Grant Investigator Research Articles

Designing an automated, privacy preserving, and efficient Digital Forensic Framework

<p class="MDPI18keywords">The digital forensic investigation field faces continual challenges due to rapid technological advancements, the widespread use of digital devices, and the exponential growth in stored data. Protecting data privacy has emerged as a critical concern, particularly as traditional forensic techniques grant investigators unrestricted access to potentially sensitive data. While existing research addresses either investigative effectiveness or data privacy, a comprehensive solution that balances both aspects remains elusive. This study introduces a novel digital forensic framework that employs case information, case profiles, and expert knowledge to automate analysis. Machine learning techniques are utilized to identify relevant evidence while prioritizing data privacy. The framework also enhances validation procedures, fostering transparency, and incorporates secure logging mechanisms for increased accountability.</p>

Cell scientist to watch – Martin Loose

ABSTRACT Martin Loose studied chemistry at the University of Heidelberg, Germany. He then joined Petra Schwille's group at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, where he obtained his PhD degree in 2010 for work on self-organization and pattern formation in the bacterial Min protein system. He then moved to Tim Mitchison's lab at Harvard Medical School, Boston, USA for his postdoc, funded by Human Frontier Science Program (HSFP) and European Molecular Biology Organization (EMBO) long-term fellowships; there, he discovered that the bacterial cell division proteins FtsA and FtsZ self-organize into dynamic cytoskeletal patterns. Martin established his independent research group at the Institute of Science and Technology (IST) Austria in 2015, supported by an European Research Council (ERC) starting grant and HFSP Young Investigator Grant. His lab studies the self-organization of bacterial cell division and small GTPase networks.

Gender Disparity in Grants and Awards at the National Institute of Health.

ObjectiveThe National Institute of Health (NIH) supports the academic career of scientists across the United States (U.S.). It promotes and sponsors scientists in conducting wide-ranging clinical and basic science research. Depending on the duration, research type, and budget, there are various types of grants awarded by NIH. Despite considerable advancement in biomedical sciences, female researchers remain underrepresented in obtaining NIH funding. Through this study, we aim to highlight the gender trends in NIH funding and grants. By doing this, we aim to facilitate effective future policymaking to help achieve gender parity in NIH grants and awards.MethodsThe data were obtained from the NIH Research Portfolio Online Reporting Tool (RePORT). The extracted data by gender were tabulated showing percentages of females as Research Grant Investigators, Research Career Development Award Recipients and Kirschstein-National Research Service Award (NRSA) Trainees and Fellows, recipients of Research Grants, Research Project Grants (RPGs), and R01 equivalent grants including types 1 or 2, over two decades (1999-2019). Absolute percentage change was also calculated and included in the tables.ResultsThe percentage of females as NIH Research Grant Investigators has increased at centers, research centers as well as for RPGs and Small Business Innovation Research and Small Business Technology Transfer (SBIR/STTR) programs. For Research Career Development Award Recipients and Kirschstein-NRSA Trainees and Fellows, the proportion of female pre-doctoral institutional trainees, post-doctoral fellows, post-doctoral institutional trainees, mentored research career awardees, and other research career awardees have steadily increased. However, there was a decrease in the percentage of female pre-doctoral fellow awardees. The percentage of females receiving all RPGs, R01-New (type 1) and R01-Renewal (type 2) grants has also decreased. ConclusionDespite an overall increase in the percentage of female researchers successfully receiving NIH grants and awards, they continue to lag compared to their male counterparts. With the increasing number of female doctoral graduates, it is imperative to address this disparity in NIH funding.

The Pediatric Neurology 2020 Research Workforce Survey: Optimism in a Time of Challenge

BackgroundThe past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces substantial challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission. MethodsOur objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society. ResultsOne hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident. ConclusionsOur survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders.

A cross-sectional study of predatory publishing emails received by career development grant awardees

ObjectiveTo investigate the scope of academic spam emails (ASEs) among career development grant awardees and the factors associated with the amount of time spent addressing them.DesignA cross-sectional survey of career...

550. Adherence and Persistency With Modern Single vs. Multi-Tablet Antiretroviral (ARV) Regimens in First Treatment of HIV in Clinical Practice

550. Adherence and Persistency With Modern Single vs. Multi-Tablet Antiretroviral (ARV) Regimens in First Treatment of HIV in Clinical Practice

1180. Addition of Chronic Kidney Disease Status to Pitt Bacteremia Score Improves Prediction of Mortality in Patients With Carbapenem-Resistant Enterobacteriaceae Infections

