bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibiotic Consumption and Antibiotic Resistance Across Organisms, Drugs, and Consumer Groups
Authors: Olesen Scott , Barnett Michael , MacFadden Derek , Lipsitch Marc , Grad Yonatan H
Published: October 2017

Background

Antibiotic consumption is considered a major driver of antibiotic resistance, but it remains unclear whether the consumption–resistance relationship is apparent for many organisms and drugs, and whether aggregate consumption is the best predictor of resistance.

Methods

We conducted a landscape assessment of the consumption-resistance relationship by comparing a 20% sample of Medicare Part D outpatient antibiotic pharmacy claims with a nationwide survey of hospital antibiotic susceptibility reports. Antibiotic consumption was summarized in individual states and hospital-referral regions (HRRs) using traditional, aggregate consumption or by metrics that account for the concentration of consumption in a few individuals (Gini coefficient). The consumption–resistance relationships for 17 organism–drug combinations were simultaneously evaluated (Spearman’s rho; linear models predicting resistance from aggregate consumption and Gini coefficient) and corrected for multiple-hypothesis testing (Benjamini–Hochberg).

Results

We identified a significant correlation between aggregate consumption of an antibiotic and an organism’s reported resistance to that antibiotic in only a few cases: quinolones and E. coli (Spearman’s rho = 0.65, adjusted P < 10−4) and E. cloacae (rho = 0.50, adjusted P = 0.006). In other cases, notably E. coli with trimethoprim–sulfamethoxazole, the distribution of antibiotic consumption among consumers has a marginal relationship with antibiotic resistance (−1.0 p.p. resistance per p.p. Gini coefficient of consumption among consumers, unadjusted P < 0.001).

Conclusion

There is a clear correlation between aggregate consumption of an antibiotic and resistance of an organism to that antibiotic in only a few cases, suggesting that antibiotic steward efforts might maximize their effectiveness by focusing on particular organisms, drugs, and consumer groups rather than overall, aggregate consumption.

Disclosures

All authors: No reported disclosures.
Incidence of UL97 Resistance Mutations in Infants with Congenital Cytomegalovirus Disease Receiving 6 Months of Oral Valganciclovir Therapy
Authors: James Scott H , Conner Ra’Shun L , Kimberlin David W , Whitley Richard , Prichard Mark N
Published: October 2017

Background

A recently completed Phase 3 randomized, controlled, double-blind, multicenter study of infants with symptomatic congenital cytomegalovirus (CMV) disease receiving 6 months of oral valganciclovir (VGCV) therapy represents the largest such population in which to evaluate treatment-emergent antiviral resistance. The most common mechanism of CMV antiviral resistance occurs through mutations in the CMV UL97 gene that confer resistance to ganciclovir (GCV). Genotypic resistance analyses were performed on infants receiving 6 months of VGCV to assess the incidence of antiviral resistance due to UL97 sequence variants.

Methods

Resistance analyses were performed by conventional DNA sequencing of the UL97 gene at multiple time points. Following CMV DNA extraction from frozen whole blood specimens, the UL97 gene was amplified with a double nested polymerase chain reaction method and sequenced to identify polymorphisms and mutations that might confer GCV resistance.

Results

Forty-six infants with symptomatic CMV disease who received a 6-month course of VGCV underwent resistance analysis to identify UL97 sequence variants. In addition to a range of natural polymorphisms known to have no effect on antiviral susceptibility, 2 subjects developed UL97 mutations known to confer resistance to GCV (A594V and G598S detected in one subject; E596G detected in another), yielding an incidence of 4%. Each of these resistance mutations occurred in specimens collected after at least 4 months of antiviral therapy. As evaluated in the original Phase 3 trial, neither of these infants showed an improvement in hearing outcome.

Conclusion

The development of treatment-emergent UL97 resistance mutations was determined in a controlled study population of infants with congenital CMV disease receiving 6 months of VGCV. This targeted resistance analysis demonstrated an incidence approaching the total incidence of antiviral resistance for CMV disease in some immunocompromised populations, such as solid-organ transplant recipients. Further studies within this study population are warranted to elucidate the risk of emerging antiviral resistance and to assess clinical impact as well as the potential need for combination antiviral therapy.

Disclosures

All authors: No reported disclosures.
Induced Hypothermia in Patients with Septic Shock and Ventilator-demanding Respiratory Failure
Authors: Itenov Theis Skovsgaard , Johansen Maria Egede , Bestle Morten , Thormar Katrin , Hein Lars , Gyldensted Louise , Lindhardt Anne , Christensen Henrik , Damby Stine Estrup , Pedersen Henrik Planck , Harmon Matthew , Soni Uday Kant , Perez-Protto Silvia , Wesche Nikolaj , Berthelsen Rasmus Ehrenfried , Skram Ulrik , Petersen Asger , Mohr Thomas , Waldau Tina , Poulsen Lone Museus , Strange Ditte , Christensen Ole , Juffermans Nicole P , Sessler Daniel , Tønnesen Else , Kristensen Dennis , Cozzi-Lepri Alessandro , Lundgren Jens , Jensen Jens Ulrik Stæhr
Published: October 2017

Background

Animal models of serious infection suggest that 24 hours of induced hypothermia improves circulatory and respiratory characteristics and enhances survival, but whether therapeutic mild hypothermia in such conditions is of clinical benefit remains unknown. We, therefore, tested whether reducing core temperature to 32–34oC in critically ill patients with septic shock and ventilator-demanding respiratory failure improves survival and reduces organ dysfunction.

