bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Phenotypic Antibiotic Susceptibility Testing Through RNA Detection
Authors: Bhattacharyya Roby , Liu Jamin , Ma Peijun , Bandyopadhyay Nirmalya , Livny Jonathan , Hung Deborah
Published: October 2017

Background

Culture-based antibiotic susceptibility testing, the gold standard, is too slow to guide early antibiotic selection, while newer genotypic methods require comprehensive knowledge of resistance mechanisms to predict phenotype. Quantitative measurement of key antibiotic-responsive transcripts offers a rapid, phenotypic assay for assessing antibiotic susceptibility, agnostic to the genetic basis for resistance.

Methods

We performed RNA-Seq on Klebsiella pneumoniae and Acinetobacter baumanii treated with ciprofloxacin, gentamicin, or meropenem for 0, 10, 30, and 60 minutes. For each, we identified 50 responsive transcripts whose expression levels differ most between susceptible and resistant organisms upon antibiotic exposure. We measured their expression using a multiplexed fluorescent RNA hybridization assay (NanoString) in 69 clinical isolates, including a “test set” of multidrug-resistant strains from the CDC, in an 8-hour assay. Gene expression data from test strains were compared against known susceptible and resistant isolates to generate a transcriptional susceptibility metric. We also designed NanoString probes to detect 5 carbapenemase genes (KPC-2, KPC-3, NDM-1, OXA-48, and CTX-M15).

Results

Across all bacteria-antibiotic pairs tested, a susceptibility metric derived from these transcriptional assays correctly grouped isolates in 167 of 173 tests (Table 1), with only 1 of 88 resistant isolates misclassified as susceptible. Five of six incorrectly grouped isolates were within one dilution of the breakpoint MIC, including the misclassified resistant isolate.

Conclusion

We demonstrate phenotypic antibiotic resistance detection based on fluorescent RNA detection in an 8-hour assay. We have previously published proof-of-concept studies that this assay may be run on a positive blood culture bottle with minimal sample processing. By coupling this phenotypic assay with detection of genetic resistance determinants (demonstrated for carbapenemases) in a single assay, strains with unexplained resistance can be prioritized for further study.

Disclosures

All authors: No reported disclosures.
Defining Aerosol Generating Procedures and Pathogen Transmission Risks in Healthcare Settings
Authors: Li Jiayu , Leavey Anna , Yang Wang , O’Neil Caroline , Wallace Meghan , Boon Adrianus , Biswas Pratim , Burnham Carey-Ann D , Babcock Hilary M
Published: October 2017

Background

Questions remain about the degree to which small particle aerosols are generated during patient care activities and whether such aerosols could transmit viable pathogens to healthcare personnel. This project measured aerosol production during common medical procedures and collected samples for pathogen recovery.

Methods

Six procedures were targeted for aerosol sampling: extubation, bronchoscopy, mechanical ventilation, noninvasive ventilation, suctioning (open or tracheostomy), and nebulized medication administration. Any patient undergoing one of these procedures was eligible for sampling, with a preference for patients with a respiratory viral infection. Baseline samples were collected when possible. Four real-time aerosol characterization instruments were used to detect small particle aerosols generated during procedures. SKC Biosamplers, placed at 3 feet and 6 feet from the patient, were used for pathogen recovery. All samples were subjected to bacterial culture; viral PCR, and viral culture were added depending on the patient’s respiratory disease profile.

Results

Samples were collected during extubation (n = 1), bronchoscopy (n = 3), mechanical ventilation (n = 13), noninvasive ventilation (n = 6), suctioning (n = 6), and nebulized medication administration (n = 9). Only nebulized medication administration exhibited differences in particle mass concentration between baseline and procedure aerosol measurements. None of the Biosampler samples were PCR positive for a respiratory virus and none had a positive influenza culture. Five samples had positive bacterial cultures, mainly with common environmental or skin contaminants such as Micrococcus luteus, Staphylococcus pasturei, and Bacillus flexus.

Conclusion

Significant small particle aerosol generation was only seen with nebulized medication administration. No viruses were recovered and minimal viable bacteria were recovered. Additional study is needed to confirm these findings and examine aerosol generation during other procedures commonly considered to be aerosol-generating.

Disclosures

C. A. D. Burnham, bioMerieux: Grant Investigator, Research grant; ThermoFisher: Consultant, Salary; Cepheid: Grant Investigator, Research grant
Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1
Authors: Emu Brinda , Fessel W Jeffery , Schrader Shannon , Kumar Princy N , Richmond Gary , Win Sandra , Weinheimer Steven , Marsolais Christian , Lewis Stanley
Published: October 2017

Background

Management of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment.

Methods

TMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks.

Results

A total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL <50 copies/ml and 17 (63%) patients had VL < 200 copies/ml. All 15 patients with VL < 50 copies/ml at Week 24 maintained viral suppression to Week 48.

Conclusion

IBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients.

Disclosures

B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner
Association Between Patient Portal Access and Viral Suppression Among People Living with HIV in a Large Southeastern Clinical Cohort
Authors: Scott Sarah , Jenkins Cathy , Rebeiro Peter , Turner Megan , Bebawy Sally , Bofill Carmen , Yan Zhou (Ellen) , Jackson Gretchen , Pettit April
Published: October 2017

Background

Viral suppression (VS) among people living with HIV (PLWH), the goal of the HIV care continuum, leads to improved patient outcomes and decreased HIV transmission. Patient portals are online tools that enable patient interaction with healthcare systems and may increase patient engagement and improve health outcomes. We examined whether portal access was associated with VS among PLWH.