BackgroundCarbapenem-resistant Enterobacteriaceae (CRE) infections are associated with high mortality. The Pitt Bacteremia Score (PBS) was developed and validated to predict mortality in bloodstream infections (BSI). The first goal of this analysis is to evaluate whether PBS also predicts mortality in non-BSI infections. Second, we determine whether adding chronic kidney disease (CKD) as a parameter to PBS improves prediction of mortality.MethodsThe Consortium on resistance against carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1) is a prospective multicenter consortium of hospitals. Each patient with CRE infection was included once at the time of the last positive culture episode. Infections were distinguished from colonization using established definitions. Relative risk regression was used to evaluate the association of PBS ≥4 and CKD with 14-day all-cause hospital mortality.ResultsFrom December 2011 to June 2016, 364 unique patients were included with the following infections: bloodstream (34%), respiratory (20%), urinary (30%), and wound (16%). Median PBS was 3 (IQR: 2–4); 45% of patients had PBS ≥4. CKD was present in 31% of patients with PBS ≥4 and 20% of patients with PBS <4. All-cause mortality within 14 days of the last positive culture episode was 20%. In multivariable analysis, PBS ≥4 was strongly associated with mortality in patients with bacteremia (PBS ≥4 adjusted RR = 6.1, 95% CI 2.5–14.6, CKD aRR = 1.5, 95% CI 0.9–2.3) and in patients with other infections (PBS ≥4 aRR = 14.0, 95% CI 4.3–44.6, CKD aRR = 1.6, 95% CI 1.0–2.7). Adding CKD as a parameter to the PBS improved mortality prediction, specifically in patients with PBS ≥4 (figure).ConclusionAs expected, PBS ≥4 was predictive of the 14-day risk of hospital mortality in this cohort of CRE bacteremic patients. In patients with other CRE infections, PBS ≥4 was also predictive of mortality. In this cohort, adding CKD to the PBS improved prediction of mortality patients with PBS ≥4.Figure: Risks and 95% confidence intervals for 14-day all-cause hospital mortality, by Pitt bacteremia score and chronic kidney disease (CKD) status.Disclosures 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. V. G. Fowler Jr., Merck: Consultant and Scientific Advisor, Consulting fee. Cerexa/Actavis/Allergan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Grant Investigator, Grant recipient. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient.Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Affinergy: Consultant and Grant Investigator, Consulting fee and Grant recipient. Locus: Grant Investigator, Grant recipient. Medical Surface, Inc.: Grant Investigator, Grant recipient. Theravance: Consultant, Consulting fee and Speaker honorarium. Green Cross: Consultant, Speaker honorarium. Grifols: Consultant, Consulting fee. xBiotech: Consultant, Consulting fee. Achaogen: Consultant, Consulting fee. Medicines Co: Consultant, Consulting fee. Novartis: Consultant, Consulting fee.Novadigm: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. D. Van Duin, Shionogi: Scientific Advisor, Consulting fee. achaogen: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Consultant, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee.

1403. Daptomycin Combined with Low Dose Ceftriaxone Prevents the Emergence of Daptomycin Resistance against Streptococcus mitis-oralis Group in an In vitro Model of Simulated Endocardial Vegetations (SEVs)

BackgroundThe viridans group streptococci (VGS) are a heterogeneous group of microorganisms that form portion of the normal oral flora of humans. Among the VGS, S. mitis-oralis is the most common cause of infective endocarditis in the developing world, as well as the leading cause of the “toxic Strep syndrome” in neutropenic cancer patients. Therapeutic options are often limited by frequent β-lactam resistance, as well as vancomycin tolerance. Daptomycin (DAP) has been suggested as an alternative therapeutic option for invasive S. mitis-oralis infections. However, the ability of these strains to rapidly evolve high-level and durable DAP-resistance (DAP-R) is problematic. Recent data have suggested the potential for combined DAP +β-lactam therapy to circumvent this issue.MethodsUsing human-simulated dosing, the activities of DAP (6, 8,10 or 12 mg/kg/day × 4 days) alone vs. DAP (6 mg/kg/day) +(CRO) (500 mg daily × 4 days or 500 mg, given once on day one) were assessed against two DAP-susceptible (DAP-S) S. mitis-oralisstrains (SF100; 351) employing a PK-PD model of simulated endocardial vegetations (SEVs).ResultsDAP alone was not bactericidal at any dose-regimen, and regrowth of high-level DAP-R isolates was observed in both strains (MIC increase from 0.5 to >64 µg/mL). Combinations of DAP +CRO at either dose-regimen yielded significant reductions in log10CFU/g amounts within SEVs for both strains (~6 log10 CFU/g and to detection limits) within 24 hours. In addition, no DAP-R strains were detected in either DAP+ CRO combination regimens over the 96-hour exposure period.ConclusionCombinations of DAP+ low-dose CRO (even single dosing) showed promise to forestall the emergence of DAP-R in S. mitis-oralis strains. Such regimens can potentially lead to optimizing treatment outcomes with DAP therapy, with minimal β-lactam exposures. Further research in relevant in vivo models and clinically is warranted to determine the most optimized DAP+ CRO dose-regimens for the prevention of emergence of DAP-R among S. mitis-oralis strains.Disclosures J. M. Miro, Abbvie: Consultant and Grant Investigator, Consulting honoraria and Research grant; Bristol-Myers Squibb: Consultant and Grant Investigator, Consulting honoraria and Research grant; Genentech: Consultant and Grant Investigator, Consulting honoraria and Research grant; Medtronic: Consultant and Grant Investigator, Consulting honoraria and Research grant; Novartis: Consultant and Grant Investigator, Consulting honoraria and Research grant; Gilead Sciences: Consultant and Grant Investigator, Consulting honoraria and Research grant; Pfizer: Consultant and Grant Investigator, Consulting honoraria and Research grant; ViiV Healthcare: Consultant and Grant Investigator, Consulting honoraria and Research grant. C. Arias, Merck & Co., Inc.: Grant Investigator, Research support; MeMed: Grant Investigator, Research support; Allergan: Grant Investigator, Research support. A. Bayer, Trellis: grant recipient, Grant recipient; Contrafect: grant recipient, Grant recipient; Theravance: grant recipient, Grant recipient. M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support; Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

992. 2016–2017 Influenza Burden of Disease and End-of-Season Influenza Vaccine Effectiveness (VE) Estimates for Preventing Influenza-Related Hospitalization Among Canadian Adults: An Analysis From the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network

