bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV Pre-Exposure Prophylaxis (PrEP) Uptake, Initiation, and Persistence in the Detroit Public Health STD Clinic
Authors: Hacker Elizabeth , Cohn Jonathan , Golden Matthew R , Heumann Christine
Published: October 2017

Background

HIV pre-exposure prophylaxis (PrEP) is an effective HIV prevention tool; however, little is known about PrEP uptake, initiation, and persistence among patients prescribed PrEP in STD clinics.

Methods

Between July 2016 and March 2017, STD clinic staff compiled reports detailing the eligibility and initiation of PrEP in the Detroit STD Clinic. Staff called all patients prescribed PrEP to determine whether they had started PrEP, were still on PrEP, and their reasons for never initiating or discontinuing PrEP. We used chi-square tests to evaluate differences in PrEP initiation and discontinuation by age and race, calculated the population’s mean duration on PrEP (persistence), and used proportional hazards regression to assess differences in persistence by age and race.

Results

A total of 161 STD clinic patients were eligible for PrEP, of whom 71 (44%) were prescribed PrEP. Of the 71 patients prescribed PrEP, staff successfully interviewed 45 (63%) a median of 113 days following their receipt of prescription. Thirty-four (76%) interviewed patients had initiated PrEP, of whom 17 (50%) had subsequently discontinued their medication a mean of 92 days (95% confidence interval [CI]: ± 23.8) following receipt of a prescription. Figure 1 illustrates the PrEP care continuum for our clinic. There was no significant difference in PrEP initiation or discontinuation by age or race. There was no significant difference in persistence by race. Ages 18–24 had the shortest mean persistence (62 days, 95% CI: ±37.5), while those ages 35–44 had the longest mean persistence (146 days, 95% CI: ± 47.3) though this was not a significant difference (hazard ratio 0.39, P = 0.28). The most common reason for not initiating or discontinuing PrEP was concern about side effects (29%).

Conclusion

Clinicians in the Detroit STD clinic prescribed PrEP for less than half of PrEP-eligible patients, only 76% of those prescribed PrEP ever filled their first prescription, and the mean duration of use among those who filled a first prescription was under 6 months. Our findings highlight the need for further evaluation of why eligible patients are not prescribed PrEP, intensified support services to encourage PrEP persistence, and improved patient counseling about potential side effects.

Disclosures

All authors: No reported disclosures.
Comfort Discussing HIV Pre-Exposure Prophylaxis with Patients Among Physicians in an Urban Emergency Department
Authors: Tortelli Brett , Char Douglas , Powderly William , Patel Rupa
Published: October 2017

Background

HIV pre-exposure prophylaxis (PrEP) is effective but underutilized in the United States. The emergency department offers an opportunity to access at-risk individuals for PrEP referral. While several studies have described provider awareness and acceptance of PrEP, these studies have focused largely on infectious diseases, HIV, and primary care specialty physicians. Thus, PrEP awareness, knowledge, and concerns among emergency physicians remain unknown. We sought to determine provider comfort in discussing PrEP with patients among emergency physicians in Missouri.

Methods

We conducted an online survey among 88 emergency physicians at Washington University in St. Louis from February 2017 to March 2017 in St. Louis, Missouri. The survey included demographics, comfort discussing PrEP, having ever heard of PrEP (awareness), knowledge of the current CDC prescribing guidelines, concerns with use, and knowing local PrEP referral information. The questions were asked on a Likert scale and dichotomously categorized. We evaluated predictors of physician comfort of discussing PrEP with patients using multiple logistic regression.

Results

Sixty-seven participants completed the survey; 64.1% were faculty. Most (79.1%) were PrEP aware, however, only 23.9% were knowledgeable of current guidelines and 22.7% of referral information. Concerns included lack of efficacy (53.7%), side effects (89.6%), and the selection for HIV resistance (70.1%). Comfort discussing PrEP was 43.3%. When adjusting for the concern of efficacy, having PrEP knowledge (OR: 5.43; CI: 1.19–30.81) and having referral knowledge (OR: 7.82; CI: 1.93–40.98) were significantly associated with comfort in discussing PrEP.

Conclusion

We found moderate PrEP awareness among emergency physicians, but also high levels of discomfort in discussing PrEP with their patients. Future provider training should include addressing misinformation surrounding the concerns with PrEP use and prescribing, reviewing current guidelines, and providing local referral resources for PrEP patient care. Emergency department settings can facilitate PrEP awareness and referral to care among at-risk patients to help reduce national HIV incidence.

Disclosures

All authors: No reported disclosures.
Evaluation of early achievement of an AUC/MIC of >400 for Vancomycin in children with methicillin-resistant Staphylococcus aureus bacteremia
Authors: Murai Takemi , Higuchi Hiroshi , Suwa Junichi , Funakoshi Hanako , Yoneda Ryuu , Ishii Sho , Araki Kotaro , Fukuoka Kahoru , Aizawa Yuta , Horikoshi Yuho
Published: October 2017

Background

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia causes morbidity and mortality in children. The standard treatment for MRSA bacteremia is vancomycin, which should achieve a 24 hour area under the curve over the minimum inhibitory concentration ratio (AUC/ MIC) of >400. Whether or not attaining AUC/ MIC >400 early in the disease course improves outcomes in children is controversial. The aim of our study was to determine whether early achievement of AUC/ MIC >400 improved outcomes in children with MRSA bacteremia.

Methods

Children whose blood culture grew MRSA between March 2010 and April 2017 at Tokyo Metropolitan Children’s Medical Center were enrolled. The exclusion criteria were no vancomycin administration, use of extracorporeal membrane oxygenation, no data on dosage and vancomycin MIC, and cases of contamination. Susceptibility testing was performed by a microdilution method. The outcomes of patients who achieved an AUC/MIC >400 at the first assessment prior to the Fourth or Fifth vancomycin dose were compared with those of patients who did not. The clinical outcomes were persistent bacteremia on Days 3 and 7, mortality at 30 days, and the recurrence of MRSA bacteremia.

