bluuebunny/crossref_metadata_2025_split huggingface dataset:
1348. In vitro Activity of Plazomicin, a Next-Generation Aminoglycoside, Against Carbapenemase-Producing Klebsiella pneumoniae
Authors: Jacobs Michael R , Good Caryn E , Abdelhamed Ayman M , Rhoads Daniel D , Hujer Kristine M , Hujer Andrea M , Rudin Susan D , Domitrovic T Nicholas , Connolly Lynn , Krause Kevin M , Richter Sandra S , Van Duin David , Kreiswirth Barry N , Bonomo Robert A ,   Antibiotic Resistance Leadership Group
Published: November 2018

Abstract

Background
Plazomicin is a next-generation aminoglycoside with in vitro activity against multidrug-resistant Gram-negative species, including carbapenem-resistant isolates. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multicenter consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae.

Methods
Minimum inhibitory concentrations (MICs) of plazomicin were determined by broth microdilution according to current CLSI guidelines against a collection of 697 carbapenem-resistant Klebsiella pneumoniae with defined carbapenem resistance mechanisms, including KPC and OXA carbapenemases. Isolates were submitted by participating CRACKLE centers.

Results
Carbapenemases present in study isolates included KPC-2 (n = 323), KPC-3 (n = 364), KPC-4 (n = 2), OXA-48 like (n = 7), and NDM (n = 1). Plazomicin MICs ranged from ≤0.12 to &gt;32 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively (figure). MICs of 689 (98.8%) isolates were ≤4 mg/L, while MICs of the remaining eight isolates were &gt;32 mg/L. Plazomicin MICs were related to specific carbapenemases present in isolates: of eight isolates with MICs &gt;32 mg/L, seven contained OXA-48 like and one contained KPC-3, suggesting that these isolates possess an aminoglycoside-resistance mechanism on the same plasmid as their carbapenemase gene, such as a 16S ribosomal RNA methyltransferase, against which plazomicin is not active.

Conclusion
Plazomicin has good in vitro potency against a collection of carbapenemase-producing K. pneumoniae, with MIC90 value of 1 mg/L and MICs of ≤4 mg/L for 98.9% of isolates.

Disclosures
M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. M. Krause, Achaogen: Employee, Salary. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, achaogen: Scientific Advisor, Consulting fee. shionogi: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee.
1355. Global Activity of Imipenem–Relebactam and Comparators Against Clinical Gram-Negative Pathogens – SMART 2017
Authors: Lob Sibylle , Kazmierczak Krystyna , Hoban Daryl , Hackel Meredith , Young Katherine , Motyl Mary , Sahm Dan 
Published: November 2018

Abstract

Background
Relebactam (REL), formerly MK-7655, is a β-lactamase inhibitor of class A and C β-lactamases that is in development in combination with imipenem (IMI). In this study, we evaluated the activity of IMI/REL against recent clinical isolates of Gram-negative bacilli (GNB) collected globally as part of the SMART surveillance program.

Methods
In 2017, 188 hospitals in 54 countries each collected up to 100 consecutive Gram-negative aerobic or facultatively anaerobic pathogens from lower respiratory tract infections, 75 from intra-abdominal infections, and 75 from urinary tract infections. MICs were determined for 41,319 GNB, including 30,864 Enterobacteriaceae and 6,933 P. aeruginosa isolates, using CLSI broth microdilution and interpreted with CLSI breakpoints; for comparison purposes, IMI susceptible breakpoints were applied to IMI/REL.

Results
Susceptibilities to IMI/REL and comparators of the 10 most commonly found Enterobacteriaceae species and P. aeruginosa are shown below.

IMI/REL showed activity &gt;90% against seven of the top 10 Enterobacteriaceae species, typically ~5 to 35 percentage points higher than the β-lactam comparators, and it was active against 89% of P. aeruginosa, ~15 to 25 percentage points higher than the β-lactam comparators. Only amikacin and colistin showed similar or higher activity for most species, with colistin showing little activity against Proteeae and Serratia.

Conclusion
IMI/REL could provide an important treatment option against infections with Gram-negative pathogens, especially since amikacin and colistin are associated with significant morbidity, including nephrotoxicity and ototoxicity, and amikacin is typically used in combination with another antibiotic.