Methods

In this multi-national trial, patients with septic shock were enrolled within 6 hours of onset of septic shock and ventilator-demanding respiratory failure and randomized 1:1, stratified by site (target sample = 560), to routine thermal management or 24 hours of induced hypothermia (target 32–34°C) followed by 48 hours of normothermia. Other aspects of care were per routine in each participating center. The primary endpoint was 30-day all-cause mortality.

Results

At the third ordinary interim analysis, after recruitment of 432 participants, the Data and Safety Monitoring Board recommended the trial be terminated for futility; the conditional power for rejection of the null hypothesis in favor of efficacy was null. In the induced hypothermia group, target temperature was reached within median 3.2 hours [IQR: 2.2, 4.8], and maintained for 24 hours [IQR: 24, 24] (Figure 1). There was no evidence for a difference in 30-day mortality risk in patients randomized to hypothermia (96/217) vs. routine thermal management (77/215): relative risk 1.24 [95% CI: 0.98, 1.56] (Figure 2). At the end of the temperature intervention (72 hours), more patients assigned to hypothermia were in continued shock (vasoactive medication 71% vs. 58%; P = 0.01), and fewer cooled patients had inflammatory control (32% vs. 47% had CRP decline of >30%, P = 0.005). More harm from cooling was seen in patients entering the trial with normal renal function and with normal platelet count (P for interaction < 0.05).

Conclusion

Among patients with septic shock and ventilator-demanding respiratory failure, induced hypothermia did not improve survival, but adversely affected the duration of shock, and inflammatory control. Induced hypothermia should not routinely be used in patients with septic shock.

Disclosures

All authors: No reported disclosures.
Prevalence and Acquisition of MRSA During Incarceration at a Large Inner-city Jail
Authors: Popovich Kyle J , Zawitz Chad , Aroutcheva Alla , Payne Darjai , Schoeny Michael , Richardson Emma , Hayden Mary K , Hota Bala , Weinstein Robert A
Published: October 2017

Background

USA300 MRSA is endemic in certain communities, with congregate settings such as urban jails potentially facilitating spread. The extent of MRSA transmission in jail is unclear, a controversy that impacts prevention strategies. We determined the prevalence of MRSA colonization at jail entrance and defined the acquisition rate during incarceration.

Methods

Men incarcerated at the Cook County Jail, one of the largest US single-site jails, were enrolled within 72 hours of intake. Surveillance cultures (nares, throat, groin) were collected to determine prevalence of MRSA colonization. A survey was administered to identify predictors of colonization. Detainees still in jail at Day30 had cultures repeated to determine MRSA acquisition rate. Univariate and multivariate analysis was performed to identify predictors of MRSA colonization.

Results

A total o 402 men (447 unique incarcerations) have so far been enrolled (77% AA, 11% Hispanic) with 92% previously in jail (20% in past 6 months). The prevalence of MRSA colonization at intake was 18.6% (83/447), with 39% of those colonized solely in the throat or groin. At 30 days: 10% (9/92) of initially negative men acquired MRSA; 14 admission positives remained colonized while 11 lost colonization. On univariate (Table), predictors of MRSA colonization at entrance to the jail were: methamphetamine use (METH), unstable housing, current skin infection, and care at an outpatient Clinic A that emphasizes comprehensive care to the LGBTQ community. In this cohort, METH use was associated with reporting being a man who has sex with men vs. not (35% vs. 9%, P < 0.001) and was common among men with care at Clinic A (18% vs. 3%, P < 0.001). On multivariate with adjustment for race/ethnicity and HIV status, current skin infection and care at clinic A were associated with MRSA. Preliminarily, sharing personal items was associated with MRSA acquisition at Day30 (OR = 5.6, 95% CI,1.3, 23.3, P = 0.02).

Conclusion

We found that a relatively high proportion of individuals enter the jail colonized with MRSA and the jail may amplify rates. Entrance colonization risk factors point to possible community reservoirs. Enrollment is ongoing but results suggest an intervention in jail could impact MRSA rates in the jail and in the surrounding community.

Disclosures

M. K. Hayden, Sage, Inc: Sage is contributing product to healthcare facilities participating in a regional collaborative on which I am a co-investigator. Neither I nor my hospital receive product., Sage is contributing product to healthcare facilities participating in a regional collaborative on which I am a co-investigator. Neither I nor my hospital receive product.; Clorox, Inc.: I have received funding from Clorox for an investigator-initiated clinical trial., Research support; CDC: Grant Investigator, Research grant
Strain-level Determination of the Contribution of Gut Microbiota to the Development of Bacteremia in Patients Undergoing Stem Cell Transplantation
Authors: Andermann Tessa , Tamburini Fiona B , Tkachenko Ekaterina , Senchyna Fiona , Banaei Niaz , Bhatt Ami
Published: October 2017

Background

Infection is a major preventable cause of transplant-related morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HCT). Bacteremia is the most common infectious complication in HCT, often occurring during periods of mucositis when the risk for microbial translocation from the intestine is increased. Prior research in HCT patients using 16S rRNA sequencing demonstrated that gut microbiota dominance by either Enterococcus spp. or Proteobacteria was associated with the development of bacteremia with Enterococcus spp. and Gram-negative organisms, respectively. No studies to date, however, have compared bacteremia isolates and gut microbiota samples at a strain-specific level using next-generation shotgun metagenomic sequencing (NGS).

Methods

In order to assess the degree of genetic similarity between bacteremia isolates and the gut microbiota, we identified patients who had undergone HCT at Stanford and developed a bacteremia between October 2015 and September 2016 for whom we had both saved blood culture isolates and stool samples within 30 days preceding bacteremia. We identified 15 patients from whom we had 17 bacteremia isolates, and performed NGS (Illumina HiSeq 4000) on stool and isolate DNA. We generated draft assemblies of isolate genomes using the SPAdes assembler, and aligned stool metagenomic reads to the draft isolate genomes using Bowtie2, filtering reads for perfect end-to-end alignment.

