bluuebunny/crossref_metadata_2025_split huggingface dataset:
1634. Meningeal Tuberculosis: Experience of a Series of Cases from Cali, Colombia, 2008 - 2018
Authors: Tello-Cajiao Maria E , Romero-Rosas Nelson , Vargas-Potes Carlos , Valencia-Sabogal jaime , García-Goez Jose 
Published: January 2021

Abstract

Background
Meningeal tuberculosis (MTB) is the most lethal and disabling form of Mycobacterium Tuberculosis infection. In Colombia, it represents the second most frequent extrapulmonary location. Co-infection with the Human Immunodeficiency Virus (HIV) is one of the factors that most impacts their clinical results. Therefore, in this article we present the experience of 10 years of managing patients with MTB, with and without HIV coinfection.

Methods
A retrospective observational study was conducted between January 2008 and December 2018, with clinical information from patients diagnosed with MTB at Teaching Hospital Fundación Valle del Lili. Using absolute and relative frequency tables, sociodemographic, clinical characteristics and treatment outcomes were described, according to HIV infection status. P values &lt; 0.05 were taken as significant and 95% confidence intervals were used for comparison of proportions.

Results
61 patients with MTB diagnosed were enrolled. They represented 6.43% of all TB locations in the institutional registry. HIV coinfection was found in 26.2% of cases (n=16). Most of patients were men (65.6%), from urban areas (78.7%), and a median age of 39 years. Acute and subacute evolution of the infection was observed in half of the patients (50.8%). Also 85% presented some degree of neurological impairment. Bacteriological demonstration was achieved in 60.6% of all cases. 88% received drugs for sensitive TB, for a median of 9.5 months, and 52.5% received concomitant steroids drugs. Of the 36 subjects with information about their outcome, 42.6% were successful at treatment, 1 failed in the non-HIV group and 9 died (1 with HIV). 77% of all deaths were associated with TB.

Conclusion
MTB generates a significant burden disease. The characteristics of its insidious clinical presentation and the difficulty in achieving bacteriological demonstration in all patients make its timely diagnostic and therapeutic approach challenging.

Disclosures
All Authors: No reported disclosures
1635. Oral Delivery of Amikacin-Lipid NanoCrystal Formulations Safely and Effectively Treat Macrolide Resistant Mycobacteria Infections in a Mouse Model of Cystic Fibrosis
Authors: Lu Ruying , Mannino Raphael J , Ordway Diane J 
Published: January 2021

Abstract

Background
In the cystic fibrosis lung, infections by intracellular pathogens, such as Mycobacteria, are problematic to treat due to a thick buildup of mucous as well as the difficulty of many anti-microbial agents, such as amikacin, to penetrate across the plasma membranes of infected cells. Lipid NanoCrystals (LNCs), mediate oral bioavailability for injectable drugs, reduce toxicity, and significantly enhance targeting to mycobacterial infected cells followed by intracellular drug delivery.

Methods
The oral efficacy of Amikacin-LNC (AmK-LNC) was evaluated in the cystic fibrosis (B6CFTRtm1UNC/CFTRtm1UNC) chronic mouse model against each of the three NTM strains having high resistance to macrolide antibiotics (M. avium subsp intracellulare 25292, M. abscesus ssp abscessus 1513, and M. abscessus ssp bolletii 1948).
Mice were infected with a pulmonary aerosol of 1x108 CFUs of the macrolide resistant strain and treated daily starting on day 28 for a total of 8 weeks with saline control, oral LP-4 CAmK Lyophilized 50 mg/kg BID, oral LP-4 CAMK Lyophilized 100 mg/kg BID, IP Amikacin (AMI) 150 mg/kg QD, or oral Clarithromycin 250 mg/kg QD. Bacterial burden was measured on day 1, 27, 42, 56 and 84 after infection by plating serial dilutions of organ homogenates on nutrient 7H11 and charcoal agar and counting CFUs after 25-30 days incubation at 32°C. Results represent the average of six experiments (n=5 mice per experiment) bacterial load was expressed as the average Log10 CFU (± SEM) cells (± SEM). ANOVA, saline control compared to drug-treated groups, * denotes the compound that resulted in the highest bacterial reduction, *p&lt; 0.05.

