bluuebunny/crossref_metadata_2025 huggingface dataset:
1433. Factors Associated with Unsuccessful Treatment Outcomes among Patients with Rifampicin Resistant Tuberculosis - Tajikistan, 2015-2020
Authors: Tilloeva Zulfiya Haybullo , Sijotkhonov Amidkhan S , Zikriyarova Sanam , Pirmahmadzoda Bobochon , Alaverdyan Sevak , Nabirova Dilyara , Horth Roberta , Dzhafarov Navruz
Published: December 2022

Background

Tajikistan has a high burden of multidrug resistant TB, including rifampicin-resistant TB (RR-TB). Treatment options are more limited and include standard treatment (T1), bedaquiline/delamanid contained individual treatment (T2), short treatment (T3), modified short treatment (T4), and bedaquiline/pretomanid/linezolid treatment (T5). To inform national treatment plans, we assessed trends in RR-TB and determined factors associated with unsuccessful treatment.

Methods

We conducted a retrospective cohort study in Dushanbe, Tajikistan, from 2015 to 2020 using patient records. Patients had successful treatment outcomes if they completed treatment or were cured, and unsuccessful if they had treatment failure, were lost-to-follow-up, or died. We report relative risk (RR) and 95% confidence interval from multivariable Poisson regression.

Results

From 2015 to 2020, there was a decrease in incidence of TB (68.6 to 47.2 per 100,000) and RR-TB (10.6 to 7.2) with a 33% drop 2019 to 2020. Proportion of unsuccessful outcomes also decreased (30% to 15% 2015-2020). Of 522 patients, 515 had RR-TB. Of these, 39% received T1, 43% T2, 15% T3, 2% T4, and 0.4% T5 (Table 1). Overall, 23% had unsuccessful treatment outcomes. Patients on T1 had higher unsuccessful outcome compared to those on T2 - T5 (31% vs 19%, 14%, 0% and 0%, respectively). Unsuccessful outcomes were associated with combined isoniazid, rifampin and streptomycin resistance, alcohol and drug use. For patients receiving T1, unsuccessful outcome was associated with unemployment (RR: 2.7; 1.1-6.8), HIV (RR: 2.3, 1.5-3.4), hepatitis C (RR: 2.2, 1.4-3.4), and concomitant disease (RR: 2.1, 1.4-3.1). For patients receiving T2, risk of unsuccessful outcome was lower for females (RR: 0.4, 0.2-0.7) (Table 2).

Conclusion

Decrease in incidence is promising. Results highlight the need to transition RR-TB patients to non-standard treatment. Closer follow-up of patients with combined resistance, alcohol or drug use, HIV, hepatitis C, and concomitant diseases may contribute to successful outcome.

Disclosures

All Authors: No reported disclosures.
1446. Quality of life and associating factors in pulmonary tuberculosis patients
Authors: Samuel Richard
Published: December 2022

Background

Quality of life is a significant issue among patients with tuberculosis and is used for evaluating treatment responses and therapeutic outcome. This study aimed to assess the quality of life in tuberculosis patients receiving anti-tuberculosis therapy for a short duration in the Vellore district of Tamil Nadu and its associated variables.

Methods

A cross-sectional study was designed to evaluate pulmonary tuberculosis patients receiving treatment under category -1 registered in the NIKSHAY portal at Vellore. A total of 165 pulmonary tuberculosis patients were recruited from March 2021 to the third week of June 2021. On obtaining informed consent, the data were collected through the telephone interview by administering WHOQOL- BREF structured questionnaire. The data were examined with descriptive and analytical statistics. Multiple regression analysis for independent quality of life variables was done.

Results

The lowest median scores, 31(25,38) & 38(25,44) was, related to psychological and environmental domains, respectively. In addition, the Man-Whitney & Kruskal Wallis showed a statistically significant variation in the mean quality of life for gender, employment status, duration of treatment, persistent symptoms, the location of residence of patients, and the stage of therapy. Age, gender, marital status, and persistent symptoms were the main associating factor.

Associating factors

Multiple linear regression (multi-variate analysis) showing factors associated with Physical, Psychological, Social & Environmental domain scores among pulmonary tuberculosis patients receiving under category -1 receiving treatment in Vellore district of Tamilnadu, South India

Conclusion

Tuberculosis and its treatment influence psychological, physical functioning, and the environmental domain of patient quality of life. Attention is required in the follow-up and treatment of patients by monitoring their quality of life.

Disclosures

All Authors: No reported disclosures.
1451. Tuberculosis among Adults Aged 65 Years and Older—Alameda County, California, 2016–2019
Authors: Wu Iris L , Chen Jennie , Shiau Rita , Chitnis Amit S , Jaganath Devan
Published: December 2022

Background

Adults aged 65 years and older represent an increasing proportion of United States (U.S.) tuberculosis (TB) cases, and their clinical complexity creates unique issues for TB management. In Alameda County, California, we examined clinical characteristics and treatment outcomes among older adults with TB disease.