Results

Enteric gram-negative bacteremia isolates were identical to those in the gut microbiota, as has been demonstrated in prior studies using older strain-typing Methods. Surprisingly, we also identified gram-positive organisms that were identical in both the blood and stool prior to bacteremia, which challenges existing dogma regarding sources of gram-positive bacteremia-causing organisms.

Conclusion

Using a highly sensitive and accurate NGS-based strain typing method, we provide evidence of translocation of organisms from the gut microbiota and subsequent bacteremia. The gut was confirmed as a source for both classic enteric gram-negative and classically non-enteric Gram-positive bacteremia in HCT patients. These findings may have implications for the origins of bacteremia in HCT patients previously classified as CLABSIs.

Disclosures

A. Bhatt, Janssen Human Microbiome Institute / Johnson and Johnson: Consultant, Consulting fee
The Gut Microbiota of Healthy Infants in the Community is a Reservoir for ESBL and Carbapenemase Producing Bacteria.
Authors: Saleem Ali , Allana Ahreen , Hale Lauren , Qureshi Shahida M , Hotwani Aneeta , Rahman Najeeb , Khan Asia , Seed Patrick , Arshad Mehreen
Published: October 2017

Background

The recent rapid rise of Extended-spectrum Β Lactamase producing Gram-negative bacteria (ESBL-GNB) has seriously threatened the treatment of common infectious diseases. Neonates have an immature immune system and a delay in appropriate treatment due to ESBL-GNB sepsis can be fatal. This problem of delayed therapy is magnified in the developing world where 99% of the deaths from community acquired neonatal sepsis occur. Additionally ESBL E. coli such as the strain ST131 are known to be persistent gut and vaginal colonizers. In animal models, these strains out-compete colonization with drug-sensitive, commensal E. coli. Gut colonization with ESBL-GNB in infants may therefore have a profound impact on their microbiome and increase their risk of sepsis. Pakistan is a lower middle income country with high antibiotic use per capita and a sharp increase in ESBL-GNB infections. Recent data show that >50% of E. coli isolates from reproductive-aged women of Pakistan are resistant to more than one class of antibiotics. We aimed to determine the rates of gut colonization with ESBL-GNB among healthy infants in a community setting.

Methods

Stool samples were collected from 100 healthy infants living in a Pakistani suburban community between the ages of 5 and 7 months. Samples were plated on MacConkey agar to select for Gram-negative bacteria. Isolates were screened for resistance against several antimicrobial classes. Molecular testing of the stool samples was done using primers targeting conserved regions of ESBL and carbapenemase genes.

Results

Forty-eight percent of the infants were positive for ESBL producing Gram-negative bacteria, the majority of which were E. coli, and 7.5% were positive for carbapenemase producers, all of which belonged to Klebsiella spp. Molecular testing showed that 85% of the infant stools were positive for TEM β-lactamase gene, 68% for the CTX-M β-lactamase gene and 33% for the KPC carbapenemase gene.

Conclusion

The widespread colonization of infants in a developing country with ESBL-GNB is highly concerning. Further, our studies have revealed that the resistome of otherwise healthy infants may be a major reservoir of antibiotic genes in the community. Gut microbiome analysis of the potential impact of colonization with antibiotic-resistant bacteria is on-going.

Disclosures

All authors: No reported disclosures.
The Effect of National Healthcare Safety Network (NHSN) Rebaselining on Community Hospital SIRs
Authors: Hostler Christopher , Moehring Rebekah W , Baker Arthur W , Smith Becky , Adcock Linda , Wood Brittain , Cook Evelyn , Crane Linda , Cromer Andrea , Lockamy Kathy , Louis Susan , Padgette Polly , Woods Christopher W , Sexton Daniel , Anderson Deverick , Lewis Sarah S
Published: October 2017

Background

The NHSN recently updated risk adjustment models and “rebaselined” Standardized Infection Ratios (SIRs) for healthcare-associated infections. The CDC expected that hospital SIRs would generally increase. However, the impact of rebaselining on individual hospitals’ SIRs was unknown. Accordingly, we assessed the impact of rebaselining on SIRs in a network of community hospitals.

Methods

We analyzed 2016 SIR data for CAUTI, MRSA LabID events, CDI LabID events, colon SSIs (COLO), and abdominal hysterectomy SSIs (HYST) from 38 hospitals in the Duke Infection Control Outreach Network (DICON). SIRs calculated using the old and new baselines were compared. Wilcoxon signed rank test was performed to determine whether hospitals’ SIRs changed significantly following rebaselining. Hospitals were ranked by SIR for each metric, and change in rank following rebaselining was determined. Meaningful change in rank was defined as increase or decrease by ≥4 places (greater than a decile). Hospitals that did not have an SIR calculated for a given metric were excluded from that metric’s analysis.

Results

Median hospital SIRs for CAUTI and CDI increased significantly after rebaselining (0.587 vs 0.307, P < 0.001; and 0.825 vs 0.783, p = 0.04, respectively). Median MRSA SIRs increased (0.903 vs 0.797, P = 0.5), and COLO and HYST SIRs decreased (0.457 vs 0.586, P = 0.1; and 0 vs 0.489, P = 0.4); however, these changes were not statistically significant (Figure 1). For all metrics, a minority of hospitals had meaningful change in SIR rank following rebaselining (Figure 2).

Conclusion

SIRs increased following rebaselining for CAUTI and CDI but did not change significantly for MRSA, COLO, or HYST. The majority of hospitals’ SIR rank did not change meaningfully following rebaselining.