Results
Oral administration of AmK-LNCs safely and effectively treated all three macrolide resistant Mycobacteria infections. Colony counts showed that oral administration of AmK-LNC resulted in CFU lung, spleen and liver counts lower than treatment with IP amikacin or clarithromycin.
Lung pathology showed that lesions were more numerous and larger in infected mice treated with clarithromycin or amikacin compared to the smaller lesions after treatment with oral AmK-LNC.
Bacterial Counts in the Lungs (A), Spleens (B) and Livers (C)

Lung Pathology

Conclusion
Conclusions
Oral administration of amikacin-LNCs safely and effectively treats macrolide resistant mycobacterial infections in a mouse model of Cystic Fibrosis.

Disclosures
Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder)
1636. Risk of Latent Tuberculosis Reactivation in Patients Treated with Checkpoint Inhibitors Immunotherapy Compared to Other Anti-Cancer Therapies including Hematopoietic Cell Transplantation
Authors: Malek Alexandre , Chaftari Patrick , dagher Hiba , Hachem Ray Y , Chaftari Anne-Marie , Viola George , Raad Issam I , Raad Issam I 
Published: January 2021

Abstract

Background
The risk of latent tuberculosis infection (LTBI) reactivation in cancer patients during checkpoint inhibitor immunotherapy (CPI) remains largely unknown. We sought to evaluate LTBI therapy and outcomes between cancer patients receiving CPI versus conventional chemotherapy (CC) and hematopoietic cell transplantation (HCT) recipients.

Methods
We conducted a retrospective cohort study of adult patients with LTBI (positive T-SPOT TB test) at MD Anderson Cancer Center between April 2016 and May 2020, who received CPI or combined with other conventional chemotherapy. Thereafter we compared each group to patients treated with other anti-cancer therapies including CC alone or HCT.

Results
We identified 106 patients with LTBI, who were analyzed into 3 distinct groups: CPI (32 patients, 30%) CC alone (37 patients, 35%), and HCT (37 patients, 35% (7 autologous versus 30 allogeneic). The majority of patients in the CPI group (97%) had solid tumors compared to 54% in the CC group. Nivolumab was the most commonly used CPI agent in 13 patients (40%), followed by pembrolizumab 10 pts (31%). In the CPI group, 20 pts (62%) received LTBI therapy that included Isoniazid (INH), versus 18 patients (49%) in the HCT group and 16 patients (43%) in the CC group (p=0.26). Only 3 patients (CC group) had TB reactivations (8%; p=0.11). None of these 3 patients had received LTBI therapy or corticosteroids prior to the diagnosis. Immune-related adverse effect (IrAEs) were reported in 11 pts (34%) patients, and 9 (82%) of them received corticosteroids. Out of 20 of CPI patients whom received INH, 4 (20%) developed possible INH-induced liver toxicities leading to interruption of medication versus 1 (6%) patient which had mild hepatitis in CC group versus none of HCT patients (p=0.09).

Conclusion
Our data suggest that latent tuberculosis reactivation remains rare, especially in the severely immunocompromised patients on CPI, CC and steroids. However, hepatotoxicity is relatively common in patients treated with CPI and INH. Therefore, caution and close laboratory and clinical monitoring is required to avoid significant hepatic injury and interruption of LTBI therapy and lifesaving oncological therapy.

Disclosures
Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)
1637. SPR720, A Novel Benzamidazole Gyrase Inhibitor, Demonstrates Potent Efficacy Against Mycobacterium avium ATCC 700898 in a Chronic C3HeBFeJ Mouse Infection Model
Authors: Verma Deepshikha , Peterson Chelsea , Cotroneo Nicole S , Stokes Suzanne , Ordway Diane J 
Published: January 2021

Abstract

Background
SPR719 (the active metabolite of phosphate prodrug SPR720) belongs to a novel class which targets the ATPase subunits of gyrase by a mechanism distinct from fluoroquinolones. SPR719 has potent antibacterial activity against nontuberculous mycobacteria strains (NTM), including Mycobacterium avium, and is under development for treatment of NTM pulmonary disease. Oral efficacy of SPR720 was evaluated alone and in combination treatment in the C3HeBFeJ chronic mouse infection model which produces necrotic granulomas, similar to humans.

Methods
Mice were infected with a pulmonary aerosol of 1x108.5 CFU of M. avium ATCC 700898, (SPR719 MIC = 2 mg/mL). Treatment started on day 28 for 8 weeks with: saline, clarithromycin 250 mg/kg (CLR) QD, SPR720 at 10, 30 and 100 mg/kg QD, or SPR720 at 50 mg/kg BID. SPR720 at 30 mg/kg QD was also combined with CLR +/- ethambutol at 100 mg/kg (EMB), or CLR + rifabutin at 100 mg/kg (RFB) +/- EMB. Mice were evaluated for bacterial burden (CFU) on days 1, 27 and 60 after infection by plating serial dilutions of organ homogenates on nutrient 7H11 and charcoal agar plates. Lung pathology was evaluated by assessing prevalence and size of pulmonary lesions.

