bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 >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

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

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

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 >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

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, >16/>16 µg/mL) and doxycycline (MIC50/90, >8/>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

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 >72 hours due to clinical worsening, leukocytosis (WBC > 10 × 109/L), fever (single temperature >100.9°F) for >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 < 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.
1385. Efficacy of Ceftazidime–Avibactam in Combination with Aztreonam (COMBINE): Solutions for Metallo-β-Lactamase Producing-Enterobacteriaceae (MBL)
Authors: Lodise Thomas P , Smith Nicholas M , Holden Patricia , O’Donnell J Nicholas , Bedard Tyler , Bonomo Robert A , Tsuji Brian T
Published: November 2018

Background

Novel antibiotics will not be available to combat the threat of MBLs until 2021. One strategy to overcome MBLs is to combine CAZ-AVI + ATM. ATM is not hydrolysed by MBLs and AVI offers protection for ATM and CAZ vs. ESBLs and AmpCs. The combination also offers a theoretical advantage to inactivating multiple PBPs by using dual β-lactam therapy. Our objective was to define optimal dosing profiles for clinical use of ATM to add to CAZ-AVI in the hollow fiber infection model (HFIM).

Methods

E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied at a 7.5 log10 CFU/mL in the HFIM. Human dosing regimens of CAZ-AVI 2 g/0.5 g q8h (2 hours infusion) and ATM 2 g q8h (2 hours infusion) were simulated in alone and in combination. Continuous infusion (CI) regimens of CAZ-AVI 6 g/1.5 g per day CI + ATM 6 g/day CI and q8h regimens were given simultaneously and sequentially (ATM given 2 hours after CAZ-AVI). Resistant subpopulations were profiled on single (ATM), double (CAZ/AVI) and triple (ATM/CAZ/AVI) drug plates containing 2/2/4, 8/8/4, or 32/32/4 mg/L over 7 days.

Results

Against E. coli ARLG-1013, ATM alone mirrored growth control (+3.14 at 168 hours) (All units Log10 CFU/mL change vs. baseline). CAZ-AVI alone showed some intrinsic activity (+1.19 at 168 hours). CAZ-AVI 2g/0.5g q8h (2 hours infusion) + ATM 2g q8h (2 hours infusion) given sequentially resulted regrowth and stasis (+0.34 at 168 hours) vs. the simultaneous combination resulted initial bactericidal activity (-3.53 killing within 28 hours) which regrew at (−0.90 at 168 hours). All CI regimens were effective. CAZ-AVI 6g/1.5g per day CI + ATM 6 g/day CI resulted in dramatic killing (up to -5.78 killing within 50 hours) which was sustained (up to -3.90 killing at 168 hours). Comparing the infusion time of CAZ/AVI + ATM on bacterial killing: CI + CI > 2 hours + 2 hours > 30 minutes + 30 minutes. CI + CI resulted in complete suppression of resistance over 7 days. Against K. pneumoniae ARLG-1002, CAZ/AVI (CI) + ATM (CI) resulted in early synergy (>5.0 log killing within 24 hours) and suppression of resistance for more than 168 hours.

Conclusion

The combination of CAZ-AVI + ATM was highly synergistic and suppressed resistance against MBL Enterobacteriaceae in HFIM. ATM efficacy in combination was driven by %T > MIC. A Phase I study will assess safety to provide patients a critically important solution against “untreatable” Gram negatives.