Methods

We evaluated demographic and clinical surveillance data from all adult TB cases in Alameda County during 2016–2019. We further reviewed public health department charts for TB cases among individuals aged 65 years and older to obtain more detailed information on co-morbidities, adverse effects, and treatment outcomes. Demographics, clinical characteristics, and outcomes were compared in younger adults (15-64) to older adults (≥ 65), who were further stratified by those aged 75 years and older. All comparisons were conducted using Fisher’s exact or Mann-Whitney U tests.

Results

Of 517 adult TB cases, 172 (33%) were older adults, and more likely to be male (68.6%), Asian (89.0%), non-U.S. born (98.3%), and have diabetes (32.6%) compared to younger adults (Table). At time of TB diagnosis, older adults were more likely than younger adults to have a negative interferon-gamma release assay result (24.6% vs. 16.0%, P=0.01), particularly among aged 75 years and older where 32.9% had a negative result. The majority of older adults with pulmonary TB had sputum smear-negative disease (58.9%) and 19.9% were culture- and polymerase chain reaction assay-negative. On anti-TB treatment, 32.5% of older adults experienced at least one adverse event, most commonly elevated liver enzymes (56.6%) and rash (32.1%). Older adults were more likely to be dead at diagnosis (3.5% vs. 0.0%, P=0.001), and were less likely to complete TB treatment (77.7% vs. 88.4% in younger adults, P=0.002), which was lowest among aged 75 years and older (72.9% vs. 84.3% in those 65-74, P=0.04). Death during treatment was higher in older adults, in particular aged 75 and older compared to 65–74 years (22.9% vs. 7.1%, P=0.01).

Conclusion

Older adults with TB disease faced several challenges, including negative diagnostic testing and poor treatment outcomes. A greater understanding of the presentation, adverse events and outcomes can guide interventions to improve TB care in this population.

Disclosures

All Authors: No reported disclosures.
1457. Epidemiology of Human Herpesvirus-6 Meningoencephalitis in Los Angeles County, 2016-2020
Authors: Ranson Elizabeth L , Ngo Van , Kuguru Karen , Halai Umme-Aiman
Published: December 2022

Background

Human herpesvirus 6 (HHV-6) is ubiquitous and a known central nervous system (CNS) pathogen. However, HHV-6 in cerebrospinal fluid (CSF) without clinical findings of meningoencephalitis (ME) may not represent true infection, but rather, asymptomatic viral reactivation, chromosomal integration, or latent activation. With the introduction in 2015 of a rapid polymerase chain reaction (PCR) multiplex panel that simultaneously tests for 14 CNS pathogens, reports of HHV-6 PCR positive ME have increased. We sought to understand the epidemiology of HHV-6 ME by evaluating reported cases in Los Angeles County (LAC) between 2016-2020.

Methods

ME is a reportable condition in LAC. We reviewed clinical, laboratory, and radiologic data for all HHV-6 PCR positive cases reported in LAC between 2016-2020. We developed case classification categories, “unlikely,” “possible,” and “likely”, based on symptoms, CSF profile, and alternative diagnoses (see Table 1).

Results

A total of 67 HHV-6 ME cases were reported (see Table 2). Reports increased over time, with one in 2016, 12 in 2017, 17 in 2018, 20 in 2019, and 17 in 2020. Median age was 9 months (range 0d-78y), and 47 (70%) were < three years old. Forty-four (66%) were male. Six (9%) were immunocompromised, including one hematopoietic stem cell transplant recipient. Nineteen (28%) had abnormal CSF, and eight (12%) received therapy for HHV-6.

Five cases (7%) were classified as “likely” HHV-6 ME, 12 (18%) “possible,” and 50 (75%) “unlikely”. The “likely” cases ranged in age from 7 months to 12 years old, and none were immunocompromised. One received antiviral therapy and was discharged to a rehabilitation facility, the other four were discharged home with full recovery.

Conclusion

The significance of HHV-6 in CSF remains challenging to determine both clinically and epidemiologically. In the setting of increased testing, increasing detection of HHV-6 in CSF may not reflect increasing rates of HHV-6 ME. The majority of reported HHV-6 ME cases were “unlikely” based on our classification. Classifying cases with alternative diagnoses as ‘unlikely” may miss cases with multiple true infections, particularly in the immunocompromised. It is important to consider clinical presentation, CSF profile and other diagnoses to understand the true burden of HHV-6 ME.

