bluuebunny/crossref_metadata_2025 huggingface dataset:
148. Fungal Disease Mortality Trends, United States, 1999–2017
Authors: Toda Mitsuru , Jackson Brendan R , Deng Li , Derado Gordana , Chiller Tom M , Benedict Kaitlin
Published: January 2021

Background

Fungal diseases can lead to substantial morbidity and mortality, although research funding has been disproportionately low compared with other infectious diseases. Despite dramatic changes in immunosuppressive therapy over the past two decades, the U.S. mortality burden of fungal diseases has not been recently assessed.

Methods

We analyzed fungal disease-associated mortality trends during 1999–2017 using multiple cause-of-death mortality records from the National Vital Statistics System. We calculated age-standardized rates for aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, unspecified mycoses, and other mycoses based on the age distribution of the 2000 U.S. population.

Results

Among over 47 million deaths, 86,058 (0.2%) people had one or more fungal diseases listed on the death certificate as an underlying or contributing cause of death (median 4,431 annually) (Figure 1). The age-standardized mortality rate was 2.2/100,000 population in 1999. By 2017, rates declined by 47% to 1.2. The largest declines occurred for pneumocystosis and cryptococcosis, diseases particularly associated with HIV, by 66–70% from 1999 to 2007 and by 3–6% from 2008 to 2017. During 1999–2017, rates for aspergillosis, candidiasis, and other mycoses declined by 46–56%, although rates for candidiasis and other mycoses increased (10% and 31%, respectively) from 2013 to 2017. Overall, the steepest declines were seen in infants and younger adults (Figure 2).

Age-standardized mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and fungal disease type, United States, 1999–2017

Age-specific mortality rates for fungal diseases as underlying and contributing cause of death, per 100,000 people, by year and age group, United States, 1999–2017

Conclusion

Fungal disease-associated mortality rates declined by half from 1999 to 2017. Improved treatment of HIV and availability of new antifungals likely influenced the decline. However, fungal diseases are still documented in thousands of deaths annually, and rates differed substantially by disease. Better prevention, diagnosis, and treatment are needed to reduce mortality from fungal diseases.

Disclosures

All Authors: No reported disclosures
168. Efficacy of the Novel gwt1 Inhibitor APX2039 in a Rabbit Model of cryptococcus Meningitis
Authors: Shaw Karen J , Giamberardino Charles D , Soltow Quinlyn A , Tenor Jennifer , Toffaletti Dena , Boua Jane-Valeriane , Marius Choiselle , Palmucci Julia R , Perfect John R
Published: January 2021

Background

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. New oral treatment options are needed that demonstrate rapid reductions in CFU in CSF and brain tissue.

APX2039 is a novel inhibitor of the fungal Gwt1 enzyme, which catalyzes an early step in glycosylphosphatidyl inositol (GPI) anchor biosynthesis. It is highly active against both C. neoformans and C. gattii and has previously demonstrated significant efficacy in a mouse delayed-treatment model of CM.

CSF Fungal Burden in Rabbits

Methods

Male New Zealand White rabbits were inoculated with C. neoformans H99 (1.4 ×106 CFU) directly into the cisterna magna. Rabbits were immunosuppressed with cortisone acetate at 7.5 mg/kg (i.m.), starting on Day -1 relative to inoculation and then administered drug daily throughout the 14-day experimental period. Treatment was initiated on Day 2 postinfection and continued through Day 14 consisting of: 50 mg/kg APX2039 PO (BID), 80 mg/kg fluconazole (FLU) PO (QD), c) 1 mg/kg amphotericin B deoxycholate (AMB) IV (QD); and vehicle control. CSF was removed via an intracisternal tap on Days 2, 7, 10 and 14 post-infection and CFU/ml was assessed. Animals were sacrificed on Day 14 and CFU/g brain tissue was assessed.

Results

APX2039 demonstrated rapid reduction in CFU in both CSF and brain tissue. The range in CFU values in rabbit CSF is shown (Figure). Reductions in CFU were statistically different from the control group for all treatment groups. APX2039 was also different from both FLU and AMB and resulted in sterilization in CSF by Day 10. Brain harvested on Day 14 demonstrated a reduction in CFU/g tissue vs control of 1.8 log10 and 3.4 log10 for FLU and AMB, respectively, while a > 6 log10 reduction (tissue sterilization) was observed for APX2039.

Conclusion

APX2039 demonstrated potent efficacy in a rabbit model of CM. The more rapid clearance in CSF than either AMB or FLU, as well as > 6 log10 reduction in brain CFU highlights the unique properties of this drug, warranting further investigation of this molecule for the treatment of CM.

Disclosures

Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Charles D. Giamberardino, Jr., MR, Box (Shareholder) John R. Perfect, MD, amplyx (Grant/Research Support)astellas (Grant/Research Support)astellas (Grant/Research Support)
171. Short-course Antimicrobial Therapy for Paediatric Respiratory Infections (SAFER): a multicentre, Randomized, Controlled, Blinded, Noninferiority Trial
Authors: Pernica Jeffrey , Harman Stuart , Kam April J , Carciumaru Redjana , Vanniyasingam Thuva , Crawford Tyrus , Dalgleish Dale , Khan Sarah , Fulford Martha , Main Cheryl L , Slinger Robert , Smieja Marek , Thabane Lehana , Loeb Mark
Published: January 2021

Background

Community-acquired pneumonia (CAP) is a common occurrence in childhood; consequently, evidence-based recommendations for its treatment are required. The study objective was to determine if, in previously healthy children presenting to the emergency department (ED), 5 days of high-dose amoxicillin led to noninferior rates of clinical cure at 14–21 days post-enrolment compared with 10 days of high-dose amoxicillin.