Disclosures

T. P. Lodise, paratek: Consultant and Scientific Advisor, Consulting fee. B. T. Tsuji, Nabriva: Consultant, Consulting fee. Achaogen: Grant Investigator, Educational grant. ARLG, DCRI: Grant Investigator, Grant recipient. NIH/NIAID: Grant Investigator, Grant recipient.
1393. A Phase 1, Randomized, Open-Label, Crossover Study in Healthy Subjects Under Fasting Conditions of Orally Administered Sulopenem Etzadroxil Alone or with Probenecid to Determine the Pharmacokinetics of Sulopenem
Authors: Dunne Michael , Aronin Steven , Dunzo Elise , Puttagunta Sailaja
Published: November 2018

Background

Antimicrobial resistance to available oral antibiotics is becoming progressively more common, precipitating the need for additional treatment options as step-down from initial intravenous (IV) therapy as well as for treatment of infections in the community. Sulopenem (CP-70,429) is a thiopenem antibiotic active against quinolone non-susceptible and ESBL-producing Enterobacteriaceae. As the key pharmacokinetic-pharmacodynamic variable correlating with efficacy for penem antibiotics is time above minimum inhibitory concentration (T > MIC), we examined the utility of probenecid, an OAT-1 inhibitor of β-lactam excretion, on the pharmacokinetic (PK) parameters for the oral prodrug of sulopenem, sulopenem etzadroxil

Methods

Twelve healthy males and females received a single oral dose of 500 mg sulopenem etzadroxil as powder in bottle either alone or co-administered with a single oral dose of probenecid 500 mg in a crossover design with a washout period of 6 days. All doses were administered under fasting conditions. Blood samples for plasma PK analysis were collected and PK parameters for sulopenem, the parent compound of sulopenem etzadroxil, were determined.

Results

Treatment

Conclusion

Probenecid increases the AUC of sulopenem by 28% in the fasted state and extends the mean time over MIC.

Disclosures

M. Dunne, Iterum Therapeutics: Employee and Shareholder, Salary. S. Aronin, Iterum Therapeutics: Employee and Shareholder, Salary. E. Dunzo, Parexel: Consultant, Consulting fee. S. Puttagunta, Iterum Therapeutics: Employee and Shareholder, Salary.
670. Estimating Bordetella pertussis Seroprevalence in Persons Aged 10–25 Years in Mexico Using the 2012 National Health and Nutrition Survey (ENSANUT): Challenges and Lessons Learned
Authors: Lopez-Gatell Hugo , Echaniz-Aviles Gabriela , Garcia-Cisneros Santa , Sánchez-Alemán Miguel Angel , Romero-Martínez Martin , Olamendi-Portugal Maria L , Alpuche-Aranda Celia M
Published: November 2018

Background

Low vaccination rates and under-detection of cases in adolescents and young adults have been implicated in the transmission of Pertussis to children. In this study, the proportion of adolescents and young adults with anti Bordetella pertussis IgG antibodies was estimated in a population-based survey in Mexico.

Methods

Frozen sera and data from 1,581 subjects—1,102 adolescents and 479 young adults (10–19 and 20–25 years old, respectively)—56% female were randomly selected from the Mexico’s National Health and Nutrition Survey (ENSANUT) 2012. CDC/FDA validated PT ELISA test was used to detect anti-pertussis toxin (PT) antibodies. A subset of 300 samples was also tested with Bp-IgG PT ELISA kit (Euroimmun AG, Lubeck, Germany®), both tests used international standards. Threshold values were established to identify vaccination or infection within the previous year, according to a US survey (Baughman et al.). Population-weighted estimates of seroprevalence were calculated.

Results

Overall Bp seroprevalence was 3.9% (95% CI: 2.3, 6.3); 3.1% (1.9, 5.0) in adolescents, and 4.9% (2.2, 11) in young adults. Seroprevalence did not significantly vary by gender, socioeconomic status, region or rural/urban location. Compared with the CDC/FDA PT ELISA, the Euroimmun® test showed 76% sensitivity, 88% specificity.

Conclusion

Booster vaccination to Bp after toddlerhood is not in the Mexican national policy; therefore, anti-PT IgG seropositivity may reasonably be attributed to recent Bp infection. Our weighted estimates of recent Bp infection, which are based on a national population-based serosurvey and a standardized serological test, represent a considerable burden of infections in adolescents and young adults that sharply contrast with the official surveillance reports. Also, the Bp-IgG PT ELISA commercial kit lower sensitivity than the CDC/FDA PT ELISA may lead underestimation of recent infections. In conclusion, assessing pertussis seroprevalence requires careful consideration of the right tests and epidemiological model for interpretation.