Results

In total 175 MRSA isolates from 50 children were identified. Of these 56 episodes were eligible for enrollment. Forty-one subjects (73.2%) were boys. The median age was 9 months (interquartile range: 1.8–120.5 months). The median initial dose of vancomycin was 40 mg/kg (interquartile range: 30–44.3 mg/kg). Among MRSA isolates, vancomycin MIC of < 0.5 mcg/mL, 1 mcg/mL and 2 mcg/mL were 1 (1.8%), 53 (94.6%) and 2 (3.6%), respectively. Fifteen patients (26.8%) achieved AUC/MIC >400 early. The two groups did not differ significantly in terms of persistent bacteremia on Days 3 (P = 0.96) or 7 (P = 0.82), mortality at 30 days (P = 0.47), or the recurrence of MRSA bacteremia (P = 1.0).

Conclusion

Children with bacteremia who achieved AUC/ MIC>400 early did not differ significantly from children who did not in terms of their clinical outcomes.

Disclosures

All authors: No reported disclosures.
Relationship between Vancomycin Area Under the Concentration-Time Curve (AUC) and Nephrotoxicity in Adults
Authors: Allen David , Townsend Mary , Drew Richard
Published: October 2017

Background

While recent data correlate vancomycin’s ratio of the area under the 24 hour time-concentration curve (AUC0−24h) to the pathogen’s minimal inhibitory concentration (MIC) of > 400 mg*hours/L with a favorable clinical outcome, data are sparse to correlate vancomycin AUC0−24h to nephrotoxicity. Our primary objective was to evaluate the relationship between vancomycin AUC0−24h and nephrotoxicity.

Methods

This single-center, retrospective cohort study was conducted at a large US tertiary-care hospital. Adults hospitalized between 08/01/13 and 08/31/14 with normal baseline renal function receiving intravenous vancomycin ≥ 72 hours were included. Vancomycin AUC0−24h was calculated for each subject utilizing computer-based Bayesian pharmacokinetic methods (BestDose™). Subjects were divided into AUC0−24h of < 700 and > 700 mg*hours/L groups. The primary endpoint of nephrotoxicity (defined as a 50% relative increase or > 0.5 mg/dl absolute increase in SCr over at least 2 consecutive days) was compared between exposure groups. Secondary objectives were to compare the incidence of nephrotoxicity with and without the following risk factors: sepsis, concomitant nephrotoxins, vancomycin troughs > 20 mg/L or doses ≥ 4 g/day, and Charlson Comorbidity Index scores.

Results

Table 1. Multivariate Model of Nephrotoxicity and Clinical Characteristics

Conclusion

A significant increase in nephrotoxicity was observed in patients with a vancomycin AUC0−24h ≥ 700 mg*hours/L. Given that this exposure threshold is within the target for efficacy for organisms with elevated MICs, further studies should be conducted to better delineate the AUC0−24h values associated with nephrotoxicity.

Disclosures

All authors: No reported disclosures.
Clinical Manifestations and Outcome of Fluoroquinolone Associated Acute Interstitial Nephritis
Authors: Farid Saira , AbuSaleh Omar , Mahmood Maryam , Garrigos Zerelda Esquer , Hamadah Abdurrahman , Nasr Samih , Leung Nelson , Sohail M Rizwan
Published: October 2017

Background

Fluoroquinolones (FQ) are among the most commonly prescribed antibiotics. Nephrotoxicity related to FQ use is infrequently reported and the mechanism of renal injury is incompletely elucidated. We describe clinical manifestations and outcome of patients with biopsy proven acute interstitial nephritis (AIN) associated with FQ use at our institution.

Methods

We conducted a retrospective review of biopsy-proven AIN attributed to FQ use at Mayo Clinic Rochester from 1993 to 2016. Cases were reviewed by a renal pathologist and attributed to FQ use by an expert nephrologist. We also reviewed and summarized all published case reports of biopsy proven AIN that were attributed to FQ use.

Results

We identified 24 patients with FQ-related biopsy-proven AIN. The most commonly used FQ was ciprofloxacin (71%) with median antibiotic treatment duration of 7 days (Figure 1). The median duration between starting FQ and the diagnosis of AIN was 8.5 (IQR: 17). Common clinical manifestations included fever (50%), flank pain (8%), and skin rash (21%). However, 17% of the patients were asymptomatic at the time of diagnosis (Figure 2). Majority (58%) of the patients recovered following discontinuation of antibiotics and returned to baseline renal function at a median of 20.5 (IQR: 15.5). Six patients required temporary hemodialysis and 9 patients received steroids.

Conclusion

Onset of FQ-related AIN can be delayed and a high index of suspicion is needed by physicians prescribing these agents. Overall outcomes are favorable with recovery to baseline renal function within 3 weeks of discontinuing the offending drug.

Disclosures

All authors: No reported disclosures.
Traditional PK-PD Indices for Efficacy – Can We Do Better?
Authors: Lakota Elizabeth A , Bader Justin C , Bhavnani Sujata M , Andes David R , Ambrose Paul G
Published: October 2017

Background

The relationship between antimicrobial activity and exposure relative to MIC is typically evaluated using one of three PK-PD indices, AUC:MIC ratio, Cmax:MIC ratio, and %T>MIC. However, under certain circumstances, none of these PK-PD indices may be the most optimal. These include when the fitted Hill functions for each of the PK-PD indices do not allow for sufficient discrimination, the variability about the fitted functions is wide, and/or the pattern of dose fractionation data is non-informative. Relationships fit using the traditional PK-PD indices may be suboptimal for drugs which exhibit extreme PK characteristics such as abnormally short or long half-lives. As described herein, we explored the use of a fourth PK-PD index for such instances, AUC/τ:MIC ratio (τ = dosing interval).