Methods

The SAFER study was a multicentre, randomized, parallel-group, multiple-blinded, controlled, noninferiority study, enrolling between 2012–2014 (single centre pilot) and then 2016–2019 (follow-up main study). Children aged 6 months – 10 years with all of the following were eligible: fever within 48h; a respiratory symptom/sign; a chest radiograph consistent with pneumonia as per the emergency MD; and a primary diagnosis of CAP. Children were excluded if they required hospitalization, had any medical comorbidities, or if they were already receiving beta-lactam antibiotic therapy. The intervention of interest was 5 days of high-dose amoxicillin followed by 5 days placebo. The control (standard care) arm received 5 days of high-dose amoxicillin followed by a different formulation of 5 days of high-dose amoxicillin. The primary outcome was clinical cure at 14–21 days post-enrolment. The pre-set noninferiority margin was 0.075 less than the clinical cure risk difference (1-sided 97.5% CI).

Results

Of the 281 participants, 119 (42%) were female; the median age was 2.6 y (25–75%ile 1.6–4.9 y). There were 140 randomized to short-course treatment and 141 to standard care. Clinical cure at 14–21 days was observed in 108/126 (86%) in the short-course arm and in 106/126 (84%) in the standard-care arm (risk difference 0.023, lower limit of 1-sided 97.5%CI -0.061). There were no participants who, after finishing amoxicillin, later deteriorated and required hospitalization for progressive CAP.

Conclusion

Short-course antibiotic therapy was noninferior to standard care for the treatment of previously healthy children with non-severe CAP diagnosed in Canadian EDs. Clinical practice guidelines should recommend no more than 5 days of amoxicillin for paediatric pneumonia management, in accordance with antimicrobial stewardship principles.

Disclosures

All Authors: No reported disclosures
173. HSV-2 Isolates from Neonates with Different Clinical Outcomes Exhibit Different in Vitro and in Vivo phenotypes
Authors: Akhtar Lisa N , Choi Sue , Hayes Cooper , Awasthi Sita , Koyuncu Orkide , Szpara Moriah , Enquist Lynn , Friedman Harvey , Longnecker Richard , Weitzman Matthew
Published: January 2021

Background

Herpes simplex virus (HSV) infection of the neonatal brain causes severe meningoencephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow different clinical courses. Some infants develop only external infection of the skin, eyes, or mouth (SEM disease), while others develop invasive infection of the central nervous system resulting in encephalitis (CNS disease). The factors that explain this clinical divergence are not well understood. While adults can be predisposed to HSV CNS infection by an innate immune defect, no such host susceptibility has been identified in neonates. Therefore, we have taken a novel approach to determine whether variations in the HSV genome contribute to infection of the neonatal brain. We recently defined the viral genetic diversity among HSV-2 isolates cultured from neonates with a range of clinical presentations. Isolates collected from neonates with CNS disease contained several unique amino acid variations in HSV proteins known to contribute to cell-to-cell spread and neurovirulence in mouse models.

Methods

To understand the relevance of these findings to neonatal CNS disease, we evaluated CNS disease- and SEM disease-associated neonatal HSV-2 isolates in neurologically-relevant in vitro and in vivo models.

Results

We found that HSV-2 isolates from neonates with CNS disease, as compared to those collected from neonates with SEM disease, displayed enhanced spread in human neuronally-differentiated SH-SY5Y or LUHMES cells and enhanced retrograde transport in rat neurons cultured in modified Campenot chambers. CNS disease-associated isolates also resulted in increased hind limb paralysis and zosteriform disease in a mouse flank scratch infection model, and increased death in a mouse direct intracerebral injection model of encephalitis. Notably, CNS disease and SEM disease-associated isolates resulted in equivalent outcomes following mouse intraperitoneal injection, suggesting similar systemic virulence.

Conclusion

These data suggest that virus-mediated differences in neuronal spread and transport may contribute to neurovirulence in neonatal HSV disease.

Disclosures

All Authors: No reported disclosures
174. Shotgun Metagenomics and Colonization by Antibiotic-resistant Bacteria in Pediatric Hematopoietic Stem Cell Transplant Recipients
Authors: Heston Sarah M , Young Rebecca R , Arshad Mehreen , Jenkins Kirsten , Martin Paul L , Ward Doyle V , Bhattarai Shakti , Bucci Vanni , Seed Patrick C , Kelly Matthew S
Published: January 2021

Background

Bacteremia in hematopoietic stem cell transplant (HSCT) recipients most frequently arises from gut bacterial translocation and is associated with a higher mortality if the organism is antibiotic-resistant. We sought to determine the impact of prior antibiotic exposure on antibiotic resistance genes (ARGs) in the gut metagenomes of HSCT recipients to inform future infection prevention strategies.

Methods

We performed shotgun metagenomic sequencing of fecal samples collected during the transplant hospitalization from children (< 18 years of age) undergoing HSCT at Duke University between 2015 and 2018. Host-decontaminated sequencing reads were aligned to the Comprehensive Antibiotic Resistance Database. We used a negative binomial regression model to determine the impact of recent therapeutic antibiotic exposure on the number of ARGs prior to HSCT.