Disclosures

All authors: No reported disclosures.
680. “There’s More to This Than Meets the Eye”: Opportunities for Infection Prevention in Optometry Clinics
Authors: Fernandes Priyanka , Oyong Kelsey , Terashita Dawn
Published: November 2018

Background

Los Angeles County Department of Public Health (LAC-DPH) investigated an outbreak of epidemic keratoconjunctivitis secondary to adenovirus between June and July 2017, and all cases were linked to a single optometry clinic. The LAC-DPH aimed to determine whether sub-optimal infection prevention practices used in the implicated clinic were commonplace within other local optometry clinics. The objective of this study was to understand infection prevention practices in optometry clinics within Los Angeles County.

Methods

LAC-DPH conducted a survey consisting of 17 questions related to infection prevention practices among a sample of optometry providers in the county. The survey was administered online (SurveyMonkey) via emails sent to a local optometric society’s listserv and in-person at a local continuing education event for optometrists. The results were analyzed and are represented as percentages.

Results

There were 42 responses, 20 via the online survey (response rate 15%) and 22 via the in-person survey (response rate 22%). The majority worked in an optometry clinic: 77.5% (n = 31). More than half had no written hand-hygiene policy (58.5%, n = 24), 46.2% (n = 18) did not wear gloves while examining patients with eye drainage and about half (48.7%, n = 18) did not use droplet precautions for patients with respiratory symptoms. The vast majority used multi-dose eye-drop vials (92.5%, n = 37) but more than 40% (n = 21) did not discard the vial if the tip came into contact with conjunctiva. The majority (68.4%, n = 26) used alcohol wipes with 70% isopropyl alcohol to disinfect tonometers, while 47.4% (n = 18) used noncontact tonometers and 23.6% (n = 9) used disposable tips (options for this question were not mutually exclusive).

Conclusion

Infection prevention practices in optometry clinics are sub-optimal and must be improved. All optometry clinics must have a hand-hygiene policy and discard multi-dose vials which come into contact with conjunctivae. While the evidence on the best disinfectant for tonometers is limited, commonly used disinfectants like 70% alcohol wipes or 3% hydrogen peroxide have been associated with adenovirus outbreaks. Current evidence suggests that infectious spread via tonometers can be prevented by using disposable covers or by disinfection with 1:10 diluted bleach.

Disclosures

All authors: No reported disclosures.
686. Use of an Influenza-Like Illness School Absenteeism Monitoring System to Identify Seasonal Influenza Outbreaks in the Community: ORCHARDS (Wisconsin, September 2014–June 2017)
Authors: Temte Jonathan , Zheteyeva Yenlik , Barlow Shari , Goss Maureen , Temte Emily , Schemmel Amber , Maerz Brad , Bell Cristalyne , Reisdorf Erik , Shult Peter , Wedig Mary , Haupt Thomas , Conway James , Gangnon Ronald , Fowlkes Ashley , Uzicanin Amra
Published: November 2018

