bluuebunny/crossref_metadata_2025_split huggingface dataset:
165. Mycobacterium tuberculosis Produces Molecules That Trigger Nociceptive Neurons to Activate Cough
Authors: Ruhl Cody , Kindt Lexy , Khan Haaris , Stamm Chelsea E , Pasko Breanna , Franco Luis , Shiloh Michael U 
Published: November 2018

Abstract

Background
A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals, and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough, thereby facilitating its spread from infected to uninfected individuals.

Methods
We used an in vitro neuronal activation bioassay to fractionate, identify, and characterize Mtb cough-inducing molecules. We also measured cough in vivo in response to pure Mtb-derived cough molecules and during Mtb infection using a guinea pig model.

Results
We found that an acellular organic extract of Mtb triggers and activates nociceptive neurons in vitro with a neuronal response that is as robust as the response to capsaicin, an established nociceptive and cough-inducing molecule. Using analytical chemistry and our neuronal bioassay, we then isolated 2 molecules produced by Mtb that activate nociceptive neurons. Both the organic Mtb extract and purified molecules alone were sufficient to induce cough in a conscious guinea pig cough model. Finally guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules.

Conclusion
We conclude that Mtb produces molecules that activate nociceptive neurons and induce cough. These findings have significant implications for our understanding of Mtb transmission.

Disclosures
All authors: No reported disclosures.
855. Impact of FDA Black Box Warning on Fluoroquinolone and Alternative Antibiotic Use in Southeastern US Hospitals
Authors: Yarrington Michael , Anderson Deverick J , Ashley Elizabeth Dodds , Jones Travis , Johnson Melissa , Lokhnygina Yuliya , Sexton Daniel , Moehring Rebekah W 
Published: November 2018

Abstract

Background
Many antimicrobial stewardship programs have set goals to reduce the use of fluoroquinolones because of risks of causing C. difficile and other adverse safety events. The US Food and Drug Administration issued a black box label warning for fluoroquinolones in June 2016 recommending avoidance of this class for treatment of uncomplicated infections.

Methods
We performed a retrospective cohort study of antimicrobial use (AU) data in 29 southeastern United States hospitals from 2013 to 2017. An interrupted time series approach with segmented negative binomial regression modeling was used to estimate the longitudinal trend and effect of the FDA safety announcement on AU rates. Fluoroquinolone and alternative antibiotic agent use rates were measured as days of therapy (DOT) per 1,000 patient days. Alternative antibiotics were analyzed individually or in groups (e.g., community-onset agent group included ceftriaxone, cefotaxime, and ertapenem).

Results
Hospital AU data for the 60-month period included a total of 6,685,950 patient days; 8 to 29 hospitals contributed AU data to estimates each month. FQ use rates declined at a consistent rate of approximately 1 DOT/1,000 patient days per month resulting in an overall 10% decrease prior to the FDA warning. A significant drop in FQ use rates occurred at the time of the announcement (P = 0.002), but there was no significant change in trend [rate ratio (RR) 0.89, 95% CI 0.79–1.01, P = 0.07, Figure 1]. Alternative antibiotic use significantly increased for the following antibiotic groups after the warning: community-onset agents (RR 1.24, 95% CI 1.11–1.38), atypical agents (RR 1.40, 95% CI 1.19–1.66), and third-generation cephalosporins (RR 1.54, 95% CI 1.19–1.65). Antipseudomonal β-lactam use remained stable (RR 0.96, 95% CI 0.88–1.05, P = 0.3).

Conclusion
Fluoroquinolone use was declining in our network prior to the FDA announcement and continued to decline after 2016. This is likely due to stewardship activities focusing on quinolone-sparing treatment guidelines. AU shifted away from FQ toward third-generation cephalosporins and atypical agents.

Disclosures
All authors: No reported disclosures.
856. Impact of Early Discontinuation of Antimicrobial Therapy on Survival in Culture-Negative Clinically Suspected Serious Infection: An Electronic Health Record-Based Analysis From 111 US Hospitals
Authors: Kadri Sameer S , Klein Eili , Gandra Sumanth , Rhee Chanu , Klompas Michael , Laxminarayan Ramanan 
Published: November 2018

Abstract

Background
Up to 40% of inpatients started on antibiotics for suspected infection have negative cultures from all tested body sites. The optimal duration of treatment for these patients is unknown.