Methods

We conducted an observational cohort study among PLWH aged ≥18 years who had ≥1 HIV healthcare provider visit at the Vanderbilt Comprehensive Care Clinic (Nashville, Tennessee) from January 1, 2011–December 31, 2015. Patient portal access was defined as being registered for a portal account at any point in the year prior. VS was defined as having ≥1 viral load (VL) measured and the last VL ≤200 copies/ml within a given year. The adjusted relative risk (aRR) of VS was estimated with modified Poisson regression and robust standard errors for multiple outcomes per individual. Models were adjusted for all covariates in the Figure and for year since first kept appointment. Missing data were multiply imputed.

Results

The study population included 4,237 PLWH; median age was 43 years (IQR 33–50), 78% were male, 41% were black, and 60% reported male–male sexual contact (MSM). Of the 57% who had portal access during the study period, median age was 42 years (IQR 31–49), 86% were male, 30% were black, and 75% were MSM. In adjusted analysis, portal access was independently associated with improved VS (aRR = 1.19, 95% CI 1.16–1.21 vs. no portal access) (Figure). Increasing age and sexual contact (vs. injection drug use) remained associated with improved VS; black race (vs. white race), lower socioeconomic status, and higher baseline VL remained associated with poor VS after accounting for portal access (Figure).

Conclusion

Portal access was independently associated with improved VS, although sociodemographic disparities in VS persisted. Additionally, there were sociodemographic disparities in patient portal access. There may be important unmeasured confounders such as health literacy and educational attainment. Additional prospective studies are needed to determine whether patient portal access leads to improved VS among PLWH.

Disclosures

P. Rebeiro, NIH: Grant Investigator, Research grant; G. Jackson, Vanderbilt Center for Effective Health Communication: Grant Investigator, Research grant; Agency for Healthcare Research and Quality: Grant Investigator, Research grant; American Medical Informatics Association: Board Member, Research support; A. Pettit, NIH/NIAID - K08AI104352: Grant Investigator, Research grant
Performance of NS3, NS5a AND NS5b Hepatitis C Virus (HCV) Antiviral Resistance Sequencing Assays
Authors: Nutt Jamie , Grantham James , Smith Marilyn , Smith Emily , Wedin Ashley , Tyler Aaron , Miralles Mauricio , Kleiboeker Steve , Wissel Mark
Published: October 2017

Background

HCV genotype 1a (HCV g1a) followed by HCV g1b, –g2, and –g3 are the most common etiologic agents in the ~3 million current HCV-infections in the US. To achieve effective therapy, antiviral drug resistance testing is often essential but not fully available. Knowledge of both the genotype and the presence of HCV mutations in the genes of the major drug targets (NS3, NS5A and NS5B) can assist in optimal treatment selection.

Methods

The HCV genotype of 1000 HCV positive clinical plasmas and sera was determined (HCVg Direct, GenMark). Ten independent Sanger sequencing assays detecting antiviral drug resistance mutations in the genes encoding NS3, NS5a, and NS5b were developed. Six of these assays address mutations in all three genes in the two most common genotypes (HCV g1a and g1b). In addition, four more assays address mutations in NS5a and NS5b of HCV g2 and g3. These mutations are resistance determinants against 11 anti-HCV drugs as shown in Figure 1. A streamlined workflow employs conventional reverse transcriptase PCR, gel electrophoresis, spectrophotometry, bi-directional Sanger sequencing and reporting. The assays were designed to cover hot spot regions and capturing all known resistance mutations in NS3, NS5a and NS5b.

Results

Consistent with previous US HCV incidence reports, g1a, g1b, g2, and g3 comprised 99% of 1000 sequentially tested HCV patient specimens (62%, 12%, 11%, and 14%, respectively). Testing of more than 20 clinical samples each for g1a, g1b, g2, and g3 resulted in successful detection of NS3, NS5a, and NS5b mutations that confer drug resistance. The design successfully permitted detection of relevant mutations known to date for all 11 drugs. The number of reportable mutations range from 20 ‒ 36, 9 ‒ 49, and 10 ‒ 29 for the NS3, NS5a, and NS5b inhibitors, respectively (Figure 1).

Conclusion

These assays provide the most comprehensive commercially available antiviral drug resistance information to date for mutations in HCV NS3, NS5A, and NS5B. This testing will assist physicians in deciding on the most appropriate treatment options for their patients.

Disclosures

J. Nutt, Viracor Eurofins Laboratories: Employee, Salary;  J. Grantham, Viracor Eurofins Laboratories: Employee, Salary; M. Smith, Viracor Eurofins Laboratories: Employee, Salary; E. Smith, Viracor Eurofins Laboratories: Employee, Salary; A. Wedin, Viracor Eurofins Laboratories: Employee, Salary;  A. Tyler, Viracor Eurofins Laboratories: Employee, Salary; M. Miralles, Viracor Eurofins Laboratories: Employee, Salary; S. Kleiboeker, Viracor Eurofins Laboratories: Employee, Salary; M. Wissel, Viracor Eurofins Laboratories: Employee, Salary
Comparison of 30- and 90-Day Mortality Rates in Patients with Cultures Positive for Carbapenem-resistant Enterobacteriaceae and Acinetobacter in Atlanta, 2011–2015
Authors: Sexton Mary Elizabeth , Bower Chris , Sukumaran Stephen , Jacob Jesse T
Published: October 2017

Background

Carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii (CRAB) pose a threat to public health, but comparisons of disease burden are limited. We compared survival in patients following cultures positive for CRE or CRAB.

