bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Antimicrobial Susceptibility Testing Profiles of Urine Isolates from Veterans to Guide Empiric Therapy for Suspected Urinary Tract Infection
Authors: Marsh Ketzela J , Mundy Lesley , Holter John J , Johnson James R
Published: October 2017

Background

Urinary tract infection (UTI) is common among patients at Veterans Affairs Medical Centers (VAMCs), many of whom are elderly men with underlying medical or urological problems. Most UTI treatment guidelines address uncomplicated UTI in women and presume knowledge of local antimicrobial susceptibility testing (AST) patterns for uropathogens, which often are unknown or are inferred from E. coli. To inform selection of empiric therapy for UTI at our VAMC, we compiled AST data for one year’s urine isolates.

Methods

We compiled AST results (bioMerieux VITEK®) for the 2,494 significant urine isolates from the Minneapolis VAMC clinical microbiology laboratory from June 2013 through May 2014. For “drug-bug” combinations that were not tested we imputed results based on local or published data, and/or expert opinion. We then calculated cumulative % susceptible for 25 relevant antimicrobial agents, overall and stratified by Gram stain group and clinical site (intensive care unit, inpatient, outpatient, community residential centers, or extended care). In ambiguous situations susceptibility was analyzed as both 0% and 100%.

Results

The 2,494 urine isolates included 946 Gram-positive and 1,548 Gram-negative organisms. Species distribution varied significantly by clinical site. E. coli represented only 27% of isolates overall (9–37%, depending on site). Enterococcus (14%) and other Gram-positives (23%) were also prevalent. Cumulative AST profiles varied significantly (i) by Gram stain group, (ii) between E. coli and other Gram-negatives, and (iii) by clinical site. No tested oral agent provided ≥ 80% overall susceptibility. Although AST data were unavailable for fosfomycin, imputation suggested 82%-95% susceptibility overall.

Conclusion

Among urine isolates from veterans, E. coli was a minor contributor and a poor surrogate for total population AST profiles. The only oral agent that provided ≥ 80% susceptibility overall was fosfomycin, suggesting that it could be an important option for empiric lower UTI therapy for veterans. Urine isolate-specific antibiograms that reflect local AST data, stratified by Gram stain group and clinical site, could improve empirical UTI therapy for veterans, as could performance of urine Gram stains.

Disclosures

J. R. Johnson, Grant Investigator, Grant recipient Merck: Grant Investigator, Grant recipient Tetraphase: Grant Investigator, Grant recipient
Contemporary Epidemiology of Catheter-Associated Urinary Tract Infections (CAUTIs) in a Tertiary Care Center: Is Foley Re-Insertion a Novel Risk Factor?
Authors: Nowbakht Cima , Boston Kelley M , Harrison Nicole , Patel Bela , Katz Jeffrey , Ostrosky-Zeichner Luis
Published: October 2017

Background

CAUTIs are one of the most common causes of hospital-acquired infections. We report on a retrospective analysis performed on prospectively collected CAUTI surveillance data from 2014 to 2016 at a large tertiary care academic hospital

Methods

A total of 181 CAUTIs by NHSN definition were reviewed to describe contemporary demographics, risk factors, microbiology, and outcomes.

Results

The 181 CAUTIs involved 178 patients. 61% were female. Events mostly occurred in an ICU setting (65%), specifically our neurosurgical unit (23%), followed by floors (24%) and intermediate units (11%). Most episodes occurred within a week after the initial catheter insertion (60%). 40% of CAUTIs occurred within an average of 5.5 days (SD ± 5.12) after a Foley re-insertion. Of the 221 cultured micro-organisms, Gram-negatives accounted for 74% (predominately K. pneumoniae and E. coli), followed by Gram-positives and yeast at 18% and 8%, respectively. 8% of organisms showed multi-drug resistance, 8% of patients developed C. difficile co-infections, 23% had concomitant bacteremia, and the length of stay averaged 28 days (SD ± 26.74). 55% of patients were discharged to another facility. 12% of patients expired and 4% were discharged to hospice

Conclusion

We describe the contemporary demographics, microbiology and outcomes of CAUTIs in a large tertiary care center. We also found that 40% of our CAUTIS are associated with a Foley removal and re-insertion event. Reasons requiring catheter exchanges and reinsertions include leakage, bleeding, obstruction, failed voiding trial, and general malfunction. Although this observation needs to be confirmed case control studies and larger observational trials, this new insight may provide an opportunity to intervene and focus infection prevention interventions in this novel high-risk population.

Disclosures

All authors: No reported disclosures.
Antibiotic Prescription Practice for Pediatric Urinary Tract Infection in a Tertiary Center
Authors: Alghounaim Mohammad , Ostrow Olivia , Timberlake Kathryn , Richardson Susan E , Science Michelle
Published: October 2017

Background

Urinary tract infection (UTI) is a leading cause for acute care visits in pediatrics. A suspected UTI diagnosis is made based on typical clinical presentation and pyuria and confirmed by significant growth in an appropriate urine sample. Prescribing antibiotics for suspected UTI is a common practice, and may lead to unnecessary antibiotic exposure. We aimed to review the practice of UTI diagnosis and management in the Emergency Department (ED) to identify targets to improve antimicrobial prescribing practices.

Methods

Children (< 18 years) who were discharged from the ED at the Hospital for Sick Children with a diagnosis of UTI between October to December 2016 were included. Patients were excluded if they were (1) under 12 weeks of age, (2) had underlying genitourinary abnormalities, (3) were admitted or transferred to another center, (4) were on antibiotics on presentation, (5) had urine testing done in another laboratory, or (6) were given conditional prescription. Demographic, clinical history, laboratory findings, and urine culture results were collected from patient charts. The sensitivity and specificity of nitrite and leukocyte esterase (LE) for UTI diagnosis were calculated. Logistic regression was used to examine the relationship between urinalysis characteristics and confirmed UTI.

