bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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, &gt;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

Abstract

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

Abstract

Background
Nephrotoxicity is a common adverse effect of polymyxin B (PMB) with reported acute kidney injury (AKI) rates of 20% to &gt;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 &lt; 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 &lt; 0.001), history of transplant (OR 4.96; 95% CI 2.14,11.48;P &lt; 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 (&gt;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

Abstract

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 &lt;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 &lt; 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&lt;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

Abstract

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 (&lt; 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

Abstract

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 &gt;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

Abstract

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&gt;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

Abstract

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 &lt; 0.001, P = 0.04, and P = 0.03, respectively) and heterozygous genotype of MMP-2 (P &lt; 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

Abstract

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 &lt; 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.