BackgroundTo inform public health decision making around influenza prevention and treatment, ongoing surveillance of the influenza burden of disease and assessment of influenza vaccine effectiveness (VE) is critical. The Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network conducts active surveillance each influenza season to characterize the burden of influenza disease and to provide estimates of influenza VE to prevent influenza-related hospitalization in Canadian adults (≥16 years of age).MethodsActive surveillance for influenza was conducted at 13 hospitals in four provinces beginning on November 15, 2016 and ending April 30, 2017. Patients admitted with any respiratory diagnosis or symptom were eligible for enrolment. Eligible patients had a nasopharyngeal swab collected and tested for influenza using polymerase chain reaction (PCR). Patients who tested positive for influenza were considered cases; patients who tested negative for influenza were eligible to become matched controls. Detailed demographic and medical information were obtained from the medical record. Influenza VE was estimated as 1 − odds ratio (OR) of influenza in vaccinated vs. unvaccinated patients × 100% using conditional logistic regression, with corresponding 95% confidence intervals (CIs).ResultsA total of 1,431 influenza cases were enrolled; the majority were influenza A (n = 1,299) and 100% of patients with known influenza A subtype were A/H3N2. Among all influenza cases, 144 (10.1%) patients were admitted to the intensive care unit (ICU) and 91 (6.4%) patients died within 30 days of discharge. Overall adjusted influenza VE for prevention of influenza-related hospitalization in all ages was 23.3% (95% CI: 2.9–39.4%), with slightly lower VE observed in patients ≥65 years (VE: 19.4%; 95% CI: −7.8–39.8%) and higher VE observed in patients <65 years (VE: 47.9%; 95% CI: 9.9–69.9%).ConclusionOverall, influenza VE was low but effective (VE: 23%) for preventing influenza-related hospitalization during the 2016–2017 season in Canada. Given the low influenza VE observed, continued assessment of influenza VE is crucial to inform immunization policy in Canada and to emphasize the importance of the development and utilization of improved influenza vaccines.Disclosures M. K. Andrew, GSK: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. sanofi pasteur: Grant Investigator, Research grant. T. F. Hatchette, GSK: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. Abbvie: Consultant, Speaker honorarium. J. McElhaney, GSK: Scientific Advisor, Speaker honorarium. sanofi pasteur: Scientific Advisor, Speaker honorarium. A. McGeer, GSK: Grant Investigator, Research grant. Hoffman La Roche: Grant Investigator, Research grant. sanofi pasteur: Grant Investigator, Research grant. A. Poirier, sanofi pasteur: Investigator, Research grant. Actelion: Grant Investigator, Research grant. J. Powis, GSK: Grant Investigator, Research grant. Merck: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Synthetic Biologics: Investigator, Grant recipient. M. Semret, GSK: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. S. Trottier, CIHR: Grant Investigator, Research grant. S. A. McNeil, GSK: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. Merck: Collaborator and Consultant, Contract clinical trials and Speaker honorarium. Novartis: Collaborator, Contract clinical trials. sanofi pasteur: Collaborator, Contract clinical trials.

1581. Impact of Colonization with Fluoroquinolone-Resistant Enterobacteriaceae on the Risk of Gram-Negative Bacteremia in Hematopoietic Stem Cell Transplant Recipients Who Receive Prophylactic Levofloxacin

BackgroundFluoroquinolone (FQ) prophylaxis is widely used to prevent bloodstream infections (BSIs) in neutropenic patients undergoing hematopoietic stem cell transplantation (HCT). In order to assess whether increasing FQ resistance threatens the effectiveness of FQ prophylaxis, we screened HCT recipients for colonization with FQ-resistant Enterobacteriaceae (FQRE) and assessed the impact of colonization on the risk of BSI.MethodsWe collected stool samples on admission for HCT and weekly until neutrophil engraftment from patients at NewYork-Presbyterian Hospital/Weill Cornell Medical Center from November 2016 to March 2018. Patients received FQ prophylaxis during neutropenia. Perianal swabs were used when stool was unavailable. Stool and swab samples were plated onto MacConkey agar with 1 μg/mL ciprofloxacin, and colonies were identified and underwent antimicrobial susceptibility testing. We determined the prevalence of colonization with FQRE on admission for HCT, the risk of acquiring FQRE, and compared the risk of BSI during the transplant admission in colonized and noncolonized patients.ResultsWe evaluated 178 HCT recipients and found that 35 (20%) had pre-transplant FQRE colonization (allogeneic: 20/89, 22%; autologous: 15/89, 17%). Thirty FQRE (86%) were Escherichia coli, 5 (14%) were Klebsiella pneumoniae, and 13 (37%) were extended-spectrum β-lactamase producers. Five (14%) of the 35 patients with pre-transplant FQRE colonization developed BSI due to an Enterobacteriaceae, and all bloodstream isolates had identical susceptibility profiles to the colonizing FQRE. In contrast, only one (1%) of 143 patients without pre-transplant FQRE colonization developed Enterobacteriaceae BSI (P = 0.001). Patients with pre-transplant FQRE colonization also had higher rates of any Gram-negative BSI (20% vs. 1%, P < 0.001), but did not have increased risk of Gram-positive BSI (6% vs. 11%, P = 0.5). Of 123 patients without initial FQRE colonization who had follow-up samples collected, 10 (8%) acquired FQRE during post-HCT neutropenia.ConclusionFQRE colonization is common on admission for HCT and is associated with decreased effectiveness of levofloxacin prophylaxis in preventing Gram-negative BSI during post-transplant neutropenia.Disclosures M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support; Allergan: Grant Investigator, Grant recipient; Merck: Grant Investigator, Grant recipient; Biomerieux: Grant Investigator, Grant recipient; Achaogen: Consultant, Consulting fee. R. Malherbe, Hardy Diagnostics: Employee, Salary. S. G. Jenkins, Merck: Grant Investigator, Grant recipient. L. F. Westblade, Accelerate Diagnostics: Grant Investigator, Grant recipient; Biomerieux: Grant Investigator, Grant recipient; Allergan: Grant Investigator, Grant recipient; Merck: Grant Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant; Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Gilead: Scientific Advisor, Consulting fee; Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant; Scynexis: Grant Investigator, Research grant; Amplyx: Grant Investigator, Research grant; Shionogi: Scientific Advisor, Consulting fee.