Results
CLR treatment for 28 days showed a significant reduction in the bacterial burden in the lung, spleen, and liver compared to the untreated control. SPR720 demonstrated a dose dependent reduction in bacterial burden, including at 100 mg/kg which showed a statistically significant reduction in the bacterial burden in the lung, spleen, and liver. CLR + EMB + SPR720 at 30 mg/kg reduction in the bacterial burden in the lung, spleen, and liver. RFB when added to the treatment regimen did not demonstrate enhanced efficacy compared the additive effect of EMB + CLR +/- SPR720. Lung pathology showed that lesions were less numerous and smaller in infected mice treated with all regimens.

Conclusion
Oral administration of SPR720 demonstrated a statistically significant reduction in the bacterial burden in all tissues with concomitant improvement in lung pathology, both alone and in combination with standard of care agents. These results support the continued development of SPR720 for treatment of NTM pulmonary infections.

Disclosures
Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder)
1643. A scoping review of pediatric latent tuberculosis care cascades: Initial steps are lacking
Authors: Campbell Jeffrey , Sandora Thomas , Haberer Jessica 
Published: January 2021

Abstract

Background
Each year an estimated 1 million children develop and ~200,000 die from tuberculosis (TB). The WHO has named identification and treatment of latent tuberculosis infection (LTBI) one of the cornerstones of efforts to eliminate TB by 2030. Identification and treatment of pediatric LTBI requires completion of a complex care cascade. While attention has been given to LTBI care cascades in adults, to date there has been no attempt to map literature on the pediatric LTBI care cascade.
Facilitators and barriers to retention in steps of the pediatric LTBI care cascade

Methods
We systematically searched PubMed, CINAHL, Cochrane and Embase databases for papers and abstracts describing screening, diagnosis, and treatment of pediatric LTBI. We categorized literature using seven step-offs in the pediatric LTBI care cascade, extrapolated from prior studies focused on adults: 1) intention to screen to initial test, 2) initial test to receipt of results, 3) receipt to referral for evaluation, 4) referral to completion of evaluation, 5) completion to treatment recommendation, 6) recommendation to treatment acceptance/initiation, and 7) initiation to treatment completion. Our aim was to assess factors that facilitated and inhibited completion of each cascade step, and to identify knowledge gaps in this literature.

Results
We identified 137 studies that met inclusion criteria. Most studies described multiple step-offs in the care cascade, although the focus of most (120/137 studies) was on initiation and completion of LTBI therapy (the final step in the care cascade). Several effective strategies to improve medication adherence were described, including selective use of nursing visits, directly observed therapy, shorter treatment regimens, and peer counseling. Reports of facilitators and barriers for retention in upstream step-offs in the cascade were scarce, revealing a lack of published evidence for how to retain children from pre-screening to treatment initiation (Table).

Conclusion
While existing literature describes LTBI treatment initiation and completion in children, our analysis reveals a lack of data guiding retention of children from LTBI screening through treatment initiation. This review highlights the need to further understand early steps of the care cascade, in order to help alleviate the burden of TB in children.

Disclosures
Jessica Haberer, MD, MS, Merck (Consultant)
1644. “And the stick to fight TB is IPT”: Perspectives on TPT Implementation Among Senior Nurses in Rural South Africa
Authors: Grammatico Megan A , Ahmed Amiya A , Grau Lauretta , Moll Anthony , Shenoi Sheela 
Published: January 2021

Abstract

Background
Tuberculosis (TB) disproportionately affects people living with HIV (PLH). The World Health Organization (WHO) has endorsed tuberculosis preventative therapy (TPT) in resource-limited settings with high HIV and TB burdens. South Africa has led global TPT efforts, yet implementation remains sub-optimal.

Methods
In a rural, impoverished region of South Africa with high TB and HIV prevalence, primary care clinic-based senior nurses were asked to participate in anonymous, semi-structured interviews assessing TPT knowledge, beliefs, and attitudes. The currently available regimen is isoniazid preventive therapy (IPT) for 12 months. Through an iterative process, a code list was generated and applied to each transcript. The data were analyzed using thematic analysis and Nvivo 12 software to identify facilitators and barriers to IPT prescribing.