Background

Schools are purported to be primary venues of influenza transmission and amplification with secondary spread to communities. We assessed K—12 student absenteeism monitoring as a means for early detection of influenza activity in the community. Methods. We conducted a 3-year, prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness-associated (a-ILI) absenteeism within the Oregon School District, Oregon, WI (OSD: enrollment = 3,900 students). Absenteeism reporting was facilitated by automated processes within OSD’s electronic student information system. Students were screened for ILI, and, if eligible, visited at home, where pharyngeal specimens were collected for influenza RT-PCR (IVD CDC Human Influenza Virus RT-PCR Diagnostic Panel) and multipathogen testing (Luminex NxTAG RPP). The study definition of a-ILI was validated for 700 children with acute respiratory infections using binomial logistic regression. Surveillance of medically attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining OSD as part of the Wisconsin Influenza Incidence Surveillance Project using the same laboratory testing. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis. Results. Influenza A and B were detected in 54 and 51 of the 700 visited students, respectively. Influenza was significantly associated with a-ILI status (OR = 4.74; 95% CI: 2.78—8.18; P < 0.001). Of MAI patients, 371 had influenza A and 143 had influenza B. a-I was significantly correlated with MAI in the community (r = 0.472; P < 0.001) with a 15-day lead time. a-ILI was significantly correlated with MAI in the community (r = 0.480; P < 0.001) with a 1-day lead time. a-TOT performed poorly (r = 0.278; P < 0.001), following MAI by 9 days (Figure 1). Conclusion. Surveillance using cause-specific absenteeism was feasible to implement in OSD and performed well over a 3-year period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can detect influenza outbreaks in the community, providing early warning in time for community mitigation efforts for seasonal and pandemic influenza.

Disclosures

All authors: No reported disclosures.
692. Effects of Regional Climatic Variability on West Nile Virus Outbreaks in the United States
Authors: Kangath Raghesh Varot , Maduraperuma Buddhika , Borges Juliana Souza , Ramachandrapai Rajasreepai
Published: November 2018

Background

Transmission of WNV to humans in the United States typically occurs between June and September since warm temperatures accelerate mosquito life cycle. Precipitation can cause increase in aquatic breeding but outbreaks often depends upon human water management. We examine epidemiology, patterns of WNV disease transmission, and identification of high-risk areas in the United States from 2003 to 2014.

Methods

Trends and relationships of WNV cases and climatic factors were analyzed among the regions of the United States from 2003 to 2014. Human WNV tabulate data and climatic data were obtained from Centers for Disease Control, and NOAA and Climate Data Guide, respectively. Canonical correspondence analysis (CCA) was performed using variables: (i) neuroinvasive disease cases, non-neuroinvasive disease cases, deaths, presumptiveviremic blood donors, (ii) precipitation, temperature, Palmer Drought Severity Index (PDSI) and population density. The CCA ordination was explained the variability between WNV disease cases andclimatic variables. Biplots were used to visualize the associations between WNV cases and climatic anomalies.

Results

We compared the state wise WNV disease cases in relation to climatic and population density in the United States from 2003 to 2014. A total of 4,064 cases in 2006, 956 cases in 2010 and, 2,141 cases in 2014 were reported in the 32 states of the United States. Colorado state reported the highest WNV cases in 2003 (2,947 cases; 33%), followed by Texas in 2012 (1,868 cases; 35%) and California in 2014 (801 case; 37%). CCA ordination showed distinguishable clustering patterns between south central (Texas, Louisiana, Mississippi, Arkansas, and Oklahoma) and northern Great Plains (North Dakota, South Dakota, and Nebraska) regions (Figure 1). High temperature and prolong drought were the most important variable predictor for high WNV outbreak.

Conclusion

Vector control methods focusing on prevention must be implemented to avoid epidemics of WNV if high temperature is leading to an unusual drought especially at the risk areas, such as Texas and California. However, high temperature with moist spell anomalies in the south central region showed a negative influence on WNV outbreak.

Disclosures

All authors: No reported disclosures.
700. Identification and Whole-Genome Sequencing (WGS) of Meropenem-Vaborbactam (MV) Resistant Klebsiella pneumoniae (MVRKP) Among Patients Without Prior Exposure to MV: Collateral Damage
Authors: Yasmin Mohamad , Chen Liang , Marshall Steven H , Kreiswirth Barry N , Perez Federico , Bonomo Robert A
Published: November 2018

Background

MV is a newly approved β-lactam/β-lactamase inhibitor combination (BLIC) for the treatment of complicated urinary tract infections (cUTI). Vaborbactam is a cyclic boronic acid BLI that was mainly developed as a potent inhibitor of KPC carbapenemases and other Ambler class A&C enzymes. Vaborbactam is inactive against metallo-β-lactamases (MBL) and certain Class D enzymes (e.g. OXA-2 and OXA-48). We encountered a case of MV-resistant Klebsiella pneumoniae (MVRKP)and sought to explore the various mechanisms of MV resistance within KP.