1399. Efficacy of Daptomycin Combination with β-Lactams for Daptomycin-resistant Enterococcus faecium Harboring LiaSR Substitutions

BackgroundDaptomycin (DAP) is one of the mainstay treatments for Enterococcus faecium infections. However, development of resistance threatens its continued viability as a treatment option. Although the mechanisms of DAP resistance in enterococci are not fully comprehended, they are associated with alterations in cell envelope phospholipids assembly which leads to repulsion of the drug from cell exterior and diversion from the cell septum. Previous data suggest that combination of DAP with β-lactams has the potential to improve patient outcomes. In this investigation, we sought to evaluate combinations of DAP with ampicillin (AMP), ceftaroline (CPT), and ertapenem (ERT).Methods E. faecium R497 harboring liaSFR mutations (DAP MIC of 16 mg/L) was evaluated in a simulated endocardial vegetation (SEV) pharmacokinetic and pharmacodynamic model over 336 hours at a starting inoculum of 109 log10 CFU/g of SEV. DAP alone at 10 mg/kg/day or DAP (6, 8, 10 mg/kg/day) in combination with AMP (2 g continuous infusion), CPT 600 mg q12h or ERT 1 g q24h were evaluated. The emergence of DAP resistance was determined daily over the course of the 14-day experiment.ResultsDAP alone was not bactericidal and high-level DAP resistance was observed (MIC increase from 16 to 256 µg/mL) for all DAP alone regimens. Combination of DAP+AMP offered a significant reduction in log10CFU/g amounts (up to 7 log10 CFU/g and to detection limits) in 24 hours in DAP10+AMP model with no further emergence of DAP resistance. Even in DAP 6 mg/kg/day with AMP (2 g), dramatic killing with no further emergence of resistance was observed. Neither CPT nor ERT in combination with DAP was effective against this strain. At higher doses of DAP (14 mg/kg/day) + CPT or ERT, a temporary (0–48 hours) CFU/g reduction was observed followed by regrowth and the further emergence of DAP resistance.ConclusionCombination of DAP + AMP offered the most encouraging results against E. faecium R497. A DAP dose sparring effect was noted with DAP + AMP but not with CPT or ERT. The reason for the discrepancy is unknown and is under further investigation. Further evaluation of DAP plus β-lactam therapy is warranted to discover the most optimized DAP and β-lactam therapy to improve patient outcome and prevent the emergence of resistance.Disclosures B. Murray, Paratek pharmaceuticals: Consultant and Scientific Advisor, Consulting fee and Speaker honorarium; Forest/Actavis: Grant Investigator, Grant recipient; Cubist/Merck: Grant Investigator, Grant recipient. C. Arias, Merck & Co., Inc.: Grant Investigator, Research support; MeMed: Grant Investigator, Research support; Allergan: Grant Investigator, Research support; M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support; Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support

1468. PCV13 Serotype Trends Over Time in Pneumococcal Community Acquired Pneumonia: Which Method(s) Work Best?

BackgroundRecent studies have shown that a 13-valent pneumococcal conjugate vaccine (PCV13) was effective at preventing vaccine-type pneumococcal community acquired pneumonia (CAPSpn) in healthy adults. With the anticipated herd immunity from routine infant immunization with PCV13 used since 2010, the benefits of adult immunization in Canada were unclear and surveillance for CAPSpn with serotype distributions was needed. This study aimed to compare PCV13 serotype trends in CAPSpn from 2010 to 2015 using various laboratory methods.MethodsActive surveillance for CAP was performed from 2010 to 2015 in adult hospitals across five Canadian provinces. Bacteremic CAPSpn cases were identified using blood culture, and nonbacteremic CAPSpn cases by sputum culture or using a PCV13-specific urine antigen detection (UADPCV13). Serotype was assigned using Quellung reaction, PCR, or UADPCV13. CAPSpn cases were categorized by laboratory test(s), age, or disease (bacteremic or nonbacteremic CAPSpn).ResultsA diagnostic test for S. pneumoniae was performed on 6,687 CAP cases. S. pneumoniae positivity decreased from 2011 to 2014, and increased again in 2015. PCV13 serotypes followed a similar trend, where the decline in PCV13 serotypes attributed to serotypes 7F and 19A was noted, and the proportion of serotype 3 increased over time. Similar trends were seen regardless of whether data were categorized by laboratory test(s), age, or disease.ConclusionOur data suggest that all methods showed similar trends in PCV13 serotype distribution over 2010 to 2015. Herd immunity through childhood immunization with PCV13 was evident, but insufficient to afford complete protection to hospitalized adults. CAPSpn remained a significant cause of morbidity and mortality in hospitalized adult, and serotype 3 seems to be persisting despite herd immunity seen with other serotypes. Ongoing surveillance is required.Disclosures T. Hatchette, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Abbvie: Consultant, Speaker honorarium. M. K. Andrew, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Sanofi Pasteur: Grant Investigator, Research grant. A. McGeer, GSK: Grant Investigator, Research grant; Hoffman La Roche: Grant Investigator, Research grant; Sanofi Pasteur: Grant Investigator, Research grant. M. Semret, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant. S. Trottier, CIHR: Grant Investigator, Research grant. S. A. McNeil, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Merck: Collaborator and Consultant, Contract clinical trials and Speaker honorarium; Novartis: Collaborator, Contract clinical trials; Sanofi Pasteur: Collaborator, Contract clinical trials.

