bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of In Vitro Activity of Ceftaroline Tested against Streptococcus pneumoniae Isolates from United States Hospitals: Results from 7 Years of the AWARE Surveillance Program (2010–2016)
Authors: Pfaller Michael A , Mendes Rodrigo E , Duncan Leonard R , Flamm Robert K , Sader Helio S
Published: October 2017

Background

Ceftaroline (CPT) is a broad-spectrum cephalosporin with activity against S. pneumoniae (SPN), including multidrug-resistant (MDR) strains. CPT fosamil is approved for clinical use in the United States (US) to treat community-acquired bacterial pneumonia (CABP). The AWARE Program monitors the in vitro activity of CPT against clinical bacteria from various infection types. We evaluated the activity of CPT against isolated SPN clinical isolates from US hospitals collected in 2010 through 2016.

Methods

A total of 8,768 isolates were consecutively collected (1 per patient) from 47 medical centers in 2010–2016 and tested for susceptibility (S) to CPT and comparator agents using CLSI broth microdilution methods. Resistant subgroups included isolates that were nonsusceptible (NS) to penicillin (PCN), ceftriaxone (CRO), amoxicillin-clavulanate (AMC), erythromycin (ERY), clindamycin (CM), and levofloxacin (LEV) as well as MDR (NS to ≥3 classes of agents) and extensively drug resistant (XDR; NS to ≥5 classes).

Results

CPT inhibited 99.99% of SPN isolates at ≤0.5 mg/L (only 1 isolate had a CPT MIC of 1 mg/L) and remained active against all SPN-resistant (R) subgroups, including PCN-NS (8.7% at ≥4 mg/L), CRO-NS (6.9% at ≥2 mg/L), MDR (21.7%), and XDR (8.4%) strains. CPT activity remained stable against all R subgroups each year. MDR and XDR frequency decreased from 25.0% and 14.1% in 2011 to 17.8% and 3.2% in 2015, respectively; and S to PCN, CRO, AMC, CM, trimethoprim-sulfamethoxazole (TMX), and tetracycline (TET) increased in the same period (Table). The CPT-NS isolate had multiple substitutions in the penicillin binding proteins (PBP), mainly PBP2x, when compared with reference sequences, and showed 31 amino acid alterations in MurM. For MDR isolates, CPT (99.9%S), tigecycline (99.9%S), linezolid (100.0%S), and vancomycin (100.0%S) were the most active agents.

Conclusion

CPT demonstrated potent and consistent (2010–2016) activity against SPN, including several R phenotypes and the less S serotypes. SPN S to many antibiotics increased from 2011 to 2015, but remained stable in 2015–2016. Increases in S rates could be related to the anti-pneumococcal vaccine PVC-13 introduced in 2010.

Disclosures

M. A. Pfaller, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; L. R. Duncan, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant; H. S. Sader, Allergan: Research Contractor, Research grant
Activity of Ceftazidime–Avibactam Against Respiratory Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin America as Part of the INFORM Global Surveillance Program, 2014–2016
Authors: Kazmierczak Krystyna , Estabrook Mark , Stone Gregory G , Sahm Dan
Published: October 2017

Background

The β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) is active in vitro against isolates producing class A, C, and some class D β-lactamases, including extended-spectrum β-lactamases, stably derepressed AmpC, and serine carbapenemases. This study evaluated the in vitro activity of CAZ-AVI and comparators against respiratory isolates of Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) collected in Latin America from 2014–2016 as part of the INFORM surveillance program.

Methods

Non-duplicate isolates from hospitalized patients with lower respiratory tract infections were collected from 24 medical centers in Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela. Susceptibility (S) testing was performed by broth microdilution and interpreted using CLSI breakpoints except for CAZ-AVI (U.S. FDA) and colistin (EUCAST; Ebaonly). AVI was tested at a fixed concentration of 4 µg/mL with doubling dilutions of CAZ. Multidrug resistance (MDR) phenotype was defined as resistant by CLSI breakpoints to sentinel agents from ≥3 drug classes. Isolates were screened for β-lactamase genes by PCR and sequencing.

Results

CAZ-AVI showed potent in vitro activity against Eba isolates (MIC90, 0.5 µg/mL; 99.3% S) and against CAZ-non-susceptible (CAZ-NS), colistin-resistant (CST-R) and MDR subsets (>93% S). CAZ-AVI activity against meropenem-non-susceptible (MEM-NS) Eba (89.7% S) was reduced due to production of metallo-β-lactamases (MBL); MEM-NS MBL-negative isolates were 100% S. CAZ-AVI showed greater in vitro activity against Pae isolates (MIC90, 32 µg/mL; 85.4% S) than CAZ (69.2% S) or MEM (59.9% S). CAZ-AVI activity against CAZ-NS, CST-R, MEM-NS, MEM-NS MBL-negative, and MDR Paeisolates (50.4–92.6% S) also exceeded that of CAZ and MEM against these resistant subsets.

Conclusion

CAZ-AVI is a potential treatment option for respiratory infections in Latin America that are caused by Eba and Pae resistant to commonly used and last-in-line agents.

Funding: This study was sponsored by AstraZeneca. The AstraZeneca product ceftazidime-avibactam was acquired by Pfizer in December 2016.

Disclosures

G. G. Stone, Pfizer: Employee, Salary AstraZeneca: Shareholder, Capital Gains
Lyophilized Fecal Microbiota Transplantation Capsules for Recurrent Clostridium difficile Infection
Authors: Dupont Hebert , Jiang Zhi-Dong , Alexander Ashley , Ajami Nadim , Petrosino Joseph F , DuPont Andrew W , Ke Shi , Jun Goo , Hanis Craig
Published: October 2017

Background

Fecal microbiota (FM) transplantation (FMT) is a highly effective treatment of recurrent C. difficile infection (rCDI). We have published data showing efficacy of fresh, frozen and lyophilized donor microbiota administered by colonoscopy. Most groups are moving toward use of frozen product given by enema and in evaluating encapsulated product for oral delivery.