Methods
Adults admitted to 111 hospitals between 2009 and 2015 with clinically suspected serious infection but negative cultures were identified. We deemed patients to have clinically suspected serious infection if blood cultures were drawn on hospital day 1 or 2 and IV or PO antibiotics were initiated on the day of or after blood culture draw and continued for ≥3 days. We compared outcomes for patients treated with 3–4 vs. ≥5 days of antibiotics. We excluded patients on vasopressors beyond day 2. We calculated odds ratios for in-hospital mortality (including discharge to hospice), C. difficile infection (CDI), subsequent sepsis, and antibiotic restarts &gt;1 day after discontinuation using logistic regression, adjusting for age, race, Sequential Organ Failure Assessment (SOFA) score, and several co-morbidities; findings were confirmed by determining the average treatment effect on the treated (ATET) using propensity matching.

Results
We identified 179,421 patients with clinically suspected serious infection. Of these, 71,786 (40%) had all negative cultures; 26,437 (37%) were treated with 3–4 days of antibiotics; and 45,349 (63%) were treated with ≥5 days. Patients treated with shorter courses were younger, had lower SOFA scores, and were less likely to have concomitant sepsis. There was no difference in mortality for short vs. long course treatment (4.7% vs. 6.5%, aOR 1.01 [95% CI 0.93–1.11]; ATET=1.002 [0.998–1.006]; P = 0.46). Patients treated with short courses were less likely to develop CDI (aOR 0.55 [0.47–0.66]) or subsequent sepsis (aOR 0.26, 0.17–0.41) but more likely to have antibiotic restarts (3.9% vs. 3.6% aOR 1.53 [1.35–1.73]). Mortality was lower, however, amongst patients with antibiotic restarts who initially received short (vs. long) courses (aOR 0.76 [0.57–1.00]).

Conclusion
We found no difference in mortality for patients with culture-negative clinically suspected serious infection treated with 3–4 days vs. ≥5 days. Patients treated with short courses had less CDI and sepsis after discontinuation of antibiotics but higher rates of antibiotic restarts. A randomized, controlled trial is warranted to confirm or refute these findings.

Disclosures
R. Laxminarayan, Merck: Board Member, Educational grant.
864. Therapeutic Immunosupression to Treat Rabies Encephalitis
Authors: S Divyashree , Shrivastava Archana , Sontakke Tushar , Venkitachalam Anil 
Published: November 2018

Abstract

Background
Rabies is nearly universally fatal with about 60,000 annual deaths globally; &lt;0.1% cases survive. Reports of therapeutic coma leading to survival are outnumbered by reports of failure. On the basis of personal discussions with a leading rabies expert (Dr Rodney Willoughby), we hypothesized that limiting CNS immune response based on CSF antibody titre (ABT) might prove useful. We report on successful use of immunosuppression in 1 patient.

Methods
A 26-year-old male was admitted with 2-day history of flu-like syndrome. He had category III dog bite on face 17 days prior. RIG was not given due to nonavailability; he had received ARV day 0, 3, 7, and 14 on time. On 4th day of admission (day 0), neurological features started—difficulty in walking and diplopia; hydrophobia was noted. Working diagnosis of rabies was made. MRI brain on day 1 showed subtle abnormal T2 and flair hyper intensities in pons, medulla, and left hippocampus. CSF (day 1) showed 105 cells; all lymphocytes. The RFFIT serum and CSF ABTs and rabies PCRs are tabulated below. Since ADEM was a possibility, he was begun on IVIg. Work up for other viral encephalitis was negative. Repeat CSF ABT on day 6 confirmed rabies. Postulating risk of death due to cerebral edema due to CNS immune response, dexamethasone (dexa) 6 mg/kg/day in 4 divided doses was begun on day 8. Serial MRI and CSF were done. Dexa taper was done based on MRI and CSF ABT. Intensive supportive care was given.