Methods

A 65-year-old nursing home resident with multiple prior hospitalizations and recent exposure to antibiotics (Timeline) developed sepsis secondary to carbapenem-resistant Klebsiella pneumoniae (CRKP) cUTI. WGS of the patient’s isolate was performed. This was followed by random screening for MV resistance and WGS of other isolates from a historical database.

Results

Results of WGS are seen in the table below. Sequencing of our patient’s isolate revealed strain ST258 with a premature stop in aa89 of OmpK35 as well as insertions at Gly134 and Asp135 (i.e., the GD repeat) of OmpK36. Furthermore, the KPC plasmid’s copy number was approximately five times higher than the chromosome. No mutations encoding efflux system AcrAB-TolC were found.

Conclusion

Resistance to MV in KP was found in isolates that predate the drug’s availability. Notably, resistance occurred in the absence of MBLs and OXAs. The mechanism seems to involve outer membrane porin mutations in OmpK35 and/or OmpK36. WGS is a useful tool in identifying the mechanism of resistance especially for newer agents.

Disclosures

All authors: No reported disclosures.
703. Mechanisms of High-Level Ceftolozane/Tazobactam (CT) Resistance Against Pseudomonas aeruginosa and Synergy Between CT and Tobramycin (TOB)
Authors: So Wonhee , Shurko James , Galega Ralph , Quilitz Rod E , Greene John , Lee Grace C
Published: November 2018

Background

Ceftolozane/tazobactam (CT) is a cephalosporin/β-lactamase inhibitor with excellent activity against multi-drug-resistant (MDR) P. aeruginosa (PSA). Several cases of CT-resistance (CT-R) development after exposure have been reported. We recovered a PSA isolate with high-level CT-R from a bacteremic patient with severe, prolonged neutropenia and 5 weeks of CT exposure. Then, multiple mutational pathways and the role of combination therapy were evaluated.

Methods

Minimum inhibitory concentrations (MIC) to CT were determined by Etest. Synergy tests between CT and tobramycin (TOB) were conducted and interpreted based on the fractional inhibitory concentration index (FICI). Furthermore, whole genome sequencing was performed. Paired-end reads were mapped and compared with reference strain PAO1. Variant analyses were conducted using CLC Genomics Workbench.

Results

The MICs for CT and TOB were >256 and 4 mg/L, respectively. The combination revealed synergistic effects (FICI < 0.5) with reduced CT and TOB MICs to 16 and 1 mg/L, respectively. Clinically, combination therapy of CT 3g q8h given over 4 hours and TOB 7 mg/kg q24h successfully cleared the bacteremia within 2 days. Genomic analysis revealed the CT-R isolate contained multiple variants in the ampC gene, including G183D associated with low level CT-R. Two additional variants in aminoacid position 79 (R79Q) and position 105 (T105A) were located inside or near helix-H2 which interacts with the Ω-loop through hydrogen-binding rendering the serine active site more pliable to accommodate larger molecules. Moreover, the CT-R isolate showed a truncated ampD and multiple mutations in mexD, mexT, mexI, and mexR, a primary regulator of mexAB-oprM. The isolate also contained the oprD mutation (Q142X) and an oprD-inactivating mutation (W417X). In addition to these chromosomal mutations, the isolate harbored OXA-50, blaPAO1, and aph(3′)-IIb.

Conclusion

High-level CT-R was likely driven by multiple mutations in the ampC region causing structural changes. While resistance to CT is worrisome, our case of a severe neutropenic patient who rapidly cleared bacteremia on CT 3g qh8 given over 4 hours plus TOB emphasizes the importance of strategic combination and dosing in combating MDR PSA.