Methods

The Georgia Emerging Infections Program performs active population-based and laboratory-based surveillance for CRE and CRAB in metropolitan Atlanta, GA. Using standard CDC definitions, we included patients who had incident carbapenem-nonsusceptible E. coli, Klebsiella spp., Enterobacter spp., or Acinetobacter baumannii isolated from urine only (noninvasive infection) or a sterile site (invasive infection) between 8/2011 and 12/2015. Death dates, verified by Georgia Vital Statistics records, were used to calculate 30- and 90-day mortality rates. We used the chi-square test for mortality rates and the log-rank test for survival analysis to 90 days to compare patients with invasive CRAB, noninvasive CRAB, invasive CRE, and noninvasive CRE.

Results

There were 535 patients with CRE (87 invasive, 448 noninvasive) and 279 (78 invasive, 201 noninvasive) with CRAB. Nearly all patients with CRE and CRAB had healthcare exposures (97.2% vs. 100%) and most were immunosuppressed (62.6% vs. 56.3%). Both 30-day (24.4% vs. 18.3%, p = 0.04) and 90-day (37.6% vs. 30.5%, p = 0.04) mortality were higher in patients with CRAB than CRE. Patients with invasive infections were more likely to die at 90 days than those with noninvasive infections (53.3% vs. 38.4%, p < 0.0001). Overall mortality rates for invasive infection were similar between CRAB and CRE at 30 (44.9% vs. 34.5% p = 0.2) and 90 days (59.0% vs. 48.3%, p = 0.2). Using survival analysis at 90 days, invasive CRAB had the worst outcomes, followed by invasive CRE, noninvasive CRAB and noninvasive CRE  (p < 0.0001, see Figure).

Conclusion

Ninety -day mortality for invasive infections with CRE and CRAB was ~50%, and patients with CRAB had lower survival than those with CRE, suggesting that prevention efforts may need to prioritize CRAB as highly as CRE in facilities with endemic CRAB. With the high proportion of healthcare exposures and immunosuppression, these infections may signify poor prognosis or directly contribute to mortality.

Disclosures

All authors: No reported disclosures.
Differences in Pre- and Post-dischcarge Methicillin-resistant Staphylococcus aureus (MRSA) infection rates by colonization status in US Department of Veterans Affairs (VA) hospitals
Authors: Nelson Richard E , Evans Martin , Jones Makoto , Samore Matthew , Kralovic Stephen , Roselle Gary , Rubin Michael
Published: October 2017

Background

Little is known about how MRSA infection rates differ between patients who are colonized on admission compared with those who acquire colonization during an inpatient stay. In addition, most studies focus on MRSA infections that are diagnosed prior to discharge while ignoring those that are identified post-discharge. The VA implemented an active surveillance program for MRSA in 2007 in which all inpatients are tested for MRSA on admission. This surveillance data along with the ability to follow patients longitudinally allowed us to estimate the difference in infection rates for those who import vs. those who acquire  MRSA colonization during their stay and to characterize post-discharge MRSA infections.

Methods

We constructed a dataset of 3,659,911 acute care inpatient admissions to 125 VA hospitals nationwide between January 1, 2008 and December 31/2015 who had surveillance tests performed for MRSA carriage. Admissions were restricted to individuals with at least 365 days of VA activity prior to admission. We categorized these admissions into 3 groups: no colonization, importation, and acquisition based on MRSA test results throughout the admission. We then captured MRSA infections in these individuals prior to discharge and at 30 and 90 days post-discharge. Infections were defined as positive MRSA cultures taken from sterile sites (including blood, catheter site, or bone).

Results

During the 8-year period, we identified 4,037 total pre-discharge MRSA infections, 2,793 MRSA infections at 30 days post-discharge, and 7,018 infections at 90 days post-discharge. During the pre-discharge time period, patients who acquired MRSA carriage were more likely to progress to an infection prior to discharge than those who imported the pathogen (RR = 2.6, P < 0.001). For patients who acquired MRSA carriage, the percentage who progressed to infection prior to discharge decreased from 2.0% in 2010 to 1.4% in 2015. The results from our analyses can be found in Figures 1–3.

Conclusion

We found that roughly half of post-discharge infections were in patients who acquired the organism pre-discharge. These may be preventable with optimal infection control. In addition, there were nearly twice as many post-discharge MRSA infections at 90 days than during the pre-discharge period.

Disclosures

All authors: No reported disclosures.
Investigating Immune Correlates of Protection to Tuberculosis Using an Ultra-Low Dose Infection in a Mouse Model
Authors: Gern Benjamin , Plumlee Courtney , Gerner Michael , Urdahl Kevin
Published: October 2017

Background

Mycobacterium tuberculosis (M.tb) is the leading infectious cause of mortality; however, there is no vaccine that confers lasting protection. To investigate the immune response to M.tb, we have developed an ultra-low dose (ULD) infection model in mice that better reflects the heterogeneous outcomes of human infection. Additionally, we have identified a blood transcriptional signature, taken at day 24, that predicts future bacterial burden after day 70.