Disclosures

D. Sexton, Centers for Disease Control and Prevention: Grant Investigator, Grant recipient; Centers for Disease Control and Prevention Foundation: Grant Investigator, Grant recipient; UpToDate: Collaborator, Royalty Recipient
Reductions in MRSA, Clostridium difficile and Intensive Care Unit (ICU) Acquired Bloodstream Infections and over 9 years from 276 United Kingdom ICUs
Authors: Batra Rahul , Wulff Jerome , Harrison David , Edgeworth Jonathan
Published: October 2017

Background

A major focus on preventing resistant organisms and hospital-acquired infections over the past 10 years has seen well-documented reductions in MRSA and C. difficileat hospital and national level. Less is known about national changes in epidemiology of bloodstream infections, and such data is important to frame future national priorities and targets.

Methods

Data from the Intensive Care National Audit and Research Centre Program on MRSA, C. difficile and VRE colonization and ICU-acquired bloodstream infections (UABSIs) from 1,195,103 consecutive patients admitted to 276 UK ICUs (excluding Scotland) from 2007 to 2015 was analyzed.

Results

MRSA and C. difficile colonizations per 1000 patients decreased significantly (MRSA admissions 38.8 to 12.03 (P = 0.00003); MRSA acquisitions 25.4 to 3.1(P = 0.0008); C. difficile admissions 10.6 to 4.1(P = 0.0001); C. difficile acquisitions 11.1 to 3.3 (p = 0.0005). Reductions predominantly occurred between 2007 and 2011 with MRSA but not C. difficile. In contrast VRE admissions and ICU-acquisitions increased from 1.9 to 5.8 (P = 0.002) and 1.5 to 5.6 (P = 0.005), respectively. There were 13,147 UABSI episodes in 11,075 (1.8%) of 621,859 patients staying >48 hours. The UABSI rate fell from 6.6 (95% CI 6.33–6.97) to 1.7 (95% CI 1.5–1.7)/1000 bed days (P < 0.0001), with the reduction taking place between 2007 and 2011 and no significant reduction since. A fixed effect model identified lower age, male sex, severity of illness, larger ICU-size, immunosuppressive therapy (but not immunosuppressive illness) as significant risk factors for UABSI. MSSA, E. coli, Enterococci, Yeast, Klebsiella sp and P. aeruginosa accounted for 73% of all recorded first UABSIs. Greatest reduction was seen for MRSA (97%), Pseudomonas aeruginosa(80%), S. aureus (77%) and Yeast (71%), with lower reductions for E. coli (54%) and Klebsiella(42%).

Conclusion

Large decreases in ICU-acquired bloodstream infections occurred across UK ICUs at the same time as reductions in MRSA and C. difficile, but rates have been static since 2011. Reductions were seen for all organisms. The observation that no material reductions in UABSIs were observed during the last 5 years of the study, despite continued focus on improving infection control practice throughout, implies that benefits from the current intervention framework have been achieved.

Disclosures

All authors: No reported disclosures.
Catheter-free Period Over 2 Days Is Associated with Better Outcome in Catheter-related Bloodstream Infection due to Candida
Authors: Matsuo Takahiro , Mori Nobuyoshi , Hoshino Eri , Sakurai Aki , Furukawa Keiichi
Published: October 2017

Background

Regardless of active antifungal drugs, mortality of candidemia remains high. Although it is well-known that central venous catheter (CVC) is one of the most important risk factors of candidemia and should be removed immediately, little is known about optimal timing of CVC replacement after removal. Here, we analyzed contributing risk factors associated with 30-day mortality for catheter-related bloodstream infection (CRBSI) due to candida and optimal timing of CVC replacement.

Methods

We conducted a retrospective cohort study at St. Luke#129; fs International Hospital between 2004 and 2015. We compared each clinical component in patients who died within 30 days and were alive at 30 days. Also, catheter-free period (from removal to replacement) was compared between group A and B. Fisher#129; fs exact test and Mann–Whitney U test were used in univariate analysis and multivariate linear regression was used for controlling confoundings.

Results

Among 228 patients (pts) with candidemia, 166 patients (73%) were on CVC at diagnosis. Of them, 144 patients (65%) removed CVC after the result of candidemia. Seventy-one patients (31%) replaced CVC. Fifteen patients (6%) died within 30 days (group A) and 56 patients (25%) were alive at 30 days (group B). Median age was 74 in group A and 72 in group B (P = 0.331) (Table 1). In univariate analysis, hematological malignancy (OR 6.75, 95% CI 1.01–44.9) and CVC replacement < 2-days after removal (OR 5.63, 95% CI 1.16–27.3) showed statistically significant increase in group A vs group B (Table 2). In multivariate analysis, CVC replacement < 2-days was independently associated with 30-day mortality (Table 3).

Conclusion

This is the first study to demonstrate the optimal timing of CVC replacement in CRBSI due to candida. CVC replacement < 2 days was an independent risk factor for 30-day mortality.

Disclosures

All authors: No reported disclosures.
Routine Cryptococcal Antigen Screening in Solid Organ Transplant Recipients: Is it Time to Save Lives and Money?
Authors: George Ige , Rajasingham Radha , Powderly William , Boulware David
Published: October 2017

Background

Cryptococcosis affects 1 in 270 solid organ transplant (SOT) recipients with high mortality. In HIV-infected patients, cryptococcal antigen (CRAG) is detectable in blood weeks to months before symptomatic infection and screening is recommended. No screening guidelines exist for SOT recipients.