Results

A total of 186 children with a median age of 4.2 (IQR 1.2, 7.3) were included; 82.3% were female. Almost all children were discharged home on antibiotics (n = 183, 98%) for a median duration of 7 days (IQR 7, 10). A total of 87 patients (46.8%) received antibiotics despite negative urine cultures and none of these patients received notification to stop. This led to 652 unnecessary antibiotic days. The presence of nitrites was the strongest predictor of UTI (OR 13.3, P < 0.001) and was highly specific. An LE result of 2+ (OR 2.4, P = 0.04) or 3+ (OR 2.23, P = 0.016) was also predictive of UTI.

Conclusion

Current practice in managing suspected pediatric UTIs in our ED resulted in significant and unnecessary antibiotic exposure. We identified targets to reduce unnecessary antibiotic exposure including improving the diagnostic accuracy of UTIs, a process to discontinue antibiotics for negative cultures and standardizing antimicrobial duration.

Disclosures

All authors: No reported disclosures.
The Impact of Biofire Filmarray Respiratory Panel on Antibiotic Usage in the Emergency Department at an Academic Medical Center
Authors: Mehta Meera , Slain Douglas , Keller Lisa , Lasala P Rocco
Published: October 2017

Background

Biofire respiratory panel is a multiplex PCR test designed to detect 17 pathogens within 1 hour. It has greater sensitivity, specificity, and number of pathogens detected compared with older testing methods. The aim of this research was to evaluate the impact of Biofire respiratory panel on antibiotic usage in the emergency department (ED) of an academic medical center.

Methods

This was an observational chart review. Patients with positive RSV or influenza rapid antigen test or PCR test, and patients with a positive Biofire test were included. RSV or influenza tests were reviewed from July to December 2015, and Biofire tests were reviewed from July to December 2016. The primary outcome was to evaluate the duration of antibiotic therapy in patients with viral respiratory infections diagnosed with RSV and influenza rapid antigen and PCR testing compared with Biofire viral respiratory panel. Secondary outcomes included virus type, antibiotic prescription rates on discharge, number of addmissions, procalcitonin levels, and oseltamivir usage.

Results

In 2016, 67% (105/155) of biofire tests were positive. The most common pathogen was rhinovirus and enterovirus (42%). Of the positive results, 23/105 (22%) received antibiotics with 6 patients having antibiotics discontinued within 72 hours. Another 6 patients had bacterial coinfections. A total of 18/105 (17%) received antibiotic prescriptions on discharge. Median days of therapy (DOT) in hospital was 1 day and median DOT for prescriptions was 8.5 days. There were 5 procalcitonin tests and no oseltamivir usage. Overall 38/105 (36%) patients were admitted to inpatient. In 2015, 3% (20/1313) of RSV (14) and influenza (6) rapid antigen and PCR tests were positive. A total of 5/20 (25%) patients received antibiotics, with 3/20 (15%) patients receiving a prescription for outpatient antibiotics. Median DOT in the hospital was 3 days and median DOT for prescriptions was 10 days. There were 2 procalcitonin tests and 2 cases used oseltamivir. Overall 19 patients were admitted.

Conclusion

Antibiotics are witheld in the majority of patients with positive Biofire testing. Most patients were treated with supportive care measures only. Biofire continues to be a useful tool to identify candidates for antibiotic avoidance in the ED at our institution.

Disclosures

All authors: No reported disclosures.
Measles Oral Swab as Field-Based Screening Test in Children
Authors: Husada Dominicus , Handayani Kartika , Puspitasari Dwiyanti , Kartina Leny , Setiono Parwati , Moedjito Ismoedijanto
Published: October 2017

Background

Indonesia suffered from measles outbreak for many times, especially in the last five years. Most patients were children. WHO used measles specific Ig M from the blood as a gold standard but this test is invasive. Anti measles Ig M oral swab has been used as an alternative however there has not been any study about this method in Indonesia. The objective of this study was to validate anti measles Ig M oral swab for the diagnosis of measles in children.

Methods

This study was performed in Dr. Soetomo Hospital in Surabaya for three months period. Children with fever and rash suspected having measles according to WHO criteria were used as samples. Inclusion criteria included age 6 month until 15 year-old, with maculopapular rash, fever for at least three days, and at least one of cough, coryza, and conjunctivitis. Immunocompromized children and those with history of fever and rash or measles vaccination in the last 8–12 weeks were excluded. A blood specimen for serum anti measles Ig M and oral swab using transudate in gingivo-cervicular sulcus were taken at the same time. Method for oral swab specimen was microimmune(EIA) captured antibody assay for measles IgM. Measles specific IgM antibodies from blood specimen were measured by Enzygnost anti measles IgM. Mc Nemar test and kappa were used to analyze the results with P < 0.05.

Results

There were fifty-six children in the study. The age range was 6 – 72 months. Boys outnumbered girls with ratio 1.6:1. Most patients came on day third-sixth of illness. As much as 75.7% of the children were not immunized. Antimeasles Ig M were truly positive by both methods in fifty sampes. Detection of Ig M antibodies were similar either by using serum or oral swab (Mc Nemar, P = 1,00). The best ROC curve to detect anti measles IgM by oral swab was shown at the value of 0.2 (sensitivity 98%, specificity 60%, Kappa 0.638 with P < 0.0001, PPV 96%, and NPV 75%) For the value of 0.5 we had sensitivity 90%, specificity 80%, PPV 98%, NPV 44%, and Kappa 0.516 with P < 0.001.

Conclusion

Anti measles IgM oral swab is highly sensitive and can be used as a field-based alternative screening method to diagnose measles infection.