Disclosures

All Authors: No reported disclosures.
1463. Association between Herpes Simplex Virus Type 1 and the Risk of Alzheimer’s Disease
Authors: Liu Luke , Jarousse Nadine , Johnston Christine , Fletcher Simon P , Iqbal Shahed
Published: December 2022

Background

There is significant unmet need of novel therapeutics for Alzheimer’s Disease (AD). A growing body of evidence suggests a role for herpesviruses in the development of AD and reduced risk of AD among patients receiving antivirals. We investigated the association between herpes simplex virus type 1 (HSV-1) diagnoses, antiviral use, and AD using real-world data.

Methods

In a matched case-control study, AD patients aged ≥ 50 years diagnosed between 2006 and 2021 were identified from IQVIA PharMetrics Plus® claims database using International Classification of Disease (ICD) codes (ICD 9 331.0; ICD 10 G30.x). Controls without any history of neurological disorders were matched in a 1:1 ratio with AD subjects on age, sex, region, database entry year, and healthcare visit numbers. HSV-1 diagnoses were identified using relevant ICD codes. Conditional logistic regression was used to evaluate the association between HSV-1 and AD. The association between antiviral use (e.g., acyclovir, famciclovir, valacyclovir) and AD was assessed by multivariate Cox proportional hazards model in patients with HSV-1 diagnosis.

Results

The study included 344,628 AD patient-control pairs. Most patients were female (65%) with a mean age of 73 (± 5) years. AD patients had more comorbidities (50% vs. 45% with ≥ 2 comorbidities) and shorter follow up time (median of 33 vs. 48 months) when compared to controls. History of HSV-1 diagnosis was present in 1507 (0.44%) AD patients vs. 823 (0.24%) controls. HSV-1 diagnosis was associated with AD (adjusted odds ratio [OR] 1.80; 95% confidence interval [CI] 1.65-1.96). In a stratified analysis, this association was more pronounced in the older age group (75+ years: OR 2.10, 95% CI 1.88-2.35; 71-74 years: OR 1.51, 95% CI 1.27-1.80; 50-70 years: OR 1.14, 95% CI 0.91-1.44). Patients with HSV-1 who used antivirals were less likely to have AD compared to those who did not use antivirals (adjusted hazard ratio 0.83, 95% CI 0.74-0.92). Similar results were observed when the analysis was extended to include all patients with AD-related dementia and matched controls.

The association between herpes simplex virus type 1 (HSV-1) and Alzheimer’s Disease (AD)/AD-related Dementia(ADRD)

Conclusion

Findings from this large real-world data study is consistent with emerging literature on HSV-1 and risk of AD and the possible protective role of antiviral drugs.

Disclosures

Luke Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Simon P. Fletcher, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Shahed Iqbal, PhD, MBBS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds.
1466. Antiretroviral (ART) Virologic Suppression (VS) and Patient Reported Outcomes (PROs) at 6 Months in the Clinical Opportunities and Management to Exploit Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) an Asynchronous Connection Key (COMEBACK) Study
Authors: Roden Lindsey , Huhn Gregory , DeMarco Camille E , Keckler Kody , Valadez Patricia Cortes , Burke Kerianne
Published: December 2022

Background

Effectively interrupting the source of transmission is a critical step in ending the HIV epidemic. COMEBACK (NCT04519970) is a 48-week single-center study in Chicago implemented in September 2020, with its main objectives to reengage lost-to-care patients and rapidly reinitiate ART to promote VS and favorable PROs.

Methods

Adults off ART ≥2 weeks, without history of significant B/F/TAF resistance or renal impairment, were rapidly started on B/F/TAF upon reengagement after same day collection of baseline labs and PROs. A retention screening assessment was used to stratify participants into case management (CM) tiers: Minimal, Moderate, or Advanced. An acuity assessment tool was adapted to determine whether participants needed additional support based on retention and VS. Currently, 80 of the expected 100 subjects are enrolled and 55 have reached the 24-week timepoint. Baseline and 6-month endpoints were analyzed for these participants.

Results

At baseline (N=55), median age was 34 years (range, 24–62), with 92.6% Black and 72.2% cisgender male. Median CD4+ was 338 cells/mm3, with a median viral load 7,402copies/mL, (range, < 40–333,350, 16.3% VS). Median time off ART was 2.6 months (range, 0.5-243). For CM, participants were stratified into Minimal (71%) and Moderate (29%) tiers; none were identified as Advanced.

Table 1 reflects tier shifts through 24 weeks.

Shifts in CM intensity differs from the HIV adherence self-efficacy PRO completed within 24 weeks, indicating that at least 50% underestimated their need to integrate and maintain adherence to ART treatment. Forty of 55 participants (72.7%) were retained-in-care at 6 months, with VS in 61.8% (N=34/55) by intention-to-treat and 85% (N=34/40) by observed analysis. No resistance to B/F/TAF was detected through 6 months.

Note: The table reflects patients retained on study at their week 24 endpoint.

