakpoints for ceftazidime were arbitrarily chosen as reference.

Results
Using ceftazidime (breakpoint ≤8 μg/mL) as a comparator, 175 of the 200 Acinetobacter isolates were susceptible to YU253911, which possessed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL. This compared favorably to all previously tested β-lactams including penicillins, cephalosporins, monobactams and carbapenems (MIC50s 2 to >16 μg/mL). Against the subset of carbapenem-resistant A. baumannii isolates, YU253911’s potency was similar with an MIC50 of 1 μg/mL. Genetic analysis showed β-lactamase genes, including OXA-23 and other carbapenemases, were common in both YU253911-resistant and susceptible strains.

Conclusion
YU253911 demonstrates promising in vitro potency against a collection of Acinetobacter isolates and compares favorably to β-lactam antibiotics. Understanding interactions with PBP agents and β lactamase inhibitors is being explored as well as further studies on the mechanism of resistance.

Disclosures
All authors: No reported disclosures.
688. In Vitro Activity of Eravacycline, a New Tetracycline Analog, and Comparators Against the Six Most Commonly Isolated Ribotypes of Clostridioides difficile
Authors: Basseres Eugenie , Miranda Julie , Gonzales-Luna Anne J , Carlson Travis J , Rashid Tasnuva , Alam M Jahangir , Garey Kevin W 
Published: October 2019

Abstract

Background
Eravacycline is a novel, tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in adults. In clinical trials, patients given eravacycline had a low likelihood of developing Clostridioides difficile infection (CDI). We hypothesized this was likely due, in part, to the in vitro susceptibility of eravacycline to C. difficile. The purpose of this study was to test the in vitro susceptibility of eravacycline vs. comparators on contemporary clinical isolates representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin.

Methods
Two hundred and thirty-four isolates from our biobank were selected from the six most common ribotypes (F001, F002, F014-020, F027, F106, and F255). Minimum inhibitory concentrations (MIC) at 24 hours were measured according to CLSI guidelines for eravacycline, vancomycin, metronidazole and fidaxomicin. MICs results were tabulated and are presented as the geometric mean by ribotype.

Results
Geometric MIC results are shown in Table 1. Eravacycline was the most potent antimicrobial tested followed by fidaxomicin, metronidazole, and vancomycin. Results were consistent amongst all ribotypes, including isolates with reduced susceptibility to vancomycin and metronidazole.

Conclusion
Eravacycline displayed potent in vitro activity against a large collection of clinical C. difficile isolates. These data provide insight into why patients given eravacycline had a low likelihood of developing CDI and support further research to better understand the use of eravacycline to prevent or potentially treat patients with CDI.

Disclosures
All authors: No reported disclosures.
694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India
Authors: Miller Alita , McLeod Sarah , Mathur Tarun , Morrissey Ian 
Published: October 2019

Abstract

Background
The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India.

Methods
A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert.

Results
As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR.

Conclusion
The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii.

Disclosures
All authors: No reported disclosures.
705. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Renal Function and in Those Requiring Hemodialysis
Authors: Wicha Wolfgang , Marbury Thomas C , Dowell James A , Lykens Lori , Leister Cathie , Ermer James , Gelone Steven P 
Published: October 2019

Abstract

Background
Renal comorbidities are common in patients hospitalized with community-acquired bacterial pneumonia (CABP). LEF, a novel pleuromutilin antibiotic (IV/oral), was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with severe renal impairment and those requiring hemodialysis (HD).

Methods
In this open-label study, subjects were allocated to 1 of 3 groups based on renal function level. Severe subjects (estimated glomerular filtration rate <30 mL/minute/1.73 m2, not on HD, Severe) were matched (gender, age, and weight) to subjects with normal renal function (estimated creatinine clearance ≥90 mL/minute, Normal). Subjects in the Normal and Severe groups received a single 1-hour 150 mg LEF infusion. Subjects in the HD group started HD within 1 hour after LEF infusion (“On-dialysis”) and on a nondialysis day (“Off-dialysis”). Blood and urine samples were collected predose and over a 36-hour period postdose for PK analysis; LEF and BC-8041 were assayed in plasma and urine with validated methods. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.

Results
23 subjects enrolled in and completed the study (n = 7, Normal; n = 8, Severe; n = 8, HD). LEF and BC-8041 pharmacokinetic parameters (table) were comparable between the Normal and Severe groups and between the On-dialysis and Off-dialysis treatment periods for the HD group. The majority of LEF and BC-8041 were excreted nonrenally in Normal and Severe subjects and were not measurably filtered into dialysate. TEAEs were reported in 2 (28.6%) subjects in the Normal group, 4 (50%) in the Severe group, and 4 (50%) in the HD group. None of the TEAEs were serious or led to study drug discontinuation. Within 4 h post-dose, the maximum mean change from baseline in the QTcF interval was 8.9, 6.6, 15.9, and 17.6 msec in the normal, severe, on-dialysis, and off-dialysis groups, respectively.

Conclusion
No dosage adjustment is required for LEF when treating subjects with severe renal impairment, and LEF can be administered without regard to HD timing. LEF was generally well tolerated in all subjects regardless of renal function status.

Disclosures
All authors: No reported disclosures.
706. In Vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against MDR Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin America During the ATLAS Global Surveillance Program 2016–2017
Authors: Lob Sibylle , Kazmierczak Krystyna , Stone Gregory , Sahm Daniel F 
Published: October 2019

Abstract

Background
Ceftazidime–avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C and some class D β-lactamases. Resistance caused by these β-lactamases often results in multidrug-resistance (MDR). This study evaluated the in vitro activity of CAZ-AVI and comparators against MDR Enterobacteriaceae and Pseudomonas aeruginosa isolates collected from patients in Latin America.

Methods
Nonduplicate clinical isolates were collected in 2016–2017 in 6 countries in Latin America. Susceptibility testing was performed using CLSI broth microdilution and interpreted using CLSI 2019 and FDA (tigecycline) breakpoints. MDR was defined as nonsusceptible (NS) (intermediate or resistant) to ≥3 of 7 sentinel drugs: amikacin, aztreonam, cefepime, levofloxacin, colistin, meropenem, and piperacillin–tazobactam.

Results
The activity of CAZ-AVI and comparators against all isolates and MDR subsets is shown in the table. MDR rates ranged from 28.4% among E. cloacae to 41.5% among K. pneumoniae. CAZ-AVI was active against >97% of Enterobacteriaceae isolates and maintained activity against >92% of MDR isolates of the examined species. No other tested drug consistently exceeded this activity. Among P. aeruginosa, CAZ-AVI was active against 87% of all isolates and 63% of MDR isolates; only colistin was more active. The two most common MDR phenotypes among Enterobacteriaceae were (1) NS to aztreonam, cefepime, and levofloxacin (n = 580, 41% of all MDR Enterobacteriaceae; 100% susceptible to CAZ-AVI) and (2) NS to aztreonam, cefepime, levofloxacin, and piperacillin–tazobactam (n = 301, 21% of all MDR isolates; 99.7% susceptible to CAZ-AVI). The two most common MDR phenotypes among P. aeruginosa were (1) NS to all sentinel drugs except colistin (n = 154, 33% of all MDR isolates; 30.5% susceptible to CAZ-AVI) and (2) NS to all drugs except colistin and amikacin (n = 97, 21% of all MDR isolates; 70.1% susceptible to CAZ-AVI).

Conclusion
These in vitro data suggest that CAZ-AVI can be an effective treatment option for infections caused by MDR Enterobacteriaceae and P. aeruginosa collected in Latin America.

Disclosures
All authors: No reported disclosures.