Methods

Previously-described ceftolozane dose-fractionation data from a study using a neutropenic murine thigh-infection model were evaluated [AAC 2013; 57(4):1577–82]. In this prior study, mice were infected with E. coli ATCC 25922 (MIC = 0.5 mg/L) or K. pneumoniae ATCC 43816 (MIC = 1.4 mg/L). Ceftolozane doses ranged from 1.56 to 1600 mg/kg/24h given q3h, q6h, q12h, or q24h. Relationships between log10 colony forming units (CFU) at 24 hours and AUC:MIC ratio, Cmax:MIC ratio, %T>MIC, and AUC/τ:MIC ratio were evaluated by pathogen and pooled using Hill-type models and non-linear least squares regression.

Results

For evaluations of data by pathogen, AUC/τ:MIC ratio best described changes in log10 CFU at 24 hours. The coefficients of determination (r2) for these pathogens were improved by 0.20 and 0.11, respectively, relative to the highest r2 achieved using any of the traditional PK-PD indices. Similar results were observed when the data were evaluated using a pooled approach (Figure 1).

Conclusion

AUC/τ:MIC ratio may be useful to evaluate drugs demonstrating the extremes of PK. Accordingly, this PK-PD index best described ceftolozane PK-PD, an agent with a very short murine plasma half-life (<15 minutes). The use of the PK-PD index that allows for the best fit of the data to the Hill function and reduced variability about the fitted function will not only improve the characterization of PK-PD but will also improve the accuracy of future dose selection analyses.

Disclosures

All authors: No reported disclosures.
At the Crossroads of Stewardship and Technology: Impact of Pharmacokinetic-Pharmacodynamic (PK-PD) Integrated Electronic Decision Support Software (EDSS) on the Treatment of Patients Infected with Pneumonia
Authors: Bader Justin C , Bulik Catharine C , Bhavnani Sujata M , Rubino Christopher M , Sweeney Kim L , Ambrose Paul G , Owens Robert C
Published: October 2017

Background

While many have advocated for the use of EDSS to enhance patient care, EDSS that incorporates PK-PD, the science behind antimicrobial stewardship, has thus far been an unattainable goal. Herein, we describe the use of such a technology and clinicians’ therapy decisions when treating patients with pneumonia.

Methods

Data for patients with pneumonia entered into EDSS over a 20-month period that were evaluated included: 1) patient demographics, creatinine clearance, and pneumonia severity score; 2) pneumonia type; 3) pathogen; 4) clinician-selected antimicrobials; 5) EDSS-presented regimens; and 6) clinician-reported outcomes. Clinicians were provided probabilities of attaining PK-PD targets associated with efficacy for both clinician-selected and EDSS-presented regimens. A regimen with a probability of PK-PD target attainment ≥90% was considered PK-PD optimized.

Results

Data for 126 cases were available. The median (min, max) age and creatinine clearance were 56.5 (18, >90) years and 72.5 (2.5, 193.3) mL/minute/1.73 m2, respectively. Pneumonia types included community-acquired (39%), healthcare-associated (30%), ventilator-associated (18%), and hospital-acquired (13%). CURB-65 pneumonia scoring was used in 66% of cases with a median (min, max) score of 3 (0, 5). The most common pathogens were P. Aeruginosa (32%), MRSA (15%), and S. pneumoniae (14%). Multi-drug-resistant pathogens comprised 15% of all pathogens. PK-PD optimized regimens were selected in only 65% of cases despite such a regimen being presented in 91% of cases. For those cases in which outcome data were available (n = 36), 81% of patients were considered improved at 48 hours while only 64% were deemed clinically improved or a success at the final outcome assessment on Days 7–10. Among those cases for whom PK-PD optimized and non-optimized regimens were selected (64 and 36%, respectively), 78 and 62% of patients had successful clinical outcomes on Days 7–10, respectively.

Conclusion

Given that patients with pneumonia represent a vulnerable population and that options for therapy can be limited, selection of optimal early therapy is crucial. PK-PD integrated EDSS presents clinicians the opportunity to optimize therapy and improve outcomes for patients with pneumonia.

Disclosures

S. M. Bhavnani, ICPD Technologies: Shareholder, stock options. C. M. Rubino, ICPD Technologies: Shareholder, stock options. P. G. Ambrose, ICPD Technologies: Shareholder, stock options.
In Vitro Antibacterial Activity of Ceftolozane/Tazobactam (C/T) Alone and in Combination with other Antimicrobial Agents against Multidrug-Resistant (MDR) Pseudomonas aeruginosa (PSA)
Authors: Monogue Marguerite , Nicolau David P
Published: October 2017

Background

Broad-spectrum antimicrobial resistance in MDR PSA isolates significantly limits our therapeutic options. C/T has been shown to be highly active against MDR PSA isolates. To assist the clinical decision-making process regarding the selection of agents and dosages for this pathogen, we performed time-kill studies assessing various C/T concentrations alone and in combination with other anti-pseudomonal agents.

Methods

Four clinical MDR P. aeruginosa isolates were selected. MICs were determined via broth microdilution methods according to CLSI. Time-kill analyses were performed in duplicate using C/T free concentrations reflective of the peak and trough of a 3g q8h dose (120/25.2 µg/mL,7.5/1.6 µg/mL) and the peak of a 1.5g q8h dose (60/12.6 µg/mL) in humans. The activity of C/T 120, 60, and 7.5 alone and C/T 7.5 in combination with free peak concentrations of FEP, CIP, CST, ATM, MEM, TZP, FOF, or AMK was tested for all isolates. Colony counts were determined at 0, 3, 6, and 24h by serial dilution plating. Synergy was defined at ≥ 2 log10 CFU reduction from the most active agent.