Disclosures

All authors: No reported disclosures.
Cytomegalovirus Management in Adult Hematopoietic Stem Cell Transplant Patients with Pre-Engraftment Viremia: A Single-Center, Retrospective, Descriptive Study
Authors: Martin Isabella , Avery Robin , Gladstone Douglas , Ambinder Richard , Tucker Noah , Valsamakis Alexandra
Published: October 2017

Background

Scant data exist regarding cytomegalovirus (CMV) viremia in hematopoietic stem cell transplant (HSCT) recipients during the pre-engraftment period. The goal of this study was to describe management of CMV in neutropenic adult HSCT patients at our institution, and to assess the possible impact of different quantitative CMV PCR tests (QPCRs).

Methods

Post-HSCT monitoring at this center includes weekly CMV QPCR from plasma. Three different QPCR assays were used sequentially during the study period (1/2010–12/2015): two with lower limits of quantification (LLOQ) of 300 and 100 copies/mL through 4/2013, and after that the FDA-approved assay with LLOQ of 137 IU/mL. Medical records of first-time HSCT patients were reviewed. Pre-/peri-engraftment CMV was defined as detectable CMV DNA with [ANC] < 1000 cells/mm3. Information collected included demographics, donor/recipient CMV serostatus, conditioning regimen, CMV QPCR and ANC results, dates of CMV treatment, CMV disease within 100 days, and death within 6 months of HSCT. Data were analyzed with STATA v14.

Results

Of 1151 total HSCT, 76 patients had a positive CMV QPCR when ANC < 1000 cells/mm3. CMV was first detected a median of 12 days (0–48) post-transplant, and was above LLOQ at a median of 28 days (0–49). 71/76 (93%) were treated at a median of 33 days post-transplant (range 4–105 days), most with valganciclovir (40) or ganciclovir (30); 1 received foscarnet initially. 5 patients with low-level viremia were monitored without treatment. At initiation of therapy, median CMV level was 1471 (range 159–22,900) copies or IU/mL and ANC was 1202 (range 28–9680) cells/mm3. Median treatment duration was 34 days (range 9–392). Only 2 patients had possible tissue-invasive CMV disease.

Conclusion

Ganciclovir and valganciclovir were used to treat most pre- and peri-engraftment CMV viremia, despite potential bone marrow toxicity. The LLOQ of different CMV QPCR tests did not affect the viral threshold for starting treatment. The time between first CMV DNA detection (median day +12) and initiation of treatment (median day +33) suggests clinicians waited for CMV DNA and/or ANC to rise before treating. With this deferred-treatment approach, the proportion of patients with tissue-invasive disease remained low.

Disclosures

All authors: No reported disclosures.
Comparison of Roche and Abbott Cytomegalovirus Quantitative PCR Assays in Allogeneic Hematopoetic Cell Transplant Recipients
Authors: Mckinnon John , Janakiraman Nalini , Samuel Linoj , Lucic Danijela , Ramesh Mayur , Abreu-Lanfranco Odaliz , Farhan Shata , Osborn Zachary , Zhou Junying , Williams Katrina , Alangaden George
Published: October 2017

Background

Human Cytomegalovirus (CMV) infection is prevalent in patients undergoing transplantion (Tx) and carries significant morbidity and mortality. Quantification of CMV viremia has improved with the use of standardized international units and new commercial real time PCR assays. This study compares the current Roche cobas AmpliPrep/cobas TaqMan CMV test (TM assay) and Abbott Molecular RealTime CMV Investigational Use Only assay (ART assay) for quantification of CMV viremia in patients receiving allogeneic hematopoietic stem cell transplants (aHSCT).

Methods

Prospective CMV positive patients, planned for aHSCT, were consented prior to Tx and followed weekly up 12 weeks post-transplant (PT) and once ~3 months PT. Matched paired plasma samples were processed and analyzed per manufacturer instructions, Henry Ford clinical laboratory processed the samples using the TM assay and the McKinnon Research Laboratory processed the paired samples using the ART assay. Parametric and non-parametric analyses were conducted as appropriate.

Results

Fourteen patients enrolled, 1 patient withdrew after entering, 1 patient died after 9 weeks PT (primary disease). Patients received peripheral blood stem cells and 84.6% received myeloablative chemotherapy. In paired samples, quantifiable CMV by TM and ART assays was detected in 6 (5 treated) vs. 8 of 13 patients respectively. ART assay detected CMV in all patients with positive paired samples, 1 detected in an unpaired sample and in 2 patients missed by TM assay (P = 0.021). Assays also differed in samples with no detection, detectable and quantifiable CMV viremia, with more frequent detection in the ART assay (P = 0.009). Time to quantifiable viremia PT by TM and ART assays was a median of 5 vs. 3 weeks (P = 0.026). Bland-Altman plot shows higher viremia levels quantified using the ART assay (P = 0.023). After week 4 PT, ART assay results inversely correlated with platelets counts (P = 0.013). CMV viremia tended to persist 1.9 weeks longer using ART vs.. TM assay (P = 0.07).

Conclusion

CMV viremia was quantified earlier, at higher levels and persisted in patients with aHSCT using the ART assay compared with the TM assay. Further study is warranted to determine clinical impact of ART assay on the management of CMV viremia.

Disclosures

J. Mckinnon, Abbott Molecular: Speaker’s Bureau, Grant recipient and Speaker honorarium D. Lucic, Abbott Molecular: Employee, Salary
Optimization of a Polymerase Chain Reaction System for Whole Genome Amplification of Human Immunodeficiency Virus Type 2 (HIV-2)
Authors: Pappoe-Ashong Prince Jonathan , Sagoe Kwamena
Published: October 2017

Background

In this study, attempts were made to amplify the whole genome of HIV-2 using polymerase chain reaction (PCR) from viral RNA and proviral DNA extracted from archived human plasma and whole blood, respectively. The aim this study is to develop a PCR system that can be used to amplify the entire genome of all known subtypes and recombinant forms of HIV-2

Methods

Proviral DNA and viral RNA were extracted from archived human whole blood and plasma using Zymo Research Viral DNA kit and Zymo Research Viral nucleic acids kit, respectively. Primers that target the conserved sites of the 3’ and 5’ long terminal repeat were selected based on in silico analysis using Snapgene® tool version 2.1.0. Eight overlapping Primers for PCR whole genome amplification of HIV-2 were also selected and used for overlap PCR amplification of whole genome of HIV-2. Long range and overlapping PCR of whole genome of HIV-2 were carried out using long range Kit (New England Biolabs Inc., Ipswich, MA, USA) and cDNA synthesized using NEB ProtoScript II for proviral DNA and viral RNA templates. Amplified whole genome of HIV-2 was gel purified and PCR confirmed using two sets of primers ENVF/ENVG and EB2/EB5 and gel electrophoresis.