Results
MRI on day 9 and day 12 showed no cerebral edema. Dexa taper was started from day 13 by half every alternate day; it was given till day 28. By day 17, there was intermittent eye opening, withdrawal to pain and some orofacial and limb movements. Further recovery had waxing and waning course. Now he is nearly 1 year post rabies encephalitis. He is unable to talk or comprehend, but can sit independently and is able to walk with support.

Conclusion
Immunosuppressive therapy with dexa to improve outcomes in rabies seems an exciting option. Optimal dose, time of start, and taper schedule need further studies. CSF ABT-based tapering appears promising. Larger studies with this approach are needed.

Disclosures
All authors: No reported disclosures.
867. Upregulated Matrix Metalloproteinase-2 Relates to Milder Hearing Impairment in Bacterial Meningitis
Authors: Savonius Okko , Roine Irmeli , Alassiri Saeed , Tervahartiala Taina , Helve Otto , Fernandez Josefina , Peltola Heikki , Sorsa Timo , Pelkonen Tuula 
Published: November 2018

Abstract

Background
Hearing impairment is a well-recognized sequela caused by bacterial meningitis, but the underlying pathophysiology remains largely unknown. Matrix metalloproteinase-2 (MMP-2) is known to affect neuronal cell damage and survival in different diseases of the brain. We investigated whether levels of MMP-2 in the cerebrospinal fluid (CSF) relate to the extent of hearing impairment in children with bacterial meningitis.

Methods
Clinical data of 179 children were obtained from a previous clinical trial examining the adjuvant treatment of bacterial meningitis in Latin America in 1996–2003. At discharge or shortly thereafter, the ability to hear was measured with brain stem evoked response audiometry or traditional pure tone audiometry. Levels of CSF MMP-2 on admission (CSF1, n = 161) and 12–24 hours later (CSF2, n = 133) were assessed by zymography. The combined results for the detected pro-form and active MMP-2 were compared with the audiological outcome of the patients.

Results
MMP-2 was detected in half of both the CSF1 and CSF2 samples. The median densitometric values with interquartile ranges (IQRs) were 0.04 (IQR 0.00–0.29) for CSF1 and 0.00 (IQR 0.00–0.33) for CSF2. Detectable MMP-2 associated with milder hearing impairment in CSF1 (P = 0.05), but not in CSF2 (P = 0.1). Patients who were deaf at discharge had lower levels of MMP-2 in both samples (CSF1, P = 0.05; CSF2, P = 0.04), compared with patients who were not deaf. A MMP-2 level over the 75th percentile in CSF1 predicted lower odds of any audiological sequelae (odds ratio 0.30, 95% confidence interval 0.14–0.68, P = 0.004).

Conclusion
The upregulation of MMP-2 in the CSF associated with a better audiological outcome in children with bacterial meningitis. The results suggest that MMP-2 might play a protective role in the development of hearing sequelae due to bacterial meningitis.

Disclosures
All authors: No reported disclosures.
869. Evaluation of Broad-Spectrum Antibiotic De-Escalation in Patients with Health-Care Associated Pneumonia (HCAP) and No Microbiological Diagnosis
Authors: Patel Twisha S , Petty Lindsay , Conlon Anna , Eschenauer Gregory , Nielsen Daniel , Vaughn Valerie , Kaye Keith S , Malani Anurag , Osterholzer Danielle , Thyagarajan Rama , Flanders Scott , Gandhi Tejal N 
Published: November 2018

Abstract

Background
Broad-spectrum (BS) antibiotics directed against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are commonly used for health-care associated pneumonia (HCAP) treatment. Many patients with HCAP do not have a microbiologically confirmed diagnosis. The goal of this study was to evaluate the impact of antibiotic de-escalation on clinical outcomes in patients with HCAP without a microbiological diagnosis.

Methods
This is a retrospective cohort study of adult, non-ICU, medical patients hospitalized with HCAP between January 2016 and February 2018 at 46 Michigan hospitals. Exclusions included extrapulmonary infection, severe immune suppression, or clinical instability on day 4. Included patients: (1) lacked any positive culture (blood/sputum); (2) started on empiric anti-P. aeruginosa and anti-MRSA therapy by hospital day 2; (3) switched to a narrow-spectrum (NS) regimen (no anti-P. aeruginosa or anti-MRSA coverage) or maintained on BS antibiotics (anti-P. aeruginosa ± anti-MRSA) by therapy day 4 (Figure 1). Mortality, readmission, Clostridium difficile infection, and adverse events from antibiotics were compared between the BS and NS groups. Data were analyzed using logistic generalized estimating equation models and inverse probability of treatment weighting.