1036. Whole Genome Sequencing Analysis of a Large Cohort of Staphylococcus epidermidis Blood Culture Positive Isolates From a Multicenter Clinical Trial

Background Staphylococcus epidermidis is a leading cause of healthcare-associated bacteremia, but the clinical course of S. epidermidis isolated from blood cultures ranges from contamination to serious deep seated infections. We tested the hypothesis that the genetic characteristics of S. epidermidis isolated from blood cultures are significantly associated with disease severity using whole genome sequencing (WGS).MethodsWe performed WGS of 163 S. epidermidis isolates from a large prospective multicenter, randomized control trial that assessed the safety and efficacy of algorithm-based treatment of patients with staphylococcal bacteremia (ClinicalTrials.gov #NCT01191840). Patient’s infection types were divided into simple (including possible contamination), uncomplicated and complicated bacteremia. Failure was defined as persistent signs and symptoms of infection at 72 hours, persistent bacteremia at 7 days, relapse, complications or overall mortality within 28 days of therapy. WGS was performed using Illumina Miseq, followed by in silico multi-locus sequence type identification and phylogenomic analysis using kSNP.ResultsOf the 163 isolates analyzed, 39 sequence types (STs) were identified with ST2 and ST5 isolates being most frequently identified (21% and 20%, respectively). ST2 and ST5 isolates were significantly more likely associated with uncomplicated and complicated infections rather than simple bacteremia (P = 0.01 by χ2 test). By multivariate regression analysis, having an ST2 or ST5 S. epidermidis bacteremia was an independent predictor of a complicated infection (odds ratio 4.28, 95% CI 1.36–13.42). Using WGS based branching points rather than sequence typing allowed for additional strengthening of the association of S. epidermidis genetic clustering and clinical infection types (figure). Although there was no significant difference in failure rates among patients infected with different STs, ST2/ST5 strains were significantly more likely to cause relapsing infections (85.7%, P = 0.02).ConclusionWGS could offer a prognostic tool in the management of S. epidermidis bacteremia. ST2 and ST5 strains may help predict a complicated bacteremia course which would warrant appropriate antimicrobial therapy. Disclosures T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. V. G. Fowler Jr., Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. Merck: Consultant and Scientific Advisor, Consulting fee. Cerexa/Actavis/Allergan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Grant Investigator, Grant recipient. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient. Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Affinergy: Consultant and Grant Investigator, Consulting fee and Grant recipient. Locus: Grant Investigator, Grant recipient. Medical Surface, Inc.: Grant Investigator, Grant recipient. Theravance: Consultant, Consulting fee and Speaker honorarium. Green Cross: Consultant, Speaker honorarium. Grifols: Consultant, Consulting fee. xBiotech: Consultant, Consulting fee. Achaogen: Consultant, Consulting fee. Medicines Co: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Novadigm: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty. The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