Results

Proviral DNA and viral RNA were successfully extracted from archived whole blood and plasma. Six primers were selected out of the 68 primer sequences retrieved using in silico analysis for long range single PCR amplification of HIV-2 whole genome. Primers P1/P8 and HIV2upA/HIV2lowA were successfully used in the whole genome amplification of HIV-2. Overlapping primers P1/P4, P6/P8, PolF/EnvG and Pol4F/EnvG covering the entire genome of HIV-2 were also successfully used in the whole genome amplification of HIV-2. The amplified whole genome fragment was confirmed to be HIV-2 by PCR using primers EB2/EB5 and EnvF/EnvG.

Conclusion

The techniques of long-range and overlapping amplification of HIV-2 whole genome may be useful in HIV-2 genotyping using viral RNA and proviral DNA. This study has led to the selection and shown novel primer combinations of already existing primers which can be used to amplify the entire genome of HIV-2.

Disclosures

All authors: No reported disclosures.
Comparison of Roche TaqMan v.2.0, Abbott RealTime and Modified Abbott Residual Viremia Assays in Testing of Routine Samples for Viremia Monitoring in HIV Care
Authors: Mckinnon John , Osborn Zachary , Taylor Tom , Zhou Jun Ying , Lucic Danijela , Clark Katelyn , Williams Katrina , Samuel Linoj
Published: October 2017

Background

Routine HIV RNA clinical monitoring frequently reports virermia (VL) as detectable, quantifiable <50 or blips >50 c/mL. To assess whether the results represent true increases or just assay variability, we designed comparisons of the Roche COBAS AmpliPrep / COBAS TaqMan HIV-1 Test version 2.0 (TM) and the Abbott RealTime HIV-1 assay (RT) to a residual viremia (RV) assay with a limit of detection of 3 c/mL, the Modified Abbott Residual Viremia assay (MARV).

Methods

HIV suppressed patients on stable therapy presenting for routine visits at the HIV clinic in Henry Ford Hospital (HFH) were prospectively enrolled. Blood samples and questionnaires were obtained at each visit. Paired plasma samples were processed and analyzed per manufacturer instructions; HFH clinical laboratory processed the samples using the TM assay and the McKinnon Research Laboratory performed the FDA approved RT assay and RV testing using the MARV assay. Parametric and non-parametric analyses were conducted as indicated.

Results

124 HIV patients are reported with a mean age of 51, mostly male (84%) and African American (64%). Mean CD4 cell counts were 661 cells/mm3. TM assay results for 196 plasma samples were not detectable (ND) 119 (61%), detectable (DT) 61 (31%) and quantifiable viremia (QV) >20 c/mL 16 (8%). 5 patients had QV over 50 c/mL. 60 tested patients (49.5%) had at least one sample either DT or QV. TM results were not correlated to CD4 cell counts, antiretrovirals, medical conditions or reported adherence (avg. 97%). 174 RT and 187 MARV paired tests were ND on 142 (81%) / 121 (65%), DT on 34 (17%) RT, and quantifiable in 0% / 34 (33%) of the samples respectively. Higher VL detection by the TM was shown compared with the RT (P = 0.005) and MARV (P < 0.001) assays. Mean QV by the MARV was 5.0 vs.. 55 c/mL on the TM assay (P < 0.001). VL for all assays trends correlated when compared for ND, DT and >20 copies/mL (P < 0.001). Bland-Altman plots show higher VL detected by TM as compared with MARV (P < 0.001) and good correlation between RT and MARV assays (P = 0.6).

Conclusion

HIV viremia is more frequently reported by TM assay as compared with the RT assay and was significantly higher than VL detected by the MARV assay. Over detection of VL by the TM assay may impact clinical decision making and increase cost of care.

Disclosures

J. Mckinnon, Abbott Molecular: Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium D. Lucic, Abbott Molecular: Employee, Salary
Experience of Sublingual Microcirculation Evaluation in Adults Patients with Severe Dengue
Authors: Rosso Fernando , Ospina Gustavo , Quiñones Edgardo , Sanz Ana Maria
Published: October 2017

Background

Severe microcirculatory changes are involved in the pathophysiological mechanisms that lead to irreversible final stages of dengue shock. We report our experience of the evaluation of sublingual microcirculation in adult patients with severe dengue

Methods

Adults patients with severe dengue (by WHO 2009 criteria) were included. Dengue diagnostics was made by positive serology for IgM / IgG, antigen NS1 or PCR. Sublingual Microcirculation (SM) was evaluated by Sidestream Dark Field imaging. Microvascular flow index (MFI), proportion of small-perfused vessels (%SVP), heterogeneity index (HI) and Total Vascular Density were calculated. All patients received Fluids Challenge (FC) at hospital admission.

Results

SM was assessed in 10 patients. The median age was 65 years [IQR: 34–70], 60% were male. Eight patients were admitted to the ICU, of which 63% required invasive ventilatory and vasoactive support. One patient died. After the fluid challenge, the median of the %SVP was 94 [IR: 97 – 77], the median of the MFI was 2.82 [IR: 2, 85 – 2, 14]. There were not significant differences in %SVP and MFI among the patients who survived. In the deceased patient, the %SVP with continuous flow was 59, 18% and the MFI was 1, 45; these values were significantly decreased compared with patients who survived. A significant negative correlation between hematocrit and %SVP, and MFI was found.