Methods

Mice were infected with an ULD (1–3 CFU) of H37Rv M.tb. Control mice were infected with 50–100 CFU. Blood was drawn at day 24 for RNA signature. At early (day 34–35), and late (day 82–83) time points, mice were injected with an intravascular label. Individual lungs were then assessed for bacterial burden, phenotypic and spatial analysis of immune cells by flow cytometry, and histocytometry, a type of immunohistochemistry that allows for imaging of >12 colors

Results

At day 35, the following cell populations were correlated with an RNA signature score predicting disease progression: ESAT-6 tetramer+ CD4+ T cells (R2 = 0.35, P < 0.01), TB10.4 tetramer+ CD8+ T cells (R2 = 0.34, P < 0.01), and B cells (R2 = 0.28, p = 0.01) within the lung parenchyma, as well as CD11b+ cells, negative for CD64, Ly6c, Ly6g and MHCII (R2 = 0.38, p < 0.01) within the lung vasculature. These same populations were correlated with elevated CFU at day 83, as well as dendritic cells (R2 = 0.53, p < 0.01). No populations were correlated with a protective RNA score. We have observed the complex spatial organization of granulomas while optimizing our histocytometry panel. This includes infected macrophages (Fig 1) interdigitated with B cell aggregates, associated with naïve T cells, interspersed with CD44+ T cells, with diffuse staining for Ki67, suggestive of tertiary lymphoid structures (Figure 2).

Conclusion

This model replicates heterogeneity of TB seen in humans, while also providing a way to correlate differences in the immune response to future outcome. We have associated distinct immune cell subsets with the failure to control TB. With a larger sample size and data from histocytometry, we will have improved resolution to discern protective elements of the immune response to TB, which we can then test mechanistically in our model.

Disclosures

All authors: No reported disclosures.
Interferon gene expression as marker of immune maturation and response to vaccination
Authors: Cao Raquel Giacomelli , Smith Bennett , Bunsow Eleonora , Heinonen Santtu , Mertz Sara , Ye Fang , Best Victoria , Klis Fiona Van Der , Smits Gaby , Mejias Asuncion , Ramilo Octavio
Published: October 2017

Background

Interferons (IFN) play a major role in regulating innate and adaptive immune responses. Studies in adults and older children demonstrated significant correlations between IFN gene expression and antibody responses to influenza vaccines. However, there is still an incomplete understanding of the role of IFN in the ontogeny of the infant immune system and how they affect the immune response to vaccines in this population. Our objective with this study is to define longitudinal age-related changes in interferon gene expression and the changes induced by routine vaccinations.

Methods

We enrolled 2 cohorts of healthy children: 81 children aged < 2 years evaluated at one-time point to assess age-dependent changes in IFN gene expression; and 47 < 1 year olds evaluated at three times, before vaccination (day (d) 0) and d7 and d30 post-vaccination. Peripheral blood samples were collected to measure: (a) immune transcriptional profiles by microarrays; (b) immune cell populations by flow cytometry, and (c) antibody titers to PCV13, Hib and DTaP in the vaccination cohort.

Results

Analysis of first cohort demonstrated significant underexpression of IFN genes (n = 120) in infants aged <6 months compared with those 12–24 months. By 9 months IFN expression was similar to the older children. IFN gene expression correlated with the numbers of neutrophils and monocytes across all age groups. The second cohort was evaluated at three time points (d0, d7, and d30) during routine vaccinations at 2, 6, and 12 months. We compared transcriptional profiles post-vaccination with d0 for each group and observed consistent overexpression of IFN-related genes at d7 in the three age groups. In 2-month-old infants, we observed significant correlations between IFN genes (TAP1, IFIT1/2/3, OASL and GBP1) at d0 (before vaccination) and increase in antibody titers of the three vaccines analyzed (r = 0.5–0.7; P < 0.05). Among the top 15 genes who have the most significant correlations, eight are exclusively induced by type I IFN, six by type II IFN, and one is shared between the two types.

Conclusion

IFN gene expression at baseline is markedly reduced in infants <6 months. Routine vaccines were associated with marked increased in IFN gene expression at 2, 6, and 12 months. Baseline IFN expression at 2 months correlated with antibody responses to vaccines.

Disclosures

O. Ramilo, Abbvie: Board Member, Consulting fee; Regeneron: Board Member, Consulting fee; Janssen: Board Member and Investigator, Consulting fee and Research grant; NIH: Grant Investigator, Research grant
Colorado’s Statewide Antimicrobial Stewardship (AMS) Collaborative Final Results. Facilitating Syndrome-Specific Interventions for Skin and Soft-tissue Infection (SSTI) and Urinary Tract Infection (UTI)
Authors: Wald Heidi , Hulett Teri , Knepper Bryan , Barber Gerard , Shihadeh Kati , Meyer Marc , Hammer John
Published: October 2017

Background

Colorado Hospital Association (CHA) led a statewide collaborative to engage hospitals in AMS, focused on interventions for UTI and SSTI. The collaborative goals were to reduce the use of fluoroquinolones (FQs) for UTIs, increase the proportion of diagnosed UTIs meeting objective criteria, reduce exposure to antibiotics with broad Gram-negative activity for SSTI, and shorten treatment durations for UTI and SSTI. We evaluated the effect of the collaborative on these measures.

Methods

Diagnostic (UTI) and treatment guidance (UTI and SSTI) were developed by a local expert panel. Collaborative methodology was used to engage local hospital AMS teams in guideline implementation. Teams submitted data for 80 cases during the baseline period (2014) and 20 cases per quarter during the intervention period (October 2015–December 2016) for each condition. Primary analyses were changes in trends of the main outcomes by interrupted time series analysis. Secondary analyses were the aggregate changes in the main outcomes between the baseline and intervention periods.