Disclosures
S. Lob, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. K. Kazmierczak, Merck: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. D. Hoban, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. M. Hackel, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee. K. Young, Merck: Employee and Shareholder, Dividends and Salary. M. Motyl, Merck: Employee and Shareholder, Dividends and Salary. D. Sahm, IHMA, Inc.: Employee, Salary. Merck: Consultant, Consulting fee.
1358. In vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Pseudomonas aeruginosa Causing Intra-Abdominal, Lower Respiratory, and Urinary Tract Infections Collected in Latin America as Part of the INFORM Global Surveillance Program, 2012–2016
Authors: Wise Mark , Kazmierczak Krystyna , Stone Gregory G , Sahm Dan 
Published: November 2018

Abstract

Background
The non-β-lactam β-lactamase inhibitor avibactam (AVI) is active against class A, C, and some class D β-lactamases, in combination with ceftazidime (CAZ) has been approved by the FDA and EMA for treatment of intra-abdominal infections (IAI), lower respiratory tract infections (LRTI), and urinary tract infections (UTI). This study reports on the in vitro activity of (CAZ-AVI) and comparators vs. P. aeruginosa collected from IAIs, LRTIs, and UTIs in Latin America as part of the INFORM surveillance study from 2012 to 2016.

Methods
For INFORM surveillance over 2012–2016 in Latin America, 1,595 nonduplicate P. aeruginosa isolates linked to IAIs, LRTIs, and UTIs were collected from 26 clinical sites in six countries. Susceptibility testing was done using broth microdilution according to CLSI guidelines and using CLSI 2018 breakpoints. CAZ was tested with AVI at a fixed concentration of 4 mg/mL. Meropenem (MEM) nonsusceptible organisms were screened for β-lactamase genes by PCR.

Results
Among the full collection of P. aeruginosa, CAZ-AVI showed consistently higher % susceptibilities than all comparators except for colistin (CST) for all infection sources. The addition of AVI to CAZ resulted in an increase in susceptibility ranging from 14.2% (IAI) to 19.5% (UTI). Against the non-metallo-β-lactamase (MBL) harboring subset, CAZ-AVI showed extremely potent activity (MIC90, 8 mg/mL) for all infection sources. In this subset, the activity of CAZ-AVI approached that of colistin for IAIs (susceptibility of 93.3% vs. 96.4%, respectively).

Conclusion
CAZ-AVI demonstrated very good in vitro activity against P. aeruginosa isolates, especially those without MBLs. More isolates were susceptible to CAZ-AVI than to MEM for all infection types.

Disclosures
M. Wise, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. K. Kazmierczak, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. G. G. Stone, Pfizer Inc.: Employee, Salary. AstraZeneca: Former Employee and Shareholder, Salary. D. Sahm, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary.
1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes
Authors: Hackel Meredith , Sahm Dan 
Published: November 2018

Abstract

Background
VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains.

Methods
MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes.

Results
FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited &gt;93% of all resistant subsets at ≤8 µg/mL.

Conclusion
Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted.

Disclosures
M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.
1362. A Novel Intravesical Antimicrobial for CAUTIs
Authors: Peterson Marnie , Kilgore Samuel , Schlievert Patrick 
Published: November 2018

Abstract

Background
As many as 1.5 million people reside in long-term care facilities in the United States. Nearly all of these patients will develop catheter-associated urinary tract infections (CAUTIs) within a month of catheterization. These infections collectively cost the healthcare system billions of dollars each year. In addition, the emergence of multi-drug-resistant ESKAPE (Enterobacter species, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus species) pathogens affects the severity of infections, increasing both morbidity and mortality. Our research group is exploring a novel, dual-acting, antimicrobial, glycerol monolaurate (GML)-containing gel to prevent and treat CAUTIs.

Methods
Pieces (7 mm in length) of RenaSil Silicone Tubing were placed in the bladders of BALB/c female mice (n = 5/group). Approximately 1 × 108 colony-forming units/mL ESKAPE pathogens (50 µL) were inoculated into the bladder, and animals were returned to cages for 18 hours. One hundred microliters of 2.5% GML Gel (50:50 mix of saline and human-approved glycols) or phosphate-buffered saline (placebo) was administered into the bladders. After 2 hours, animals were euthanized and colony-forming units in bladders and on catheters were determined, and histological analysis of bladders was performed.