Conclusion

Initial fluid challenge, that identifies and treats volume depletion, could correct microcirculation abnormalities evaluated by SDF imaging. However, in the patient who did not respond to this challenge, significant alterations of the MFI and the %SVP were evidenced. There is a need for more studies to improve our understanding of the role of microcirculation evaluation in these patients.

Disclosures

All authors: No reported disclosures.
Clinically Important Resistance among Salmonella enterica Serotype Typhi Isolates—United States, 2003–2015
Authors: Medalla Felicita , Watkins Louise Francois , Chatham-Stephens Kevin , Reynolds Jared , Bicknese Amelia , Friedman Cindy
Published: October 2017

Background

Salmonella Typhi (Typhi) causes typhoid fever, accounting for an estimated 5,700 illnesses and 623 hospitalizations per year in the United States. Most infections are acquired during travel to regions outside the United States where typhoid fever is prevalent and antimicrobial resistance is a problem. Fluoroquinolones (e.g., ciprofloxacin) are considered the treatment of choice for susceptible Typhi infections due to their superior ability to concentrate intracellularly and in bile, however, nonsusceptibility has been associated with treatment failure or delayed response. Azithromycin and ceftriaxone are treatment options. We describe antimicrobial susceptibility among Typhi isolates in the United States and the implications for management.

Methods

The National Antimicrobial Resistance Monitoring System at CDC conducts susceptibility testing on all Typhi isolates submitted by public health laboratories. We used broth microdilution to determine minimum inhibitory concentrations (MICs) to agents representing 9 antimicrobial classes and categorized isolates according to criteria from the Clinical and Laboratory Standards Institute. We defined ciprofloxacin nonsusceptibility as MIC ≥0.12 μg/mL, ciprofloxacin resistance as MIC ≥1, azithromycin resistance as MIC ≥32, and ceftriaxone resistance as MIC ≥4.

Results

From 2003–2015, isolates were tested from 4,550 patients; 2,760 (61%) were ciprofloxacin nonsusceptible, 4% were ciprofloxacin resistant. One isolate was azithromycin resistant and none were ceftriaxone resistant. Ciprofloxacin nonsusceptibility increased from 39% in 2003 to 66% in 2015; resistance increased from 0.3% to 8%. Median age of patients was 23 years (range 1–99 years), 53% were male, most were from the Northeast (33%) or the West (29%), and 74% had an isolate from blood.

Conclusion

Two thirds of Typhi isolates exhibited ciprofloxacin nonsusceptibility, which has increased over the last decade, and full resistance is increasing. Clinicians should be aware of high rates of fluoroquinolone nonsusceptibility when selecting empiric therapy and should tailor antimicrobial treatment to susceptibility results when feasible. Azithromycin and ceftriaxone remain important treatment options.

Disclosures

All authors: No reported disclosures.
Broad In Vitro Activity Analysis of Tedizolid Compared with Other Agents against a Global Collection of Gram-Positive Isolates Causing Bloodstream Infections (2014–2016)
Authors: Mendes Rodrigo E , Shortridge Dee , Sader Helio S , Duncan Leonard R , Flamm Robert K
Published: October 2017

Background

Tedizolid (TZD) is an oxazolidinone derivative with oral and intravenous formulations approved for the treatment of acute bacterial skin and skin structure infections in the US, European countries, and other regions. This study evaluated TZD’s and comparators’ activity against a collection of clinical isolates causing bloodstream infections (BSI).

Methods

A total of 7,284 gram-positive isolates collected during the Surveillance of Tedizolid Activity and Resistance (STAR) Program for 2014–2016 were included. Bacteria were identified by standard algorithms and MALDI-TOF-MS. Susceptibility (S) testing was performed by CLSI methods, and interpretation used CLSI and EUCAST criteria.

Results

This Staphylococcus aureus collection contained 33.8% methicillin-resistant isolates. TZD was the most potent agent tested against all S. aureus (MIC50/90, 0.12/0.12 µg/mL; 100.0%S) and the MRSA subset (Table). Other tested agents described in Table also had in vitro MRSA coverage. 15.6% of enterococci were vancomycin-resistant, which were mostly Enterococcus faecium (59.8%). Linezolid (LZD), ampicillin, daptomycin (DAP), and vancomycin (VAN) showed equivalent MIC50 values (1 µg/mL) against E. faecalis, but these MIC50 results were 8-fold higher than TZD (MIC50, 0.12 µg/mL). Although LZD and DAP were highly active (98.9–99.4%S) against E. faecium, TZD MICs were 8- to 16-fold lower that LZD and DAP. Ceftaroline (CPT) showed the lowest MIC values against Streptococcus pneumoniae, whereas TZD and VAN were similarly active. TZD and CPT showed the lowest MIC90 values against viridans group streptococci, while CPT, ceftriaxone, and penicillin had the lowest MIC90 results against β-hemolytic streptococci.

Conclusion

TZD had potent activities against this global population of gram-positive clinical isolates that caused BSI. This in vitro potency and a favorable pharmacodynamic profile may suggest TZD is a promising candidate for treating BSI caused by gram-positive isolates, especially E. faecium.

Disclosures

R. E. Mendes, Merck: Research Contractor, Research grant; D. Shortridge, Merck: Research Contractor, Research grant; H. S. Sader, Merck: Research Contractor, Research grant; L. R. Duncan, Merck: Research Contractor, Research grant; R. K. Flamm, Merck: Research Contractor, Research grant
Lysin CF-301 Demonstrates In Vitro Synergy with Conventional Antibiotics against Staphylococcus aureus
Authors: Sauve Karen , Jandourek Alena , Cassino Cara , Schuch Raymond
Published: October 2017

Background

CF-301 is a novel, recombinantly-produced bacteriophage-derived lysin (cell wall hydrolase) and is the first agent of this class to enter clinical development in the US for the treatment of bacteremia including endocarditis due to S.aureus. This study evaluated the in vitro activity of CF-301 combined with each of 7 antistaphylococcal antibiotics including those considered to be current standard of care treatments for S.aureus bacteremia (daptomycin, vancomycin, oxacillin, nafcillin, and cefazolin) as well as linezolid and telavancin.