872. PROPHETIC: Predicting Pneumonia in Hospitalized Patients in the ICU—A Model and Scoring System

BackgroundProspectively identifying patients at highest risk for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) by implementing a risk assessment scoring tool may help focus prevention efforts, optimize the screening process to improve clinical trial feasibility, and enhance development of new antibacterial agents.MethodsWithin the intensive care units (ICU) of 28 US hospitals, between February 6, 2016 and October 7, 2016, patients hospitalized >48 hours and receiving high levels of respiratory support were prospectively followed for meeting the definition of HABP/VABP recommended in US FDA draft guidance. Patient demographics, medical comorbidities, and treatment exposures were recorded. The association between candidate risk factors and odds of developing HABP/VABP was evaluated with a multivariable logistic regression model. Risk factors were selected using backward selection with α = 0.1 for model inclusion. A web-based scoring system was developed to estimate the risk of HABP/VABP from the risk factors identified.ResultsA total of 5,101 patients were enrolled, of whom 1,005 (20%) developed HABP/VABp. 4,613 patients were included in the model, excluding 488 (10%) with HABP/VABP at or before enrollment. There are 15 variables included in the model. APACHE II admission score >20 (P < 0.001, OR 2.14, 95% CI 2.00–2.29), admission diagnosis of trauma (P < 0.001, OR 3.31, 95% CI 1.90–5.74), frequent oral or lower respiratory tract suctioning (P < 0.001, OR 2.33, 95% CI 1.81–2.99), and receipt of enteral nutrition (P < 0.001, OR 2.31, 95% CI 1.69–3.16) were the key drivers of increased pneumonia risk. The model demonstrated excellent discrimination (bias-corrected C-statistic 0.861, 95% CI 0.843–0.880). The web-based scoring system can be accessed via this link: https://ctti-habpvabp.shinyapps.io/web_based_tool/.ConclusionUsing a web-based scoring system, ICU patients at highest risk for developing HABP/VABP can be accurately identified. Prospective implementation of this tool may assist in focusing additional prevention efforts on the highest risk patients and enhance new drug development for HABP/VABP.Disclosures S. P. Bergin, CTTI: Investigator and Scientific Advisor, Research support and Travel to study related meetings. A. Coles, CTTI: Investigator and Scientific Advisor, Salary. S. B. Calvert, CTTI: Employee, Salary. M. J. Zervos, CTTI: Investigator, Research support. A. C. Bardossy, CTTI: Investigator, Research support. M. Kollef, CTTI: Investigator, Research support. M. J. Durkin, CTTI: Investigator, Research support. M. Sims, CTTI: Investigator, Research support. C. Greenshields, CTTI: Investigator, Research support. B. A. Kabchi, CTTI: Investigator, Research support. H. K. Donnelly, CTTI: Collaborator and Scientific Advisor, Research support and Salary. P. Tenaerts, CTTI: Employee, Salary. P. Gu, CTTI: Collaborator, Research support and Salary. V. G. Fowler Jr., CTTI: Investigator and Scientific Advisor, Research support and Salary. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee, Grant recipient and Research support. Cerexa/Actavis/Allegan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Investigator, Grant recipient, Research support and Salary. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient. Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Achaogen: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Arsanis: Consultant, Consulting fee. Affinergy: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cerexa: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. Grifols: Consultant, Consulting fee. Medicines Co.: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Novadigm: Consultant, Consulting fee. Theravance: Consultant, Consulting fee and Speaker honorarium. xBiotech: Consultant, Consulting fee. Green Cross: Consultant, Speaker honorarium. T. L. Holland, CTTI: Investigator and Scientific Advisor, Research support and Salary.

2379. Multicenter Evaluation of Ceftazidime–Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

BackgroundThe increasing prevalence of multidrug-resistant (MDR) Gram-negative bacteria (GNB) represents an urgent public health threat. Ceftazidime–avibactam (CZA) is a novel cephalosporin/β-lactamase inhibitor with activity against MDR GNB including carbapenem-resistant Enterobacteriaceae (CRE). Real-world experience with CZA in the treatment of MDR GNB is accumulating but remains limited by the small number of patients thus far described. We sought to build upon prior reports by describing the clinical characteristics and outcomes of a diverse cohort of patients with MDR GNB infections treated with CZA.MethodsRetrospective, multicenter, cohort study of patients treated with CZA (≥72 h) for suspected or confirmed MDR GNB (resistant to ≥1 antibiotic in ≥3 classes) infections between 2015 and 2018. The primary outcome was clinical failure defined as a composite of 30-day mortality, 30-day recurrence, or worsening signs and symptoms while on CZA. Independent predictors of clinical failure were sought through multivariable logistic regression analysis.ResultsA total of 114 patients were included. The median (IQR) age was 65 (53, 74), the median Charlson Comorbidity Index was 4 (2, 6), and the median APACHE II score was 20 (14, 28). CRE and MDR Pseudomonas aeruginosa were isolated in 74 (66%) and 31 (28%) of cases, respectively. The predominant sources were respiratory (40%) and urinary tract (20%). Blood cultures were positive in 10% of cases. Combination therapy (≥48 h) was used in 40%. Among carbapenem-resistant Klebsiella pneumoniae (n = 34), 97% were susceptible to CZA. The resistant isolate was positive for NDM and OXA. Clinical failure, 30-day mortality, and recurrence were 28%, 13% and 5%, respectively. Independent predictors of clinical failure were immune compromise (aOR 6.25, 95% CI 1.30, 30.11), Glasgow Coma scale ≤ 12 (aOR 3.76, 95% CI 1.30, 10.88), primary bacteremia or respiratory source (aOR 2.96, 1.07–8.17) and age less than 65 (aOR 2.87, 95% CI 1.09, 7.61).ConclusionThe use of CZA was associated with a clinical failure rate of 28% which compares favorably with historical controls of MDR GNB infections. Future investigations evaluating long-term outcomes and comparative studies are needed to more precisely define the role of CZA in MDR GNB infections.Disclosures S. L. Davis, Achaogen: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee. Nabriva: Scientific Advisor, Consulting fee. Zavante: Scientific Advisor, Consulting fee. M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

289. International Validation of a Methicillin-Resistant Staphylococcus aureus (MRSA) Risk Assessment Tool for Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