Results

Median age of the 77 children included in these analyses was 4.8 years, and 58% were male. Hematological malignancy was the transplant indication for 42% of children, and 87% of transplants were allogeneic. In the 654 longitudinal samples, we identified 926 unique ARGs, conferring resistance to 31 classes of antibiotics. The median number of ARGs per sample was 24 (interquartile range: 13, 49). The most common ARGs detected were dfrF (conferring resistance to trimethoprim), tetO (tetracyclines), and tetW (tetracyclines), each detected in >65% of samples. Of the 66 children with fecal samples collected prior to HSCT, 70% of children received therapeutic antibiotics in the 2 weeks prior to enrollment. Accounting for transplant indication, sex, and age, the incidence of ARGs was 47% higher in children who received recent therapeutic antibiotics (incidence rate ratio 1.47; 95% CI (1.03–2.13); p=0.04).

Conclusion

ARGs are commonly found in the gut metagenomes of pediatric HSCT recipients prior to HSCT and are associated with recent receipt of therapeutic antibiotics. Future directions for this dataset include determining the ability of ARGs in the metagenome to predict clinical outcomes, including mortality and infections. Understanding the colonization and acquisition of ARGs could inform infection prevention strategies and empiric therapies and lead to improved infectious outcomes in these high-risk patients.

Disclosures

All Authors: No reported disclosures
180. Impact of Pneumococcal Conjugative Vaccine on Antibiotic Resistant Invasive Pneumococcal Disease in the United States
Authors: Bajema Kristina , Gierke Ryan , Farley Monica M , Schaffner William , Thomas Ann , Reingold Art , Harrison Lee , Lynfield Ruth , Burzlaff Kari , Petit Susan , Barnes Meghan , Torres Salina , Beall Bernard , Pilishvili Tamara
Published: January 2021

Background

Antibiotic-nonsusceptible invasive pneumococcal disease (NS-IPD) in the United States declined dramatically following the introduction of pneumococcal conjugative vaccines (7-valent, PCV7 in 2000, replaced by the 13-valent, PCV13 in 2010). We evaluated the long-term impact of PCV13 on NS-IPD.

Methods

IPD cases were identified through CDC’s Active Bacterial Core surveillance during 2005−2018. We applied 2012 Clinical and Laboratory Standards Institute breakpoints to minimum inhibitory concentrations determined by broth microdilution (2005−2014) or whole genome sequencing (2015−2018) and classified non-susceptible isolates as those intermediate or resistant to ≥1 antibiotic class. Isolates were serotyped and classified as PCV13 or non-vaccine type (NVT). Incidence rates (cases per 100,000) were calculated using United States Census Bureau population denominators.

Results

From 2005 to 2018, NS IPD incidence decreased from 8.5 to 3.2 among children < 5 years old and from 13.0 to 9.4 among adults ≥ 65 years old. Incidence of vaccine-type NS-IPD decreased in all age groups (Figure 1), while incidence of NVT NS-IPD increased in all age groups (Figure 2). The greatest absolute increase in NVT NS-IPD occurred among adults ≥ 65 years from 4.7 in 2005 to 7.2 in 2018. PCV13 serotypes contributed to 62% of NS-IPD (36% of NS-IPD caused by serotype 19A alone) in 2005−2009, and 27% of NS-IPD in 2014−18 (8% of NS-IPD caused by 19A). During 2014–18, NVTs 35B (11%), 33F (9%), 22F (9%), and 15A (9%) were the most common NS-IPD serotypes.

Figure 1. Incidence of vaccine type antibiotic non-susceptible invasive pneumococcal disease by age group, 2005−2018.

Figure 2. Incidence of non-vaccine type antibiotic non-susceptible invasive pneumococcal disease by age group, 2005−2018.

Conclusion

NS-IPD incidence decreased following PCV13 use in the United States, driven by reductions in PCV13 serotypes. Recent increases in NVT NS-IPD, most pronounced among older adults, have started to erode PCV impact on NS-IPD. PCVs in development that contain serotypes 22F and 33F could help to further reduce NS-IPD.

Disclosures

Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)
181. Antimicrobial Use in the Time of COVID-19 – Data from 84 VA Facilities
Authors: Goetz Matthew B , Graber Christopher J , Jones Makoto M , Stevens Vanessa W , Glassman Peter A , Rubin Michael
Published: January 2021

Background

The VA initiated an antimicrobial stewardship program in 2011, which includes participation in the Center for Disease Control (CDC) Antimicrobial Use Option, educational webinars, training programs for antimicrobial stewards, required staffing & reporting, and quality improvement initiatives, that has led to ongoing decreases in antimicrobial therapy nationwide. With the onset of the COVID-19 pandemic, however, there are several factors that may contribute increases in antimicrobial use (increased presentations of lower respiratory tract infection, concern for bacterial co-infection with SARS-CoV-2, etc.). We sought to compare patterns of antibacterial use in the VA from January – May 2020 with corresponding time periods in prior years.

Methods

Data on antibacterial use from 2015 – 2020 were extracted from the VA Corporate Data Warehouse for acute inpatient care units in 84 VA facilities (facilities which provide limited acute inpatient services were excluded). To control for seasonal effects, only data from January to May for each year were included in the analysis. Days of therapy (DOT) per 1000 days-present (DP) were calculated and stratified by CDC-defined antibiotic classes.

