bluuebunny/crossref_metadata_2025 huggingface dataset:
1602. Comparative Activity of Ceftolozane-Tazobactam (C/T) and Ceftazidime-Avibactam (CZA) against Pseudomonas aeruginosa (PSA) from Patients with Cystic Fibrosis (CF)
Authors: Lasko Maxwell J , Nicolau David P , Kuti Joseph L
Published: January 2021

Background

Acute pulmonary exacerbations (APE) are a frequent cause of hospitalization for patients with CF. PSA is among the most common pathogen implicated in CF APE. Due to repetitive antibiotic courses, multidrug resistance (MDR) must be considered leaving few available intravenous antibiotic options. CZA and C/T are newer anti-PSA antibiotics that have been used to treat CF APE, but little data are available to compare their in vitro activity.

Methods

Non-duplicate, contemporary, clinical PSA (n=105) isolates were acquired from 85 patients during CF APE from 3 US hospital systems. MICs were assessed in at least triplicate by reference broth microdilution for C/T, CZA, aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), ciprofloxacin (CIP), levofloxacin (LVX), meropenem (MEM), piperacillin/tazobactam (TZP), and tobramycin (TOB). Current CLSI breakpoints were used to define susceptibility. Activity was further assessed in MDR, CAZ and MEM non-susceptible (NS) phenotypes.

Results

The mean patient age at isolate retrieval was 31 years (IQR: 21-43), and 20% were under 18 years. Mucoid morphology was observed in 48 (46%) isolates, and MDR defined in 41 (39%). Rates of susceptibility (MIC50/MIC90/%S) were: C/T (1/4/92%), CZA (2/8/90%), CAZ (4/64/68%), TZP (8/256/67%), TOB (2/32/63%), MEM (1/32/58%), ATM (8/64/57%), FEP (8/≥128/50%), CIP (2/8/27%), and LVX (4/16/24%). A mucoid phenotype did not alter %S (non-mucoid vs. mucoid) for C/T (93 vs. 92%) or CZA (91 vs. 88%). Among the 41 MDR PSA, activity was 2/16/83% and 4/16/76% for C/T and CZA, respectively. C/T, CZA, and MEM %S was 77, 69, and 23% for the 35 CAZ-NS isolates. C/T, CZA, and CAZ %S was 84, 77, and 39% for MEM-NS isolates.

Conclusion

These contemporary PSA from patients with CF displayed low susceptibility rates to most β-lactams, fluoroquinolones, and tobramycin, and MDR was common. C/T and CZA retained similarly high susceptibility against these isolates, including MDR strains and CAZ-NS/MEM-NS phenotypes. These data justify that both CT and CZA may be considered for CF APE due to PSA non-susceptible to current standard of care treatment options.

Disclosures

David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))
1610. Epidemiology and Treatment Heterogeneity in Acinetobacter baumanii Infections
Authors: Caffrey Aisling , Appaneal Haley J , Lopes Vrishali , LaPlante Kerry
Published: January 2021

Background

Acinetobacter baumannii is known as a highly resistant organism causing serious infections in intensive care populations. However, the epidemiology of infections caused by Acinetobacter baumannii and approaches to treatment are not well described in a national healthcare system.

Methods

Our retrospective cohort study included patients with positive Acinetobacter baumannii cultures collected from any source during hospitalizations at Veterans Affairs (VA) medical centers nationally from January 2010 to April 2019. We evaluated patient characteristics and utilized exposure mapping to identify treatment patterns, including treatment heterogeneity. Heterogeneity was defined as patterns of antibiotic treatment (drug and duration) not shared by any other patient.

Results

Our study included 7,551 admissions with positive Acinetobacter baumannii cultures. The mean age was 66.7 years (±12.1) and 97.4% were male. Most patients were admitted from other healthcare facilities (59.2%) and 20.8% were in intensive care during the admission. Most patients had their culture collected on the day after admission and the median time to culture completion was 4 days (interquartile range 3-5). Acinetobacter baumannii cultures were most commonly obtained from urine (33.6%), followed by skin and soft tissue (25.3%), lung (21.8%), blood (9.2%), and bone/joint (5.0%). The median length of hospital stay was 11 days, with inpatient mortality and 30-day mortality rates of 11.6% and 12.5%, respectively.