Methods

We performed a cost-effectiveness analysis of CRAG screening amongst SOT recipients. We estimated costs of screening from Medicare reimbursement of $16.49 for CPT 87899 (Infectious agent antigen detection by immunoassay). We determined the number at risk from a large cohort of 42,634 adult SOT recipients from ICD-9 CM billing data from HCUP State Inpatient Databases of Florida (2006–2012), New York (2006–2011), and California (2004–2010). Cost of screening was compared with the cost of inpatient hospitalization.

Results

Among 42,634 adult SOT recipients, 158 (0.37%) developed cryptococcosis at a median time of 15.5 months (range 0.1 -80) after transplant. During the 43 month follow-up, there was approximately 2.5% annual mortality. The estimated cost of hospital care for cryptococcal meningitis per person is approximately $70,000 in 2016 with current explosive cost of flucytosine at ~$29,000 per 2 weeks. Thus, the total estimated cost of hospital care in the cohort would be $11.0 million in 2016. In comparison, the cost to screen all 42,634 SOT recipients every three months would be $8.8 million. If CRAG screening could detect 75% of asymptomatic cryptococcal antigenemia prior to symptomatic disease requiring prolonged hospitalization, it would be approximately cost neutral ($11.5 million), and even cost saving if above 80% of hospitalizations are averted. Alternatively stated, for every one hospitalization avoided, 4245 persons could be CRAG screened for similar cost and likely better outcome.

Conclusion

Assuming the ability of routine screening to identify 75% of patients who would develop invasive cryptococcosis; CRAG screening every 3 months among SOT recipients likely would be at least cost neutral to the healthcare system. Antecedent duration of cryptococcal antigenemia prior to symptomatic disease in Non-HIV/SOT cohorts to inform optimal screening intervals should be further studied. Prospective SOT cohorts should validate this approach to save lives in a cost-effective manner.

Disclosures

All authors: No reported disclosures.
Galidesivir, a Direct-Acting Antiviral Drug, Abrogates Viremia in Rhesus Macaques Challenged with Zika Virus
Authors: Lim So-Yon , Osuna Christa , Lakritz Jessica , Chen Elsa , Yoon Gyeol , Taylor Ray , MacLennan Steve , Leonard Michael , Giuliano Enzo , Mathis Amanda , Berger Elliot , Babu Ys , Sheridan William , Whitney James
Published: October 2017

Background

Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infection in humans is associated with serious neurological and reproductive complications. No antiviral or protective vaccine is yet available. Galidesivir an adenosine analog is a potent viral RNA-dependent RNA polymerase inhibitor with demonstrated broad-spectrum antiviral activity.

Methods

We have conducted four pre-clinical studies in rhesus macaques to assess the safety, antiviral efficacy and dosing strategies of galidesivir against ZIKV infection. Collectively, we have challenged 70 rhesus macaques by various routes using 1x105 TCID50of a Puerto Rican ZIKV isolate. We have evaluated galidesivir therapy administered via IM injection as early as 90 minutes and up to 72 hours after subcutaneous (SC) ZIKV challenge, and as late as 5 days after intravaginal (IVAG) challenge. In these studies, we evaluated the efficacy of a range of loading and maintence doses of galidesivir. The highest dose evaluated has been a loading dose of 100mg/kg BID followed by a maintenance dose of 25mg/kg BID for nine days. We followed multiple endpoints, including ZIKV RNA levels in plasma, urine, saliva, and cerebrospinal fluid. Immune activation, complete blood counts, chemistries and galidesivir pharmacokinetics were also monitored.

Results

Galidesivir was well-tolerated in all studies. All untreated controls developed high-level plasma viremia, and had readily detectable ZIKV RNA in CSF, saliva and urine post-infection. Animals treated in the first 24 hours after SC ZIKV challenge did not develop plasma viremia and were either negative or had significantly reduced ZIKV RNA in bodily fluids. Animals treated with galidesivir later (up to 72 hours) were partially protected; they had detectable plasma ZIKV RNA, but the onset was delayed and/or magnitude significantly reduced compared with controls. Animals infected IVAG were protected by galidesivir treatment up until day 5 after infection, with no blood viremia and significant reductions in ZIKV RNA in the CSF as compared with controls.

Conclusion

Galidesivir dosing in rhesus macaques was well-tolerated and offered significant protection against ZIKV infection. These results warrant continued study and clinical evaluation.

Disclosures

R. Taylor, BioCryst Pharmaceuticals: Employee, Salary; S. MacLennan, BioCryst: Employee, Salary; M. Leonard, BioCryst: Employee, Salary; E. Giuliano, BioCryst: Employee, Salary; A. Mathis, BioCryst Pharmaceuticals: Employee, Salary; E. Berger, BioCryst: Employee, Salary; Y. Babu, BioCryst: Employee, Salary; W. Sheridan, BioCryst Pharmaceuticals: Employee, Salary
Environmental and Climatic Risk Factors for Zika and Chikungunya Virus Infections in Rio de Janeiro, Brazil, 2015–2016
Authors: Fuller Trevon , Calvet Guilherme A , Estevam Camila Genaro , Brasil Patricia , Angelo Jussara Rafael , Smith Thomas B , Bispo Di Filippis Ana M
Published: October 2017

Background

The objective of the present study was to identify drivers of the ZIV epidemic in the state of Rio de Janeiro to predict where the next hotspots will occur and prioritize areas for vector control and eventual vaccination once available.

Methods

To assess climatic and socio-economic drivers of arbovirus epidemics, we mapped rainfall, temperature, and sanitation infrastructure in the municipalities where individuals with laboratory confirmed cases of arboviral infection resided using our spatial pattern risk model.