Conclusion

VS was high for participants retained-in-care, but lapses in retention and shifts toward more intense CM were likely due to social determinants of health challenges, including incarceration, housing insecurity, and COVID-19-related disruptions in healthcare.

Disclosures

Gregory Huhn, MD, MPHTM, Eli Lilly: Advisor/Consultant|Eli Lilly: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Jannsen: Advisor/Consultant|Jannsen: Grant/Research Support|Merck: Advisor/Consultant|Viiv: Advisor/Consultant|Viiv: Grant/Research Support.
1682. An Exciting New Approach: Isolation and characterisation of bacteriophages against MDR Acinetobacter baumannii
Authors: Chowdhury Souradeep , Rathor Nisha , Chaudhry Rama
Published: December 2022

Background

The modern advances in the fields of Medicine and Surgery depend entirely on our ability to treat and prevent infections. However, the rising incidence of antimicrobial resitance in both community and hospital settings has proved to be increasingly challenging. In 2017, WHO published a list of ‘priority pathogens’; antibiotic-resistant bacteria which posed the greatest threat to human health. Among them, A. baumannii was recognized as a critical priority pathogen due to its significant role in nosocomial infections. There was a growing call for new avenues in antimicrobial therapy. One such endeavour was to revisit an old therapeutic option against MDRO, viz. bacteriophage therapy. Numerous instances of successful phage therapy have already been published, with many more becoming available each day.

Methods

A total of fifty (50) multidrug resistant isolates of A. baumannii were collected. We attempted to isolate bacteriophages from hospital sewage water, against these collected strains, using standard procedure. Then the host range of the isolated phages were analysed against those 50 collected isolates. The lytic activity was confirmed using spot and plaque assays, following the techniques used by Newase et al, with some modifications. The isolated phages were then purified and stained following methods of Ellis et al, with some modifications, and visualised by a ThermoScientific Talos L120C transmission electron microscope (TEM).

Graphical Workflow

This depicts the workflow of the study. Created with BioRender.com

Results

A total of three (3) bacteriophages were isolated from the hospital sewage, and their lytic activity against A. baumannii strains were confirmed by the spot assay which showed clear zones on bacterial lawns. The phages, named vB_AbaS_SRNAIIMS002, vB_AbaS_SRNAIIMS008 and vB_AbaP_SRNAIIMS010, showed central clear zones surrounded by halos, in the plaque assay. Finally, all 3 bacteriophages were visualised by TEM, and two of them had morphology suggestive of siphoviridae family, with long tails, while the third had a short stubby tail, characteristic of the podoviridae family.

Conclusion

The study concludes that 3 novel bacteriophages were isolated from sewage water, all of which were active against MDR A. baumannii strains. This provides impetus to further research towards phage therapy as a novel therapeutic option against MDROs.

Disclosures

All Authors: No reported disclosures.
1702. Platelet Counts in Contezolid Complicated Skin and Soft Tissue Infection Phase 2 and Phase 3 Clinical Trials
Authors: Fang Edward , Yang Huahui , Yuan Hong
Published: December 2022

Background

Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococccus (VRE). Nonclinical and Phase 1 (Ph1) clinical data indicate CZD may cause less myelosuppression, particularly with longer duration therapy, and with reduced risk of monoamine oxidase inhibition compared with linezolid (LZD). In Phase 2 (Ph2) and Phase 3 (Ph3) complicated skin and soft tissue infections (cSSTI) clinical trials, CZD was compared with LZD with dosing for 7-14 days, and noninferiority was demonstrated in the Ph3 study. Overall safety was comparable to LZD, and the most common treatment emergent adverse events (TEAEs) in both the CZD and LZD groups were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD. In June 2021, CZD was approved in China for cSSTI. Sequential therapy with intravenous contezolid acefosamil (CZA; double prodrug of CZD) followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and acute bacterial skin and skin structure infection (ABSSSI) clinical trials. Because DFI requires longer treatment (14-28 days), changes in platelet counts with therapy ≥11 days were evaluated in completed Ph2 and Ph3 CZD cSSTI studies.

Methods

In Ph2 and Ph3 cSSTI studies, mean percent changes in platelet counts from baseline (BSL) to the end of therapy (EOT) visit were compared for all subjects in the safety analysis sets (SS) who received CZD 800 mg and LZD, and also the subjects who received ≥11 days of therapy.

Results

In the Ph2 and Ph3 cSSTI studies, the mean platelet count values for LZD subjects decreased compared with CZD subjects, and the difference was greater in subjects who received ≥11 days of therapy.

Conclusion

In Ph2 and Ph3 cSSTI clinical trials with treatment durations of 7-14 days, mean platelet counts did not decrease for CZD subjects while mean values for LZD subjects did decline, consistent with nonclinical and Ph1 clinical data. Differences were more significant in subjects who received ≥11 days of therapy. In the current Ph3 global DFI study which compares 14-28 days of CZA/CZD to LZD, evaluation of hematological safety is an important outcome measure.