Results

From 2015 – 2019, total antibiotic use from January to May decreased by a mean of 9.1 DOT/1000 DP per year. In contrast, from 2019 to 2020, antibiotic use over the same months increased by 26.4 DOT/1000 DP (Table). Increases were observed in all drug classes except for a decrease in narrow spectrum ß-lactam antibiotics. Total antibiotic DOT in 2020 increased by 27.9 and 7.3 DOT/1000 DP in facilities in the highest and lowest terciles of use in 2019 (Figure).

Table – Trends in Yearly Antibiotic Use by CDC Drug Class, 2015 to 2019 versus 2019 to 2020

Figure – Facility Specific Total Antibiotic Use in 2019 and Change in Use from 2019 to 2020

Conclusion

We observed a broad increase in antibacterial use during the initial surge of COVID-19 cases in VA facilities that abruptly reversed steady reductions in use over the prior 4 years. The degree to which this increase reflects potentially appropriate use in the setting of increased patient vulnerability and provider uncertainty, inappropriately decreased provider thresholds for initiating or continuing therapy, or stresses on the structure and staffing of antimicrobial stewardship programs requires further study.

Disclosures

All Authors: No reported disclosures
182. increasing Odds of Resistance for Subsequent Urinary e. Coli Isolates
Authors: Frisbie Lauren , Weissman Scott , Kapoor Hema , D’Angeli Marisa A , Salm Ann , Rabinowitz Peter M
Published: January 2021

Background

Annual cumulative antibiograms are routinely used by clinicians to guide selection of empirical antibiotic therapies. CLSI guidelines recommend that these antibiograms to analyze data yearly, include only final, verified results, include bacterial species with > 30 isolates and to include only the first isolate for each species/patient instance per analysis period. Handling multiple isolates from individual patients in cumulative antibiograms is a controversial topic within the antimicrobial stewardship community. Current practice favors removing subsequent isolates, thereby discarding data reflecting impact of selective antibiotic pressure on resistance patterns in recurring urinary tract infection (UTI).

In this study we analyzed a five-year data set of deidentified outpatient antibiotic results from a commercial laboratory to determine whether there were significant differences in resistance patterns between first and subsequent isolates from the same patient.

Methods

The 5-year antibiotic susceptibility data was restricted to urinary Escherichia coli (EC) isolates. Patient occurrence(s) of urinary EC were categorized by frequency: 1st occurrence, 2nd occurrence, 3rd occurrence, and 4th or greater occurrence. A logistic regression analysis using a binary outcome for resistance and independent variable of patient isolate occurrence was run for amoxicillin-clavulanate, ampicillin, ceftriaxone, ciprofloxacin, gentamicin, levofloxacin, nitrofurantoin, and trimethoprim-sulfa.

Results

From a logistic regression analysis, we estimate that for each occurrence in the data, an isolate’s odds of resistance were higher for every increase in a patient’s number of occurrences in the data for all antibiotics reported with p values < 0.0001.

Table 1: Odds ratios (OR) of resistance for each subsequent urinary EC isolate occurrence over 5 years

Conclusion

Our findings suggest that individuals with higher numbers of urinary EC occurrences have more resistant EC than the first EC occurrence, with effects that vary by antibiotic class. Although traditional antibiograms include only the first occurrence of urinary EC from a single patient, this approach may underestimate levels of reservoir resistance in a community. Such an underestimation likely impacts efficacy of empiric therapeutic choice, healthcare outcomes, and cost.

Disclosures

All Authors: No reported disclosures
184. Seven vs. 14 Days Treatment Duration for Afebrile Men with Urinary Tract Infections; A Randomized Clinical Trial
Authors: Drekonja Dimitri , Johnson James R , Carla Amundson , Kuskowski Michael , Trautner Barbara
Published: January 2021

Background

Trials show that shorter-duration therapy is effective for many infectious diseases, but the optimal duration for UTI in men is unknown. Observational data suggests shorter-duration performs as well as longer-duration therapy, but trial data shows men with febrile UTI (a small but important subset of patients) do worse with 7 vs. 14 days of therapy. We performed a randomized controlled trial of afebrile men with UTI to determine whether 7 days of treatment was non-inferior to 14 days.

Methods

Men with symptomatic UTI at 2 VA hospitals were enrolled. Inclusion criteria included male gender, outpatient treatment, prescribed 7 to 14 days of ciprofloxacin or trimethoprim/sulfamethoxazole, and new onset of at least 1 of: dysuria, frequency, urgency, hematuria, costovertebral angle tenderness, and perineal, flank, or suprapubic pain. Exclusion criteria included UTI treatment in the past 14 days, symptoms due to a non-UTI diagnosis, and inadequate empiric treatment. Enrolled subjects took their clinically-prescribed medications days 1–7, then study medication days 8–14. Study medications were placebo or the originally prescribed antimicrobial, different in appearance from the original medication. The primary outcome was percentage of subjects with symptom resolution 14 days after completion of active therapy. Secondary outcomes included recurrence of UTI and adverse events. A pre-specified minimally clinically significant difference of 10% was selected, with a P value of 0.05 considered to be significant. Primary analysis was per-protocol; intention-to-treat performed as secondary analysis.

Results

Enrollment totaled 273, with 272 randomized to 7 (n = 136) vs. 14 (n = 136) days of antimicrobials. Mean age was 67.8 (SD 11.6), with a mean Charlson comorbidity index of 1.3 (SD 1.6). Overall, 254 subjects were in the per-protocol analysis. Symptom resolution occurred in 122 of 131 (93.1%) subjects receiving 7 days treatment, and 111 of 123 (90.2%) receiving 14 days (difference 2.9%, 95% CI -4.7 to 10.5% P = .50), confirming non-inferiority. Intention-to-treat analysis (n = 272) showed similar results.