Treatment heterogeneity was high, with 88.5% of admissions having different antibiotic treatment patterns (drug and duration), with a median time to first change of 1 day and median of 3 changes. Only 2% of the admissions were treated with polymyxins and 3.0% with colistin. Carbapenems were used in 18.9% of the admissions and extended-spectrum cephalosporins in 31.7% of the admissions.

Conclusion

In VA hospitals, Acinetobacter baumannii infections are observed in both critical and non-critical patient populations, mostly among patients with healthcare exposures. Acinetobacter baumannii infections were found to have various sources of infection, mostly from urine and skin and soft tissue, and approaches to treatment were highly varied.

Disclosures

Aisling Caffrey, PhD, Merck (Research Grant or Support)Pfizer (Research Grant or Support)Shionogi (Research Grant or Support) Haley J. Appaneal, PharmD, Shionogi, Inc. (Research Grant or Support) Kerry LaPlante, PharmD, Merck (Advisor or Review Panel member, Research Grant or Support)Ocean Spray Cranberries, Inc. (Research Grant or Support)Pfizer Pharmaceuticals (Research Grant or Support)Shionogi, Inc. (Research Grant or Support)
1611. Evaluating Clinical Outcomes and Efficacy of Daptomycin in Combination with a Beta-Lactam for the Treatment of Vancomycin-Resistant Enterococcus (VRE) Bacteremia
Authors: Irusta Nerea , Vega Ana , Natori Yoichiro , Abbo Lilian M , Abbo Lilian M , DeRonde Kailynn
Published: January 2021

Background

In-vitro studies have shown synergistic bactericidal activity with daptomycin (DAP) plus β-lactam antimicrobials against vancomycin resistant enterococci (VRE). There is a paucity of data regarding clinical outcomes with this combination in VRE bloodstream infections (BSI). The purpose of this study was to assess the efficacy of DAP plus a β-lactam with in-vitro activity vs. other therapies for treatment of VRE BSI.

Methods

IRB-approved, single-center, retrospective study of patients with VRE BSI from 01/2018-09/2019. Patients were excluded if < 18 years old, pregnant, or incarcerated. The primary outcome was time-to-microbiological clearance. Secondary outcomes included infection-related mortality, 30-day all-cause mortality, and incidence of recurrent BSI within 30 days of index culture. Targeted DAP doses were ≥ 8mg/kg and based on MIC. Factors associated with significance for outcomes, via univariate analysis, were evaluated with multivariable logistic regression (MLR), removed in a backward-step approach.

Results

A total of 85 patients were included, 23 of which received DAP plus a β-lactam. The comparator arm included linezolid or DAP monotherapy. Patients with combination therapy had significantly higher Charlson Comorbidity Index (CCI) (p=0.013) and numerically higher Pitt Bacteremia scores (PBS) (p=0.087) (Table 1). There was no difference seen in the primary outcome (Table 2). Secondary outcomes are provided in Table 2. The presence of polymicrobial infection and higher PBS were significantly associated with infection-related mortality (p=0.008 and p=0.005, respectively) by MLR. A Mann Whitney U test indicated that presence of infection-related mortality was greater for patients with higher MICS (U=20.5, p=0.06). The presence of an underlying source may be related to recurrence of BSI (p=0.075).

Table 1: Patient Characteristics

Table 2. Primary and Secondary Outcomes

Conclusion

We did not find a significant difference in time-to-microbiological clearance, although patients treated with DAP and a β-lactam had higher CCI and PBS. These results are limited by retrospective design, small sample size, and potential selection bias. Prospective randomized studies are needed to further validate these findings.

Disclosures

All Authors: No reported disclosures
1614. Gwt1 Inhibitor, APX2104, Protects Against Invasive Aspergillosis in Neutropenic Mouse Model
Authors: Shaheen Shareef , Allen John , Cole D Chris , Asfaw Yohannes , Juvvadi Praveen , Shwab E Keats , Kapoor Mili , Shaw Karen , Steinbach William
Published: January 2021

Background

Aspergillus fumigatus is the leading cause of invasive aspergillosis (IA), a lethal infection among immunocompromised patients. Guideline-recommended antifungal therapy against IA is a triazole antifungal, with other secondary options including an echinocandin and amphotericin B. Concerns about drug-host toxicity and antifungal resistance have been globally reported, so new, safe, and effective therapeutics are imperative.