Results
GML Gel was bactericidal against ESKAPE pathogens at 2 hours post-treatment. Subsequent histological analysis of bladders from infected and noninfected mice showed that GML Gel was not toxic to bladder tissue.

Conclusion
Our results in this murine catheter infection model indicate that the newly formulated GML Gel may be useful in prevention and treatment of CAUTIs.

Disclosures
M. Peterson, Hennepin Life Sciences: Board Member, Consulting fee. S. Kilgore, Hennepin Life Sciences: Employee, Salary. P. Schlievert, Hennepin Life Sciences: Board Member, Consulting fee.
1368. Assessment of the In Vivo Efficacy of Human-Simulated Epithelial Lining Fluid (ELF) Exposure of Meropenem/Nacubactam (MEM/NAC) Combination Against β-Lactamase-Producing Enterobacteriaceae in Neutropenic Lung Infection Model
Authors: Asempa Tomefa E , Motos Ana , Abdelraouf Kamilia , Bissantz Caterina , Zampaloni Claudia , Nicolau David P 
Published: November 2018

Abstract

Background
NAC is a novel dual action β-lactamase inhibitor with in vitro activity against class A, class C, and some class D β-lactamases and antibacterial activity against Enterobactaeriaceae. NAC is being developed as a combination therapy with MEM for the treatment of serious Gram-negative bacterial infections. This study evaluated the efficacy of the human-simulated ELF exposure of MEM/NAC, compared with those of MEM or NAC alone against β-lactamase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model.

Methods
Eight clinical MEM-resistant Enterobacteriaceae isolates harboring various β-lactamases (IMI, KPC, OXA, TEM, SHV, and AmpC) were utilized in the study. MEM and MEM:NAC (1:1) combination MICs were determined in triplicate via broth microdilution. ICR mice were rendered transiently neutropenic, and lungs were inoculated with 50 µL bacterial suspensions of 107 CFU/mL. Regimens in mice that simulated the human ELF exposures following doses of MEM 2g q8h and NAC 2g q8h (1.5 hours infusions) as monotherapies and in combination were established. Treatment mice received MEM human-simulated regimen (HSR), NAC HSR, or MEM/NAC HSR and control mice were vehicle-dosed. Treatment was started 2 hours after inoculation and continued for 24 hours. Efficacy was assessed as the change in log10CFU/lung at 24 hours compared with 0 hours controls.

Results
MEM and MEM/NAC MICs were 8–512 and 0.5–8 mg/L, respectively. The average log10CFU/lung at 0 hours across all isolates was 6.26 ± 0.26. Relative to 0 hours control, the mean bacterial growth at 24 hours in the untreated control mice, MEM HSR, and NAC HSR treatment groups were 2.93 ± 0.29, 2.72 ± 0.42, and 1.75 ± 0.80 log10CFU/lung, respectively. MEM/NAC HSR resulted in up to 2-log bacterial reduction in isolates with MEM/NAC MIC ≤4 mg/L.

Conclusion
MEM/NAC human-simulated ELF exposure produced enhanced efficacy against MEM-resistant β-lactamase-producing Enterobacteriaceae isolates with MEM/NAC MIC ≤4 mg/L. These data support a potential role for MEM/NAC for treatment of lung infections due to β-lactamase-producing Enterobacteriaceae and warrant further studies.
This project has been funded in part under HHS BARDA Contract HHSO100201600038C.

Disclosures
C. Bissantz, F Hoffmann La Roche Ltd.: Employee, Salary. C. Zampaloni, F. Hoffmann-La Roche Ltd.: Employee, Salary. D. P. Nicolau, Hoffmann-La Roche Ltd.: Grant Investigator, Grant recipient.
1374. Integrated Safety Summary of Omadacycline: A Novel Aminomethylcycline Antibiotic
Authors: Opal Steven , File Thomas M , Van Der Poll Tom , McGovern Paul , Tzanis Evan , Chitra Surya 
Published: November 2018

Abstract

Background
Omadacycline (OMC) is a novel aminomethylcycline with activity against Gram-positive, many Gram-negative, anaerobic, and atypical pathogens. It is in clinical development as once-daily oral (PO) and intravenous (IV) monotherapy for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Cumulative safety results from Phase 3 clinical trials are reported.