Methods

This was a prospective, randomized study of subjects with rCDI (≥ 3 episodes) treated with encapsulated lyophilized FM 100 g given once or 100 g given on two successive days (total 200 g) vs. frozen FM product 100 g given by single retention enema, between March 2015 and February 2017. The clinical outcome was absence of CDI during the 60 days after FMT. The subjects were followed for 6 months for safety. In a subset recipients, microbiome composition by 16S rRNA gene profiling were analyzed on stools obtained pre- and day 2, 7, 14, 30, 60 and 90 days after FMT.

Results

A total of 54 subjects were enrolled (37/54; 69% female) with a median age of 71 years (range: 20–97). In the first 14 subjects treated, cure rates for oral capsules 100 g FM was 5/8 (63%) vs. 6/6 (100%) for those receiving 100 g frozen FM by enema (P = 0.209). In the second phase of the study cure rate for oral capsules 200 g FM was 17/18 (91%) vs. 20/21 (94%) for the subjects treated by enema by 100 g of frozen product (P = 0.782). No side effects were felt to be related to the procedure or the FMT products were recorded during 6 months follow-up. Two subjects died during follow-up between 3 and 6 months after study due to underlying medical conditions felt to be unrelated to FMT. Microbiota analysis were performed on 40 subjects of which 19/40 (48%) had received capsules. Figure showed that restoration of the intestinal microbiome diversity and Taxa began apparent by 2 days after FMT in both groups and resembled the donor product by 2 weeks with stabilization of the microbiota diversity and Taxa persisting for the 90 days of observation.

Conclusion

Administration of encapsulated, lyophilized FM resulted in durable restoration of intestinal microbiome diversity comparable to results seen with frozen product given by enema.

Disclosures

All authors: No reported disclosures.
Discordance of SHEA/IDSA Clostridium difficile Disease Severity Scale in Solid Organ Transplant Patients
Authors: Lee Tiffany , McCoy Christopher , Alonso Carolyn D , Snyder Graham M , Rogers Christin , Richards Katelyn , Hirsch Elizabeth B , Mahoney Monica V
Published: October 2017

Background

Solid organ transplant (SOT) patients are at high risk for Clostridium difficile infections (CDI) due to chronic immunosuppression and a propensity to receive antimicrobials. Management of CDI in SOT patients poses unique challenges as this population has disease-altered clinical and laboratory parameters. The objective of this study was to assess concordance between various CDI severity scales and the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) guidelines.

Methods

This retrospective study included all SOT recipients with a first CDI episode following transplant and time-matched (2:1) to non-SOT patients experiencing first CDI episodes between 2008 and 2016. The primary endpoint was concordance rates of CDI episodes considered mild-moderate or severe/severe-complicated in published CDI scales compared with the SHEA/IDSA guidelines. We also sought to compare the distribution of CDI severity across all scales between SOT and non-SOT patients.

Results

Overall, 32 SOT patients and 64 non-SOT patients were included. The SOT group had significantly higher leukopenia rates at CDI diagnosis; however, the magnitude of serum creatinine change did not differ between groups. According to the SHEA/IDSA scale, CDI episodes in SOT recipients were categorized as mild-moderate and severe/severe-complicated in 23 (72%) and 9 (28%) patients, respectively. Overall concordance rates among SHEA/IDSA guidelines and other scales ranged from 28% to 72%. Concordance rates were highest for mild-moderate CDI with Belmares and for severe/severe-complicated CDI with ESCMID (Table 1). No scale evenly categorized SOT and non-SOT patients across all severities (Figure 1).

Conclusion

Severity scales with heavy emphasis on white blood cell counts may not adequately categorize SOT patients. Immunocompromised status may need to be considered on its own when categorizing CDI severity and prescribing therapy.

Disclosures

C. D. Alonso, Merck: Grant Investigator and Scientific Advisor, Research grant sanofi pasteur: Investigator and Scientific Advisor, Research support GSK: Investigator, Research support; E. B. Hirsch, Merck: Grant Investigator, Grant recipient The Medicines Company: Speaker’s Bureau, Speaker honorarium
Durability and Long-Term Clinical Outcomes of Fecal Microbiota Transplant (FMT) Treatment in Patients with Recurrent C. difficile Infection
Authors: Mamo Yafet , Woodworth Michael , Sitchenko Kaitlin , Dhere Tanvi , Kraft Colleen
Published: October 2017

Background

Fecal microbiota transplant (FMT) has been shown to be safe and effective for treatment of recurrent C. difficile infection (RCDI). The aim of this study is to determine factors impacting the durability of FMT and assess patient long-term clinical outcomes and satisfaction with the procedure.

Methods

Eligible patients who had received FMT for RCDI at Emory Hospital between July 1, 2012 and December 31, 2016 were contacted via telephone for a follow up survey. Of 232 patients who received FMT, 27 were deceased and 15 were unable to be reached with listed phone number. Of the remaining 190 eligible patients, 137 patients completed the survey.