Results

MICs of the 4 MDR P. Aeruginosa isolates are in Table 1. As the C/T concentrations increased, bacterial reduction improved, achieving a mean (±SD) log10CFU change from 0 h of 0.03 (±0.67), −1.19 (±1.03), −2.59 (±0.86) with C/T 7.5, 60, 120, respectively. C/T 7.5 was synergistic with CST (PSA C8-21, PSA C45-10) and FOF (PSA C28-5, PSA C14-22) in two of four isolates. No synergy was observed with double β-lactam therapy or CIP. AMK alone achieved maximal bacterial kill; therefore, synergy could not be assessed.

Conclusion

C/T 3g and 1.5g q8h peak concentrations demonstrate killing against the MDR PSA. CST and FOF were synergistic with C/T in vitro. Our findings aide in identification of novel treatment options and dosing regimens for the treatment of MDR P. Aeruginosa.

Disclosures

D. P. Nicolau, Merck: Investigator and Speaker’s Bureau, Research support.
Influence of Polymyxin B Dose on Development and Recovery of Acute Kidney Injury
Authors: D’Agostino Lydia , Martin Elena , Yin Michael , Kubin Christine J
Published: October 2017

Background

Nephrotoxicity is a common adverse effect of polymyxin B (PMB) with reported acute kidney injury (AKI) rates of 20% to >60%. Data on PMB dosing to optimize efficacy while minimizing toxicity are limited. Previous studies suggest higher doses improve outcomes but are also associated with more AKI. Data are needed to evaluate optimal dosing and contributing factors to minimize AKI and to evaluate renal recovery.

Methods

Retrospective study evaluating PMB in adults at NewYork-Presbyterian Hospital from 2012 to 2016. Patients who received PMB dosed twice daily for ≥2 days were included. Patients on renal replacement therapy within 48 hours prior to PMB or with AKI at time of PMB initiation were excluded. A classification and regression tree (CART) analysis was performed to identify the PMB dose most predictive of AKI which defined the breakpoint for high- vs. low-dose PMB cohorts for all subsequent comparisons. The primary outcome was to determine whether high-dose PMB independently predicted AKI. Secondary outcomes included in-hospital mortality, time to AKI, and recovery of renal function.

Results

246 patients were included: majority were male (59%) with median age 41 years. Median PMB dose was 2.9 mg/kg/day or 180 mg/day for a median duration of 10 days. AKI occurred in 64% and 38% had recovery of renal function by hospital discharge. The breakpoint for high-dose PMB determined by CART was 160 mg/day, putting 104 in low-dose and 142 in high-dose groups. High-dose PMB was associated with AKI compared with low-dose PMB on univariable (75% vs.. 49%, P < 0.001) and multivariable (OR 3.43; 95% CI 1.68,6.99; P = 0.001) analyses. Concomitant vancomycin (OR 3.34; 95% CI 1.74,6.41;P < 0.001), history of transplant (OR 4.96; 95% CI 2.14,11.48;P < 0.001), and previous PMB exposure (OR 2.37; 95% CI 1.23,4.57; P = 0.01) were also identified as independent predictors of AKI. No significant differences were found for in-hospital mortality (28% vs. 21%, P = 0.326), renal recovery (37% vs. 41%, P = 0.723), time to AKI (median 5 vs. 6 days, P = 0.125) between groups.

Conclusion

High-dose PMB (>160 mg/day) was independently associated with AKI as well as concomitant vancomycin, history of transplant, and previous PMB exposure. High-dose PMB did not have a significant impact on in-hospital mortality, recovery of renal function, or time to development of AKI.

Disclosures

M. Yin, Gilead Sciences: Consultant, Consulting fee.
Dengue IgG Seropositivity and Zika Viral Load
Authors: Read Jennifer , Alvarado Luisa I , Torres-Velasquez Brenda , Munoz-Jordan Jorge L , Beltran Manuela , Capre Sheila , Adams Laura , Torres-Torres Sanet , Santiago Gilberto , Rivera Lillian , Rivera-Sánchez Aidsa , Lorenzi Olga D , Sharp Tyler , Garcia-Gubern Carlos , Waterman Stephen
Published: October 2017

Background

Secondary dengue virus (DENV) infections are typically more severe than primary infections. It is not known whether previous DENV infection is associated with higher Zika virus (ZIKV) quantitative RT-PCR results (viral loads (VLs)) in areas endemic for DENV such as Puerto Rico. Our objective was to analyze the association between previous DENV infection (DENV IgG-positive) and ZIKV VL among children with symptomatic ZIKV infection enrolled in the Sentinel Enhanced Dengue and Acute Febrile Illness Surveillance System (SEDSS) in Puerto Rico.

Methods

The study population for this analysis comprised individuals <18 years of age enrolled in SEDSS during 2016 who were ZIKV PCR-positive in serum (using the CDC Trioplex RT-polymerase chain reaction (RT-PCR) assay) within 5 days post-onset (DPO) of symptoms. ZIKV VLs (genome copies/mL) were determined using an RNA standard curve generated from the RT-PCR assay target amplicons. An in-house ELISA was used to ascertain the presence or absence of serum DENV IgG. Trends were assessed using Jonckheere-Terpstra and Chi-square for proportions tests. The Mann–Whitney-Wilcoxon test was used to compare medians. Linear regression modeling was used to determine the association between DENV IgG and ZIKV VL.