Methods
This pooled safety analysis is based on 2,150 subjects: OASIS-1 (N = 645), OASIS-2 (N = 735) in ABSSSI; OPTIC (N = 770) in CABP. Comparators were linezolid (LZD) 600 mg IV then PO in ABSSSI (n = 689); moxifloxacin (MOX) 400 mg IV then PO in CABP (n = 388). Safety parameters included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and electrocardiogram (ECG) findings.

Results
A total of 1,073 subjects received OMC: 705 received OMC IV then PO (ABSSSI, n = 323; CABP, n = 382); 368 received OMC PO only for ABSSSI. Overall, 60.6% were male and 91.6% white; mean age ranges were 44.7–45.1 and 60.9–62.1 years in ABSSSI and CABP studies, respectively. TEAEs were observed in 47.5% (OMC), 41.2% (LZD), and 48.5% (MOX) of subjects, with gastrointestinal events the most common TEAEs. Serious TEAEs were low (3.6% OMC, 1.9% LZD, 6.7% MOX). Nausea (14.9% OMC, 8.7% LZD, 5.4% MOX) and vomiting (8.3% OMC, 3.9% LZD, 1.5% MOX) were the most frequently reported TEAEs. Diarrhea was observed in 2.4% OMC, 2.9% LZD, and 8.0% MOX subjects, with no cases of Clostridium difficile in OMC-treated subjects. Most TEAEs were mild to moderate and did not result in study drug discontinuation (3.1% OMC, 1.5% LZD, 7.0% MOX); 4 OMC, 1 LZD, and 0 MOX subjects discontinued for nausea and vomiting. Frequency of hepatic TEAEs was similar for OMC, LZD, and MOX: 4.3% OMC, 4.1% LZD, and 4.5% MOX subjects had post-baseline ALT &gt;3× upper limit of normal. Vital signs and ECGs had comparable clinically notable values post-baseline in each treatment group. Known tetracycline class adverse events such as fungal infections were similar in all groups.

Conclusion
Pooled analyses demonstrate a favorable OMC safety profile, consistent with its tetracycline heritage. OMC was generally well tolerated in subjects with ABSSSI and CABP, with infrequent treatment discontinuations.

Disclosures
T. M. File Jr., BioMerieux: Consultant, Consulting fee; Curetis: Consultant, Consulting fee; Melinta Therapeutics: Consultant, Consulting fee; Merck: Consultant, Consulting fee; Motif Bio: Consultant, Consulting fee; Nabriva Therapeutics: Consultant and Investigator, Consulting fee and Research grant; Paratek Pharmaceuticals: Consultant, Consulting fee; Pfizer: Consultant, Consulting fee. T. Van Der Poll, Paratek Pharmaceuticals: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary.
1377. Omadacycline In Vitro Activity Against a Molecularly Characterized Collection of Clinical Isolates with Known Tetracycline Resistance Mechanisms
Authors: Mendes Rodrigo E , Castanheira Mariana , Armstrong Eliana S , Steenbergen Judith N , Flamm Robert K 
Published: November 2018

Abstract

Background
Omadacycline is a novel aminomethylcycline that recently completed Phase 3 clinical trials for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). This study evaluated the activity of omadacycline against a broad collection of recent (2016) clinical isolates with molecularly characterized tetracycline resistance mechanisms.

Methods
A total of 177 Gram-positive and -negative clinical isolates were identified as carrying acquired tetracycline resistance genes and were included in this study. Isolates were previously subjected to next-generation sequencing followed by screening of known tetracycline resistance mechanisms. Susceptibility testing and interpretation were performed according to CLSI methods.