Results

The median time-period between FMT and follow up was 22 months. Median number of failed antibiotic courses for RCDI before FMT was 4. Overall, 82% (113/137) of patients experienced resolution of RCDI post-FMT (non-RCDI group) while 18% (24/137) of patients had recurrence of CDI post-FMT (RCDI group). In the RCDI and non-RCDI groups, antibiotic use post-FMT for non- C. difficile-related infections was 75% and 38% (P = 0.0004), respectively. PPI use post-FMT was 38% and 31% (P = 0.28), and probiotic use post-FMT was 63% and 41% (P = 0.026) in the RCDI and non-RCDI groups, respectively. There were 18 hospitalizations in the RCDI group and 9 were related to C. difficile complications; of the 36 hospitalizations in the non-RCDI group, only 1 was related to chronic complication of a previous C. difficile infection. Overall, 11% of patients reported improvement or resolution of medical conditions not related to CDI post-FMT while 33% reported diagnosis of a new medical condition or development of new symptoms; none of the new medical conditions or symptoms were attributable to the procedure. In all, 95% of patients indicated willingness to undergo FMT in the future if they experience another bout of C. difficile infection.

Conclusion

The findings show that FMT is a highly effective treatment option for RCDI with a cure rate, defined as resolution of RCDI post-FMT or recurrence attributable to antibiotic use post-FMT, of 96% (131/137) in the study group. Furthermore, clinical outcomes and patient satisfaction post-FMT indicate the safety of the procedure.

Disclosures

All authors: No reported disclosures.
Fecal Microbiota Transplantation (FMT) for Recurrent/Refractory Clostridium difficile Infection (CDI) in Pediatric Immunocompromised Patients: A Single-center Experience
Authors: Kwendakwema Natasha , Jensen M Kyle , Pavia Andrew , Knackstedt Elizabeth Doby
Published: October 2017

Background

CDI is a common cause of bacterial diarrhea, especially in immunocompromised patients. Fecal Microbiota Transplanation (FMT) has been shown to be an effective treatment for recurrent and refractory CDI. The outcomes of FMT treatment for recurrent CDI have been well described in adult populations; however, the data for immunocompromised (IC) patients especially among children are limited. We describe the experience of FMT for treatment of CDI in immuncompromised pediatric patients.

Methods

We collected clinical data for IC patients <21 years in our pediatric institution who had received FMT for recurrent, refractory, and/or severe CDI. IC patients included those with: solid organ transplantation (SOT) receiving immunosuppressive medications; neoplasm; hematopoietic stem cell transplantation (HSCT); inflammatory bowel disease (IBD) requiring immunosuppressive medication(s). We collected demographic and clinical data, as well as outcomes, including: resolution of diarrhea, CDI relapse, and adverse events within 3 months post-FMT.

Results

We performed 37 pediatric FMT for recurrent, refractory, and/or severe CDI between September 2012 and February 2017. Of these, 12 were immunocompromised children: 2 with SOT; 3 with neoplasm and/or HSCT; and 7 with IBD on immunosuppressive medication(s). Median age was 11.9 years old (range 3–16 years). 6 (50%) experienced resolution of diarrhea within 1 week post-FMT, and 9 (67%) were C. difficile negative within 3 months of FMT (3 patients did not have follow-up testing). None had CDI relapse within 3 months post-FMT. 3 (25%) had adverse event(s) within 3 months post-FMT, 2 of whom had SAEs: 1 had graft rejection at 2 months post-FMT which ultimately required re-transplantion and 1 had aspiration pneumonitis immediately following FMT. 4 (50%) of the IBD patients had disease remission (clinical, biologic, and/or histologic) in the 3 months post-FMT.

Conclusion

FMT appears to be effective and reasonably safe for recurrent CDI in immunocompromised pediatric patients. However, the small numbers limit conclusions, especially about safety. Larger multicenter studies are needed to precisely determine safety and efficacy in this specialized population.

Disclosures

All authors: No reported disclosures.
Comparative Effectiveness of Vancomycin vs. Metronidazole in Mild Clostridium difficile Infections, and Potential Impact on Subsequent Vancomycin-Resistant Enterococcus (VRE) Isolation
Authors: Youngster Ilan , Lazarovitch Zipora , Bondorenco Marina , Mengesha Betlehem , Toledano Limor , Kachlon Yael , Marchaim Dror
Published: October 2017

Background

The epidemiology and clinical characteristics of Clostridium difficile infections (CDI) have evolved dramatically in the past decade. Vancomycin is the treatment of choice for moderate to severe CDI, with superior cure rates observed in comparative trials. However, controlled comparative efficacy data pertaining to mild CDI is lacking. Furthermore, the potential impact of vancomycin treatment on subsequent Vancomycin-Resistant Enterococcus (VRE) isolation rates remains unknown at the individual patient level.

Methods

A Retrospective cohort analysis was executed at the Assaf Harofeh Medical Center, Israel, from 2010 to 2015. Adult patients (>18 years) with a first episode of acute CDI, determined per pre-established criteria, were enrolled. The efficacy of vancomycin vs..metronidazole was evaluated in the subset of patients with mild CDI. The outcomes of patients, who received vancomycin or metronidazole (but not both), were compared by Cox regression. A prediction score was used to control for possible confounders associated with being treated with vancomycin. The independent association of oral vancomycin treatment during the acute CDI and later (up to 18 months) VRE isolation was analyzed using Cox regression.

Results

A total of 413 patients with CDI were included in the study. The majority were elderly (median age 75 years, range 19–120), and had extensive comorbidities (mean Charlson’s combined condition score 6.7 ± 3.4) and significant acute illness indices (35% with severe to fulminant Horn index). Among 126 patients with mild disease, no differences were observed in terms of clinical outcomes between vancomycin or metronidazole treatment. Metronidazole remained non-inferior even after incorporating a prediction score to control for confounders associated with being a “vancomycin case”. Ten patients had new post-CDI VRE isolation. In multivariable analysis, oral vancomycin treatment during the acute CDI was the strongest independent predictor for later isolation of VRE (aOR=6.7, P = 0.04).