Disclosures

All authors: No reported disclosures.
704. Klebsiella pneumoniae Carbapenemase and Verona Integron-Encoded Metallo-β-Lactamase Among Carbapenem-Resistant Enterobacteriaceae in Kentucky
Authors: Spicer Kevin , Roser Lynn , Flinchum Andrea
Published: November 2018

Background

Klebsiella pneumoniae carbapenemase (KPC) and Verona integron-encoded metallo-β-lactamase (VIM) have been the most commonly identified carbapenemases among carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) in Kentucky since 2013. Understanding the frequency and epidemiology of these CP-CRE can help inform prevention strategies.

Methods

We reviewed reports of KPC- and VIM-producing CRE from January 2013 through December 2017. CRE became reportable in Kentucky in February 2015 and statewide request to laboratories and healthcare facilities for isolate submission for mechanism testing was made in September 2017. Prior to that time, mechanism testing for CRE was conducted at a limited number of laboratories or during outbreak investigations. Demographic data included age, sex, and inpatient or outpatient status. Descriptive analyses were performed.

Results

As of December 31, 2017, a total of 156 CP-CRE isolates had been identified (124 KPC, 31 VIM, 1 NDM), with an increase from 2013 (n = 13) to 2017 (n = 48). KPC was identified in isolates from 124 patients; VIM was identified in isolates from 26 patients, with 4 patients (15%) having multiple organisms with the mechanism. KPC was identified most commonly from Klebsiella pneumoniae (57/124, 46%); VIM was identified most commonly from Enterobacter cloacae (14/31, 45%). KPC was found in 6 different Enterobacteriaceae genera; VIM in 4. KPC-producing CRE were identified in 22 acute-care and long-term acute-care facilities in 14 counties, with nine reporting >2 isolates. Fifteen percent (19/124) of KPC-producing CRE were isolated from outpatients. VIM-producing CRE were identified in two acute-care facilities located in two urban areas; one was from an outpatient. Patients with VIM were younger than those with KPC (43 vs. 60 years, P < 0.001).

Conclusion

KPC is the predominant carbapenemase in Kentucky and is more widely disseminated than VIM, which has been limited to two facilities. CRE reporting and mechanism testing have yielded a greater understanding of regional CRE epidemiology and has the potential to facilitate response efforts to slow further spread.

Disclosures

All authors: No reported disclosures.
707. Clarifying the Role of CrrB in Polymxyin-resistant Klebsiella pneumoniae Clinical Isolates Utilizing a Novel CRISPR-Cas9 System
Authors: McConville Thomas , Giddins Marla , Macesic Nenad , Uhlemann Anne-Catrin
Published: November 2018

Background

Polymyxin resistance (PR) threatens the mainstay of therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections. While mgrB disruption accounts for most cases of PR, missense mutations in crrB have been proposed as an alternative pathway for PR through PmrA/B/C upregulation of the pmrHFIJKLM operon. It remains unknown if CrrB acts as a positive or negative regulator on its downstream targets.

Methods

We assembled a CRISPR-Cas9 system for gene knockouts (KO) in CRE K. pneumoniae (CRKP) using zeocin as a selectable marker. We chose a polymyxin susceptible (PS) and a PR isolate with a missense mutation in crrB (L87V) (NR5337 and NR5083, respectively) for KO. Isolates were transformed with a crrB KO plasmid, grown with zeocin selection, induced with arabinose, and plated on low-salt LB-zeocin/arabinose. KOs were confirmed via PCR and Sanger sequencing. Polymyxin susceptibility was performed with broth-microdilution. Gene expression was determined by qRT-PCR of cDNA extracts.

Results

Colistin MIC following crrB KO of NR5337 (PS) remained unchanged. In contrast, crrB KO of NR5083 (PR), decreased polymyxin MIC (MIC >128 to 1.0 μg/mL). qRT-PCR of NR5083 did not show increased expression of pmrA/C, nor pmrK. NR5083 ^crrB showed a small decrease in phoQ expression, compared with NR5083, but similar expression of phoP, pmrA/C and pmrK (Table 1).