Methods

In vitro, CLSI standards were upheld as we tested APX2041, voriconazole, caspofungin, and amphotericin B against various A. fumigatus strains. In vivo we assessed toxicity and efficacy of APX2104 in immunocompromised mice respectively. Neutropenia was induced with 150 mg/kg of cyclophosphamide on days -2/+3 and 250 mg/kg of cortisone acetate on days -1/+6. Immunocompromised mice were infected in an inhalation chamber via 12 mL of aerosolized spores of A. fumigatus CEA10 at a concentration of 1x109 spores/mL (Day 0). Treatment started day +1 and ended day +7.

Results

In vitro, APX2041, the active-form of APX2104, has over a 16-fold lower minimum effective concentration (MEC) when compared to voriconazole, caspofungin, and amphotericin B against various A. fumigatus strains, including echinocandin- and azole-resistant strains.

In vivo, given preliminary pharmacokinetic data, APX2104 was tested in non-infected immunocompromised mice at 60 mg/kg and 78 mg/kg once per day (QD). Deaths due to toxicity were seen only at a dose of 78 mg/kg, so 60 mg/kg was set as a safe dose for our in vivo efficacy studies. In IA-challenged neutropenic mice, treatment with either posaconazole (20 mg/kg BID) or APX2104 (60 mg/kg QD) equally prolonged survival in 14 of 15 (93%) mice 14 days post-infection (p= 0.985). Untreatment control yielded a survival of 3 of 15 (20%) 14 days post-infection (p= < 0.001). Consistent with our survival studies, H&E and GMS histological samples also demonstrated that APX2104 treatment decreased fungal burden within the lungs of neutropenic mice when compared to the untreated group.

Conclusion

Future studies will test the efficacy of APX2104 and posaconazole against azole antifungal resistant strains in vivo, as our preliminary findings suggest that APX2104 is a plausible solution to cure IA disease and combat antifungal resistance.

Disclosures

All Authors: No reported disclosures
1619. Meta-analysis of Randomized Control Trials Evaluating New Beta-Lactamase Combination Antibiotics
Authors: Wilson Geneva M , Fitzpatrick Margaret A , Walding Kyle , Gonzalez Beverly , Suda Katie J , Evans Charlesnika T
Published: January 2021

Background

Ceftolozane/ Tazobactam (C/T), Ceftazidime/ Avibactam (C/A), Meropenem/ Vaborbactam (M/V) and Imipenem/ Relebactam (I/R) are new combination beta-lactam/ beta-lactamase inhibitor antibiotics primarily used to treat multidrug-resistant (MDR) Gram-negative infections. This study synthesized outcomes of comparative observational studies and randomized control trials (RCTs) that evaluated clinical success of these antibiotics compared to other therapies.

Methods

PubMed, EMBASE, and Google Scholar were searched from January 1st, 2013 through October 1st, 2019 for comparative observational studies and RCTs of C/T, C/A, M/V and I/R in patients with pneumonia, complicated intra-abdominal and urinary tract infections. Study and patient demographics were collected along with clinical and microbiological success rates. Meta-regression analysis was used to determine the pooled effectiveness of C/T, C/A, M/V, and I/R. Heterogeneity and publication bias were assessed via I2 values and funnel plots, respectively.

Results

Literature search returned 1,645 results. After exclusion criteria, 21 publications representing 6,246 patients were retained: 16 RCTs (8 C/A, 3 C/T, 3 I/R, 2 M/V) and 5 comparative observational studies (3 C/A, 2 C/T). Pooled risk ratios for clinical success showed that all four antibiotics were non-inferior to comparator antibiotics (0.99 (95% CI (0.97-1.01)). Eleven of the sixteen RCTs evaluated microbiological success; pooled risk ratio was 1.08 (95% CI 1.04-1.13), indicating that older therapies were more successful at microbiological eradication than newer antibiotics. Only 6 of the included studies (3 RCTs and 2 observational studies) focused on patients with MDR infections. Limiting the analysis to MDR RCTs did not change the overall conclusions.

Conclusion

Although older therapies had slightly higher microbiologic clearance, pooled clinical success rates for C/A, C/T, M/V, and I/R were non-inferior to older therapies, including in studies focused on patients with MDR infections. Additional studies are needed to further evaluate these drugs’ effectiveness for treatment of MDR infections.