Conclusion

Our study suggests that metronidazole should remain the recommended treatment of choice for mild CDI, due to clinical non-inferiority and an apparent association between vancomycin therapy and subsequent VRE isolation on an individual patient level analysis.

Disclosures

All authors: No reported disclosures.
Epidemiology of Clostridium difficile infection Among Patients with Newly Diagnosed or Relapsed Acute Leukemia: A Single-center Experience
Authors: Garcia Alexandra Franco , McMillen Tracy , Chow Hoi Yan , Eagan Janet , Sun Janine , Kamboj Mini
Published: October 2017

Background

Patients undergoing treatment for hematologic malignancy are at a higher risk for developing Clostridium difficile infection (CDI). We sought to determine the epidemiology of toxigenic C. difficile (TCD) carriage and CDI incidence among patients undergoing with newly diagnosed or relapsed acute leukemia.

Methods

Serial stool samples were collected from 92 patients with new or relapsed acute leukemia admitted at Memorial Sloan Kettering Cancer Center between August 26, 2011 to January 22, 2013. Only the first hospitalization during this time period was included. Screening was performed by toxigenic culture and polymerase chain reaction for tcdB gene regardless of symptoms of diarrhea. Genotyping was done by Multi Locus Sequence Typing (MLST). Acquisition of TCD, development of CDI, and associated clinical variables were recorded.

Results

A total of 92 patients were enrolled in the study. The mean age was 54.3 (median 57.5, range 21–86), 51 were male (55%). The majority (86, 93%) had newly diagnosed acute leukemia and 7% had relapsed disease. 60 patients (65%) had recent healthcare-related exposure, among these were 35 (38%) patients newly referred another facility. The most common chemotherapy regimen was Daunorubicin + Cytarabine in 71 subjects (77%). Systemic antibiotics of any duration during the same hospitalization were used in 89 patients (97%). Median length of stay (LOS) was 30.5 days (range 6–140 days).

Among the 92 subjects, 17 developed CDI within 90 days (18%), 12 (71%) had CDI during the index admission. Five among these 12 had known TCD colonization, genotyping of colonizing and CDI strains from the same patients were identical for all patients. CDI in subsequent hospitalizations occurred in 5 patients, 4/5 were new acquisitions. One patient with TCD colonization never developed CDI.

53 subjects (58%) underwent stem cell transplant at a median time of 4 months (range 2–19 months), 8 (15%) developed CDI within 30 days of the transplant admission.

Conclusion

CDI is exceedingly common among patients with acute leukemia. Acquisition of TCD and CDI occurs early in the treatment course. Approximately half of infections occur in patients with known TCD colonization. Extended LOS and high antibiotic usage are contributors to the high burden of CDI among this population.

Disclosures

All authors: No reported disclosures.
Increasing Economic Burden of Inpatient Clostridium difficile Infection in the United States: National Trends in Epidemiology, Outcomes, and Cost of Care from 2000 to 2014
Authors: Lee Ru Min , Fishman Neil O
Published: October 2017

Background

There is limited data addressing the epidemiology, costs, and outcomes of Clostridium difficile infection (CD) in hospitalized patients in the United States (U.S.). This study aims to estimate the characteristics, outcomes, and economic burden of patients hospitalized for CD in the US.

Methods

The Nationwide Inpatient Sample (NIS) database was used to obtain data from 2000–2014. The NIS contains data from over 7 million hospitalizations in the US per year, generalizable to the American population. The NIS was queried for ICD-9 codes for either a primary or secondary diagnosis of CD (008.45). Information for demographic data, length of stay (LOS), mortality, and hospital charges was evaluated.

Results

There were 1,256,783 total discharges from 2000–2014 with CD as the primary diagnosis and 4,204,338 total discharges during the same period with CD listed as any diagnosis. The number of hospitalizations with CD as primary diagnosis increased from 31,782 in 2000 to 107,760 in 2014. The number of hospitalizations with CD listed as any diagnosis increased from 134,518 to 361,945. Mean LOS decreased from 6.8 to 5.8 days and mean charges per hospitalization increased from $15,810 to $35,898 during the same time period. Aggregate charges increased from $0.51 billion to $3.87 billion annually. Inpatient mortality of CD hospitalizations decreased from a 4.03% in 2005 to 1.67% in 2014. Approximately 42% of those admitted for CD were male and 58% were female.

Conclusion

This study demonstrates that the number of hospitalizations for CD has increased by 339% from 2000 to 2014. Inpatient mortality of CD has decreased, likely from earlier recognition and treatment of CD. The direct cost of admissions with CD as primary diagnosis is nearly $4 billion per year. Our findings affirm that CD infection is an epidemic that remains a significant source of morbidity and mortality with substantial hospitalization and cost burden. This data can be used to support a return on investment for intervention strategies to prevent CD transmission and for new therapies.

Disclosures

All authors: No reported disclosures.
Declining Rates of Clostridium difficile infections (CDI) in Veterans Affairs (VA) Long-term Care Facilities (LTCF)
Authors: Evans Martin , Simbartl Loretta , Singh Maninder , Kralovic Stephen , Roselle Gary
Published: October 2017

Background

Clinically-confirmed hospital-onset CDI rates declined 15% in VA acute care facilities after implementation of a CDI Prevention Initiative in July 2012. A similar initiative was launched in VA LTCFs in February 2014. The Initiative featured a four-part bundle emphasizing 1) environmental management, 2) hand hygiene, 3) contact precautions for suspected or documented CDI cases, and 4) and institutional culture change where infection control becomes everyone’s business. This is a report of subsequent CDI rates in VA LTCFs.