Results

Of the 319 individuals who met inclusion criteria, 163 have dengue IgG assays completed to date. Of these, 90/163 (55%) were DENV IgG-positive and 73/163 (45%) were DENV IgG-negative, and did not vary by sex (P = 1.00). However, the proportion of patients with DENV IgG-positivity increased with age (P < 0.001) (Figure). Overall, the median (interquartile range, IQR) ZIKV VL was 23,110 (7,452–84,003), and did not vary by age (P = 0.11) or sex (P = 0.33). However, the median ZIKV VL varied by DPO: 26,230 (DPO<3; n = 117), 15,159 (DPO≥ 3; n = 46), P = 0.002. The median (IQR) ZIKV VLs were: 24,073 (10,938–73,130) in DENV IgG-negative specimens and 22,658 (7,332–89,322) in DENV IgG-positive specimens (P = 0.91). Linear regression indicated no association between DENV IgG and ZIKV VL (P = 0.54).

Conclusion

DENV IgG-positivity increased with age among children with symptomatic ZIKV infection. ZIKV VLs did not vary by age, but decreased with increasing DPO. There was no association between DENV IgG and ZIKV VL.

Disclosures

All authors: No reported disclosures.
Challenges of Zika Virus Testing in Pregnancy in the Setting of Local Mosquito-Borne Transmission
Authors: Kwal Jaclyn , Bartlett Michelle , Crane Anise , Greissman Samantha , Gunaratne Naiomi , Lardy Meghan , Picon Michelle , Starker Rebecca , Tse Colette , Rodriguez Patricia , Gonzalez Ivan , Curry Christine
Published: October 2017

Background

Zika Virus (ZIKV) infection in pregnancy is a major clinical concern. The CDC recommended that pregnant women living in an area with a ZIKV travel notice undergo ZIKV screening in the first and second trimesters of pregnancy. This study investigated the consequences of this screening on clinical management.

Methods

An IRB approved retrospective chart review was conducted using laboratory records of ZIKV testing on pregnant patients from January through December 2016 at multiple tertiary care centers in Miami, FL. Serum and/or urine samples were collected, based on CDC guidelines at the time, and evaluated for PCR and/or IgM evidence of ZIKV infection. Positive ZIKV PCR results indicated acute phase of infection. Previous infection was suggested by positive IgM antibody, but required confirmatory ZIKV plaque reduction neutralization testing (PRNT) testing due to IgM antibody cross reactivity with other flaviviruses.

Results

During 2016, 2,327 pregnant women were screened for ZIKV infection. At the peak in August 2016, 607 (26%) patients were tested and only 31 (5.1%) tests resulted within the month. Of those screened, 113 (4.85%) women tested positive for ZIKV PCR and/or IgM. In October 2016, 40 (35.4%) positive screening tests were received, the most positives resulting in a month. Confirmatory ZIKV PRNT testing was performed on those who were ZIKV IgM positive and PCR negative, with a total of 92 results received. Eighty-eight women were considered positive, 49 confirmed with positive titers (≥10). There were 28 women with negative titers (< 10), thus a false positive ZIKV screening rate of 30.4%, and 15 results were pending. Of women with false positive IgM screening, a median of 1 (range 0–4) additional ultrasound was done between receipt of the initial positive ZIKV screening and the subsequent receipt of the negative PRNT testing. Delays of results led to 21 (24%) positive tests reported after delivery and hospital discharge. Additionally, 18 (20.5%) women who tested PRNT positive had their originating sample drawn during admission for delivery with results available only after discharge.

Conclusion

Both delays in ZIKV testing results and false positive screening with ZIKV IgM led to challenges in counseling and clinical care of pregnant women living in an area of ongoing ZIKV transmission.

Disclosures

All authors: No reported disclosures.
Efficacy of Galidesivir against Ebola Virus Disease in Rhesus Monkeys
Authors: Warren Travis , MacLennan Steve , Mathis Amanda , Giuliano Enzo , Taylor Ray , Sheridan William
Published: October 2017

Background

The recent re-emergence of Ebola virus in the Democratic Republic of the Congo serves as a stark reminder of the 2013–2016 Ebola virus (EBOV), which resulted in >11,000 deaths. To date, there are no approved therapeutics or vaccines for EBOV disease (EVD). Galidesivir (BCX4430) is an adenosine nucleoside analogue designed to inhibit viral RNA polymerase activity indirectly through non-obligate RNA chain termination. Galidesivir exhibits in vitro antiviral activity against a broad spectrum of negative- and positive-sense RNA viruses. In vivo, galidesivir has shown antiviral activity against various viruses and provides 100% protection against Marburg virus disease in cynomolgus macaques, when administered either 1 or 2 days post infection. Initial exploratory studies in a rhesus macaque model of EVD showed that 25 mg/kg galidesivir administered twice daily (BID) IM beginning immediately following viral challenge protected 100% (6 of 6) of animals.

Methods

Pharmacokinetic modeling based on galidesivir levels in healthy and EBOV-infected animals predicted that a loading-dose regimen could decrease time to steady-state, potentially advantageous when extending the time of treatment initiation. To test the efficacy of a loading dose regimen, 100 mg/kg was administered BID either 2 or 3 days after challenge, followed by maintenance doses of 25 mg/kg BID for a total duration of 11 days.

Results

Six of 6 (100%) rhesus monkeys survived after receiving loading doses on day 2, and 4 of 6 (67%) animals survived after receiving loading doses beginning day 3. In the dosing regimen that conferred 100% protection, the animals exhibited either no behavioral depression or only mild and transient behavioral depression. In all treated groups, there was a significant reduction of plasma viral RNA concentrations during the acute phase of disease.

Conclusion

Galidesivir protects rhesus monkeys against an otherwise lethal EBOV challenge. Administered by IM injection, Phase 1 human clinical studies of single and multiple ascending doses have shown galidesivir to be generally safe and well tolerated up to 10 mg/kg daily for seven days. Additional clinical studies are planned to evaluate the safety and tolerability of galidesivir administered by IV infusion. Supported by NIAID (NIH), HHSN272201300017C.