BackgroundAnti-MRSA antibiotic under- and overprescribing for ABSSSI is common. To address this, we previously developed an MRSA risk assessment tool using prior literature and patient data from a single health system in Detroit, Michigan, USA. The objective of this study was to validate this risk assessment tool internationally.MethodsMulticenter, international, prospective cohort study. Inclusion: age ≥ 18 y; purulent ABSSSI from July 2016 to March 2018. Exclusion: no culture; osteoarticular infection; bite wounds; odontogenic infections. Patient MRSA risk scores were computed using the following criteria (point value): previous MRSA infection/colonization (2); previous hospitalization (1); previous antibiotics (1); chronic kidney disease (1); intravenous drug use (1); HIV/AIDS (1); diabetes with obesity (1). The likelihood ratio of each patient’s score was used to convert local surveillance MRSA percentage (prior probability) into an individual patient estimated MRSA probability (posterior probability). The predictive performance of local surveillance MRSA percentage, MRSA risk score, and estimated MRSA probability were quantified using the area under the Receiver Operating Characteristic curve (aROC) and compared using the Hanley and McNeil method.Results203 patients from 7 international sites included. The most common infection types were wound (28.6%), abscess (25.1%), and cellulitis with an abscess (20.7%). MRSA was observed in 33% of patients and ranged from 10% in Beijing, CN to 58.8% in Mexico City, MX. MRSA was significantly more prevalent among patients with higher MRSA risk scores (Figure 1). The MRSA risk score aROC (95% CI) [0.748 (0.678–0.819)] was significantly greater than local surveillance MRSA percentage [0.646 (0.569–0.722)] (P = 0.016). The estimated MRSA probability aROC [0.781 (0.716–0.845)] was significantly greater than local surveillance MRSA percentage (P < 0.001) but not the MRSA risk score (P = 0.192). ConclusionThe MRSA risk score and estimated MRSA probability were significantly more predictive of MRSA ABSSSI compared with local MRSA surveillance percentage. Further study, including potential impact of this MRSA risk assessment tool on prescribing patterns are required before widespread application.Disclosures K. Claeys, Nabriva: Scientific Advisor, Consulting feeMelinta: Scientific Advisor, Consulting fee. M. Dryden, Motif BioSciences: Board Member, Consulting fee. M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

2381. Ceftolozane/Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains With Genetically Defined Resistance

Background Pseudomonas pneumonia is a life-threatening infection with high mortality, particularly in neutropenic patients. The efficacy of current antimicrobial therapy with extended spectrum penicillins (ESPs) and anti-pseudomonal cephalosporins (ASCs) is limited by emergence of resistance. Ceftolozane/tazobactam is a novel cephalosporin with in vitro activity against isolates of Pseudomonas aeruginosa that are resistant to ESPs and ASCs. In order to assess the antimicrobial effect of ceftolozane/tazobactam in treatment of Pseudomonas pneumonia, we investigated this new agent in the treatment of experimental Pseudomonas pneumonia in persistently neutropenic rabbits infected with different strains of genetically defined mechanisms of resistance.Methods Pseudomonas pneumonia was established in a rabbit model by direct endotracheal inoculation of P. aeruginosa 1 × 108–109 CFUs for tracheobronchial colonization that evolves into bronchopneumonia. Four treatment groups were studied: ceftolozane/tazobactam, ceftazidime (CTZ), piperacillin/tazobactam (TZP), and untreated controls (UC). Rabbits were dosed IV to achieve humanized doses of ceftolozane/tazobactam 3g (2g/1g) Q8h, CTZ 2g Q8h, and TZP 4.5g Q8h. Four isolates of P. aeruginosa were studied: pan-susceptible (PS), OPRD porin loss (OPRDPL), efflux pump expression (EPE), and AmpC hyperexpression (ACHE). Profound, persistent neutropenia was maintained with cytosine arabinoside and methylprednisolone. Treatment was continued for 12 days.ResultsTreatment with ceftolozane/tazobactam resulted in ≥105 reduction in residual pulmonary bacterial burden caused by all 4 strains (P ≤ 0.01). This antibacterial activity coincided with reduction of lung weight (P < 0.05), which is a marker of organism-mediated pulmonary injury. CTZ was less active in ACHE-infected rabbits, while TZP had less activity in EPE, ACHE, and OPRDPL strains. Survival was prolonged in ceftolozane/tazobactam and CTZ treatment groups in comparison to that of TZP and UC (P < 0.001).ConclusionCeftolozane/tazobactam is highly active in treatment of experimental P. aeruginosa pneumonia in persistently neutropenic rabbits, including infections caused by strains with the most common resistant mechanisms.Disclosures C. A. DeRyke, Merck: Employee, Salary. D. L. Culshaw, Merck: Employee, Salary. L. Caro, Merck: Employee and Shareholder, Salary and stock options. M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Achaogen: Consultant, Consulting fee. T. J. Walsh, Merck: Grant Investigator, Research grant. Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Scynexis: Grant Investigator, Research grant. Amplyx: Grant Investigator, Research grant. Shionogi: Scientific Advisor, Consulting fee.

1227. Development of a Clinical Prediction Model for Mortality in Methicillin-Resistant Staphylococcus aureus Bacteremia

BackgroundMethicillin-resistant Staphylococcus aureus bloodstream infection (MRSA BSI) is associated with high mortality despite advances in medical care. Mortality prediction may have a profound impact on clinical decision making and risk stratification. Widely used scoring systems such as the Acute Physiology and Chronic Health Evaluation (APACHE) II Score and the Pitt Bacteremia Score were derived in the general critical care and Gram-negative BSI populations, respectively and may be less precise in MRSA BSI. We sought to develop a predictive model (PM) for 30-day mortality in patients with MRSA BSI based on characteristics readily assessable at initial evaluation.MethodsRetrospective, singe-center, cohort study in adults with MRSA BSI 2008 to 2018. Patients who did not receive active therapy within 72 hours of index culture were excluded. Independent baseline demographic, clinical and infection predictors of 30-day mortality were identified through multivariable logistic regression analysis with bootstrap resampling and coefficient shrinkage. The PM was derived using a regression coefficient-based scoring method. PM discriminatory ability was assessed using the c-statistic. The optimal threshold score was determined using the Youden Index (J).ResultsA total of 455 patients were included and 30-day mortality was 16.3%. The PM consisted of five variables and a potential total score of 33. Points were assigned as follows: age (9 points ≥90 years, 6 points 80–89 years, 5 points 70–79 years, 0 points <70 years); Glasgow Coma Scale (8 points ≤9, 5 points 10–13, 0 points ≥14); 7 points infective endocarditis or pneumonia; 5 points serum creatinine ≥ 3.5 dl/L; and four points respiratory rate <10 or >24. The PM c-statistic was 0.860 (95% CI 0.818, 0.902). The PM score with the maximum J value was 13. Thirty-day mortality was 5.2% vs. 44.5% for PM score <13 vs. ≥13 points, respectively (P < 0.001). The sensitivity, specificity, positive predictive value (PV), negative PV, and accuracy using a threshold of 13 points were 77.0%, 81.4%, 44.5%, 94.8%, and 80.7%, respectively.ConclusionOur findings demonstrate a weighted combination of five independent variables readily assessable at initial evaluation can be used to predict, with high discrimination, 30-d mortality in MRSA BSI. External validation is required before wide-spread clinical use.Disclosures M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research supportTheravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