Methods

Multidrug Resistant Organism prevention coordinators at each of the 132 VA reporting sites entered monthly CDI case data from February 2014 to December 2016 into a central database. A clinically-confirmed (CC) LTCF-onset CDI case was defined as a resident with clinical evidence of illness (i.e. diarrhea or histopathologic or colonoscopic evidence of pseudomembranous colitis) and a non-duplicate, non-recurrent positive diagnostic laboratory test collected ≥48h after admission. Quarterly CDI case rate trends were evaluated using negative binomial regression accounting for admission prevalence and diagnostic test type and compared with rates during a 24-month baseline period before implementation of the LTCF Initiative.

Results

During the 35-month analysis period, there were 145,421 admissions, 9,844,927 resident-days, and 1,480 CC-LTCF-onset CDI cases nationwide for a pooled CDI LTCF-onset rate of 1.50/10,000 resident-days. The use of nucleic acid amplification testing (NAAT) increased from 77.8% to 83.5% of facilities during the analysis period. CC-LTCF-onset CDI rates decreased 36% (P < .0001 for trend) (Figure 1).

Conclusion

As with acute care, LTCF-onset CDI case rates declined coincident with implementation of an initiative featuring a four-part bundle of interventions.

Disclosures

All authors: No reported disclosures.
The Clostridium difficile Infection – Daily Symptoms (CDI-DaySyms™) Patient-Reported Outcome (PRO) Questionnaire: Final Validation and Responder Thresholds
Authors: Talbot George H , Kleinman Leah , Davies Evan W , Hunsche Elke , Roberts Laurie , Nord Carl Erik
Published: October 2017

Background

Patient perspectives on their disease are undoubtedly important in clinical trials and in practice. To date, no patient-reported outcome (PRO) questionnaire assessing symptoms of Clostridium difficile infection (CDI) has been developed following FDA guidance. The CDI-DaySyms™ is a new comprehensive measure of a broad range of local and systemic CDI symptoms (not only diarrhea) that patients report as meaningful. Objectives were to: finalize the CDI-DaySyms™ items (questions); assign them to domains (concepts); evaluate the questionnaire’s measurement properties; and define responder thresholds.

Methods

Blinded data from a sub-study of two Phase III trials (NCT01987895 and NCT01983683) in CDI patients were analyzed following FDA guidance for validating PRO questionnaires. Patients completed the CDI-DaySyms™ daily from Day 1 until end of treatment. Items were selected for inclusion in the final questionnaire based on a range of validation analyses, input from expert clinicians, and findings from prior qualitative patient research. Responder-threshold analyses used Day-3 data to align with the rapid symptom improvement generally seen in response to CDI therapy.

Results

Data were analyzed for 168 CDI patients (median age 60 years; 67.9% female; 81.5% mild/moderate, 11.3% severe, 7.1% unknown disease severity; 80.4% first CDI occurrence, 19.6% first recurrence). Three of the 13 items in the draft CDI-DaySyms™ were deleted; the remaining 10 were statistically assigned to three domains measuring different symptom concepts (Figure). Individual items in each domain correlated strongly with one another and their domain. Domain scores demonstrated acceptable consistency over time in stable patients, were sensitive to change, and correlated in expected directions with scores of other relevant symptom and disease-severity measures. Responder thresholds were defined as score changes of -1.00, -0.80, and -0.70 for Diarrhea, Abdominal, and Systemic/Other Symptoms domain scores, respectively.

Conclusion

The CDI-DaySyms™ is a valid measure of diarrhea and other CDI symptoms useful in assessing response to therapy. It has good measurement properties, and with only 10 items can be easily administered in clinical trials and in practice.

Disclosures

G. H. Talbot, Actelion: Board Member, Consultant and Scientific Advisor, Consulting fee; L. Kleinman, Actelion: Consultant, Research support;   E. W. Davies, Actelion: Employee, Salary; E. Hunsche, Actelion: Employee and Shareholder, Salary; L. Roberts, Actelion: Consultant, Research support; C. E. Nord, Actelion: Scientific Advisor, Consulting fee
Line of Service-Specific Performance and Antibiotic Prescribing Habits Following Introduction of a Two-Step Diagnostic Approach Using NAAT Followed by Enzyme Immunoassay in Cancer Patients with Suspected Clostridium difficile Infection
Authors: Chao Andrew , Yalamanchili Harika , Guevara Eduardo Yepez , Bhatti Micah , Aitken Samuel L , Okhuysen Pablo
Published: October 2017

Background

Patients with cancer are at an increased risk for C. difficile infection (CDI). A two-step approach with a Nucleic Acid Amplification Test (NAAT) followed by enzyme immunoassay (EIA) increases diagnostic sensitivity and specificity and can be used to guide antibiotic therapy. We retrospectively investigated the relative performance of the two-step approach in cancer patients with solid tumors (ST), hematologic malignancies (HS), and hematopoietic stem cell transplant recipients (HSCT).

Methods

We identified 204 patients with a positive NAAT test for CDI as determined by GI multiplex (Biofire) or by Illumigene (Meridian, Bioscience) in whom a reflex EIA was performed for C. difficile A/B toxins between November 2015 and February 2017. Patients were stratified into ST, HM, HSCT groups. We compared the proportion of discordant NAAT+, EIA- results among the three groups. We then compared the clinical presentation and antibiotic use for patients in the NAAT+/EIA- to those with NAAT+/EIA+ results.