Results
Among 22 nurses at 14 primary health clinics, 86% were female, median age 39 (IQR 31-54.8) years, with median 10.5 (IQR3-18) years of health care experience. Nurses felt that TPT was effective at preventing TB. Barriers to implementation included limited time to counsel patients due to understaffing in high-volume clinics and lack of documentation of IPT prescription in patients’ charts, which limited effective follow-up. Nurses certified in Nurse-Initiated Management of Antiretroviral Therapy (NIMART) expressed confidence in their IPT knowledge, but those not certified wanted additional training. Nurses identified patient-level factors impeding TPT implementation, including transportation, HIV-related stigma, mobility, particularly among men, and pill burden associated with length of IPT (12 months) with concurrent daily chronic medications. Facilitators included availability of IPT in both hospitals and primary care clinics, and capacity for task-shifting to other healthcare professionals (counselors, staff nurses). The impending rollout of 3HP (12 weeks of isoniazid-rifapentine) was viewed favorably.

Conclusion
Nurses identified limited time to counsel PLH and lack of standardized training programs as the main barriers to implementation of TB preventative therapy. Addressing these barriers will be critical to successful implementation of new TPT regimens.

Disclosures
All Authors: No reported disclosures
1647. Breast Tuberculosis: A Diagnostic Challenge
Authors: Hammami Fatma , Koubaa Makram , Chakroun Amal , Rekik Khaoula , Smaoui Fatma , Elleuch Emna , Marrakchi Chakib , Jemaa Mounir Ben 
Published: January 2021

Abstract

Background
Breast tuberculosis is a rare disease accounting for less than 0.1% in developed countries and 3-4% in high incidence regions. Its diagnosis remains challenging as it closely mimics breast cancer and abscess. We aimed to study the epidemiological, clinical and therapeutic features of breast tuberculosis.

Methods
We conducted a retrospective study including all patients hospitalized in the infectious diseases department for breast tuberculosis between 2000 and 2018.

Results
We enrolled 17 women with a mean age of 40 ±12 years. Nine patients came from rural area (52.9%). Two patients (11.7%) had a history of tuberculosis. None of our patients had a family history of tuberculosis, nor breast cancer. The duration of symptoms varied from one month to a year. At the time of diagnosis, three patients were pregnant (17.6%) and one patient (5.8%) was lactating. The most common clinical symptoms were mastalgia (88.2%), palpable breast lump (88.2%) and fever (76.5%). The average size of the breast lump was 5 ±2 cm. Eight patients (47%) had associated signs of inflammation, 11 patients had axillary lymphadenopathy (64.7%) and four patients had nipple discharge (23.5%). The diagnosis was confirmed by histopathological proof in 14 cases (82.4%) and bacteriological proof in three cases (17.6%). The tuberculin skin test was positive in 10 cases (58.8%). The mean duration of antitubercular therapy was 10 ±1 months. Excision of the mass were indicated in 10 cases (58.8%) and a mastectomy in 2 cases (11.7%). Two cases of relapse were noted (11.7%).

Conclusion
Breast tuberculosis should be suspected in front of breast abscess or inflammation with poor response to antibiotic treatment, especially in patients from endemic countries.

Disclosures
All Authors: No reported disclosures
138. Focused Outpatient Antibiograms: Time for Widespread Implementation?
Authors: Manandhar Sabina , Cook Paul P , Schwartz Michael D , Duncan Heather M 
Published: January 2021

Abstract

Background
Significant antimicrobial use occurs in outpatient settings, making this an important area for expanding stewardship. Data show over 260 million annual prescriptions in the U.S. Family practitioners prescribed the most antibiotic courses (24%)1. Urinary Tract Infections (UTI) comprise one of the most common indications for antibiotics. In this study, antibiogram data were compiled for urinary isolates of E coli collected from all outpatients as well as Family Medicine-specific (FM) clinics in an academic medical center in Eastern NC. The objective is to identify susceptibility variations for E. coli from urine isolates specific to combined outpatient and academic FM clinics compared to composite non-intensive care unit (ICU) data. Also, assess impact of providers’ knowledge/access to a focused antibiogram on choice of empiric therapy.