2391. Liposomal Vancomycin and Cefazolin Combinations for S. aureus Biofilms

BackgroundBiofilms are sophisticated communities of matrix-encased and surface-attached bacteria that exhibit a distinct and specific resistant/tolerant phenotype to almost all antibacterial agents, with activity reduced 10- to 1,000-fold. Interestingly, this augmented resistance rapidly reverts when bacteria detach from the biofilm and return to a planktonic state. However, in this in vitro pharmacokinetic and pharmacodynamic (PK/PD) model we are able to expose biofilms to shear rates that are consistent with human interface and mimic antibiotic penetration and diffusion pathways from serum antibiotic concentration in humans.MethodsMethicillin-susceptible ATCC 29213 and MRSA 494 strains were evaluated. Initial susceptibility tests were performed by broth microdilution method. Time kill studies were performed to identify synergy patterns for liposomal and commercial antibiotics. Biofilm eradication was investigated using antibiotics vancomycin (VAN) (commercial) vs. liposomal VAN (VAN-L) (Patent#17-1460) and also combination of VAN- cefazolin (commercial) vs. liposomal vancomycin and liposomal cefazolin (CFZ-L) (Patent# 17-1460) in biofilms for strain MRSA 494. Biofilms were generated overnight using the BioFlux Microfluidic system (Fluxion BioSciences) at constant and continuous shear rates to optimize biofilm attachment and creation. Perfusion of antibiotic solutions (free peak concentration) was applied over a 24 h time period. Time lapse pictures were recorded to determine antibiotic biofilm eradication rates over 18h of incubation and pictures were analyzed using Bioflux Montage software.ResultsMIC values demonstrated a 2-fold reduction for liposomal vancomycin vs. commercial vancomycin. Also, combination of liposomal VAN MIC in presence of CFZ-L showed a 15.87-fold reduction in comparison to commercial VAN for 494. Overall, our biofilm results demonstrated a 43.6% improved eradication using VAN-L and CFZ-L combination in comparison to commercial VAN-CFZ combination. We also observed 5.7% improved eradication using VAN-L vs. commercial VAN.ConclusionLiposomal form of VAN and CFZ combinations are a promising approach to improved efficacy and reduced VAN resistance in S. aureus biofilms.Disclosures M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

2433. Evaluation of Meropenem (MEM) in Combination With Colistin (COL) Against Colistin-Resistant Extensively Drug-Resistant (XRD) Gram-Negative Bacteria

BackgroundThe treatment of XDR Gram-negative bacilli poses a significant clinical challenge with limited treatment options. Colistin-resistant XRD Gram-negative bacteria are becoming more commonplace in the clinical setting. Combination therapy is resorted to for treatment of such strains. The objective of this in-vitro study was to evaluate the synergistic effect of the combination with COL and MEM against Colistin-resistant XDR Gram-negative bacilli.MethodsIn this study, a total of 30 Colistin-resistant XDR Gram-negative clinical isolates were evaluated, including five isolates of Pseudomonas aeruginosa, twenty-four isolates of Acinetobacter baumannii and one isolate of Klebsiella pneumonia. Minimum inhibitory concentrations (MICs) were determined with COL and MEM for each strain by broth microdilution. COL and MEM MICs were measured in the presence of 0.25- to 0.5- × the MIC of the other antibiotic to determine the ability to lower MIC values. Time-kill assays were performed with each agent alone and in combination to evaluate the potential for synergistic interactions. Additive and synergistic effects were defined as 1- to 2-log10 and ≥ 2-log10 reductions in CFU/mL from the most active single agent at 24 hours, respectively.ResultsAll isolates were resistant to COL (MIC90 32 mg/L), whereas all bacteria with except one A. baumannii, were resistant to MEM (MIC90 >64 mg/L). Zero- to greater than nine-fold decrease in MEM MICs were observed in combination with COL at 0.25- to 0.5 × MIC. COL MICs decreased by 0 to >8-fold when combined with MEM. MEM plus COL demonstrated synergistic activity against 70% strains tested and additive in 3% of the tested strains at 24 h in time-kill. The combination was indifferent in 26% of the tested strains.ConclusionThese data indicate that the addition of MEM to COL therapy in colistin resistant XDR Gram-negative bacteria demonstrate synergistic or additive effects against a majority of XDR Gram-negative bacteria. The combination might be a promising therapeutic option for treatment of these problem pathogens.Disclosures M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.