Results

Twenty-seven acute care hospitals (bed range 15–567) participated in the collaborative. Data were reported for 1,530 UTI and 722 SSTI cases from the baseline period and for 2,514 UTI and 1,030 SSTI cases from the intervention. Interrupted time series analyses of the main outcomes are shown in Figure. The trend in exposure to FQs for UTIs decreased significantly from baseline to the intervention (P = 0.03). Changes in the trends for the other outcomes did not reach statistical significance. In the secondary analyses, exposure to FQs declined from 49% at baseline to 40% during the intervention (UTI), and the proportion of diagnosed UTIs meeting objective criteria increased from 51% to 54% (P = 0.10). Among SSTI cases, exposure to antibiotics with broad Gram-negative activity declined from 61% to 53% (P = 0.001), and the median duration of therapy declined from 13 to 11 days (P < 0.0001).

Conclusion

A statewide collaborative successfully engaged hospitals to participate in AMS. Intended changes in prescribing practices for the collaborative were observed; however, the degree of success varied by outcome. Additional work is needed to explore factors associated with success or lack thereof among the individual hospitals.

Disclosures

H. Wald, Colorado Hospital Association: Consultant, Consulting fee; T. Hulett, Colorado Hospital Association: Consultant and Employee, Salary; G. Barber, Merck: Speaker’s Bureau, Speaker honorarium
Measles CEA
Authors: Hyle Emily
Published: October 2017

Background

Most measles importations are due to returning US travelers infected during international travel. We projected clinical outcomes and assessed cost-effectiveness of pretravel evaluation for measles immunity and MMR vaccination among eligible adult US international travelers.

Methods

We designed a decision tree to investigate pretravel evaluation compared with no evaluation from the societal perspective. Data from the Global TravEpiNet Consortium and published literature informed input parameters (Figure 1). Outcomes included measles cases averted per 10 million travelers, costs, and the incremental cost-effectiveness ratio (ICER, Δcosts/Δmeasles cases averted); we considered ICERs < $100,000/measles case averted to be cost-effective. We performed sensitivity analyses to assess the impact of varying the probability of exposure based on travel destination, and the percentage of travelers with pre-existing measles immunity.

Results

In the base case, departure after pretravel evaluation resulted in 16 measles importations and 46 transmissions per 10 million travelers and cost $132 million, vs without pretravel evaluation (26 importations and 87 transmissions per 10 million travelers, costing $22 million). Pretravel evaluation averted 51 measles cases per 10 million travelers with an ICER of $2.2 million per case averted. Results were most sensitive to the probability of measles exposure and the traveler’s pre-existing immunity (Figure 2). Pretravel evaluation was cost-effective for travelers to Asia if pre-existing measles immunity was <80%. Evaluation was always cost-effective for travelers to Africa when pre-existing immunity was less than 100% and became cost saving when the percentage of immune travelers was lower (<70%). Travelers who were more likely to be non-immune and were visiting destinations with higher probabilities of exposure were most likely to benefit from pretravel evaluation for measles immunity at excellent economic value.

Conclusion

As risk of measles exposure increases and likelihood of travelers’ pre-existing immunity decreases, it can be cost-effective or cost saving to assess US international travelers’ measles immunity status and vaccinate with MMR prior to departure.

Disclosures

All authors: No reported disclosures.
Analysis of Invasive Pneumococcal Infections Due to 13-Pneumococcal Conjugate Vaccine Serotypes at 8 US Children’s Hospitals During 2014 to 2016
Authors: Kaplan Sheldon L , Barson William J , Lin Philana Ling , Romero Jose R , Bradley John S , Tan Tina , Givner Laurence B , Hoffman Jill , Hulten Kristina , Mason Edward O
Published: October 2017

Background

The 13-Valent Pneumococcal Conjugate Vaccine (PCV13) was licensed in 2010 and is directed against serotypes (ST) 1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Details of cases of invasive pneumococcal disease (IPD) due to PCV13 ST since 2010 in the US are sparse. We describe IPD cases due to PCV13 ST seen at 8 US children’s hospitals over years 2014 to 2016 which may aid in understanding why some IPD cases due to these ST have persisted.

Methods

Children with IPD have been prospectively identified at 8 children’s hospitals in the US since 1993. Data from 2014 through 2016 were analyzed. Demographic, clinical data and number and dates of PCV doses were collected on case report forms and isolates were sent to a central laboratory for serotyping. PCV doses are counted if IPD occurred > 2 weeks after a dose.

Results

PCV13 ST accounted for 19.7% (27/137), 26.8% (30/112) and 26% (33/127) of IPD cases in 2014, 2015 and 2016, respectively. ST 3, 19A and 19F accounted for 90% of the PCV13 ST IPD cases. >50% of the children had received ≤2 doses of PCV13 prior to IPD. (Table) Of the 30 children with 0 doses of PCV, 15 were of an age at diagnosis for which ≥ 2 doses of PCV was recommended. An underlying condition was noted in 18. For PCV13 ST, the types of IPD were pneumonia (n = 39), mastoiditis (n = 15), bacteremia (n = 15), meningitis (n = 12) and other sites of infection (n = 9). Whereas the numbers of yearly cases were similar for ST3 (12, 10, 13) and ST19A (8, 10, 6), the numbers for 19F increased slightly (3, 8, 10).

Conclusion

Four to 6 years after PCV13 was introduced, PCV13 ST (especially ST 3, 19A and 19F) accounted for about 25% of IPD in children. For all of the PCV13 ST, over half of these IPD cases occurred in children who had received ≤ 2 doses of the recommended PCV schedule; 25% of cases occurred in children who had not received any doses but were of the age at diagnosis that at least 2 PCV doses should have been received. Additional PCV13 ST IPD cases may be preventable if the PCV13 schedule is followed as recommended.