Results

Overall an EIA+ result was found in 53 (26%) patients. The proportion of patients with NAAT+/EIA+ results was significantly different between the three lines of service; ST 31/86 (36%), HM 16/62 (26%), and HSCT 6/56 (11%) P < 0.01. A trend towards a higher proportion of positive results was observed for ST compared with the HM group (P = 0.06). Results were similar between the HM and HSCT group. However, patients in the ST were more likely to have a positive EIA when compared with HSCT patients (36% vs. 11% P < 0.01). Clinical presentation and healthcare-association were similar in all three groups regardless of the EIA result. Despite the low proportion of EIA+ confirmatory results, the majority of patients (196/204 96%) received antibiotic therapy targeting CDI. Discontinuation of CDI antibiotics prior to 10 days of therapy was similar in the EIA+ (12%) vs. EIA- (10%).

Conclusion

The relevance of discordant results needs to be interpreted in the context of the line of service/patient care unit. The presence of CDI as determined by NAAT/EIA is low in patients with other potential causes of diarrhea such as in HSCT recipients. A substantial proportion of cancer patients are treated unnecessarily for CDI.

Disclosures

All authors: No reported disclosures.
Using Clinical Decision Support to Improve Evidence Based Testing and Diagnosis of Clostridium difficile Infection
Authors: Miller Bahnsen , O’Neal Catherine , Hamer Diana
Published: October 2017

Background

Diagnosing Clostridium difficile infection (CDI) requires clinical understanding of the disease and knowledge of diagnostic testing limitations. It is important for providers to utilize CDI testing only in patients with suspected disease. Real-time polymerase chain reaction (PCR) assays are sensitive but cannot differentiate between symptomatic and asymptomatic patients. Individual hospitals have reported a 50% to 100% increase in the rate of CDI after substituting toxin tests with molecular tests such as PCR. We conducted a quality improvement project, implementing clinical decision support in ordering diagnostic testing of CDI, while measuring the number of diagnostic tests ordered and positive results.

Methods

We implemented evidence based clinical decision support into Cerner order entry system on March 1, 2016. The Cepheid Xpert C. difficile molecular test is used for diagnosis of CDI at our facility. The decision support included a message stating Òuse the test with caution in patients who are receiving tube feeds or recent laxative useÓ and prompted ordering providers to select one of three indications for using the test: 3 or more diarrheal stools per 24 hour period, leukocytosis with abdominal pain, or ileus. A control chart was used to monitor the number of tests ordered and positive tests per month (inpatient adults) for a total of 24 months; 14 months pre-intervention and 10 months post-intervention.

Results

A decrease in the number of tests ordered per month was seen post intervention. Average number of monthly tests ordered was 207 pre-intervention and 163 post-intervention. After controlling for patient-days per month, there was a 13.5% decrease in the number of tests ordered from a mean of 14.29 vs.. 12.37 tests per thousand patient-days per month. This resulted in special cause variation (Figure 1). There was no special cause variation detected with the number of positive PCRs per month, pre and post intervention.

Conclusion

Implementing decision support into the electronic medical record may assist providers with evidence-based utilization of the C. difficile PCR by decreasing unnecessary testing. This decrease may also have an impact on overall hospital costs, antibiotic utilization, and public reporting related to CDI.

Disclosures

All authors: No reported disclosures.
An Assessment of 2016 National Healthcare Safety Network (NHSN) and National Electronic Disease Surveillance System (NEDSS) Clostridium difficile Infections (CDI) in Nebraska
Authors: Pedati Caitlin , Sullivan Madison , Drake Margaret , Keyser Alison , Safranek Tom , Tierney Maureen
Published: October 2017

Background

In 2016 all acute care hospitals, inpatient rehab facilities, and PPS-exempt cancer facilities in Nebraska were required to report laboratory identified (LabID) Clostridium difficile infections (CDIs) to the National Healthcare Safety Network (NHSN). Test results indicating CDIs must be reported to the Nebraska Department of Health and Human Services (NDHHS) via the National Electronic Disease Surveillance System (NEDSS). NHSN and NEDSS represent unique sources of CDI reports in Nebraska.

Methods

The NHSN Nebraska database was queried for CDIs reported in 2016. All lab tests indicating a CDI in 2016 were extracted from NEDSS. These extracts were analyzed to assess descriptive epidemiologic variables and compared for differences.

Results

In 2016 there were 1,546 CDI LabID events reported to NHSN Nebraska from 28 facilities. There were 249 outpatient CDIs and 1,297 inpatient CDIs. Infections were further characterized as community-onset (N = 773), community-onset, healthcare facility associated (N = 206), and hospital onset (N = 567). An average of 128 CDIs were reported per month (range: 111–155).

In 2016 there were 2,177 lab results indicating a CDI reported to NEDSS among Nebraska residents from 42 facilities. Patient ages ranged from 4 months to 104 years (mean = 58 years). An average of 181 CDIs were reported per month (range: 151–218).

Comparison of the two data sources found 781 reports among 591 unique patients at 11 facilities that were made to NHSN and were not in NEDSS. Additionally, there were 1,092 reports from 931 unique patients at 12 facilities that were made to NEDSS and should have been made to NHSN but were not. There were 9 shared facilities that accounted for the majority of these discrepancies.

Conclusion

NHSN and NEDSS represent two unique data sources that allow for a more comprehensive assessment of CDIs. The number and type of facility that report to each system is slightly different but there is some overlap. Therefore, this comparison allows for detection of a greater number of reports overall and also provides an opportunity for data validation. This assessment identified discrepancies in reporting among 9 facilities that can be targeted for further collaborative efforts to improve CDI reporting and management in Nebraska.