Disclosures

Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.
1705. Filamentous Hemagglutinin Polyclonal Antibodies Protect against Multidrug resistant Gram-negative bacteria
Authors: Youssef Eman , Alkhazraji Sondus , Singh Shakti , Gebremariam Teclegiorgis , Ibrahim Ashraf
Published: December 2022

Background

Multidrug-resistant (MDR) Gram-negative bacteria (GNB) are among the major healthcare-associated infections and have high mortality especially in immunocompromised patients. Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) are classified as “critical organism” by CDC. Therefore, new anti-infective therapies are critically needed. Our studies showed that passive immunization using antibodies against Candida Hyr1 peptide#5 are protective in AB pneumonia mouse model and this was attributed to the structure homology between Candida Hyr1 and AB Filamentous hemagglutinin protein B (FhaB). In this study, we identified FhaB epitopes that shared sequence homology with Candida Hyr1 peptide#5. We aim to evaluate antibody-based therapy targeting these epitopes against AB and PA infection.

Designing and evaluating FhaB peptides that share sequence similarity to Hyr1#5

In vivo protection of FhaB antibodies in mouse model on different MDR GNB A) AB B)PA

Methods

Sequence homology was done using BLAST online tool. FhaB peptides and their polyclonal antibodies (pAbs) were commercially produced. Indirect ELISA was done to test recognition FhaB peptides to Hyr1#5 Abs. Binding ability of FhaB pAbs was tested against AB and PA using flow cytometry. The efficacy of pAbs in protecting against AB- or PA-induced pneumonia was studied in immunosuppressed CD1 mice by administering 30 µg of pAbs (i.p.) on Day +1 relative to infection. Survival of mice served as an endpoint.

Results

We identified seven FhaB peptides that shared ∼50% sequence homology with Hyr1#5. These peptides are conserved among many GNB including AB and PA. Two peptides (FhaB#4 & FhaB#5) showed strong binding to Hyr1 Abs in ELISA. The pAbs generated against these two peptides showed ∼90% and 50% binding to AB and PA, respectively. Finally, pAbs targeting FhaB#4 protected mice from lethal dose of both AB and PA with 70% and 40% survival efficacies, respectively (p< 0.05).

Conclusion

We used FhaB to generate protective pAb against MDR AB and PA. Our results warrant the further development of these Ab as novel immunotherapeutics against MDR GNB.

Disclosures

All Authors: No reported disclosures.
1709. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against MDR Enterobacterales and Pseudomonas aeruginosa Collected in Latin America, ATLAS Global Surveillance Program 2018-2020
Authors: Wise Mark , Stone Gregory , Sahm Daniel F
Published: December 2022

Background

Multidrug-resistant (MDR) Gram-negative bacteria are an increasing worldwide problem. Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C, and some class D β-lactamases, enzymes that contribute to MDR. This study examined the in vitro activity of CAZ-AVI and comparators against MDR Enterobacterales and Pseudomonas aeruginosa isolates collected from patients in Latin America.

Methods

9193 non-duplicate Enterobacterales (Ent) and 3225 P. aeruginosa (Psa) isolates from were collected from 36 sites in 10 Latin American countries as part of ATLAS 2018-2020. Antimicrobial susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2022 breakpoints. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin (AMK), aztreonam (ATM), cefepime (FEP), colistin (CST), levofloxacin (LVX), meropenem (MEM), and piperacillin-tazobactam (TZP). Ent isolates testing with meropenem MICs >1 µg/mL and Escherichia coli, Klebsiella pneumoniae, K. oxytoca, K. variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs >1 mg/L were genetically screened for β-lactamases. Psa with meropenem MIC >2 µg/mL were screened in 2018-2019. In 2020, approximately 25% of qualifying Psa were screened.

Results

The activity of CAZ-AVI and comparators against all isolates and the MDR subsets is shown in the table. CAZ-AVI was active against the full collection of Enterobacterales isolates with 96.7% of the population susceptible and an MIC90 value of 1 µg/mL, and maintained considerable activity against the MDR subset, inhibiting 86.5% of the isolates, a value higher than comparator agents. For the full collection of Psa, 86.6% of the isolates were susceptible to CAZ-AVI, again the highest %S among the comparator drugs. Versus the MDR subset of Psa, CAZ-AVI displayed a 45.8% susceptibility rate, approximately 10% higher than the nearest comparator, amikacin.

Conclusion

The in vitro data suggest that CAZ-AVI can be an effective therapeutic for infections caused by MDR Enterobacterales in Latin America. MDR among P. aeruginosa remains challenging, although a significant percentage are inhibited by CAZ-AVI.