Results
Omadacycline demonstrated MIC50 values of 0.06–0.12 µg/mL against Gram-positive isolates carrying tet genes. Similar MIC results (0.06–0.12 µg/mL) were obtained against Gram-positive organisms carrying tet(K), tet(L)/tet(M) or tet(M). Omadacycline (MIC50/90, 0.12/0.25 µg/mL) and tigecycline (MIC50/90, 0.06/0.25 µg/mL) showed similar MIC results when tested against Staphylococcus aureus carrying tet(K). While tetracycline was less active (0.0–78.6% susceptible) against Tet(K)-producing S. aureus, doxycycline (MIC50/90, 0.5/0.5 µg/mL; 100.0% susceptible) was active in vitro. Omadacycline (MIC90, 0.25–2 µg/mL) and tigecycline (MIC90, 0.12–1 µg/mL) showed potent MIC results against Gram-positive isolates carrying tet(L) and/or tet(M). Tetracycline and doxycycline had MIC90 values of ≥8 µg/mL. Omadacycline (MIC90 4–32 µg/mL) and tigecycline (MIC90 0.5–2 µg/mL) were active against Gram-negative isolates harboring tet(A), tet(B) or tet(D) or a combination of tet. Tetracycline (MIC50/90, &gt;16/&gt;16 µg/mL) and doxycycline (MIC50/90, &gt;8/&gt;8 µg/mL) had elevated MIC50 and MIC90 results against these isolates.

Conclusion
Results presented here indicate that omadacycline is not adversely affected by tet genes present in contemporary Gram-positive and -negative clinical isolates, a characteristic that differs from the legacy tetracycline agents.

Disclosures
R. E. Mendes, Paratek Pharmaceuticals: Research Contractor, Research support. M. Castanheira, Paratek Pharmaceuticals: Research Contractor, Research support. E. S. Armstrong, Paratek Pharmaceuticals: Employee, Salary. J. N. Steenbergen, Paratek Pharmaceuticals: Employee and Shareholder, Salary. R. K. Flamm, Paratek Pharmaceuticals: Research Contractor, Research support.
1381. Impact of Total Body Weight on Efficacy of Ceftriaxone in Obese Patients
Authors: Wagner Jamie L , Loper J Taylor , Morrison Austin R , Stover Kayla R , Barber Katie E 
Published: November 2018

Abstract

Background
Ceftriaxone (CRO), while highly protein bound, retains a small volume of distribution. Obese patients have larger volumes of distributions and higher clearance than nonobese patients. The effect of these differences on the pharmacokinetics and efficacy of CRO remain unclear.

Methods
This retrospective cohort study included adult in-patients who received CRO for ≥72 hours as definitive monotherapy from July 2015 to July 2017. Patients were excluded if there was a lack of adequate source control at 72 hours or if there was a polymicrobial infection requiring multiple antibiotics. Obesity was defined as BMI ≥30 kg/m2. The primary outcome was clinical treatment failure, defined as changing therapy at &gt;72 hours due to clinical worsening, leukocytosis (WBC &gt; 10 × 109/L), fever (single temperature &gt;100.9°F) for &gt;72 hours, or readmission to the hospital within 30 days for re-infection. Secondary outcomes included discharge disposition and 30-day readmission.

Results
One hundred one patients were included: 39 obese patients and 62 nonobese patients. Median [IQR] age was 62 [51–70] years; 55% males. Median weight was 103 [95–120] kg in obese patients vs. 66 [58–77] kg in nonobese patients (P &lt; 0.001). There were no differences in comorbidities (Charlson 3[1–5] obese vs. 2[1–4] nonobese; P = 0.293). Infection sources were similar: urinary tract (54% obese vs. 52% nonobese; P = 0.827), respiratory (28% obese vs. 23% nonobese; P = 0.524), bloodstream (20% obese vs. 23% nonobese; P = 0.806). The most common causative organism was E. coli (48%). There were no differences in CRO regimen between groups (1g q24h: obese 54% vs. nonobese 69%; P = 0.115). Treatment failure occurred in 24 (61%) obese patients compared with 25(40%) nonobese patients (P = 0.038). Obese patients had delayed resolution of leukocytosis (54% vs. 29%, P = 0.013). Eight patients died (13% obese vs. 5% nonobese; P = 0.255); 82% of patients were not readmitted within 30 days.

Conclusion
Obese patients treated with ceftriaxone had higher rates of treatment failure compared with nonobese patients. While not statistically significant, there was numerically higher mortality in obese patients compared with nonobese patients. Obese patients may be slow to recover from infection when treated with CRO.

Disclosures
All authors: No reported disclosures.