Disclosures

All Authors: No reported disclosures
1621. Novel Beta-lactam Beta-lactamase Inhibitors Against Alternative Antibiotics for the Treatment of Complicated Urinary Tract Infections and Pyelonephritis Caused by Carbapenem-resistant Enterobacterales
Authors: Green Bliss , Meredith Jacqueline , Ackley Renee , McCarter Maggie S , Polk Christopher
Published: January 2021

Background

There is little data on the comparative efficacy or safety of carbapenem-resistant Enterobacterales (CRE)-targeted beta-lactam beta-lactamase inhibitors (BL-BLI), including ceftazidime/avibactam (CZA) and meropenem/vaborbactam (MVB), versus alternative antibiotics for the treatment of CRE complicated urinary tract infections/acute pyelonephritis (cUTI/AP). The objective of this study was to evaluate rates of clinical failure in patients with CRE cUTI/AP treated with CRE-targeted BL-BLI vs. alternative regimens.

Methods

This was a multicenter, retrospective cohort study of adults admitted with a CRE cUTI/AP treated with CRE-active antibiotic(s), including combination therapy, for at least 48 hours between January 2012 and June 2019. Exclusion criteria included CRE colonization, non-urinary source co-infection, non-Enterobacterales cUTI/AP, or mortality within 48 hours of index culture. The primary outcome was clinical failure, defined as continued symptoms or recurrence at 30 days from index culture. Secondary outcomes included 90-day recurrence and 30-day readmission. Safety outcomes included treatment-limiting adverse effects, non-treatment limiting nephrotoxicity, and C. difficile infection.

Results

A total of 47 patients were included (BL-BLI, n=16; alternative, n=31). Alternative regimens contained aminoglycosides, carbapenems, polymyxins, and tigecycline and utilized combination therapy more often (32.3% vs. 6.3%, p=0.046). Clinical failure occurred in 12.5% of patients in the BL-BLI group vs. 38.7% in the alternative group (p=0.063). Higher rates of 90-day recurrence (25.8% vs. 18.8%) and 30-day readmissions (51.6% vs. 31.3%) occurred in the alternative group vs. the BL-BLI group but were not statistically significant (Table 2). There were clinically significant rates of nephrotoxicity in the alternative group (45.2%) compared to the BL-BLI group (18.8%), contributing largely to the difference in treatment-limiting adverse effects (29% vs. 0%, p=0.017).

Table 1: Antibiotic Data

Table 2: Efficacy Outcomes

Table 3: Safety Outcomes

Conclusion

In this retrospective study, no difference in clinical failure resulted among groups; however, there was significantly more treatment-limiting adverse effects in the alternative group compared to the BL-BLI-based regimens, driven by nephrotoxicity.

Disclosures

All Authors: No reported disclosures
1627. Tedizolid is Well-tolerated Among Patients Receiving Prolonged Treatment Courses, Including Those Who are Intolerant of Alternative Agents
Authors: Smith Brandon , Marini Rachel V , Spigelmyer Amy , Clarke Lloyd , Shields Ryan K
Published: January 2021

Background

Tedizolid (TZD) is approved for acute bacterial skin and skin structure infections (ABSSSI), but often used for complicated infections to avoid linezolid (LZD) adverse events (AE), particularly when long-term treatment is indicated. This studied aimed to characterize the tolerability of TZD, including patients (pts) receiving prolonged treatment.

Methods

Retrospective review of pts who received TZD > 72 hours. Thrombocytopenia was defined as a 50% decrease from baseline platelet count. Favorable clinical outcome was defined as completing therapy without an AE or hospital readmission within 30 days.