Disclosures

S. MacLennan, BioCryst: Employee, Salary. A. Mathis, BioCryst Pharmaceuticals: Employee, Salary. E. Giuliano, BioCryst: Employee, Salary. R. Taylor, BioCryst Pharmaceuticals: Employee, Salary. W. Sheridan, BioCryst Pharmaceuticals: Employee, Salary.
Diagnostic accuracy of CSF cell index and corrected CSF white blood cell count in healthcare-associated ventriculitis and meningitis after intracranial hemorrhage
Authors: Jenkinson Helena , Habib Onaizah , Salazar Lucrecia , Hasbun Rodrigo
Published: October 2017

Background

The diagnosis of healthcare-associated meningitis and ventriculitis (HCAMV) in patients with intracranial hemorrhage (ICH) is challenging. The purpose of this study was to evaluate the diagnostic accuracy of routine cerebrospinal fluid (CSF) studies including a cell index and a corrected white blood cell (WBC) count.

Methods

Case control study of adult patients with the diagnosis of ICH and HCAMV at a large tertiary care hospital in Houston, Texas from 2003 to 2016. Cases were defined as patients with ICH and HCAMV as documented by a positive CSF culture. Controls were selected as patients with ICH without evidence of HCAMV, no previous antibiotic therapy and a negative CSF culture. Cases and controls were matched 1:2 by age, Glasgow Coma Scale (GCS) and Apache II scores. Cell index was calculated using the following formula: (CSF leukocytes / CSF erythrocytes) / (blood leukocytes / blood erythrocytes). Corrected WBC count was calculated using the following formula: CSF leukocytes - (CSF erythrocytes/1,000). Area under the curve of receiver operating characteristic (AUC-ROC) and 95% confidence interval (CI) for CSF cell index greater than or equal to absolute value of 1, corrected CSF WBC count greater than 5 K/uL, CSF lactate greater than 4 mmol/L, and CSF glucose less than 40 mmol/L, respectively, were calculated in order to determine the accuracy of these studies.

Results

A total of 120 patients with ICH were included in this study; 40 patients had proven HCAMV whereas 80 patients had ICH with no evidence of HCAMV. Matching of cases and controls by age, GCS, and Apache II score was appropriate (p>0.05). The AUC-ROC values for CSF cell index, corrected CSF WBC count, CSF lactate, and CSF glucose were all low at 0.609 (95% CI = 0.449–0.768), 0.731 (95% CI = 0.589–0.872), 0.719 (95% CI = 0.573–0.864), and 0.609 (95% CI = 0.449–0.768), respectively.

Conclusion

This study demonstrated poor accuracy of CSF cell index, corrected CSF WBC count, CSF lactate, and CSF glucose in diagnosis of HCAMV after ICH.

Disclosures

R. Hasbun, Biomeriaux: Consultant, Consulting fee. Biofire: Speaker’s Bureau, Speaker honorarium. Merck: Speaker’s Bureau, Speaker honorarium. Pfizer: Speaker’s Bureau, Speaker honorarium. Medicine’s Co: Speaker’s Bureau, Speaker honorarium.
Brain Abscess Risk Associated with Genotypic Polymorphism of the Matrix Metalloproteinase-1, -2, -3, and -9 in North Indian Population
Authors: Mishra Priyanka , Prasad Kashi Nath , Singh Kamini , Sahu Rabi Narayan , Prakash Swayam , Ojha Bal K
Published: October 2017

Background

Brain abscess develops in response to a parenchymal infection due to pyogenic bacteria. MMPs (matrix metalloproteinases) play vital role in many infectious and central nervous system (CNS) diseases. The present study evaluated the association of specific alleles/ genotypes of MMP-1, -2, -3, and -9 with brain abscess.

Methods

A total of 100 brain abscess patients and 100 healthy controls were included in the study. Predisposing factors were identified in 70 brain abscess patients. Out of 100 brain abscess samples, 66 were culture positive. MMP-1-1607 1G/2G, MMP-2- C-1306-T, MMP-3 -1171 5A/6A, and MMP-9 C-1562Tgenotypes were detected by PCR-RFLP. Levels of these MMPs were determined in patients’ sera by ELISA and correlated with different genotypes.

Results

The genotypic distributions of MMP-1-1607 1G/2G, MMP-2- C-1306-T, MMP-3 -1171 5A/6A, and MMP-9 C-1562T were significantly different between patients and controls. Homozygous genotype of MMP-1, -3, and -9 (P < 0.001, P = 0.04, and P = 0.03, respectively) and heterozygous genotype of MMP-2 (P < 0.001) showed significant association with brain abscess. Individuals with mutant genotypes had elevated levels of these MMPs. Furthermore, heterozygous (5A/6A and C/T, respectively) genotypes of MMP-3 and -9 also showed significant association with brain abscess patients having predisposing factors. When comparison was made between culture positive and culture negative results, of MMP-1 2G/2G and MMP-9 T/T, C/T genotype showed significant association with culture positive patients

Conclusion

Polymorphism of MMP-1-1607 1G/2G, MMP-2- C-1306-T, MMP-3 -1171 5A/6A, and MMP-9 C-1562T polymorphisms lead to increased production of these molecules, which appear to be a risk for the development of brain abscess in North Indian population.