Disclosures

S. L. Kaplan, Pfizer: Grant Investigator and Speaker at PCV13 Launch Meeting in China, Research grant and Speaker honorarium; J. S. Bradley, Merck & Co., Inc.: Investigator, Research support
Changes in Pneumonia Incidence and Infant Mortality 5 Years Following Introduction of the 13-valent Pneumococcal Conjugate Vaccine in a “3+0” Schedule in Nicaragua
Authors: Becker-Dreps Sylvia , Blette Bryan , Briceno Rafaela , Aleman Jorge , Hudgens Michael G , Moreno Gilberto , Ordonez Ana , Rocha Julio , Weber David J , Amaya Erick
Published: October 2017

Background

Streptococcus pneumoniae causes an estimated 826,000 deaths of children in the world each year and many health facility visits. To reduce the burden of pneumococcal disease, many nations have added pneumococcal conjugate vaccines to their national immunization schedules. Nicaragua was the first country eligible for funding from the GAVI Alliance to introduce the 13-valent pneumococcal conjugate vaccine (PCV13), provided to infants at 2, 4, and 6 months of age. The goal of this study was to evaluate the population impact of the first five years of the program.

Methods

Numbers of visits for pneumonia, pneumonia-related deaths, bacterial meningitis, and infant deaths between 2008 and 2015 were collected from all 107 public health facilities in León Department. Vital statistics data provided additional counts of pneumonia-related deaths that occurred outside health facilities. Adjusted incidence rates and incidence rate ratios (IRRa) in the vaccine (2011–2015) and pre-vaccine periods (2008–2010) were estimated using official population estimates as exposure time.

Results

The IRRa for pneumonia hospitalizations was 0.70 (95% confidence interval [CI]: 0.66, 0.75) for infants, and 0.92 (95% CI: 0.85, 0.99) for one year olds. The IRRa for post-neonatal infant mortality was 0.56 (95% CI: 0.41, 0.77). In the population as a whole, ambulatory visits and hospitalizations for pneumonia, as well as pneumonia-related mortality and rates of bacterial meningitis were lower in the vaccine period.

Conclusion

Five years following program introduction, reductions were observed in health facility visits for pneumonia in immunized age groups and infant mortality, which would be hard to achieve with any other single public health intervention. Future study is warranted to understand whether the lack of a booster dose (e.g.,, at 12 months) may be responsible for the small reductions in pneumonia hospitalizations observed in one year-olds as compared with infants.

Disclosures

S. Becker-Dreps, Pfizer: Consultant and Grant Investigator, Consulting fee and Research grant; D. J. Weber, Pfizer: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium
Assessment of Candida auris Response to Antifungal Drugs Using Time–Kill Assays and an Animal Model
Authors: Ben-Ami Ronen , Ashkenazi Liat , Berman Judith , Korolker Nuphar , Novikov Anna
Published: October 2017

Background

Candida auris is an emerging nosocomial pathogen that is resistant to Fluconazole and variably susceptible to other systemic drug classes. Treatment with echinocandins has been recommended based on MICs in the susceptible range, but supporting in vivo data is lacking.

Methods

We tested the MIC of C. auris strains (n = 12) to fluconazole, voriconazole, posaconazole. anidulafungin, amphotericin B and flucytosine. Representative C. auris strains from Israel and South Africa, and a reference C. albicans strain were analysed using time–kill curve assays. Fungicidal activity was defined as reduction of ≥3 log from baseline CFU/ml. Response to caspofungin treatment was assessed in BALB/c mice immunosuppressed with cyclophosphamide and inoculated with 7 × 107C. auris cells by tail vein injection. Mice were treated from day +1 to day +7 with caspofungin (IP) at doses of 1 or 5 mg/kg and compared with sham-treated controls. Survival was assessed daily. Kaplan-Meier survival analyses were performed and treatment arms were compared using the log-rank test.

Results

Drug susceptibility results (MIC50 and MIC90) were: fluconazole, 64 and 128 mg/l; voriconazole, 0.5 and 24 mg/l; posaconazole, 0.5 and 27 mg/l; anidulafungin, 0.03 and 0.06 mg/l; amphotericin B, 2 and 8 mg/l; flucytosine, 0.3 and 1 mg/l. Time–kill curve analyses showed log reduction from baseline CFU concentration of −3.0 to −2.8 for fluconazole (MIC ×1), 5.6–6.1 for amphotericin B (MIC ×4) and −0.4 to −0.9 for caspofungin (MIC ×16), consistent with fungicidal activity of amphotericin B and weak fungistatic activity of caspofungin. In the mouse model, survival rate was similar with sham treatment (33%) and treatment with caspofungin 1 mg/kg/day (44%) and 5 mg/kg/day (22%), P = 0.7.

Conclusion

Despite generally low MIC, caspofungin has only mild fungistatic activity on C. auris and no effect on survival in a mouse infection model. Amphotericin B has fungicidal activity against C. auris.

Disclosures

All authors: No reported disclosures.
Risk Factors and Mortality Associated with Candida krusei Bloodstream Infections
Authors: Kronen Ryan , Lin Charlotte , Hsueh Kevin , Powderly William , Spec Andrej
Published: October 2017

Background

Candida krusei (CK) candidemia is associated with high mortality, but whether this is due to underlying comorbidities in affected patients or the organism itself is unknown. We analyzed factors associated with C. krusei candidemia and its outcomes.