Methods
Data were electronically obtained from the microbiology laboratory at Vidant Health (VH), a large regional system serving over 1.4 million people from 29 counties in Eastern NC. All urine cultures with E. coli from 9/2018 - 9/2019 were included. Two focused antibiograms were then developed via MedMind.
A pre and post intervention survey was conducted with FM practitioners, including residents. Intervention was defined as a brief talk to educate providers about variations identified via focused antibiograms. Survey results were compared to assess for intent to change practice.

Results
Pre-survey data are noted in Figure 1. Post-survey changes are described in Figure 2 noting that 100% of respondents now felt a need to have access to focused antibiogram data.
There were 1107 E coli urinary isolates for all outpatients and 104 for FM clinics only. Figure 3 highlights key differences in antibiogram data, especially enhanced susceptibilities for common antibiotics in FM-specific clinics when compared to composite institutional data.
Pre-Intervention Survey

Post-Intervention Survey

Comparison of Antibiogram

Conclusion
Composite hospital antibiograms may not be optimal for determining empiric UTI treatment in the community and antibiotic selections thought to be suboptimal in an institution may be effective in outpatient settings. Thus, antibiograms developed specifically for outpatient clinics, especially in academic centers, have potential to greatly enhance appropriate care.

Disclosures
Paul P. Cook, MD, Contrafect (Grant/Research Support, Scientific Research Study Investigator)Gilead (Grant/Research Support, Scientific Research Study Investigator)Leonard-Meron (Grant/Research Support, Scientific Research Study Investigator)Lilly (Grant/Research Support, Scientific Research Study Investigator)
1653. Estimation of country-specific tuberculosis antibiograms using a wide and deep neural net on a large genomic dataset
Authors: Dixit Avika , Freschi Luca , Vargas Roger , Groeschel Matthias , Chen Michael , Tahseen Sabira , Kamal S M Mostofa , Ismail Nazir A , Farhat Maha 
Published: January 2021

Abstract

Background
Improved estimates of drug resistant tuberculosis (TB) burden are needed to aid control efforts. The World Health Organization (WHO) currently reports estimates for rifampin resistance (RR) or multidrug resistance (MDR) at the national level. Resistance rates to other first-line and second-line agents, e.g. ethambutol, pyrazinamide, and aminoglycosides, are rarely available, even at the country level. Our objective was to generate country and drug specific resistance prevalence estimates (antibiograms) using in silico phenotype prediction and curated public and surveillance Mycobacterium tuberculosis (MTB) genomic data.

Methods
We curated MTB genomes either by sequencing or from published literature and excluded genomes that did not meet our quality criteria (i.e. at least 10X depth in &gt;95% of the genome). A machine learning model previously trained to predict phenotypic resistance in MTB with high accuracy, a wide and deep neural net (WDNN), was used to predict resistance to ten drugs. We corrected for resistance oversampling in genomic data by conditioning on RR and using country specific surveillance MDR/RR rates reported by the WHO.

Results
Of the 49,851 MTB genomes curated, 33,873 isolates met quality criteria. Of these, geographic data was available for 22,838 genomes. Antibiograms were generated for nine first- and second-line drugs for 36 countries. Among countries with at least 100 isolates, a high rate of resistance to fluoroquinolones and second line injectables was seen among isolates from the Republic of Moldova (15.4% [CI = 13.7-16.7%] moxifloxacin resistant, 6.3% [CI = 5.5-6.8%] kanamycin resistant, n = 330) and Russian Federation (9.3% [CI = 9.1-9.4] moxifloxacin resistant, 5.4% [CI = 5.3-5.5%] kanamycin resistant, n = 1011) (Figure 1).
Figure 1: Antibiograms created using genotypic data for isolates from Republic of Moldova (n=330, rifampin-resistance rate correction: 29%, range 26-31% among new tuberculosis cases);and Russian Federation (n=1011, rifampin-resistance rate correction 35%, range 34-35%, among new tuberculosis cases. rif: rifampin, inh: isoniazid, pza: pyrazinamide, emb: ethambutol, str: streptomycin, cap: capreomycin, amk: amikacin, kan: kanamycin, moxi: moxifloxacin

Conclusion
The estimation of antibiotic resistance prevalence in MTB for pyrazinamide, ethambutol and second-line agents can be aided by the use of in silico models of drug resistance. A high rate of resistance to second-line drugs precludes large scale roll out of short-course WHO regimens for treatment of MDR-TB for empiric use in certain countries. The use of whole genome sequencing for resistance surveillance can inform policy on optimal national regimen choice for TB treatment.

Disclosures
All Authors: No reported disclosures