Disclosures

All authors: No reported disclosures.
Meningitis in the Kaiser Permanente Northern California (KPNC) Pediatric Population 2012 through 2016 and Its Association with Prior Traumatic Brain Injury (TBI)
Authors: Chu Victoria , Carpenter Diane , Postlethwaite Debbie , Harriman Kathleen , Glaser Carol
Published: October 2017

Background

The incidence of meningitis, particularly bacterial meningitis, is decreasing due to widespread vaccine use with etiologies still due to relatively common organisms. However, risk factors for the development of meningitis are largely unknown. We describe the epidemiology of meningitis among the pediatric population of KPNC and assess the association between prior TBI and meningitis.

Methods

We conducted a retrospective descriptive study among KPNC pediatric patients (1 month-18 years) between July 2012 - June 2016 with an ICD-9 meningitis diagnosis. Charts were reviewed to a.) verify and classify the meningitis diagnosis and b.) ascertain prior TBI history. Cases were classified as confirmed, probable, or possible based on clinical course, CSF culture, PCR, and CSF profile. The proportion of meningitis cases with a history of TBI was compared with the published rate of TBI in the general pediatric population.

Results

Of 266 cases reviewed, 146 cases were verified as meningitis with 19 confirmed/probable bacterial [(S. pneumoniae (7), E. coli (3), S. Agalactiae (3), N. meningitidis (2), S. Aureus (1), and not otherwise specified (3)] and 50 confirmed/probable viral [(enterovirus (44), HSV2 (4), HSV1 (1), and WNV (1)] etiologies. An additional 77 possible cases included primarily viral etiologies (65) and a minority of possible bacterial (6) or infection-related inflammatory (6) etiologies. 120 were excluded. The overall meningitis and confirmed bacterial meningitis estimated incidence rate was 17.9 per 100,000 and 2.7 per 100,000, respectively. Twenty meningitis cases (13.7%) had a history of TBI (all of which were concussions) compared with the concussion rate in the general pediatric population reported by AL Zhang et al of 0.7% (P < 0.001).

Conclusion

Our results are consistent with recent studies showing a decline in bacterial meningitis. Enteroviral meningitis remains the leading cause of identified etiologies. However, in a sizable proportion of cases there was no specific pathogen identified. An increased risk of developing meningitis may be associated with TBIs.

Disclosures

All authors: No reported disclosures.
A Primary Amebic Meningoencephalitis Case Associated with Rafting on an Artificial Whitewater River
Authors: Cope Jennifer , Murphy Jennifer , Kahler Amy , Gorbett Daniel , Ali Ibne , Taylor Brandi , Corbitt Lisa , Roy Shantanu , Lee Nicole , Roellig Dawn , Brewer Scott , Hill Vincent
Published: October 2017

Background

Naegleria fowleri is a climate-sensitive thermophilic ameba found in freshwater that causes primary amebic meningoencephalitis (PAM; 0–8 infections per year in the U.S.) when it enters the nose and migrates to the brain. Patient exposure to water containing the ameba typically occurs in warm freshwater lakes and ponds during recreational water activities. In June 2016, an 18-year-old woman died of PAM after traveling to North Carolina, where she participated in whitewater rafting on an artificial whitewater river.

Methods

To determine water exposures, we reviewed medical records and conducted interviews with family and individuals who had traveled with the case-patient. To further investigate the artificial whitewater river as a possible exposure source, we visited the whitewater facility and collected water, biofilm, and sediment samples from the facility and from the nearby natural river. We performed select water quality tests onsite and tested for the presence of N. fowleri by culture and real-time PCR in the laboratory.

Results

Interviews revealed that the case-patient’s most probable water exposure in the 10 days before becoming ill occurred while rafting on an artificial whitewater river during which she was thrown out of the raft and submerged underwater. The ~11.5 million gallons of water in the whitewater facility were filtered, subjected to UV light, and occasionally chlorinated. Heavy algal growth was noted. The free chlorine residual was 0.05 mg/L, turbidity was 6.7 NTU, and water temperature was 30°C in the whitewater facility during the site visit. All 11 water-related samples taken from the facility were positive for N. fowleri. Of 5 samples taken from the natural river, 1 sediment sample was positive for N. fowleri.

Conclusion

This investigation documents a novel exposure to an artificial whitewater river as the likely exposure causing PAM in this case. Conditions in the whitewater facility (warm, turbid water with little chlorine and heavy algal growth) rendered the water treatment ineffective and provided an ideal environment for N. fowleri to thrive. The combination of natural and engineered elements at the whitewater facility create a challenging environment to control the growth of N. fowleri.

Disclosures

All authors: No reported disclosures.
Varicella-zoster virus Neurovasculitis (VZV-NV) in the Setting of Autoantibodies to Interferon alpha (anti-IFNα)
Authors: Ansari Rahila , Zerbe Christa , Lisco Andrea , Rosen Lindsey , Holland Steven , Bonomo Robert A
Published: October 2017

Background

VZV-NV resulting in CNS damage is rare in immunocompetent hosts. Humoral immunity protects against acquiring VZV, and T-cell mediated immunity shields against reactivation of the latent virus. Individuals who are immunocompromised due to T-cell mediated defects can present with systemic VZV.

Methods

Case report of a previously healthy man who developed VZV-NV associated with autoantibodies to IFNα.

Results

A previously healthy 64 year-old man developed an acute T3 Brown-Sequard syndrome. Symptoms progressed to include bilateral lower extremity weakness, ptosis, ophthalmoplegia, and encephalopathy. Magnetic resonance imaging (MRI) showed diffuse T2 hyperintensities with enhancement throughout the spine and brain, including enhancement of his meninges, roots, and cranial nerves. Successive cerebrospinal fluid (CSF) studies revealed increasing B-cell lymphocytosis, (maximum 661 cells/mcl), and CSF protein (maximum 242 mg/dL). CSF PCR was positive for VZV and IgM antibodies. Further testing showed anti-IFNα autoantibodies in the plasma and CSF. Serum anti-IFNα fluorescence intensity was 30 times normal, and his plasma blocked IFNα-induced STAT-1 phosphorylation in normal monocytes. Treatment with acyclovir and methylprednisolone resulted in improvement. Repeat LP following treatment revealed 32 WBC/mcl with normal protein. Follow-up MRI did not show any new lesions. Three years after initial presentation, he continues to be stable without clinical relapses, or subclinical changes on MRI. Serum studies were positive for VZV IgG and negative for IgM. CSF PCR was positive for VZV. Lastly, serum anti-IFNα fluorescence intensity remained 25 times normal, and his plasma continued to block IFNα-induced STAT-1 phosphorylation in normal monocytes.