Disclosures

All Authors: No reported disclosures.
1710. In Vitro Activity of Cefepime-Taniborbactam and Comparators Against a Global Collection of Carbapenem-Resistant Enterobacterales and Carbapenem-Resistant Pseudomonas aeruginosa With and Without Carbapenemases
Authors: Wise Mark , Hackel Meredith , Sahm Daniel F
Published: December 2022

Background

Carbapenem-resistant Enterobacterales (CRE) and P. aeruginosa (CRPA) present treatment difficulties owing to numerous possible resistance mechanisms, including the carriage of carbapenemases. Taniborbactam is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with activity against serine-, and NDM & VIM metallo-β-lactamases (Ambler Classes A, B, C and D). The activity of the investigational combination cefepime-taniborbactam (FTB) and comparator agents was evaluated against a recent global collection of carbapenemase and non-carbapenemase producing CRE and CRPA.

Methods

13,731 Enterobacterales and 4,619 P. aeruginosa isolates collected from 56 countries in 2018-2020 were a part of this study. MICs of cefepime with taniborbactam fixed at 4 µg/mL and comparators were determined according to CLSI guidelines and interpreted using 2022 CLSI breakpoints. CRE and CRPA were defined by resistance to meropenem. Organisms with FTB MIC ≥16 µg/mL were characterized by whole genome sequencing, while those resistant to meropenem were screened for acquired β-lactamase carriage by multiplex PCR followed by Sanger sequencing.

Results

Among the 637 CRE identified, 596 were found to carry a carbapenemase while the remaining 41 did not. For the carbapenemase-positive CRE, 89.8% and 94.5% of isolates were inhibited at ≤8 µg/mL and ≤16 µg/mL FTB, respectively, both values significantly greater than comparators (Table). For carbapenemase-negative CRE, 92.7% of isolates were inhibited at ≤8 µg/mL FTB, and 95.1% were inhibited at ≤16 µg/mL, again higher %s than comparators. Against carbapenemase-negative CRPA (n=703), FTB was the most active agent among the comparators, with 82.6% inhibited at ≤8 µg/mL and 94.9% inhibited at ≤16 µg/mL. Versus CRPA carrying carbapenemases (n=245), 61.9% were inhibited at ≤8 µg/mL FTB and 72.5% were inhibited at ≤16 µg/mL FTB.

Conclusion

FTB displayed substantial in vitro activity against CRE and CRPA regardless of whether they harbored carbapenemases. More isolates of each group were inhibited by FTB at ≤8 µg/mL than were susceptible to all tested β-lactam/β-lactamase inhibitor combinations. These data support the continued development of FTB as a potential new therapeutic antibacterial agent.

Disclosures

All Authors: No reported disclosures.
1717. In Vitro Activity of Aztreonam-Avibactam Against Enterobacterales Isolated from Pediatric and Adult Patients Collected During the ATLAS Global Surveillance Program, 2017-2020
Authors: Estabrook Mark , Arhin Francis , Sahm Daniel F
Published: December 2022

Background

The rapid spread of antimicrobial resistance among clinically isolated Enterobacterales (Eba) continues to threaten public health. Aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBLs) and avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases. ATM-AVI is being developed for use against drug-resistant isolates of Eba, especially those co-producing MBLs and other β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Eba collected in 2017-2020 from pediatric and adult patients as part of the ATLAS global surveillance program.

Methods

Non-duplicate clinical Eba isolates were collected from 239 sites in 55 countries in Europe, Latin America, Asia/Pacific (excluding mainland China and India), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2022 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC >1 µg/mL, and Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC >1 µg/mL.

Results

MIC90 values for ATM-AVI of 0.12 µg/ml were observed for Eba isolates collected from both pediatric and adult patients. Against all Eba isolates, ≤8 µg/ml of ATM-AVI was sufficient to inhibit 99.97% (pediatric) and 99.95% (adult), whereas ATM alone inhibited only 72.0% and 75.9% of these isolates at ≤8 µg/ml, respectively (table). Among isolates that screened positive for an MBL, MIC90 values were 0.25 µg/ml (pediatric) and 0.5 µg/ml (adult). Among MBL-positive isolates, ATM-AVI inhibited 100% (pediatric) and 99.9% (adult) at concentrations ≤8 µg/ml. In contrast, ATM alone only inhibited 19.0% (pediatric) and 25.3% (adult) of isolates carrying MBLs at ≤8 µg/ml.

Conclusion

Based on MIC90 values, ATM-AVI demonstrated potent in vitro activity against Eba isolated both from pediatric and adult patients. The capability of AVI to potentiate ATM against MBL-positive isolates warrants its continued development.