Methods

MICs for CF-301 were determined using a new AST medium for broth microdilution recently endorsed by the CLSI for use with CF-301. The testing medium consisted of cation-adjusted MHB supplemented with 25% horse serum and 0.5 mM DTT. Synergy was determined by checkerboard microdilution using the fractional inhibitory concentration index (FICI) for each combination in triplicate. For each antibiotic tested, an FIC mean was derived from each set of checkerboards by averaging 3 consecutive FIC values along the growth/no growth interface for each plate. Thus, 9 values were, used to generate the final mean. Synergy was defined as an FICI of ≤0.5; indifference was >0.5 to <2; and antagonism was ≥2. Each combination was examined against 10 MSSA and 10 MRSA strains.

Results

CF-301 synergized with daptomycin and vancomycin against each MSSA and MRSA strain, with FICI values between 0.254 and 0.5. Synergy was similarly observed against all 20 strains tested with oxacillin and nafcillin (FICI = 0.25–0.5); for the third β-lactam, cefazolin, synergy was observed with 17 strains (FICI = 0.75, for the remaining 3 strains). CF-301 synergized with televancin against 70% of the strains (FICI = 0.375–0.5), and was indifferent with the remainder (FICI = 0.625–1). CF-301 synergized with linezolid against 55% of the strains (FICI = 0.375–0.5), and was indifferent with the remainder (FICI = 0.625–0.75).

Conclusion

The broadly synergistic activity of CF-301 with conventional antistaphylococcal antibiotics against MSSA and MRSA suggests that CF-301 may afford therapeutic benefit by potentiating the activity antibiotics to treat serious infections for which there is an unmet medical need to improve outcomes.

Disclosures

K. Sauve, ContraFect Corp: Employee, Salary; A. Jandourek, ContraFect Corp: Employee, Salary; C. Cassino, ContraFect Corp: Employee, Salary; R. Schuch, ContraFect Corp: Employee, Salary
Synergistic Antiviral Activity of S-033188/S-033447, a Novel Inhibitor of Influenza Virus Cap-Dependent Endonuclease, in Combination with Neuraminidase Inhibitors In Vitro
Authors: Kitano Mitsutaka , Yamamoto Atsuko , Noshi Takeshi , Kawai Makoto , Yoshida Ryu , Sato Akihiko , Shishido Takao , Naito Akira
Published: October 2017

Background

S-033447, an active form of orally available prodrug S-033188, is a novel small molecule inhibitor of cap-dependent endonuclease that is essential for influenza virus transcription and replication. In this study, we evaluated the inhibitory effect of S-033188 in combination with neuraminidase inhibitors on the replication of influenza A/H1N1 virus in cultured cells.

Methods

The inhibitory effects of S-033447 in combination with NA inhibitors on the cytopathic effect of A/PR/8/34 strain in Madin–Darby canine kidney cells cultured for 2 days were tested and EC50 were determined. The combination index (CI), which were obtained when S-033188 and NA inhibitor were added at the closest ratio of each EC50 value, were used for the evaluation of these combinational effects (Table 1). CI values were calculated by the Chou and Talalay method, in which combinational effect were determined according to the criteria as follows: synergistic if CI ≤ 0.8, additive if 0.8 < CI < 1.2, and antagonistic if CI ≥ 1.2.

CI = (DA/A + B)/DA + (DB/A + B)/DB + (DA/A + B × DB/A + B)/(DA × DB)

DA: the EC50 of S-033447

DB: the EC50 of NA inhibitor

DA/A + B: the concentration of S-033447 giving 50% inhibition in combination with NA inhibitor at the closest ratio of each EC50 value

DB/A + B: the concentration of NA inhibitor giving 50% inhibition in combination with S-033447 at the closest ratio of each EC50 value

Results

All CI values were lower than 0.8, under the condition that both S-033447 and NA inhibitor (oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate) were added at the closest ratio of each EC50 value (Table 1).

Conclusion

S-033447 in combination with oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate synergistically inhibited the replication of influenza A/H1N1 virus in MDCK cells.

Disclosures

All authors: No reported disclosures.
In Vitro Activity of Ceftolozane-Tazobactam vs. Antimicrobial Non-Susceptible Pseudomonas aeruginosa Clinical Isolates Obtained from Across Canada as Part of the CANWARD Study, 2008–2016
Authors: Walkty Andrew , Adam Heather J , Baxter Melanie , Lagace-Wiens Philippe , Karlowsky James , Hoban Daryl , Zhanel George
Published: October 2017

Background

Ceftolozane-tazobactam (C/T) is a novel β-lactam β-lactamase inhibitor combination with a broad spectrum of activity that includes Pseudomonas aeruginosa. The purpose of this study was to evaluate the in vitro activity of C/T and relevant comparators vs. a large collection of antimicrobial non-susceptible (NS) P. aeruginosa clinical isolates obtained from patients across Canada (CANWARD, 2008–2016).

Methods

From January 2008 to December 2016, inclusive, 12 to 15 sentinel hospitals across Canada submitted clinical isolates from patients attending ERs, medical and surgical wards, hospital clinics, and ICUs (CANWARD). Each center was asked to annually submit clinical isolates (consecutive, one per patient/infection site) from blood, respiratory, urine, and wound infections. Susceptibility testing was performed using broth microdilution as described by CLSI. Multidrug-resistant (MDR) P. aeruginosa were defined as isolates that tested NS to at least one antimicrobial from ≥3 classes. Extensively drug-resistant (XDR) P. aeruginosa were defined as isolates that tested NS to at least one antimicrobial from ≥5 classes.