Conclusion

Treatment with 7 days of antimicrobials was non-inferior to 14 days for symptom resolution. Afebrile men with UTI should not be treated beyond 7 days.

Disclosures

All Authors: No reported disclosures
185. Despite the Availability of Free Testing and Care Testing for Extragenital Sexually Transmitted Infections in a Cohort of Hiv-infected Department of Defense Beneficiaries Is Low and Similar to the Rates Observed Nationwide
Authors: Ganesan Anuradha , Wang Xun , Blaylock Jason M , Okulicz Jason , Maves Ryan C , Colombo Rhonda , Utz Gregory , Schofield Christina , Kronmann Karl , Lalani Tahaniyat , Garges Eric , Agan Brian
Published: January 2021

Background

Background- Current guidelines recommend annual extragenital [EG] testing for all sexually active men who have sex with men (MSM), and every 3−6 months for MSM at risk for sexually transmitted infections (STIs). Compliance with this guideline is low and testing rates among MSM with HIV have ranged between 30–46%. Financial disincentives (such as the lack of reimbursement for EG testing) may contribute to the lower EG testing rates. To examine if access to free testing improves EG testing rates, we used data from the US Military HIV Natural History Study (NHS), a cohort comprised of HIV-infected Department of Defense beneficiaries with access to care and free testing.

Methods

Methods- Among NHS participants with a follow-up visit between 1/1/2013 and 1/1/2018, genital (primarily urine samples) and EG testing rates (pharyngeal and rectal) were calculated and temporal trends examined. Multivariate logistic regression analysis was used to examine factors associated with EG testing. In a sub-set of participants who answered a risk behavior survey we examined risk-related information.

Results

Results- Of the 1971 male participants who had a NHS visit during the study period, 1962 (99.5%) had genital and 1419 (72%) had EG testing performed at least once. Annual genital and EG testing rates ranged between 96 - 98% and 33% - 46% respectively. No temporal trends were observed in EG testing rates. EG testing rates were higher in those with a history of gonorrhea, chlamydia or syphilis in the year prior, ranging between 50 and 67%. EG testing was more likely to occur in those who were younger and those with a prior history of STI (Table 1). In a subset of participants with risk behavior information, those who reported being MSM were more likely to be tested [Referent heterosexual; Odds Ratio 2.35 [95% CI 1.60–3.46].

Conclusion

Conclusion-Despite the availability of free EG testing, EG testing rates were low in the NHS and similar to those observed nationwide This contrasts with the genital testing rates which were well over 95%, suggesting provider/patient related barriers are likely driving the lower testing rates. To improve testing rates further study is required to fully characterize indications for EG testing and potential provider- and/or patient-related barriers to EG testing.

Disclosures

All Authors: No reported disclosures
192. The Use of Area Under the Curve to Determine Therapeutic Vancomycin Dosing in Skin and Soft Tissue Infections
Authors: Dea Lauren , Johns Scott T , Ma Ariel
Published: January 2021

Background

The vancomycin AUC/MIC target ratio of 400 to 600 mg*h/L that is recommended (level IA+) in the 2020 IDSA/ASHP vancomycin TDM guidelines is appropriate for patients with complicated MRSA infections; using lower targets for less complicated infections may reduce the risk for nephrotoxicity without compromising efficacy. The current methodology surrounding vancomycin AUC/MIC targets is unrefined, with no source specific targets identified, especially for relatively lower risk MRSA infections such as skin and soft tissue infections (SSTIs).

Methods

This was a retrospective observational study of hospitalized patients at the Veterans Affairs Health Care System in San Diego, CA with a SSTI and prescribed intravenous vancomycin between January 1, 2016 and December 31, 2019. Patients included were adults, 18 years of age and older, treated with IV vancomycin with ≥1 measured concentration for at least one of the ICD-10 CM codes for SSTI. Patients were excluded if they had any of the following SSTIs: (1) osteomyelitis; (2) infection related to chronic ulcers or wounds; (3) head SSTI; (4) peri-rectal SSTI; (5) human or animal bite SSTI; (6) SSTI related to retained foreign body; (7) necrotizing SSTI; (8) surgical site infection. Patients were also excluded if they were undergoing dialysis or had severe immunosuppression.

Results

A total of 722 patients on vancomycin for a SSTI were identified from the database query for screening, and 243 (34%) met inclusion criteria for the study. Classification and Regression Tree (CART) modeling identified a calculated AUC of >253 as having the highest correlation with clinical success. Clinical cure was significantly different between the AUC ≤253 (6/9 [67%]) and AUC >253 (214/234 [91%]) cohorts (p=0.043). There were no differences in hospital length of stay or duration of vancomycin therapy. Nephrotoxicity occurred in seven patients, all of who had AUC >253.

Conclusion

Overall treatment success in patients with SSTIs was associated with a vancomycin AUC >253, which is lower than the guideline recommended range of 400–600. Identification of vancomycin AUC targets for other low risk sources of infection, such as UTIs, is needed to prevent vancomycin overexposure.