Disclosures

All Authors: No reported disclosures.
1718. In Vitro Activity of Imipenem/Relebactam against Class C β-lactamase-Positive Enterobacterales in the Asia/Pacific Region: SMART 2018-2020
Authors: Lob Sibylle , Estabrook Mark , Chen Wei-Ting , Siddiqui Fakhar , Young Katherine , Motyl Mary , Sahm Daniel F
Published: December 2022

Background

Imipenem/relebactam (IMR) is a combination of imipenem/cilastatin with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. We evaluated the activity of IMR and comparators against AmpC- and extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae as well as against isolates of intrinsic AmpC-producing Enterobacterales species that were collected in 9 countries in Asia/Pacific as part of the global SMART surveillance program.

Methods

In 2018-2020, 48 clinical laboratories in Australia, Hong Kong, Malaysia, New Zealand, Philippines, South Korea, Taiwan, Thailand, and Vietnam each collected up to 250 consecutive, aerobic or facultative, gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2022 CLSI breakpoints. Isolates that were ertapenem- (2018 only), imipenem-, IMR-, or ceftolozane/tazobactam-nonsusceptible were screened by PCR and Sanger sequencing for β-lactamases.

Results

As shown in the table, IMR maintained activity against ≥96% K. pneumoniae and E. coli that carried ampC with or without ESBL as well as against those intrinsic ampC carriers (except S. marcescens, 92.7%) among which no additional β-lactamases other than ESBLs were identified. The addition of relebactam increased the susceptibility to imipenem alone by 8-55 percentage points for K. pneumoniae and E. coli carrying AmpC with or without ESBL. Among intrinsic ampC carriers, the largest increase was seen among K. aerogenes (28 percentage points). Relebactam restored susceptibility to 97.3% of imipenem-nonsusceptible (NS) ampC-positive K. pneumoniae (n=73) and to 95.7%, 98.6%, and 37.7% of imipenem-NS isolates of E. cloacae complex (n=92), K. aerogenes (n=147), and S. marcescens (n=61) that carried no acquired β-lactamases. Among the imipenem-NS S. marcescens isolates, 50.8% tested with an IMR MIC of 2 µg/mL, which would be susceptible according to EUCAST guidelines.

Conclusion

IMR showed strong activity against clinical Enterobacterales isolates that carried either acquired or intrinsic ampC with or without ESBL collected in Asia/Pacific.

Disclosures

Fakhar Siddiqui, MD, MBA, Merck & Co., Inc.: employee|Merck & Co., Inc.: Stocks/Bonds Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds.
1722. In vivo Activity of Imipenem/XNW4107 Human-Simulated Regimen against Serine Carbapenemase-Producing Acinetobacter baumannii and Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model
Authors: Fratoni Andrew J , Berry Angela , Yuan Haitao , Liu Xiao , Chen Xi , Wu Yuchuan , Nicolau David P , Abdelraouf Kamilia
Published: December 2022

Background

Imipenem (IPM)/XNW4107 is a novel β-lactam/β-lactamase inhibitor with in vitro activity against serine carbapenemase-producing Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales. Herein, we evaluated the in vivo activity of an IPM/XNW4107 human-simulated regimen (HSR) against clinical OXA-23- and OXA-24-producing A. baumannii as well as KPC- and GES-producing P. aeruginosa using a neutropenic murine thigh infection model.

Methods

Seven A. baumannii and 4 P. aeruginosa isolates were included. IPM and IPM/XNW4107 MICs (XNW4107 fixed at 8 mg/L) were tested in triplicate by broth microdilution. One thigh of neutropenic ICR mice (6 mice per group) was inoculated with ∼107 CFU/mL bacterial suspensions. HSR that mimicked the clinical exposures of IPM 500 mg q6h alone or in combination with XNW4107 250 mg q6h each as 1 h infusion were developed in the murine model. In efficacy studies, two hours after inoculation, placebo, IPM 500 mg q6h 1 h infusion HSR, or IPM/XNW4107 500/250 mg q6h 1 h infusion HSR were administered subcutaneously. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls.

Results

Isolates were IPM resistant (MICs 16 - > 64 mg/L). IPM/XNW4107 A. baumannii and P. aeruginosa MIC ranges were 1-16 and 1- 8 mg/L, respectively. Across all examined isolates, 0 h mean ± SD bacterial burden was 5.86 ± 0.32 log10 CFU/thigh. The 24 h increase in bacterial burden was 2.68 ± 0.91 log10 CFU/thigh in the sham controls. IPM HSR monotherapy groups showed mean increase in bacterial burden of 2.34 ± 0.95 log10 CFU/thigh. Bacterial kill with IPM/XNW4107 500/250 mg q6h 1 h infusion HSR ranged from -0.46 ± 1.69 to -3.77 ± 0.15 and -2.33 ± 0.25 to -3.76 ± 0.57 among A. baumannii and P. aeruginosa isolates, respectively. IPM/XNW4107 500/250 mg q6h 1 h infusion HSR produced > 1-log kill against 6/7 examined A. baumannii with the exception of A. baumannii 160 (IPM/XNW4107 MIC 16 mg/L) and 4/4 P. aeruginosa as well as > 2-log kill against 4/7 A. baumannii and 4/4 P. aeruginosa.