Results

86 pts accounting for 102 courses were included. Median age of pts was 57 years and 43% were immunocompromised. Median duration of TZD therapy was 8 days (range: 4 – 350) and 32% of courses were >14 days. Common indications were ABSSSI (n=42), bacteremia (n=15), intra-abdominal infection (n=11), and pneumonia (n=10). 47% and 5% of courses were associated with MRSA or VRE and M. abscessus, respectively. 44% of TZD courses were preceded by treatment failure or AE associated with alternative therapies. AEs attributed to LZD were documented in 13 patients: thrombocytopenia (n=11), lactic acidosis (n=1), or both (n=1). Serotonergic agents were administered during 76% of TZD courses; however, no patient developed serotonin syndrome. 8% of TZD courses were stopped prematurely due to AEs that included thrombocytopenia (n=3), gastrointestinal intolerance (n=2), confusion (n=1), eosinophilia (n=1) and thrombocytopenia with lactic acidosis (n=1). All cases of thrombocytopenia occurred in pts with baseline platelets < 100,000 cells/L. 79% of pts receiving > 14 days of TZD completed therapy successfully without AEs. Among pts who failed alternative therapies, 74% were able to tolerate TZD and completed therapy. Overall, 80% of courses were completed with a favorable outcome.

Clinical Outcomes of Extended TZD Therapy

Conclusion

The safety of prolonged TZD treatment is not well-described. In our experience, TZD was well-tolerated, including among pts who failed alternative therapy. No pt receiving concomitant serotonergic agents developed serotonin syndrome and thrombocytopenia occurred exclusively among pts with low baseline platelets. Treatment courses >14 days were not associated with an increase in the rate of AEs.

Disclosures

Rachel V. Marini, PharmD, Merck (Research Grant or Support) Ryan K. Shields, PharmD, MS, Allergan (Advisor or Review Panel member, Research Grant or Support)Entasis (Advisor or Review Panel member)Melinta (Research Grant or Support)Menarini (Consultant)Merck (Advisor or Review Panel member, Research Grant or Support)Shionogi (Advisor or Review Panel member, Research Grant or Support)Summit (Advisor or Review Panel member)Tetraphase (Research Grant or Support)Venatorx (Advisor or Review Panel member, Research Grant or Support)
1630. What is Treatment Time Zero Among Hospitalized Patients with Bacteremia?
Authors: Caffrey Aisling , Lopes Vrishali
Published: January 2021

Background

Common operational definitions of antibiotic exposures in infectious diseases research do not accurately reflect actual treatment, as daily changes in clinical presentation (i.e. improvement, worsening) and clinical information (i.e. causative organism, susceptibilities) lead to frequent changes in treatment, both within empiric and definitive treatment periods. Common definitions create periods of ‘ignored’ exposures, and we’ve previously shown that antibiotic treatments during ‘ignored’ periods vary widely. Therefore, we assessed the distribution of important time points for antibiotic treatments for Staphylococcus aureus bacteremia.

Methods

Our retrospective cohort study included hospital admissions in the national Veterans Affairs (VA) Healthcare System with S. aureus positive blood cultures from 2010 to 2018. Admissions with inappropriate initial antibiotic therapy for S. aureus were excluded. We implemented daily exposure mapping to identify antibiotic exposures and changes in treatment on each day of the admission until discharge, or 30 days post-admission for longer stays, and in relation to the culture final report date.

Results

We identified 21,947 admissions meeting our inclusion criteria. Antibiotic initiation most often occurred on the culture collection date (68.7%) or the day after (22.6%). Median time to the culture final report date from the culture collection date was 4 days (interquartile range [IQR] 3 to 5). Among those with changes in therapy (n=19,392, 88.4%), median time to first change in therapy was 2 days prior to the culture final report date (IQR -3 to -1). The first change in therapy occurred before the culture final report date for 76.3% of admissions and on the culture final report date for 11.9% of admissions. Further changes were common on the culture final report date (49.5%) and the day after the final report date (45.3%).

Conclusion

Changes in antibiotic therapy are common prior to finalization of culture reports. While initial culture results and provider knowledge of these initial results are not date/time-stamped, initial change within a reasonable period from culture collection appears to be more accurate in defining empiric and definitive treatment periods than commonly used operational definitions.

Disclosures

Aisling Caffrey, PhD, Merck (Research Grant or Support)Pfizer (Research Grant or Support)Shionogi (Research Grant or Support)
1631. Mycobacterium septicum: A 6-year Clinical Experience from a Tertiary Hospital and Reference Laboratory
Authors: Go John Raymond U , Campioli Cristina G Corsini , Saleh Omar Abu , Wilson John , Deml Sharon , Wengenack Nancy
Published: January 2021

Background

Mycobacterium septicum is a rapidly growing non-tuberculous mycobacterium. It is a ubiquitous organism capable of causing infections in both healthy and immunocompromised individuals. Only a few cases have been reported to date, and standard therapeutic regimens, and optimal treatment duration have not been defined.