Conclusion

Polymyxin MIC decreased >128 fold after crrB KO in a PR isolate, but colistin MIC remained unchanged after KO in a PS isolate. CrrB mutations in PR isolates may confer a gain of function with CrrB acting as a positive regulator on its downstream targets. Contrary to previous literature, no upregulation of pmrA/C and pmrHFIJKLM was detected. Differences in crrB mutations or clonal background may explain this finding. CRISPR-Cas9 may serve as a reliable system for genetic manipulation of CRKP. Further data on the impact of individual crrB missense mutations are needed.

Disclosures

A. C. Uhlemann, Merck: Investigator, Grant recipient.
708. Incidence and Relatedness of Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Infections in Previously Colonized or Infected Patients
Authors: Tang Sarah Si Lin , Teo Jocelyn , Chlebicki Piotr , Kwa Andrea L
Published: November 2018

Background

In patients with history of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CPCRE), the need for CPCRE targeted treatment in subsequent sepsis episodes is unclear. We determine the likelihood of CPCRE infection (CI) in patients previously colonized (PC) or infected (PI) with CPCRE and relatedness of both episodes.

Methods

Adult inpatients with CPCRE isolated from any site in June 2012–May 2014 at a tertiary-care hospital were prospectively followed for 2 years to assess for subsequent CI. Bacteria isolates from paired episodes were subjected to Illumina HiSeq2500 and multilocus sequence typing.

Results

Six of 25 (24%) PI and 11 of 152 (7%) PC patients had subsequent CI—overall incidence was 9.6%. KP was most commonly implicated. While bacteria species differed in four cases, the carbapenemase type was conserved in all but one. Those with initial bacteremia, intra-abdominal (IA) or lung infection (n = 6) were five times more likely to develop CI. Only 33% of PI vs. 62% of PC patients had subsequent infections of the same clonal group. For PC, KP (OR 9.3) and OXA carbapenemase (OR 12.8) significantly predicted for subsequent CI. In PI, chronic renal failure requiring dialysis (OR 70.2) and KPC enzyme (OR 14) were predisposing factors. In-hospital mortality was observed in six cases.

Conclusion

Incidence of CI in carriers is low. Patients with IA and respiratory CI in the preceding 93 days are candidates for CPCRE treatment; empiric therapy should be active against the carbapenemase identified in the index episode.

Disclosures

All authors No reported disclosures.
710. Increased Clinical Failure Rates Associated with Reduced Metronidazole Susceptibility in Clostridioides difficile
Authors: Gonzales-Luna Anne , Shen Wan-Jou , Dotson Kierra , Lancaster Chris , Endres Bradley , Hossain Feroz , Begum Khurshida , Cernoch Patricia , Perez Katherine , Tisdel Naradah , Barrett Miriam , Muldrew Kenneth L , Alam M Jahangir , Garey Kevin , Hurdle Julian
Published: November 2018

Background

Current national guidelines suggest limiting metronidazole (MTZ) use due to increased treatment failures in patients with Clostridioides difficile infections (CDI). However, the reason for these increased failure rates is unclear. We hypothesized an increase in the minimum inhibitory concentration (MIC) of MTZ to C. difficile may contribute to these poor response rates. The objective of this study was to examine clinical response rates in patients with CDI who received MTZ monotherapy vs. other therapies stratified by MTZ susceptibility.

Methods

Stool samples that tested positive for C. difficile (2017–2018) were collected from two large academic hospital systems in Texas. C. difficile was isolated from stool and visually screened for growth on heme-containing agar plates with MTZ at 2 mg/L (defined as reduced susceptibility). Blinded investigators reviewed electronic medical records to identify the treatment received and determine clinical success or failure for each patient. Treatment failure rates were assessed in patients that received MTZ monotherapy vs. other therapies stratified by MTZ susceptibility. Results were analyzed using multivariate logistic regression analysis.