Results

From March 2015 to May 2016, 3,916 participants from 58 municipalities in the state of Rio de Janeiro were tested for dengue, Chikungunya (CHKV), and ZIKV by RT-PCR and enzyme immunoassays. During the same period, 69,256 suspected cases of dengue, CHKV, and ZIKV were reported to the Rio Health Department, including 23,983 of dengue, 44,572 of ZIKV, and 701 of CHKV. Laboratory confirmed cases included 29 cases (0.7%) of dengue, 1,717 of ZIKV (43.8%), and 2,170 of CHKV (55.4%). Rains in Rio began in October 2015 and were followed one month later by the largest wave of the ZIKV epidemic (Figure 1). ZIKV cases markedly declined in February 2016, which coincided with the start of a CHKV outbreak. Rainfall predicted ZIKV and CHKV in Rio with a lead-time of 3 weeks each time. Social and environmental variables predicted the number of cases. The temporal dynamics of ZIKV and CHKV in Rio de Janeiro are explained by the shorter incubation period of the viruses in the mosquito vector; 2 days for CHKV vs 10 days for ZIKV.

Conclusion

The association between rainfall and ZIKV reflects vector ecology, as the larval stages of Aedes aegypti require pools of water to develop. Rainfall in October 2015 would have produced such pools resulting in increased mosquito abundance likely contributing to the ZIKV epidemic in humans the following month. The decrease in ZIKV in February 2016 and the increase in CHKV likely arose due to within-vector competition. The Pan American Health Organization’s ZIKV Strategic Plan states that controlling arboviruses requires mapping their social and environmental drivers. Our findings contribute to such control efforts.

Disclosures

All authors: No reported disclosures.
Fatty Liver Disease in HIV: Predictors and Response to Statin Therapy
Authors: El Kamari Vanessa , Hileman Corrilynn O , Mccomsey Grace
Published: October 2017

Background

Liver disease has emerged as a leading cause of mortality and morbidity in HIV. Much of the current challenge in liver disease is related to nonalcoholic fatty liver disease (NAFLD). In HIV-uninfected populations, statin therapy has been suggested as potential intervention, but no such data is available in HIV. The aims of this study are to investigate the effect of rosuvastatin on hepatic steatosis in HIV infection, measured by Liver Fat Score (LFS) and to assess the natural history and predictors of changes in hepatic steatosis over 96 weeks.

Methods

This is a secondary analysis of the SATURN-HIV trial, in which HIV+ adults on stable ART with HIV-1 RNA < 1,000 copies/mL and LDL-cholesterol < 130mg/dL were randomized to 10mg daily rosuvastatin or placebo. Changes in LFS and in markers of systemic inflammation and monocyte activation were assessed from entry through week 96. Spearman correlations, multivariable linear regression and logistic regression were used to study relationships among variables.

Results

Overall, 147 patients were randomized (n = 72 to rosuvastatin n = 75 to placebo); 78% were male, 68% African Americans, 8% had chronic hepatitis C and mean age and BMI were 46 years and 29kg/mm2. A significant increase in LFS over 96 weeks was seen in both the placebo and statin arms (p = 0.01 and p < 0.01 respectively, p = 0.49 between groups). Furthermore, the progression from no-steatosis (LFS ≤ -0.64) at baseline to steatosis (LFS > -0.64) at week 96 was higher in rosuvastatin arm (OR = 4.3, p = 0.03), and remained statistically significant after adjusting for demographics, HOMA (baseline and change over 96 weeks), hepatitis C, heavy alcohol use and HIV parameters. Baseline LFS was independently associated with IP-10 (β = 0.82, p = 0.03) and sCD163 (β = 0.43, p = 0.005), and the increase in LFS over 96 weeks was independently associated with IP-10 (β = 2.85, p = 0.02).

Conclusion

In HIV+ subjects on ART, hepatic steatosis increased over time, regardless of statin treatment, and was independently associated with markers of immune activation. The progression from non-steatosis to hepatic steatosis was greater on statin. Despite its effective role in reducing cardiovascular disease risk and inflammation, statin therapy does not appear effective in hepatic steatosis.

Disclosures

C. O. Hileman, Gilead: Medical Advisory Board, Research support; G. Mccomsey, Gilead: Consultant, Consulting fee and Research support; BMS: Consultant, Consulting fee and Research support; GSK/ViiV: Consultant, Consulting fee and Research support; ICON: Consultant, Consulting fee; Merck: Investigator, Research support
Vaccine effectiveness against influenza-associated hospitalization among children aged < 13 years using a hospital-based surveillance system in Minnesota, 2013 – 2016
Authors: Fowlkes Ashley , Friedlander Hannah , Steffens Andrea , Como-Sabetti Kathryn , Boxrud Dave , Bistodeau Sarah , Strain Anna , Ferdinands Jill M , Chaves Sandra S , Reed Carrie , Lynfield Ruth
Published: October 2017

Background

Due to marked variability in circulating influenza viruses each year, annual evaluation of the vaccine’s effectiveness against severe outcomes is essential. We used the Minnesota Department of Health’s (MDH) Severe Acute Respiratory Illness (SARI) surveillance to evaluate vaccine effectiveness (VE) against influenza-associated hospitalization over three influenza seasons.

Methods

Residual respiratory specimens from patients admitted with SARI were sent to the MDH laboratory for influenza RT-PCR testing. Medical records were reviewed to collect patient data. Vaccination history was verified using the state immunization registry. We included patients aged ≥6 months to < 13 years, after which immunization reporting is not required, hospitalized from the earliest influenza detection after July through April each year. We defined vaccinated patients as those ≥1 dose of influenza vaccine in the current season. Children aged < 9 years with no history of vaccination were considered vaccinated if 2 were doses given a month apart. Partially vaccinated children were excluded. We estimated VE as 1 minus the adjusted odds ratio (x100%) of influenza vaccination among influenza cases vs. negative controls, controlling for age, race, days from onset to admission, comorbidities, and admission month.