Methods

A retrospective analysis of hospitalized patients with candidemia was conducted at our institution between 2002 and 2015. Data were collected on demographics, comorbidities, medications, procedures, central lines, vital signs, and labs. Univariable logistic and Cox regression were used to identify potential risk factors associated with CK and mortality, respectively. Multivariable analyses were then constructed parsimoniously from these variables.

Results

Of 1,873 candidemia events, 59 were due to CK. In multivariable analysis, CK candidemia was predicted by hematologic malignancy (OR 8.9, 95% CI [4.1, 19.7]), stomach cancer (OR 14.6, 95% CI [2.9, 72.5]), absolute neutrophil count (OR 2.4, 95% CI [1.2, 4.8]), and the use of prophylactic azole antifungals (OR 2.2, 95% CI [1.1, 4.3]), monoclonal antibodies (OR 5.7, 95% CI [2.0, 15.8]), and penicillin β-lactamase inhibitors (OR 2.5, 95% CI [1.3, 4.8]). The C-statistic was 0.86 (95% CI [0.81, 0.91]). The crude mortality rates were 86.4% for CK candidemia and 63.6% for non-CK candidemia. Although CK was associated with higher mortality in univariable Cox regression (Figure 1, HR 1.8, 95% CI [1.3, 2.4]), this relationship was no longer significant (HR 1.2, 95% CI [0.8, 1.7]) with the addition of the following confounders: hematologic malignancy (HR 0.9, 95% CI [0.7, 1.1]), absolute neutrophil count (HR 1.7, 95% CI [1.4, 2.2]), stomach cancer (HR 1.0, 95% CI [0.5, 1.9]), coagulopathy (HR 1.0, 95% CI [0.9, 1.2], and prophylactic corticosteroids (HR 1.4, 95% CI [1.2, 1.7] (Figure 2).

Conclusion

A similar set of patient characteristics is associated with both CK infection and increased mortality, suggesting that patients with CK candidemia are at higher risk of mortality due to underlying illness rather than organism-specific mechanisms.

Disclosures

W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant Gilead: Scientific Advisor, Consulting fee Astellas: Grant Investigator, Research grant A. Spec, Astellas Pharma US, Inc.: Grant Investigator, Research grant
Risk Factors for Candidemia as Compared with Patients with Negative Blood Cultures Placed on Empiric Micafungin
Authors: Carr Amy , Berhe Mezgebe
Published: October 2017

Background

Numerous risk factors have been linked to invasive candidiasis; however, they are nonspecific and often trigger empiric antifungal therapy in a large number of patients. Identification of more precise predictors could promote judicious use of empiric echinocandins. Ultimately, this could decrease antifungal exposure, development of resistance, and associated costs.

Methods

This was a retrospective review of patients admitted to Baylor University Medical Center from 10/1/14 to 10/25/16. Patients with positive blood cultures for Candida spp. were compared with a randomly selected cohort of patients on empiric micafungin for 3 or more days and with blood cultures negative for Candida spp. This study excluded patients on prophylactic antifungals and patients with positive abscess cultures but negative blood cultures for Candida spp. Data was analyzed using the χ 2 test, t-test comparing means, and logistic regression as applicable.

Results

There were 127 patients with candidemia and 134 patients without candidemia on empiric micafungin. Factors associated with candidemia included positive 1,3-β-d-glucan assay (86.4% vs. 33.3%, P < 0.001), total parenteral nutrition (TPN) (26.0% vs. 15.7%, P = 0.040), and multifocal Candida colonization (35.3% vs. 4.5%, P < 0.001). Patients without candidemia on empiric micafungin were more likely to receive antibiotic therapy in the previous 10 days (55.9% vs. 79.9%, P < 0.001) and more likely to be taking immunosuppressive medications (11.0% vs. 30.6%, P < 0.001). There was no difference in mean length of stay (25.5 days vs. 27.3 days, P = 0.631) or 30-day all-cause mortality (32.3% vs. 23.9%, P = 0.131) between patients with candidemia and patients on empiric micafungin, respectively.

Conclusion

A negative 1,3-β-d-glucan assay in patients without multifocal Candida colonization or receiving TPN was inversely correlated with invasive candidiasis, as defined by candidemia. Therefore, the absence of these factors may be used to deescalate empiric micafungin therapy. Risk factors for candidemia identified in this study are consistent with previously published literature. These findings highlight an opportunity to improve empiric micafungin prescribing patterns at our institution.

Disclosures

All authors: No reported disclosures.
Breakthrough Invasive Candidiasis in Children
Authors: Dong Sara , Antonara Stella , Stanek Joseph , Ardura Monica I
Published: October 2017

Background

Breakthrough invasive candidiasis (bIC) has been described in adults, but the epidemiology and outcomes in children are unknown.

Methods

Retrospective cohort analysis of children diagnosed with IC from 9/1/09 to 1/30/17. bIC was defined as isolation of Candida spp. from sterile site despite receiving ≥3 doses of antifungal (AF) to which isolate is susceptible. Clinical and microbiological data, management, and outcomes were collected. Non-parametric and logistic regression statistics were applied.