Methods

We conducted a retrospective chart review of all patients seen at Mayo Clinic in Rochester, MN from July 2014 to March 2020 from whom Mycobacterium septicum was isolated in culture by our clinical microbiology laboratory.

Results

There were 12 patients identified with M. septicum infection – 7 males and 5 females. The average age was 67 years, with an age range of 48 to 80 years. Seven of 12 isolates obtained were from sputum samples. Only one patient was on immunosuppressive medication. Three cases were considered clinically significant infections for which directed anti-mycobacterial therapy was instituted. In two of these three cases, co-infection with Mycobacterium avium complex (MAC) was seen. Underlying structural lung disease was present in the two cases of pulmonary infections. Peritoneal dialysis catheter-related peritonitis was seen in the third case. All the isolates were susceptible to amikacin, ciprofloxacin, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole (TMP-SMX). The isolates were resistant to clarithromycin and doxycycline.

Patient Characteristics, Associated M. septicum Illness, and Therapy Provided

Antimicrobial Susceptibility Profiles of the Mycobacterium septicum Isolates, MIC (mcg/mL) and Interpretation

Patient Demographics and Specimen Source of Mycobacerium septicum Isolates

Conclusion

M. septicum is an unusual cause of non-tuberculous mycobacterial infection. The presence of a foreign body may increase the risk of infection. Individuals with underlying structural lung disease are also likely to be at increased risk of developing pulmonary infection. Generalized treatment recommendations are limited by the lack of prospective controlled trials; hence, optimal antibiotic regimen and treatment duration have not been firmly established. Susceptibility testing should be performed to guide treatment selection, but the use of combination therapy with potentially empiric agents like amikacin, ciprofloxacin, imipenem, linezolid, moxifloxacin, and TMP-SMX as demonstrated in this small study, can be considered. A high rate of macrolide resistance was noted in our study.

Disclosures

All Authors: No reported disclosures
1633. Improving the diagnosis of extra-pulmonary tuberculosis (EPTB): experience from north India
Authors: Sharma Anchal , Sharma Kusum , Modi Manish , Sharma Aman
Published: January 2021

Background

Rapid and accurate diagnosis of extra-pulmonary tuberculosis (EPTB) is imperative for early treatment and better patient outcome. Loop-mediated Isothermal Amplification (LAMP) is a promising nucleic-acid amplification assay. LAMP assay could be carried out in simple water bath under isothermal conditions in 60 minutes, and can be performed in any laboratory even in rural setting in resource poor endemic countries. We evaluated LAMP assay using two different target regions LAMP primers specific for Mycobacterium tuberculosis complex for the diagnosis of EPTB.

Methods

LAMP assay using 6 primers (each for IS6110 and IS1081) specific for Mycobacterium tuberculosis complex were performed on patients suspected of EPTB on various EPTB samples(CSF, Synovial fluid, Lymaphnode and tissue biopsies and various other samples) of 150 patients (50 confirmed, 100 suspected) Clinically suspected of EPTB and 100 non-TB control subjects.

Results

Overall LAMP test (using any of the two targets) had sensitivity and specificity of 96% and 100% for confirmed (50 culture positive) EPTB cases. In 100 clinically suspected but unconfirmed EPTB cases, LAMP was positive in 87 out of 100 cases (87%). Sensitivity of IS6110 LAMP, 1S1081 LAMP and IS6110 PCR for clinically suspected cases was 78 (78%), 84 (84%) and 70 (70%), respectively. In total 150 EPTB patients, the overall sensitivity of microscopy, culture, IS6110 PCR, IS6110 LAMP, 1081 LAMP and the LAMP test (if any of the two targets were used) were 4%, 33.3%, 74.6%, 82.66%, 87% and 92%, respectively. Specificity of all the tests was 100%. There were 8 cases which were missed by IS6110 LAMP and 2 cases by 1081 LAMP.

Conclusion

LAMP assay using two targets is a promising technique for rapid diagnosis of EPTB in 60 minutes especially in a resource poor setting who are still battling with this deadly disease.

Disclosures

All Authors: No reported disclosures
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

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 < 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

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< 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

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

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

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

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

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

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)