Results

Among 2198 SARI patients, 763 (35%) were vaccinated for influenza, 180 (8.2%) were partially vaccinated, and 1255 (57%) were unvaccinated. Influenza was detected among 202 (9.2%) children, and significantly more frequently among children aged ≥5 years (17%) compared with younger children (7.4%). The adjusted VE in 2013–14 was 68% (95% Confidence Interval: 34, 85), but was non-significant during the 2014–15 and 2015–16 seasons (Figure). Estimates of VE by influenza A subtypes varied substantially by year; VE against influenza B viruses was significant, but could not be stratified by year. VE was impacted when live attenuated influenza vaccine recipients were excluded.

Conclusion

We report moderately high influenza VE in 2013–14 and a point estimate higher than other published estimates from outpatient data in 2014–15. These results, underscore the importance of influenza vaccination to prevent severe outcomes such as hospitalization.

Disclosures

All authors: No reported disclosures.
Improving Antimicrobial Use by Implementing the CDC Antimicrobial Stewardship Core Elements Across a Diverse Healthcare System
Authors: Lane Michael A , Hays Amanda , Newland Helen , Zack Jeanne , Newland Jason
Published: October 2017

Background

With increasing national focus on reducing inappropriate antimicrobial use, state and national regulatory mandates require hospitals to develop robust antimicrobial stewardship programs (ASP).

Methods

BJC HealthCare is a 13 hospital healthcare system serving the St. Louis, mid-Missouri, and Southern Illinois region and includes adult and pediatric academic medical centers, as well as community and critical access hospitals. In 2015, BJC system leaders engaged relevant clinical and executive stakeholders at each hospital to champion formation of a multidisciplinary system ASP Council. A comprehensive gap analysis was performed to assess current stewardship resources and activities. BJC system clinical leads facilitated the development of hospital specific leadership support statements, identification of hospital pharmacy and medical leaders, and all mandated educational components. To facilitate tracking, reporting and improvement activities, a robust antimicrobial use data dashboard was created. Each hospital has a dedicated ASP team that is supported by the system clinical leads. Hospital learnings are shared at monthly system ASP meetings allowing for broad dissemination.

Results

By leveraging system resources, all 13 BJC HealthCare hospitals met all Joint Commission requirements by January 2017. BJC’s model of ASP allows for the development of broad-based stewardship activities including development of education modules for patients and providers, and clinical decision support tools while allowing individual hospitals to implement activities based on local needs and resource availability. Local hospital teams have developed treatment guidelines, targeted antibiotic pharmacy review, “handshake” stewardship models, and allergy testing protocols. Central support of local hospital ASP has resulted in a 7.6% system decrease in tracked antimicrobial use, including a 16.5% reduction in quinolone usage. Additionally, the C. difficilestandardized infection ratio decreased from 1.08 to 0.622 since program initiation.

Conclusion

Despite significant differences in hospital resources, a system-supported ASP model focused on implementing the CDC core elements can result in significant reductions in antimicrobial use.

Disclosures

J. Newland, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant
Phylogenetic Analysis of an Unusual Increase in Salmonella enterica serovar Paratyphi A Infection among Travelers Returning from Myanmar
Authors: Matono Takashi , Morita Masatomo , Izumiya Hidemasa , Kaku Mitsuo , Ohnishi Makoto
Published: October 2017

Background

The proportion of enteric fever cases caused by Salmonella enterica subspecies enterica serovar Paratyphi A (S. Paratyphi A) has recently been increasing in Asian counties, which is a public health concern. In 2015, an unusual increase in S. Paratyphi A infection among Japanese travelers returning from Myanmar was noted, while there is little information on this uptrend in Myanmar.

Methods

Isolates from travelers who returned with enteric fever from 2005 to 2015 were analyzed in order to determine country-specific notification rates (epidemiological investigation). The notification rate was defined as cases returning from each country per 100,000 Japanese travelers who visited to the country. S. Paratyphi A isolates collected from 2001 to 2015 were analyzed by whole-genome sequencing (microbiological investigation).

Results

Yearly notification trends indicated that enteric fever was potentially endemic to Myanmar (5–16 cases/100,000 travelers); the trends were similar to those observed in India (4–21 cases/100,000 travelers). A rapid increase in S. Paratyphi A infection occurred from 2012–2014 (2–4 cases/100,000 travelers) to 2015 (13 cases/100,000 travelers). A phylogenetic tree, constructed based on analysis of 105 S. Paratyphi A isolates (33 and 30 related to Myanmar and Cambodia, and 42 controls), revealed that most Myanmar- and Cambodia-related isolates formed clusters in the same lineage (Figure 1). Additionally, Myanmar-related isolates from 2015 harbored identical phage type 1 and were genetically closely related [each isolates had 0–10 single-nucleotide polymorphisms (SNPs), mostly within 0–7 SNPs] (Figure 2), yielding a wider SNP range than outbreak-associated isolates from Cambodia in 2013 (within a SNP distance of 0–6).

Conclusion

Epidemiological trends and molecular subtyping suggested a possible outbreak of S. Paratyphi A infection occurred in Myanmar in 2015. The recent uptrend of S. Paratyphi Ainfection in Myanmar is important for travelers and clinicians since infection cannot be prevented by typhoid vaccination.

Figure 1. Polygenetic tree of 105 S. Paratyphi A isolates

Figure 2. SNP analyses of S. Paratyphi A isolates from Myanmar in 2015 (A) and Cambodia in 2013 (B).