Disclosures

All Authors: No reported disclosures
199. Short versus Extended Antibiotic Treatment with a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients with Fever of Unknown Origin: A Randomized Multicenter Noninferiority Trial
Authors: de Jonge Nick A , Sikkens Jonne , Zweegman Sonja , Beeker Aart , Ypma Paula , Herbers Alexandra , Vasmel Wies , de Kreuk Arne , Coenen Juleon , Lissenberg-Witte Birgit , Budding Andries , Kramer Mark , Van Agtmael Michiel , Janssen Jeroen
Published: January 2021

Background

In hematology patients with high risk neutropenia due to intensive chemotherapy the optimal antibiotic treatment duration for fever of unknown origin (FUO) is unknown. Early antibiotic discontinuation has been advocated to reduce unnecessary exposure to broad-spectrum antibiotics, but there is limited evidence for the safety of this strategy. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment for neutropenic patients with FUO.

Methods

Multicenter, open-label, randomized clinical trial in 6 centers in the Netherlands. Hematology patients with FUO during high risk neutropenia (≥7 days) were eligible for participation. Eligible patients who gave informed consent were randomly assigned (1:1) to either the short treatment arm, where the carbapenem was discontinued after 72 hours, irrespective of presence of fever, or the extended treatment arm, where the carbapenem was continued for ≥ 9 days until afebrile for 5 days or end of neutropenia (EON), whichever came first. The primary endpoint was treatment failure defined as a composite of recurrent fever or a carbapenem-sensitive infection between day 4 and day 8 and septic shock or death from day 4 until EON. Secondary endpoints included all-cause and infection-related mortality until 30 days post-EON. We used 10% as noninferiority margin.

Trial Intervention Flowchart

Results

Between December 2014 and August 2019 292 patients were included. Risk of treatment failure in the modified intention-to-treat analysis (mITT) was 23.5% (32/136) in the short treatment versus 18.3% (24/131) in the extended treatment arm (adjusted risk difference (ARD) 3.7% (90% CI -2.6% to 9.9%)) and in the per-protocol analysis 27.9% (29/104) versus 18.2% (22/121) (ARD 8.9% (90% CI 0.6% to 17.2%). Short treatment was non-inferior to extended treatment in the mITT population, but not in the per protocol population.

All-cause mortality until 30 days post-EON was significantly higher in the short treatment group: 3.7% (5/136) versus 0.8% (1/131) (ARD 2.8%, 95% CI 1.3 to 4.4%), but infection-related mortality until 30 days post-EON was not statistically different between the treatment arms.

Primary and Secondary Endpoint Results

Subgroup Analyses Results

Bloodstream infections after day 3

Conclusion

Short treatment with a carbapenem in neutropenic patients with fever was noninferior to extended treatment with regard to treatment failure.

Conclusion Summary

Disclosures

All Authors: No reported disclosures
315. Alternating Magnetic Fields (AMF) and Antibiotics Eradicate Biofilm on Metal in a Synergistic Fashion
Authors: Wang Qi , Vachon Jonathan , Pybus Christine A , Shaikh Sumbul , Chopra Rajiv , Greenberg David E
Published: January 2021

Background

Hundreds of thousands of human implant procedures require surgical revision each year due to infection. Implant infections are difficult to treat with conventional antibiotics due to the formation of biofilm on the device surface. We have developed a non-invasive method to treat metal implant infections using alternating magnetic fields (AMF). The outer surface of a metal implant is heated when exposed to AMF, and we hypothesize that this heating can be used to eradicate biofilm or sensitize them to antibiotics (Fig 1). This study investigated the interaction of biofilm and antibiotics in vitro.

Fig 1. Scheme showing the principle of AMF treating metal implant infection (MII).

Methods

P. aeruginosa (PAO1) and Staphylococcus aureus (UAMS1) biofilms were cultured on stainless steel rings. The biofilms were then treated as in Fig 2, receiving a series of AMF exposures every 12 hours. Each dose of AMF was comprised of multiple 3s-AMF exposures every 5 min, with a peak ring temperature of 65 °C. Biofilms were incubated in the presence or absence 0.5 mg/mL ciprofloxacin or ceftriaxone. At the end of 12 and 24 hours, samples were harvested and colony forming units (CFU) were calculated.

Fig 2. AMF treatment design.

Results

AMF alone resulted in a transient decrease in CFU which recovered by the second dose. Antibiotics alone resulted in an ~2-log decrease in CFU at 24 hours. However, the combination of AMF plus cipro showed a synergistic response with a >4-log decrease (Fig 3a). Confocal microscopy confirmed these findings. This effect was not limited to Pseudomonas aeruginosa as similar synergistic responses were seen with Staphylococcus aureus and ceftriaxone (Fig 3b).

Fig 3 The bacteria number (CFU) change during 24 hr AMF and antibiotics treatment session. a) P. aeruginosa (PAO1) treated with AMF and ciprofloxacin. b) Staphylococcus aureus (UAMS1) treated with AMF and ceftriaxone.

Conclusion

When combined with antibiotics, AMF displays a synergistic effect in eradicating biofilm. This effect was seen in different pathogens and in multiple antibiotics. Synergy was seen at different target temperatures as well. This interaction has important implications for deployment of this innovative non-invasive approach to treating biofilm-related infections on metal implants.