Results
Of 363 patients with HCAP included, 73 (20%) were switched to an NS regimen. Of 290 patients maintained on anti-PSA BS regimens, 47.6% also continued anti-MRSA therapy. The median age was 72 (IQR, 61–81) and Charlson comorbidity index was 4 (IQR, 2–6) of the entire cohort. Baseline characteristics were similar between BS and NS groups, except more patients had chronic kidney disease in the BS group. On multivariable analysis, no other baseline factors were found to be associated with use of BS antibiotics on day 4. Both total and IV antibiotic duration were longer in the BS group (10 vs. 8 days, P = 0.002, and 4 vs. 3 days, P &lt; 0.001, respectively). On adjusted analysis, there were no differences in patient outcomes (Figure 2).

Conclusion
Among patients with HCAP started on empiric MRSA and PSA coverage without microbiological diagnosis, clinical outcomes were similar in patients switched to an NS antibiotic and those maintained on BS antibiotics. Our findings suggest a potential role for antimicrobial stewardship in promoting antibiotic de-escalation in this population.

Disclosures
All authors: No reported disclosures.
875. Sex Differences in Academic Achievement and Faculty Rank in Academic Infectious Diseases
Authors: Manne-Goehler Jennifer , Kapoor Neena , Blumenthal Daniel , Stead Wendy 
Published: November 2018

Abstract

Background
Sex differences in faculty achievement in academic medicine have been described, but little is known about these differences in infectious diseases (ID). This study assesses differences in faculty rank between female and male infectious disease faculty with academic appointments at US medical schools.

Methods
We analyzed a complete database of US physicians with medical school faculty appointments in 2014. This database consists of a linkage between the American Association of Medical Colleges faculty roster and a comprehensive physician database from Doximity, a professional networking website for doctors and includes physician age, sex, years since residency completion, publications, National Institutes of Health grants, and registered clinical trials for all academic physicians by specialty. We estimated sex differences in key metrics of academic achievement, including publications and faculty rank, among faculty physicians within ID. Multivariable regression models with medical school-specific fixed effects were used to assess sex differences in full professorship by specialty and the relationship between these factors and achieving the rank of full professor within ID.

Results
Among 2,016 academic ID physicians [Female: 742 (37%)], women accounted for 48.1% of assistant professors, 39.7% of associate professors, and 19.2% of full professors, when compared with men at each level. Women faculty members were younger than men (mean: 48.4 years vs. 54.0 years, P &lt; 0.001) and had fewer total (mean: 24.1 vs. 37.8, P &lt; 0.001) and first/last author publications (mean: 16.7 vs. 32.2, P &lt; 0.001). In adjusted models, the rate of full professorship (vs. assistant or associate) among female compared with male infectious disease physicians was large and highly significant (absolute adjusted difference = −8.0%; 95% confidence interval [CI]: −11.9% to −4.1%). This adjusted difference was greater in ID than in cardiology (−4.7%, 95% CI: −7.9% to −1.3%), hematology (−1.5%, 95% CI: −6.2% to 3.2%), or endocrinology (−0.2%, 95% CI: −4.9% to 4.6%).

Conclusion
Significant sex differences in publications and achieving the rank of full professor exist in academic ID, after adjustment for multiple factors known to influence these outcomes. Greater efforts should be made to address equity in academic ID.

Disclosures
All authors: No reported disclosures.
920. A Sharp Fall in Antibiotic Use in Infants Is Correlated With a Population-Wide Reduction in Asthma Incidence for Children Under 5
Authors: Patrick David , Mamun Abdullah , Rasali Drona , Rose Caren , Marra Fawziah 
Published: November 2018

Abstract

Background
Antibiotic use in infants &lt;1 is associated with increased relative risk (~1.5) for childhood asthma in cohort studies. This may be mediated by removal from the infant microbiome of organisms shown to protect against asthma, a hypothesis supported by experiment. We launched this study to see whether reductions in antibiotic use at population level are associated with benefit by way of asthma reduction.