Conclusion

This is the first identified case of CNS VZV-NV in the setting of binding and blocking autoantibodies to IFNα in the serum and CSF. Elevated serum and CSF levels of anti-INFα may impair natural killer, T-cell and neuronal antiviral activity. Disruption of T-cell mediated immunity due to anti-IFNα could cause an adult-onset immunocompromised state with severe VZV reactivation. The association of high-titer neutralizing autoantibodies to INFα in an adult with CNS VZV is novel and may be clinically relevant.

Disclosures

All authors: No reported disclosures.
PCR Array Profiling of Antiviral Genes in Human Embryonic Kidney Cells Expressing Human Coronavirus OC43 Structural and Accessory Proteins
Authors: Beidas Meshal , Chehadeh Wassim
Published: October 2017

Background

Human coronavirus OC43 (HCoV-OC43) causes common cold, and is associated with severe respiratory symptoms in infants, elderly and immunocompromised patients. HCoV-OC43 is a member of Betacoronavirus genus that includes also the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) coronaviruses. Both SARS-CoV and MERS-CoV were shown to express proteins with the potential to evade early innate immune responses. However, the ability of HCoV-OC43 to antagonise the intracellular antiviral defences has not yet been investigated. The objective of this study was to investigate the role of HCoV-OC43 structural (membrane and nucleocapsid) and accessory (ns5a and ns2a) proteins in the modulation of antiviral gene expression profile in human embryonic kidney 293 (HEK-293) cells using PCR array analysis.

Methods

HCoV-OC43 membrane (M), nucleocapsid (N), ns5a and ns2a mRNA were amplified and cloned into the pAcGFP1-N expression vector (Clontech), followed by transfection in HEK-293 cells. Expression of M, N, ns5a and ns2a proteins were confirmed by indirect immunofluorescence test. Three days post-transfection, the cells were challenged by Sendai virus. The Human Antiviral Response PCR array system (Qiagen) was used to profile the antiviral gene expression in HEK-293 cells, using the fold regulation comparison and the manual normalisation methods.

Results

Around 50–60 genes were downregulated by HCoV-OC43 proteins, the most prominent genes being those critical for the activation of transcription factors involved in the antiviral response like interferon regulatory factors (IRFs) and activator protein 1 (AP-1). Among the most important downregulated genes were those coding for Interferons (IFNs) mitogen-activated protein kinases (MAPKs), pro-apoptotic and pyroptotic proteins (Caspases, cathepsins, tumour necrosis factor), pro-inflammatory cytokines (Interleukins), pattern recognition receptors (PRRs; toll-like receptors and NOD-like receptors) and their signaling transduction proteins (TICAM1, MAVS).

Conclusion

This study shows for the first time that similarly to SARS-CoV and MERS-CoV, HCoV-OC43 has the ability to downregulate the transcription of genes critical for the activation of different antiviral signaling pathways.

Disclosures

All authors: No reported disclosures.
Risk Factors for Herpes Zoster: a Systematic Review and Meta-Analysis
Authors: Kawai Kosuke , Yawn Barbara P
Published: October 2017

Background

Well-recognized risk factors for herpes zoster (HZ), commonly known as shingles, are age and immunosuppression. Numerous studies have investigated other various risk factors for HZ in recent years. The objective of our study is to systematically review studies examining risk factors for HZ and discuss implications based on the updated evidence.

Methods

We performed a literature search using PubMed, Embase, and Web of Science and included studies that examined risk factors for HZ. Random effects model was used to summarize the risk ratio (RR) or odds ratio (OR) and 95% confidence interval (CI).

Results

Of the 3450 studies screened, we included 84 studies in the systematic review and conducted meta-analysis in 62 studies. Women are at increased risk of HZ compared with men (pooled adjusted RR = 1.31; 95% CI: 1.27, 1.34). Black individuals have almost half the risk of HZ than White individuals (pooled RR = 0.54; 95% CI: 0.47, 0.63). Family history was found to be a risk factor for HZ (pooled OR = 3.59; 95% CI: 2.39, 5.40). Autoimmune diseases, including rheumatoid arthritis (pooled RR = 1.67; 95% CI: 1.41, 1.98) and systemic lupus erythematous (RR = 2.10; 95% CI: 1.40, 3.15), were associated with an elevated risk of HZ. Other comorbidities were associated with an increased risk of HZ, with the pooled RRs ranging from 1.25 (95% CI: 1.13, 1.39) for asthma to 1.30 (1.17, 1.45) for diabetes mellitus, and 1.31 (95% CI: 1.22, 1.41) for chronic obstructive pulmonary disease. Statin use was also associated with a modest increased risk of HZ (pooled RR = 1.14; 95% CI: 1.11, 1.17). Recent physical trauma increased risk of HZ by almost two-fold (pooled RR = 2.56; 95% CI: 1.97, 3.33).

Conclusion

In addition to age and immunocompromised conditions, our review shows that female sex, race/ethnicity, family history, and comorbidities are risk factors for HZ. Efforts are needed to better understand risk factors and to increase the uptake of zoster vaccination.

Disclosures

B. P. Yawn, GSK: Consultant and Scientific Advisor, Consulting fee