Disclosures

All authors: No reported disclosures.
Cap-dependent Endonuclease Inhibitor S-033188 for the Treatment of Influenza: Results from a Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Study in Otherwise Healthy Adolescents and Adults with Seasonal Influenza
Authors: Portsmouth Simon , Kawaguchi Keiko , Arai Masatsugu , Tsuchiya Kenji , Uehara Takeki
Published: October 2017

Background

Cap-dependent endonuclease (CEN) resides in the PA subunit of influenza virus polymerase and mediates the “cap-snatching” process during viral mRNA biosynthesis. S-033188 is a potent, selective, small molecule inhibitor of CEN. Here we report clinical and virologic outcomes from a global Phase 3 study CAPSTONE-1.

Method

This was a multicenter, randomized, double-blind, placebo- and active-controlled study. Key eligibility criteria included 12–64 years of age, fever (axillary temperature ≥38.0°C), ≥1 general symptom and ≥1 respiratory symptom (moderate to severe), and ≤48 hours from symptom onset. Patients between 20 and 64 years of age were randomized in 2:2:1 ratio to receive a single oral administration of S-033188, placebo, or 75 mg oseltamivir BID for 5 days. Patients between 12 and 19 years of age were randomized in 2:1 ratio to receive either a single oral administration of S-033188 or placebo. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in the infected intent to treat population. Viral titer and RNA content were determined from pre- and postdose nasal/throat swabs.

Result

A total of 1436 patients were randomized. TTAS was significantly shorter in the S-033188 group than that in the placebo group (median TTAS: 53.7 hours vs. 80.2 hours, P < 0.0001). Median time to cessation of viral shedding was 24 hours in patients treated with S-033188, compared with 72 hours in those treated with oseltamivir (P < 0.0001) and 96 hours for placebo (P < 0.0001). Patients in the S-033188 group had significantly greater reductions from baseline in both viral titer and RNA content than those in oseltamivir or placebo groups at all time-points until Day 3 (compared with oseltamivir) or Day 5 (compared with placebo). S-033188 was generally well tolerated, with overall incidence of treatment-emergent adverse events lower than that seen with oseltamivir.

Conclusion

Treatment with S-033188 was superior to placebo in alleviating influenza symptoms, and superior to both oseltamivir and placebo in virologic outcomes. Safety profile of S-033188 compared favorably with that of oseltamivir.

Disclosures

S. Portsmouth, Shionogi Inc.: Employee, Salary. K. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary. M. Arai, Shionogi & Co Ltd: Employee, Salary. K. Tsuchiya, Shionogi & Co., Ltd.: Employee, Salary. T. Uehara, Shionogi & Co., Ltd.: Employee, Salary.
Ethanol Lock Treatment and Secondary Prophylaxis for Central Line-Associated Bloodstream Infection in Pediatric Hematology and Oncology: A Randomized, Double-Blind, Placebo-Controlled, Intervention Trial
Authors: Wolf Joshua , Connell Tom , Allison Kim J , Tang Li , Richardson Julie , Branum Kristen , Borello Eloise , Gaur Aditya , Hakim Hana , Su Yin , Mechinaud Francoise , Hayden Randall , Monagle Paul , Worth Leon , Curtis Nigel , Flynn Patricia M
Published: October 2017

Background

Central line-associated bloodstream infection (CLABSI) commonly affects children with cancer and hematological disorders, with significant attributable costs and morbidity. Treatment failure, comprising persistent infection, infection relapse or new infection, occurs in ~50% of cases. Adjunctive ethanol lock therapy (ELT) has been proposed to prevent failure, but has never been tested in a prospective controlled study.

Methods

A prospective, dual-center, double-blind, block-randomized, placebo-controlled trial of ELT (70% ethanol in water) for CLABSI, given as treatment (2 hours per lumen per day) for 5 days, followed by secondary prophylaxis (2 hours per lumen up to 3 days per week) for 24 weeks, in children with oncologic or hematologic disorders (NCT01472965). Risk of treatment failure was compared between intervention and control groups according to proportional and cumulative incidence models, using intention-to-treat and per-protocol analyses. The study was discontinued at a pre-specified futility analysis.

Results

Of 94 evaluable participants, 48 were randomized to ELT and 46 to placebo; groups were similar at baseline for all measured variables. Forty-one (43.6%) participants had treatment failure (11 early failure, 9 relapse, and 21 reinfection). There was no difference between patients receiving ELT or placebo for risk of treatment failure (43.8% vs. 43.5%; P = 0.9) or for cumulative incidence of treatment failure in intention to treat (Figure 1) and per-protocol analyses (Figure 2). Catheter occlusion was significantly more common in participants receiving ethanol (58.3% vs. 32.6%, P = 0.01) but other adverse events, including LFT elevations (14.6% vs. 26.1%) and infusion reactions (18.8% vs. 8.7%), were not significantly different between groups.

Conclusion

Although observational studies suggested ELT might be effective for treatment of CLABSI in pediatric oncology, we found no benefit in treatment outcome and an increase in adverse effects. These results may not apply to patients receiving dialysis or with fungal CLABSI as these were not well-represented. Routine use of ELT for CLABSI in children with oncologic or hematologic disorders is not recommended.