Results

3229 P. aeruginosa isolates were obtained as a part of CANWARD. The in vitro activity of C/T and relevant comparators is presented below.

Conclusion

C/T demonstrated excellent in vitro activity vs. antimicrobial NS P. aeruginosa clinical isolates, including MDR, XDR, and meropenem NS subsets. It may prove useful in the treatment of infections caused by these organisms.

Disclosures

D. Hoban, Abbott: Research relationship, Research support Achaogen: Research relationship, Research support Astellas: Research relationship, Research support Merck Canada: Research relationship, Research support Merck USA: Research relationship, Research support Paratek Pharma: Research relationship, Research support Pharmascience: Research relationship, Research support Sunovion: Research relationship, Research support Tetraphase: Research relationship, Research support The Medicines Co.: Research relationship, Research support Zoetis: Research relationship, Research support; G. Zhanel, Achaogen: Research relationship, Research support Astellas: Research relationship, Research support Merck Canada: Research relationship, Research support Merck USA: Research relationship, Research support Paratek Pharma: Research relationship, Research support Pharmascience: Research relationship, Research support Sunovion: Research relationship, Research support Tetraphase: Research relationship, Research support The Medicines Co.: Research relationship, Research support Zoetis: Research relationship, Research support
Antimicrobial Activity of Dalbavancin and Comparator Agents Tested against Gram-Positive Clinical Isolates Causing Bone and Joint Infections in United States (US) Medical Centers (2011–2016)
Authors: Sader Helio S , Mendes Rodrigo E , Flamm Robert K , Pfaller Michael A
Published: October 2017

Background

Bone and joint infections (BJI) comprise a series of disorders, including septic arthritis, osteomyelitis, and prosthetic joint infections. We evaluated the activity of dalbavancin (DALBA) against pathogens isolated from BJI in US hospitals.

Methods

A total of 744 organisms collected from 55 hospitals in 2011–2016 were evaluated, including 463 S. aureus, 88 coagulase-negative staphylococci (CoNS), 104 β-haemolytic streptococci (BHS), 60 E. faecalis, and 29 viridans group streptococci (VGS). Bacteria were identified by standard algorithms and MALDI-TOF-MS. Susceptibility testing was performed by CLSI methods (M07-A10); interpretation of MIC results used CLSI (2017) and EUCAST (2017) criteria.

Results

S. aureus (62.2%) was the most common pathogen associated with BJI, followed by BHS (14.0%) and CoNS (11.8%). All S. aureus (41.5% methicillin-resistant [MRSA]) isolates were susceptible (S) to DALBA, linezolid (LNZ), teicoplanin (TEI) and vancomycin (VAN), while daptomycin (DAPTO) and clindamycin (CLI) showed susceptibility rates of 99.8% and 87.7% (CLSI), respectively. DALBA MIC results (MIC50/90, ≤0.03/0.06 μg/mL) were ≥8-fold lower compared with DAPTO (MIC50/90, 0.25/0.5 μg/mL) against all S. aureus. Among CoNS, (61.4% MRSA), DALBA (MIC50/90, ≤0.03/0.06 μg/mL) was the most potent agent, followed by DAPTO (MIC50/90, 0.25/0.5 μg/mL), LNZ (MIC50/90, 0.5/1 μg/mL), and VAN (MIC50/90, 1/2 μg/mL). DALBA inhibited all E. faecalis isolates at ≤0.25 μg/mL (FDA S breakpoint), except for 3 VAN-resistant (VanA) isolates. High susceptibility rates for ampicillin (98.3%; CLSI), DAPTO (100.0%), LNZ (100.0%), TEI (93.3%) and VAN (93.3%) were obtained against E. faecalis. DALBA, DAPTO, LNZ, ceftriaxone, penicillin, and VAN were active against all BHS (100.0%S), while DALBA (MIC50/90, ≤0.03/0.06 μg/mL; 100.0%S) was the most active agent against VGS, inhibiting all isolates at ≤0.06 μg/mL. Ceftriaxone, LNZ, DAPTO, and VAN were also active against VGS (93.1 – 100.0%S; CLSI), whereas CLI (82.8%S) had marginal activity.

Conclusion

DALBA demonstrated potent in vitro activity against common gram-positive isolates causing BJI (2011–2016) and appears to be a viable candidate for treating BJI/osteomyelitis caused by gram-positive cocci.

Disclosures

H. S. Sader, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant; M. A. Pfaller, Allergan: Research Contractor, Research grant
Cefepime-Zidebactam (WCK 5222) Activity Tested against Gram-negative Organisms Causing Bloodstream Infections Worldwide
Authors: Sader Helio S , Castanheira Mariana , Streit Jennifer M , Duncan Leonard R , Flamm Robert K
Published: October 2017

Background

Zidebactam (ZID), a bicyclo-acyl hydrazide, is a β-lactam enhancer with a dual mechanism of action involving selective and high binding affinity to Gram-negative (GN) PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime (FEP) combined with ZID against GN organisms causing bloodstream infections (BSI) in hospitals worldwide.

Methods

A total of 2,094 isolates from 105 medical centers were evaluated. Isolates were collected from Europe (1,050), USA (331), Latin America (LA; 200) and the Asia-Pacific region (AP; 393) in 2015, and China (120) in 2013 by the SENTRY Program. Susceptibility (S) testing was performed by reference broth microdilution method against FEP-ZID (1:1 ratio) and comparators. The collection included 1,809 Enterobacteriaceae (ENT), 170 P. aeruginosa (PSA) and 115 Acinetobacter spp. (ASP).