Disclosures

All Authors: No reported disclosures
316. Application of New Consensus Definition Identifies High Numbers of Fracture Related Infections with Negative Cultures
Authors: Weinert-Stein Kaitlyn E , Slater Julia C , Sagi Henry C , Powers-Fletcher Margaret , Palacio Federico
Published: January 2021

Background

Fracture related infection (FRI) is a severe complication in trauma surgery but defining the full impact of these infections has been challenging with the lack of clear diagnostic criteria. This is particularly problematic for culture-negative FRI (CNFRI), which lack pathogen identification to guide antimicrobial therapy. However, new consensus definition and criteria for the diagnosis of FRI (Table) may help reduce the risk of diagnostic error. The purpose of this study was to determine the proportion and clinical characteristics of CNFRI cases at a level I trauma hospital using the new diagnostic criteria.

Methods

Laboratory reports were used to identify all patients with at least one specimen submitted for microbiology culture by an orthopedic surgeon at our trauma I level hospital in Cincinnati, Ohio during a three-year study period. This cohort was refined by an electronic medical record (EMR) review to select patients that met the diagnostic criteria for suspected/confirmed FRI. The specimen details and results of the cultures were recorded for the first orthopedic surgeon collection for each suspected FRI case. Clinical data, including fracture characteristics, surgical treatment, antibiotic utilization, and patient outcomes were also extracted from the EMR for each case.

Results

A total of 246 patients were identified with at least one culture specimen; 35.8% (n = 88) of these were deemed suspected/confirmed FRI based on consensus guidelines. The cultures for the first orthopedic surgery collection on these FRI were negative for 35% (n = 31). The most common location for CNFRI were proximal lower extremity fractures (52%), a distribution different from that of culture positive (Figure). Culture positive FRI were predominated by Staphylococcus aureus (39%) followed by gram negative rods (23%).

Conclusion

This retrospective cohort study identified a sizable proportion of CNFRI at our trauma center using the recently published consensus definition. While further analysis is necessary to determine the exact impact of these new criteria, this suggests that clearer definitions may facilitate improved recognition of CNFRI. Because of the relatively high rates of CNFRI, efforts to standardize laboratory diagnostic processes and case management will be required.

Disclosures

Henry C. Sagi, MD, FACS, Conexxions (Board Member)GLW trauma (Consultant)GLW trauma (Shareholder)Stryker (Consultant)
320. Does Guideline-Based Management of Diabetic Foot Osteomyelitis Reduce Risk of Further Proximal Amputations?
Authors: Lee Eugene , Pupaibool Jakrapun , Certain Laura
Published: January 2021

Background

The antibiotic management of diabetic foot osteomyelitis involving surgical limb-sparing amputation is controversial. While there are several guidelines that provide recommendations regarding antibiotic therapy for diabetic foot osteomyelitis after amputation, we do not know of any studies that show that adherence to guidelines improves clinical outcomes. We assessed whether adherence to antibiotic choice and duration in accordance with our institution’s guidelines, which are based on IDSA guidelines, reduced risk of future amputations.

Methods

We conducted a retrospective cohort study of 110 patients with diabetic foot osteomyelitis treated with limb-sparing amputations at a VA hospital. We collected relevant clinical data such as patient comorbidities, antibiotic allergies, labs, imaging, culture data, histopathologic reports, pre-op and post-op antibiotics. We used our institutional guidelines, which are based on the 2012 IDSA Guidelines for the Diagnosis and Treatment of Diabetic Foot Infections, to assess antibiotic choice and duration for diabetic foot osteomyelitis therapy after amputation. We stratified cases as either adherent or non-adherent based on whether antibiotic choice and duration were both in accordance with our institutional guideline. For each case, we recorded the primary outcome of further proximal amputation occurring within six months or death from all causes within three months.

Results

We found a significant difference in primary outcomes between the groups that were treated with antibiotics adherent with guidelines and antibiotics non-adherent with guidelines. For patients who were treated with antibiotics that were non-adherent to guidelines, 15 of 36 (42%) patients needed further amputation or died. Of the patients treated according to guidelines, 12 of 74 (16%) patients needed further amputation or died. There was a statistically significant difference between these two groups (p=0.004).

Conclusion

Our study showed that guideline-based antibiotic therapy for diabetic foot osteomyelitis treated with amputation significantly lowered rates of further amputation compared to antibiotic therapies that were not adherent to guidelines.

Disclosures

All Authors: No reported disclosures
323. First case of Prosthetic joint infection due to Nocardia veterana-elegans
Authors: Fazili Tasaduq , Bansal Ekta , Garner Dorothy C , Bajwa Vijendra
Published: January 2021

Background

Nocardia are Gram-positive filamentous bacteria that cause Nocardiosis, a rare opportunistic infection. The most common site of infection is the lungs, with metastatic spread usually to the central nervous system. Prosthetic joint infection due to Nocardia is very rare.

Methods

We report the first case of prosthetic joint infection due to Nocardia veteran-elegans, and review the literature regarding Nocardia septic arthritis, with particular attention to prosthetic joint infection.

Results

The patient was a 35 year old male with history of Hodgkin’s Lymphoma for which he received chemotherapy previously, poorly controlled diabetes, motor vehicle accident in 2003 with right open tibial plateau fracture requiring hardware placement, who was admitted with a two week history of right knee pain and swelling. Knee aspiration revealed purulent fluid and synovial culture grew Nocardia species. He underwent right knee arthrotomy and debridement with removal of hardware. The Nocardia species was speciated as N. veterana-elegans, sensitive to trimethoprim/sulfamethoxazole, linezolid, clarithromycin, imipenem and amikacin. He was placed on oral linezolid for four weeks, which was then switched to oral trimethoprim/sulfamethoxazole, with a plan for a six month course of therapy. He has completed two months of therapy thus far and is doing well clinically.