Disclosures

All authors: No reported disclosures.
Effect of Dry Heating on Physicochemical Properties of Pregelatinized Rice Starch
Authors: Lee Su‐Jin , Yang Yu‐Jin , Chung Hyun‐Jung , Lim Seung‐Taik
Published: October 2017

Japonica and indica rice starches (10% w/w) were pregelatinized in a boiling water bath for 5 or 10 min and subsequently heat‐treated in a dry state for 0, 1, 2, or 3 h at 130°C to examine the effects of dry heating on pasting viscosity, paste clarity, thermal properties, X‐ray diffraction pattern, and gel strength of pregelatinized starches. Heat treatment obviously changed the physicochemical properties of pregelatinized rice starch. The pregelatinized rice starches had higher peak viscosity and final viscosity than the corresponding native rice starches. Heat treatment of pregelatinized rice starch for 1 h increased the peak viscosity, but treatment for 2 or 3 h decreased the peak viscosity compared with the unheated pregelatinized rice starch. The indica rice starch exhibited more substantial changes in pasting viscosity than did japonica rice starch during heat treatment. The melting enthalpy of the endothermic peak occurred at 90–110°C, and the intensity of the X‐ray diffraction peak at 20° was increased by dry heating, possibly owing to the enhanced amylose‐lipid complexes. The dry heat treatment of pregelatinized starch caused an increase in paste clarity and a decrease in gel strength.
Sensitivity of Phacidiopycnis spp. Isolates from Pome Fruit to Six Pre- and Postharvest Fungicides
Authors: Ali Emran Md. , Pandit Laxmi K. , Mulvaney Katie A. , Amiri Achour
Published: October 2017

Phacidiopycnis washingtonensis and P. pyri cause speck rot and Phacidiopycnis rot on apple and pear, respectively. Infection occurs in the orchard and remains latent, and symptoms appear after months of storage. Decay management relies on orchard sanitation and pre- and postharvest fungicides. In a 2017 survey, speck rot accounted for 6.4% of apple decay in central Washington, whereas Phacidiopycnis rot accounted for 3.9 and 6.7% of total pear decay in Washington and Oregon, respectively. Sensitivities of baseline populations of 110 P. washingtonensis and 76 P. pyri isolates collected between 2003 and 2005 to preharvest fungicides pyraclostrobin (PYRA) and boscalid (BOSC) and to postharvest fungicides thiabendazole (TBZ), fludioxonil (FDL), pyrimethanil (PYRI), and difenoconazole (DFC) were evaluated using a mycelial growth inhibition assay. Mean effective concentrations necessary to inhibit 50% growth (EC50) of P. washingtonensis were 0.1, 0.3, 0.8, 1.8, 2.1, and 4.8 µg/ml for FDL, PYRI, TBZ, DFC, PYRA, and BOSC, respectively. Respective mean EC50 values for P. pyri were 0.2, 0.6, 1.6, 1.1, 0.4, and 1.8 µg/ml. The sensitivity of exposed P. washingtonensis and P. pyri populations collected in 2017 revealed potential shifts toward BOSC and PYRA resistance. The efficacy of the six fungicides to control isolates of each pathogen with different in vitro sensitivity levels was evaluated on apple and pear fruit. FDL, DFC, and PYRI controlled both Phacidiopycnis spp. regardless of their EC50 values after 5 months of storage at 0°C in a regular atmosphere. The consistent occurrence of Phacidiopycnis spp. will require continuous monitoring and development of disease management strategies based on fungicide phenotypes and efficacy of existing fungicides assessed herein.
The Pediatric Cardiac Intensive Care Unit Parental Stress Model
Authors: Lisanti Amy Jo , Golfenshtein Nadya , Medoff-Cooper Barbara
Published: October 2017

This descriptive, qualitative study used directed content analysis to explore and clarify specific foci of parental stress for mothers of infants with complex congenital heart disease in the pediatric cardiac intensive care unit (PCICU). The PCICU Parental Stress Model was used as the guiding theoretical framework. Three focus groups were conducted with 14 mothers of infants who were being cared for in a PCICU at a large mid-Atlantic children's hospital. Data provided themes to support and refine the PCICU Parental Stress Model that can be used to guide practice, education, and future research in this unique population and setting.
Low-dose Aspirin Inhibits Cardiac Sympathetic Activation and Vagal Withdrawal Response to Morning Rising
Authors: Yasumasu Tomiya , Takahara Kazuo , Otsuji Yutaka
Published: October 2017

Aspirin is known to interfere with platelet function and can protect individuals at risk of sudden death. However, this property of aspirin is less defined for cardiac autonomic activity. We assessed pulse rate variability by spectral analysis and measured plasma eicosanoid levels before and after administration of 81-mg aspirin to 12 healthy subjects over a 60-degree head-up tilt test in the morning. In upright posture, low-dose aspirin decreased both the normalized unit value of low-frequency (normalized LF) power (mean ± SD, 82.5 ± 4.5 vs. 77.5 ± 6.5 nu, P = 0.01) and LF/HF ratio (6.0 ± 2.1 vs. 4.7 ± 2.7, P = 0.02) and augmented the normalized unit value of high-frequency power (15.0 ± 4.4 vs. 19.8 ± 6.4 nu, P = 0.004). It simultaneously upregulated plasma 6-keto-PGF1α level (13.4 ± 6.8 vs. 19.7 ± 12.8 pg/mL, P = 0.04) and inhibited plasma thromboxane B2 (TXB2) level (11.6 ± 7.3 vs. 6.3 ± 4.2 pg/mL, P = 0.003). In the upright posture, both before and after aspirin, there was a significant direct correlation between plasma TXB2 levels and the normalized LF power (r = 0.42, P = 0.04) as well as between the plasma TXB2/6-keto-PGF1α ratio and the normalized LF power (r = 0.50, P = 0.01). Administration of low-dose aspirin in healthy people inhibits cardiac sympathetic activation and vagal withdrawal response to morning rising through an alternation of the TXA2/PGI2 balance.