Results

FEP-ZID was very active against ENT (MIC50/90 of ≤0.03/0.12 μg/mL) with 99.9 and 100.0% of isolates inhibited at ≤4/4 and ≤8/8 μg/mL, respectively, and retained potent activity against carbapenem-resistant (CRE; n = 44; MIC50/90, 1/4 μg/mL), multidrug-resistant (MDR), and extensively drug-resistant (XDR) isolates (Table). Amikacin (AMK; MIC50/90, 2/4 μg/mL; 97.7% S) was also very active against ENT, and colistin (COL; MIC50/90, 0.12/>8 μg/mL) inhibited only 87.3% of isolates at ≤2 μg/mL. FEP-ZID was highly active against PSA, including isolates resistant to other antipseudomonal β-lactams, MDR (MIC50/90, 4/8 μg/mL) and XDR (MIC50/90, 4/8 μg/mL) isolates. Among the comparators, COL (MIC50/90 of ≤0.5/1 μg/mL; 100.0% S) and AMK (MIC50/90, 4/16 μg/mL; 91.2% S) were the most active agents against PSA. FEP-ZID (MIC50/90, 16/32 μg/mL) was 4-fold more active than FEP against ASP.

Conclusion

FEP-ZID (WCK 5222) exhibited potent in vitro activity against a large worldwide collection of GN isolates from BSI, including MDR and XDR isolates. These results support further clinical development of WCK 5222 for treating BSI.

Disclosures

H. S. Sader, Wockhardt Bio Ag: Research Contractor, Research grant; M. Castanheira, Wockhardt Bio Ag: Research Contractor, Research grant; J. M. Streit, Wockhardt Bio Ag: Research Contractor, Research grant; L. R. Duncan, Wockhardt Bio Ag: Research Contractor, Research grant; R. K. Flamm, Wock: Research Contractor, Research support
In vitro Activity of Cefiderocol Against Gram-Negative Clinical Isolates Collected from Urinary Track Source: SIDERO-WT-2014/SIDERO-WT-2015
Authors: Tsuji Masakatsu , Hackel Meredith , Echols Roger , Yamano Yoshinori , Sahm Dan
Published: October 2017

Background

The global rise of carbapenem resistant Gram-negative bacteria such as carbapenem-resistant Enterobacteriaceae (CRE) and carbapenem-resistant non-fermenting bacteria is alarming and become threats to patient as only a few drugs remain active (e.g. colistin). Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin with potent activity against a wide variety of Gram-negative pathogens including carbapenem-resistant strains. This study evaluated the in vitro activity of cefiderocol and comparator agents against clinical isolates collected from urinary track source from North America.

Methods

A total of 3,323 Enterobacteriaceae, 263 Acinetobacter spp, 509 Pseudomonas aeruginosa, and 38 Stenotrophomonas maltophilia collected from the USA and Canada in 2014–2016 were tested. MIC was determined for cefiderocol, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI 2016 guidelines. All testing was done at IHMA, Inc. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth. Based upon CLSI breakpoints, carbapenem-non-susceptible (CarbNS) strains were defined as follows: MEM: MIC ≥2 µg/mL for Enterobacteriaceae, ≥4 µg/mL for non-fermenters. Quality control testing was performed on each day of testing by using E. coli ATCC25922 and P. aeruginosa ATCC27853.

Results

Cefiderocol exhibited in vitro activity against 4,133 strains of Gram-negative bacteria with an overall MIC90 of 0.5 µg/mL. At 4 µg/mL cefiderocol inhibited the growth of 99.9% of the all isolates. MIC90 of cefiderocol against CarbNS Enterobacteriaceae was 4 µg/mL although MIC90 of other comparators were >64 or >8 (CST) µg/mL. The cefiderocol MIC90value was 1 µg/mL for CarbNS non-fermeneters.

Conclusion

Cefiderocol demonstrated potent in vitro activity against Enterobacteriaceae, A. baumannii, P. aeruginosa, and S. maltophilia isolates collected from a UTI source, with greater than 99.9% of isolates having MIC values ≤4 µg/mL. These findings indicate that this agent has high potential for treating cUTI infections caused by these problematic organisms, including isolates resistant to colistin.

Disclosures

M. Tsuji, Shionogi & Co.: Employee, Salary; M. Hackel, IHMA: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee; Y. Yamano, Shionogi & Co.: Employee, Salary
In Vivo Efficacy of Tigecycline-based Therapy Against Vibrio vulnificus Sepsis: Comparison with pre-Existing Regimens
Authors: Eun Kim Seong , Choi Su-Mi , Kim Hee Kyung , Oh Tae Hoon , Kim Uh Jin , Kang Seung Ji , Park Kyung-Hwa , Jung Sook-In , Jang Hee-Chang
Published: October 2017

Background

The mortality of Vibrio vulnificus sepsis is still high, despite the application of various antibiotic regimens. In-vivo efficacy of tigecycline against V. vulnificus has not been examined.

Methods

Time-kill assay was performed to evaluate the presence of in-vitro antibiotic synergism. The cytotoxicity of V. vulnificus was measured by using the lactate dehydrogenase assay, and rtxA1 toxin gene transcription was measured by β-galactosidase assay. Subcutaneous injection of V. vulnificus was performed with 1 × 108 CFU on iron-overloaded female BALB/c mouse, then intraperitoneal antibiotic therapy was initiated 2 hours after bacterial inoculation.

Results

In vitro time-kill assay reveals synergism between tigecycline and ciprofloxacin. Inhibitory effects of tigecycline on rtx A1 transcription (66%) and cytotoxicity (59%) were comparable to those of ciprofloxacin (64% and 53%), but superior to those of minocycline (76% and 69%) or cefotaxime (86% and 83%; P < 0.05, each). Survival of tigecycline-treated mice were significantly higher than those of mice treated by current regimens (P < 0.05, each; Table). At Vibrio vulnificus sepsis mice inoculating 1 × 109 CFU, survival rate for tigecycline-plus-ciprofloxacin was significantly higher than that of tigecycline (0%; 0/19) or tigecycline-plus-cefotaxime (0%; 0/19) (P < 0.05, each; Table).

Conclusion

Tigecycline-plus-ciprofloxacin showed superior in-vivo efficacy to pre-existing regimens.

Disclosures

All authors: No reported disclosures.