Results

A total of 172 C. difficile isolates were included of which 55.8% displayed reduced susceptibility to MTZ. Clinical success rates with MTZ varied based on disease severity (mild-moderate: 80.4%; severe/severe-complicated: 64%). Treatment success rates were higher in patients infected with MTZ susceptible isolates (88.4%) compared with those infected with isolates showing reduced MTZ susceptibility (60.5%; P = 0.004.) In multivariate logistic regression after controlling for disease severity, patients infected with strains displaying reduced MTZ susceptibility and treated with MTZ were more likely to experience treatment failure compared with patients with susceptible isolates (OR = 6.8; 95% CI:1.96–23.8; P = 0.003). In patients given non-MTZ-based therapies, reduced susceptibility to MTZ was not predictive of failure to other treatments.

Conclusion

This is the first report to demonstrate that increased clinical failure rates for MTZ monotherapy are associated with reduced susceptibility to MTZ.

Disclosures

K. Garey, Summit Therapeutics: Collaborator, Research support.
714. Predictors of Influenza-Associated Hospitalization and Pneumonia in a Pediatric Population in Bangkok, Thailand
Authors: Sawani Ali , Suwanpakdee Detchvijitr , Watanaveeradej Veerachai , Weg Alden , Ellison Damon , Klungthong Chonticha , Phonpakobsin Thipwipha , Kerdpanich Phirangkul , Phiboonbanakit Danabhand , Gibbons Robert , Fernandez Stefan , Macareo Louis , Yoon In Kyu , Jarman Rick , Simasthien Sriluck , Anderson Kathryn
Published: November 2018

Background

Influenza infection in children can be severe, resulting in complications such as pneumonia, but may be mitigated by early recognition and administration of antivirals. In this study, we identified risk factors for hospitalization and pneumonia in a pediatric population presenting with influenza-like illness (ILI) in Thailand.

Methods

Our study included pediatric patients (age < 18 years) presenting with ILI to inpatient and outpatient departments at a public hospital in Bangkok, Thailand, from 2009 to 2016. ILI was defined as fever plus cough or sore-throat, and pneumonia was defined as either lung radiographic or pulmonary examination abnormalities. Demographic and clinical data, as well as nasal and throat swabs, were collected during a one-time interview with patients presenting with ILI. Influenza infections were confirmed via RT-PCR testing of respiratory specimens. Retrospective chart review was used to collect data on individuals with influenza admitted for inpatient care.

Results

5,968 children (33.6%) were enrolled with ILI, of whom 1,530 (25.6%) were confirmed to be influenza by RT-PCR, of which 25.5% were influenza A(H1N1)pdm09, 31.5% influenza A(H3N2), and 43.0% influenza B. 124 (8.1%) patients were admitted, and 41 of these children (33.1%) developed pneumonia. Predictors of hospitalization included younger age (4.1 yrs for inpatients vs. 5.6 yrs) and higher presenting temperature (38.6C for inpatient vs. 38.0C) (both P < 0.05). Among children hospitalized with influenza, influenza subtype was not associated with pneumonia risk. Co-detection of Klebsiella pneumoniae was associated with an increased risk of pneumonia (P < 0.05. Patients with pneumonia were younger (4.1 yrs with vs. 6.4 yrs, P = NS), had a longer interval from fever onset to presentation at the hospital, and required longer hospital stays. Risk of pneumonia was decreased in patients who received oseltamivir within 48 hours of fever onset (odds ratio 0.36, 95% confidence interval 0.16–0.91).

Conclusion

Post viral pneumonia is a potentially serious complication of influenza, requiring longer hospitalization stay and affecting more than one-third of hospitalized pediatric patients with influenza. The risk of pneumonia can be reduced with early presentation for clinical care and prompt administration of oseltamivir following fever onset.

Disclosures

All authors: No reported disclosures.