Results

There were 92 patients with IC, 23 of which were bIC (Table 1). Underlying conditions included GI (n = 26), hem/onc (n = 17), prematurity (n = 16), cardiac (n = 15), HCT (n = 4), SOT (n = 5), and other (n = 9). Patients received an azole (n = 17), micafungin (n = 5), or amphotericin B (n = 1) for median of 20 days [3–522] before bIC as: prophylaxis (n = 8), targeted therapy (n = 5), or empiric fever driven therapy (n = 10). bIC was caused by non-albicans Candida in 16/23 (70%) cases. Compared with IC controls, children with bIC had increased ICU admission, vasopressor use, mechanical ventilation, and renal failure (all with P < 0.01). In multivariate analysis, immunosuppression was an independent risk factor for bIC (OR 39.4, 95% CI 7.5–205). Death attributable to IC occurred in bIC group (n = 3, P = 0.04).

Conclusion

bIC in our cohort was caused most frequently by non-albicans Candida spp. and associated with significantly worse outcomes, including mortality.

Disclosures

All authors: No reported disclosures.
QTc Prolongation in Patients Receiving Triazoles and Amiodarone
Authors: Cook Katherine , Sraubol Thitinan , Campbell Kristen Bova , Mourad Ahmad , Stiber Jonathan , Perfect John R , Johnson Melissa
Published: October 2017

Background

Prolonged QT interval may lead to ventricular arrhythmias, torsade de pointes and sudden death. Triazole antifungals are often administered to inpatients with cardiac disease and with other QT prolonging drugs. Amiodarone is a commonly used antiarrhythmic that can prolong QT and be proarrhythmic but safety of co-administering these agents in the clinical setting is not known.

Methods

We conducted a retrospective, observational cohort study of adult inpatients at Duke University Medical Center who received concomitant systemic azoles and amiodarone from 2007 to 2013. Included subjects had ≥1 electrocardiogram (EKG) performed while receiving either agent alone within 1 month of starting concomitant therapy (baseline, BL) and ≥1 follow-up (FU) EKG after ≥2 days of concomitant therapy. A paired t-test was used to assess the maximum change in corrected QT interval (QTc, Bazett’s correction) from BL to FU. Logistic regression was used to evaluate predictors of FU QTc ≥500 ms (age, race, gender, and BL QTc ≥500 ms). Patient discharge diagnoses of ventricular arrhythmias or other cardiac events were reviewed to assess clinical outcome.

Results

Of 816 subjects identified, 252 had EKG results eligible for analysis. Azoles received were fluconazole (86.5%), voriconazole (11.5%), posaconazole (1.6%) or itraconazole (0.4%). Subjects were a median of 65 (IQR 25–88) years of age, 64.3% male and 78.6% Caucasian. Median duration of concomitant therapy was 7 days (IQR 4–11 days). Mean maximal change in QTc was +32 ms from BL (95% CI 26.2–38.6, P < 0.0001). 25.4 and 48.8% of subjects had a BL and FU QTc ≥500 ms, respectively. BL QTc ≥500 ms but not age, race, or gender was associated with FU QTc ≥500 ms (OR 6.32 95% CI 3.21–12.43). Thirty-day all-cause mortality was 26.2%. No cardiac events were apparent in relation to concomitant azole-amiodarone therapy.

Conclusion

Prolongation of the QTc interval was frequently observed in this cohort of patients receiving azoles and amiodarone. Clinical impact is challenging to assess in this critically ill, complex patient population but appears to be limited. Additional analyses are needed to further evaluate safety of azoles in the setting of other QTc prolonging agents.

Disclosures

All authors: No reported disclosures.
Epidemiology and Risk Factors for Antifungal Resistance in Patients with Candidemia
Authors: Aldardeer Namareq , Albar Hadeil , Alattas Majda , Qutub Mohammed , Alraddadi Basem
Published: October 2017

Background

Candida is a common nosocomial blood pathogen associated with high mortality. Data on antifungal resistance from Saudi Arabia is scarce. The objective of this study is to examine epidemiology, risk factors for antifungal resistance, and outcome among patients with candidemia.

Methods

A retrospective study conducted at King Faisal Specialist Hospital and Research Center-Jeddah branch (KFSHRC-J) The study included all patients 18 years and older with positive blood culture for candida over a 5-year period (2012–2016).

Results

We identified 92 cases of candidemia. The mean age was 59 years SD (18). Candida galabrata was the most prominent species 33 (36%) followed by Candida parapsilosis 22 (24%), Candida albican 20 (22%), Candida tropicalis 13 (14%), Candida krusei 2 (2%), and others 2 (2%).

Resistance to fluconazole was identified in 14 (15%) cases, four of them were also resistance to voriconazole. Among cases resistance to fluconazole, seven (50%) cases were C. parapsilosis, two (14%) of each C. galabrata, C.krusei, and C. Albicans and one (7%) was C. tropicalis. In univariate analysis, previous exposure to echanicancdin and mechanical ventilation within 3 months were associated with fluconazole resistance candidemia (12(15%) vs 7(50%), (P = 0.007), 28(36%) vs 10(71%), (P = 0.014), respectively). Patients with fluconazole resistance candida had a longer length of intensive care unit stay (median 26 days (IQR 6–40) days and 12 days (IQR 7–36)), respectively. Length of hospital stay was longer in patients with fluconazole resistance compared with nonresistance (median 83 days (IQR 29–199 days) and (31 days (IQR 17–75), respectively. Thirty-day mortality of patients fluconazole resistance compared with non-resistance cases was not significant 43 and 55%, respectively (P = 0.28).

Conclusion

In our cohort, Candida galabrata is the most common species causing candidemia. Increasing fluconazole resistance candida parapsilosis is alarming. More regional epidemiological antifungal resistance studies are required to confirm this finding.

Disclosures

All authors: No reported disclosures.