Nocardia is an uncommon cause of septic arthritis. We found only 37 cases reported in the English literature thus far. Amongst these, only six involved prosthetic joints, including our case, which is the first one to be caused by N. veterana-elegans.Three cases were caused by N. nova and one each by N. farcinica and asteroides. Septic arthritis due to Nocardia has a favorable outcome with a combination of surgical debridement and prolonged antimicrobial therapy of three to six months. For prosthetic joint infections, removal of hardware seems to carry a better prognosis. Trimethoprim/sulfamethoxazole is the preferred antimicrobial, including for bone and joint infection, although susceptibilities can vary amongst the different species.

Conclusion

Nocardia is an uncommon cause of septic arthritis. Prosthetic joint infection is very rare. Prognosis is fair with a combination of hardware removal and prolonged antibiotic therapy.

Disclosures

All Authors: No reported disclosures
326. More Specialties, Less Problems: Creating collaborative competency between Infectious Disease, Podiatry, and Pathology co-managing diabetic foot infections
Authors: Jhaveri Vimal V , Sullivan Chrsitopher , Ward Ashley , Giurini John , Karchmer Adolf W , Stillman Isaac , Davis Roger , Freed Jason , LaSalvia Mary , Stead Wendy
Published: January 2021

Background

According to the 2016 and 2017 National Health Interview Survey, 9.7% of the US population is estimated to have diabetes mellitus (either type 1 or type 2). 1 Among patients with diabetes, there is a 15% lifetime risk of developing a foot ulcer, making it an extremely common medical problem seen in both outpatient and inpatient settings.2 In fact, Medicare spends $9–13 billion/year on diabetic foot osteomyelitis (DFO).3 Despite this high prevalence and cost, experts have not agreed on a set of diagnostic criteria for diagnosing DFO, 4 nor the optimal antibiotic management.5 For example, while traditionally diabetic foot osteomyelitis has been treated with 4–6 weeks of IV antibiotics in the United States, oral antibiotics have been shown to be effective with similar cure rates in multiple studies 6–8, non-inferior in a Cochrane review,5 and are recommended in the most recent (2012) Infectious Disease Society of America (IDSA) DFO clinical practice guidelines.9

Methods

Representatives from ID, Podiatry, and Pathology collaborated to develop consensus on aspects of management of DFO. We created an educational session, inviting providers from all three departments to develop consensus on some of the controversial aspects of DFO. We assessed for knowledge gain by having these providers complete a pre-test survey as well as a post-test survey 2 weeks after the intervention.

Results

27 providers completed both a pre and post-tests after attending the educational session. Significant improvements were observed in learners understanding of duration of antibiotic treatment and the role of oral antibiotics in certain cases of diabetic foot osteomyelitis to obviate the need for an unnecessary intravenous antibiotics and Peripherally Inserted Central Catheter (PICC) lines. Additionally, by working as an interdisciplinary group, many solvable misunderstandings were identified, and processes were adjusted to improve the quality and efficiency of care provided to these patients.

Figure 1: Results of the Pre- and Post- Assessment

Conclusion

This multidisciplinary, educational session regarding management of DFO led to improved provider knowledge and collaborative competency between these three departments. Further study is being completed assessing patient outcomes before and after this intervention and will be available by IDWeek.

Disclosures

All Authors: No reported disclosures
329. Performance of Next Generation Sequencing in Isolating a Pathogen in Pediatric Osteoarticular Infections
Authors: Ramchandar Nanda , Burns Jessica , Pennock Andrew , Cannavino Christopher R , Farnaes Lauge
Published: January 2021

Background

Osteoarticular infections are often encountered in the pediatric population. Therapy is guided by isolation of a putative organism, however, operative cultures are often negative. Next generation sequencing (NGS) allows for more sensitive sampling of body compartments generally considered sterile. We sought to evaluate the utility of NGS in comparison to culture in detecting a pathogenic organism in acute osteomyelitis and septic arthritis in children.

Methods

This was a single-site study to evaluate the utility of NGS in comparison to culture in detecting a pathogenic organism in acute osteomyelitis and septic arthritis in children. Eligible patients were all patients with osteomyelitis or septic arthritis admitted to Rady Children’s Hospital from July 2019 through July 2020. We excluded any patients with bone or joint surgery within 30 days prior to admission. Operative samples were chosen at the surgeon’s discretion (joint aspirate, synovium, or bone) based on operative findings. We compared NGS testing to standard care culture from the same site.

Results

We enrolled 41 subjects. NGS of the operative samples identified a pathogen in 26 (63.4%) patients versus 18 (43.9%) by culture. Operative culture missed the diagnosis in 10 cases, though PCR identified the organism in 6 of those cases (5 were cases in which Kingella kingae was identified). In 4 subjects, NGS identified a putative organism where standard care testing (either PCR or culture) was negative. NGS was falsely positive in 1 subject and falsely negative for one other subject. Sensitivity was 96.3% (CI 95%, 81.0–99.9%) and Specificity was 92.9% (CI 95%, 66.1–99.8) for NGS versus 64.3% (CI 95%, 44.1–81.4) and 84.6% (CI 95%, 54.6–99.9%) for culture respectively.

Conclusion

In this single site prospective study of pediatric osteoarticular infections, we demonstrate improved sensitivity and specificity of NGS testing when compared to standard culture.

Disclosures

All Authors: No reported disclosures