Methods
We obtained antibiotic prescribing data from BC PharmaNet, a population-based database that captures all outpatient prescribing for British Columbia, Canada (n = 4.7 million). We focused on prescriptions in children &lt;1 and calculated prescription rate per 1,000 population per year. We obtained asthma incidence data from the BC Ministry of Health Chronic Disease Registry. Asthma case identification uses a standard case definition making use of community and hospital diagnostic codes as well as asthma drug data from BC’s universal physician billing, hospital and drug databases. We focused on age-stratified asthma incidence for children aged 1–4. The correlation between antibiotic prescription rate in children &lt; 1 and asthma incidence in the following year was estimated using the Spearman test.

Results
Antibiotic prescribing for all age groups fell 9.5% between 1999 and 2013. The rate for infants &lt;1 dropped 58% from 1,014 to 427 prescriptions per 1,000 population/year. Between 2000 and 2014, asthma incidence (ages 1–4) fell 26% from 27.3 (95% CI: 26.5–28.0) to 20.2 (95% CI: 19.5–20.8) per 1,000 population/year. These trends were strongly correlated: Spearman’s rho = 0.81 (P = 0.0002). The magnitude of fall in asthma incidence is slightly greater than that predicted based on calculated population attributable risk for antibiotic exposure.

Conclusion
The population health benefit from antibiotic stewardship in infants may not be confined to slowing the emergence of resistance and could include a reduced risk of asthma. As this is a population-based ecological study, a reduction in other risk factors may also have contributed to the fall in asthma incidence. This promising trend should be further studied at individual level within a large cohort study.

Disclosures
All authors: No reported disclosures.
922. Barriers to Pediatric Staff Nurse Participation in Antimicrobial Stewardship Programs (ASP) Linked to Organizational Culture
Authors: Monsees Elizabeth , Popejoy Lori , Goldman Jennifer , Jackson Mary Anne , Lee Brian R 
Published: November 2018

Abstract

Background
Increasing nurse engagement in Antimicrobial stewardship programs (ASP) is a national initiative. We previously reported results from a stewardship survey where nurses indicated being confident to perform ASP practices, yet identified barriers to stewardship participation. Seventeen barriers were identified, with many centered around hospital culture such as lack of inclusion in rounds, power differentials, and nurse input not actively sought. To further understand organizational and cultural barriers which may influence nursing stewardship engagement, we used responses from the Agency for Healthcare Research and Quality (AHRQ) Patient Safety survey to evaluate nursing perception on hospital culture.

Methods
Data from the 2017 AHRQ survey were used. Nurses working on noninpatient floors (e.g., post anesthesia care units) were excluded. For this analysis, we included 4 domains pertinent to stewardship initiatives: communication, information exchange, teamwork within and across units. Composite scores within each domain were calculated. Scores were stratified by Intensive Care Nursery (ICN), Pediatric Intensive Care Unit (PICU), Oncology (Onc), medical-surgical (med-surg) units, and dual units (e.g., float pool).

Results
A total of 424 nurses participated in the survey; 138 (33%) ICN, 90 (21%) PICU, 42 (10%) Onc, 168 (40%) med-surg, and 23, (5%) dual. The majority of nurses had been employed by the hospital for 0–5 years (237; 56%) with 76 (18%) having more than 15 years. The majority of nurses expressed neutrality with communication. Approximately 20% disagreed with the level of information exchange. Nurses perceived teamwork within a unit more favorably than teamwork across units. Responses were relatively consistent across units.

Conclusion
Successful ASP require interdisciplinary collaboration and communication. Barriers related to communicating and exchanging information may limit nursing engagement. Assessments already used at hospitals could potentially guide methods of integrating nurses into stewardship with AHRQ data offering another lens to assess factors influencing behaviors to steward. A thorough understanding of nurses’ perceived work climate may inform engagement strategies.

Disclosures
All authors: No reported disclosures.