Disclosures

All authors: No reported disclosures.
Direct and Indirect Impact of 13-valent Pneumococcal Conjugate Vaccine (PCV13) on Invasive Pneumococcal Disease (IPD) Among Children and Adults in the U.S.
Authors: Pilishvili Tamara , Gierke Ryan , Farley Monica , Schaffner William , Thomas Ann , Reingold Arthur , Harrison Lee , Lynfield Ruth , Zansky Shelley M , Petit Susan , Miller Lisa , Baumbach Joan , Beall Bernard , Whitney Cynthia
Published: October 2017

Background

In February 2010, PCV13 was introduced for routine use among children aged < 5 years. In June 2012, PCV13 was recommended for use in series with 23-valent polysaccharide vaccine (PPSV23) for adults ≥19 years with select medical conditions, and in August 2014, for all adults ≥65 years. We evaluated the direct and indirect effects of PCV13 6 years post-introduction on invasive pneumococcal disease (IPD).

Methods

IPD cases (isolation of pneumococcus from sterile sites) were identified among residents of Active Bacterial Core surveillance (ABCs) sites during July 2007–June 2016. Isolates were serotyped by Quellung, PCR, or whole genome sequencing and classified as PCV13 or non-vaccine type (NVT). Incidence changes were estimated as percent changes (one minus rate ratio) and 95% confidence intervals (95% CI) between pre-PCV13 (2007–2009) and two post-PCV13 periods (July 2014–June 2015 and July 2015–June 2016).

Results

ABCs identified 31,190 IPD cases between 2007 and 2015, with 2,750 cases among children <5 years and 10,930 among those ≥65 years. During the two post-PCV13 periods, overall IPD rates were 33%-62% lower relative to 2007–2009 among all age groups, including <5 years and ≥65 years (Figure). Significant reductions in PCV13-type IPD incidence were observed for all age groups during both post-PCV13 periods, with incidence 84% (q95% CI 78, 88%) and 68% (95% CI 63, 73%) lower in 2015–2016 among children < 5 years and adults ≥65 years, respectively. PCV13-type IPD reductions were driven by serotypes 19A and 7F. IPD due to non-vaccine types also declined significantly among children < 5 years (−27%, 95% CI –42, –9%) and adults ≥65 years (-24%, 95% CI –34, –14%). PCV13-type IPD incidence did not differ significantly between the two post-PCV13 periods.

Conclusion

IPD incidence declined among children and adults in the U.S. following PCV13 introduction among children. The lack of difference in PCV13 rates between 2014–2015 and 2015–2016 suggests no measurable early impact of PCV13 introduction among adults ≥65 years. To date, we found no evidence of significant replacement disease with non-PCV13 types. Further work is needed to explain reductions in non-vaccine type disease observed in the post-PCV13 era.

Disclosures

W. Schaffner, Pfizer: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Novavax: Consultant, Consulting fee; Dynavax: Consultant, Consulting fee; Sanofi-pasteur: Consultant, Consulting fee; GSK: Consultant, Consulting fee; Seqirus: Consultant, Consulting fee; L. Harrison, GSK: Scientific Advisor, Consulting fee
Risk Predictive Model for 90-Day Mortality in Candida Bloodstream Infections
Authors: Lin Charlotte , Kronen Alyssa , Hsueh Kevin , Powderly William , Spec Andrej
Published: October 2017

Background

Candida bloodstream infections (CBSI) continue to be associated with high mortality, despite changes in antifungal treatment and diagnostics.

Methods

All patients age 18 or greater with a first episode of CBSI by blood culture from 1/2002 to 1/2015, admitted to Barnes-Jewish Hospital, a tertiary referral hospital in St. Louis, MO, were included. We collected data on demographics, comorbidities, laboratory values, vital signs, indwelling devices, and medical treatments of interest from the electronic medical record. We analyzed the potential predictor variables using univariate logistic regression. Variables associated with mortality were considered for model inclusion. The final model was built using multivariable binary logistic regression. A predictive equation was created, and a receiver–operator curve (ROC) was calculated to determine the appropriate cut-off points and c-statistic.

Results

Of the 1873 episodes of CBSI identified, 789 (42%) resulted in death in 90 days. The variables included in this model were age (40–49: OR 0.463, 95% CI 0.291–0.736; 50–69: 0.542, 0.342–0.860; ≥70: 0.560, 0.400–0.785); history of CAD (1.616, 1.171–2.230), chronic liver disease (2.247, 1.327–3.806); maximum heart rate (1.496, 1.126–1.989) and temperature (0.537, 0.408–0.708); AST (1.817, 1.343–2.459) and platelet count (1.563, 1.178–2.073); the presence of ventilator (1.847, 1.321–2.582), urinary catheter (1.365, 1.008–1.847), two or more central lines (1.658, 1.020–2.694); removal of lines after positive culture (0.259, 0.181–0.370); ophthalmology consult during admission (0.441, 0.329–0.592); thoracentesis/chest tube (3.827, 1.550–9.448); diagnosis of secondary malignancy (2.131, 1.488–3.053); whether antimetabolites (2.119, 1.353–3.318), dapsone (4.507, 1.450–14.012), linezolid (1.605, 1.059–2.435), quinolones (1.384, 0.998–1.920) were ordered 90 days before positive culture. An ROC curve was calculated with an internal c-statistic of 0.806.

Conclusion

We created a risk predictive model for 90-day mortality in patients with CBSI, with 81% probability of predicting mortality. This model can lead to development of point-of-care applications to aid decision-making regarding escalation/de-escalation of care.

Disclosures

W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant Gilead: Scientific Advisor, Consulting fee Astellas: Grant Investigator, Research grant A. Spec, Astellas: Grant Investigator, Grant recipient