Conclusion

IPM/XNW4107 500/250 mg q6h 1 h infusion HSR showed potent in vivo activity against serine carbapenemase-producing A. baumannii and P. aeruginosa. These data support the consideration of IPM/XNW4107 for the treatment of serious infections due to these organisms in clinical trials.

Disclosures

Haitao Yuan, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xiao Liu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xi Chen, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Yuchuan Wu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds David P. Nicolau, PharmD, Shionogi: Grant/Research Support Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support.
1726. Patterns of Isavuconazole Use for Invasive Fungal Infections
Authors: Gow-Lee Vanessa , Chesdachai Supavit , Gile Jennifer , Akhiyat Nadia , Harris Courtney E , Abu Saleh Omar M
Published: December 2022

Background

Isavuconazole (ISA) is a relatively recent triazole antifungal with several attractive qualities and so increased clinical experience and data on the use of ISA are desirable. However, the data on the pattern of ISA use in invasive fungal infections (IFI) is limited.

Methods

We conducted a retrospective study of patients with probable or proven IFI treated with ISA at Mayo Clinic from 1/1/2015 to 4/1/2020 to examine temporal trends and characteristics of ISA use.

Results

The use of ISA rose over this period, from 4 cases in 2015 to 42 cases in 2019. Of 131 patients identified, ISA was used as the initial antifungal in 15 (11.5%) patients and as the secondary agent in 116 (88.5%) patients. The most cited reasons for choosing ISA as first-line therapy were drug-drug interactions (5, 33%) and baseline QTc prolongation (3, 20%). In cases of ISA used as a secondary agent, the reasons for transitioning to ISA were QTc prolongation (22, 19%), followed by judged failure of the primary therapy (20, 17%), drug-drug interactions (12, 10%), and various toxicities with the first agent. ISA was discontinued early in 81 (62%) patients. Common reasons for early discontinuation were patient death or comfort care (27, 33%), intolerance (18, 22%), failure of therapy (17, 21%), cost or access (6, 7%), drug-drug interaction (3, 4%), issues with absorption or drug delivery (3, 4%), and microbe susceptibility (1, 1%). ISA was judged successful and used as definitive treatment in the remaining 50 (38%) patients. About 30 patients took >1 year of ISA, and no major adverse effects from long-term therapy were noted.

Conclusion

Although ISA is approved for pulmonary aspergillosis and mucormycosis, we found that few patients were treated with ISA as either primary or salvage therapy. In cases where it was used, shortening the QTc and fewer drug-drug interactions were its most attractive qualities. Although it is a newer azole, the morbidity common with other antifungals should prompt more studies on ISA’s efficacy to increase clinicians’ confidence in this option.

Disclosures

All Authors: No reported disclosures.
1728. Real world experience with cefiderocol for multi drug resistant gram negative bacterial infection in a tertiary hospital
Authors: Rondain Patricia Isabella , Ramdeen Sheena , Norman Sarah J
Published: December 2022

Background

Increasing rates of antibiotic resistance has emerged as one of the top concerns in health care. New resistance mechanisms such as carbapenemase production present a challenge in treating common infections. Novel antibiotics are being developed to tackle these pathogens, and one of the newest drugs in this arsenal is cefiderocol, a siderophore cephalosporin. Real-world data regarding the clinical use and outcomes of cefiderocol is limited.

Methods

A single-center, retrospective chart review was completed from July 2020 to March 2022 and included adult patients who received at least one dose of cefiderocol. Patient baseline characteristics were obtained along with other variables related to the primary infection. The primary outcome was clinical failure defined as 30 day mortality following cefiderocol administration. Secondary outcomes were development of resistance to cefiderocol, clearance of bacteremia, adverse drug reactions, and hospital length of stay.

Results

Cefiderocol was dispensed in 22 unique patient encounters. It was most often used to treat respiratory tract (45.4%, 10/22) and cardiac device infections (40.9%, 9/22). Most infections were polymicrobial, however, the most common organisms isolated were Pseudomonas aeruginosa and Klebsiella pneumoniae. The clinical failure rate was 22.7% (5/22). One patient developed resistance to cefiderocol throughout the hospitalization. Eight patients were treated for bacteremia, and 87.5% (7/8) demonstrated microbiological cure. Minimal side effects were observed in this cohort; two patients developed diarrhea, and one of whom had confirmed C. difficile colitis. The median length of stay was 24 days.

Conclusion

This cohort of patients demonstrated that cefiderocol can be used in a variety of multidrug resistant infections including bacteremia. Although limited by a small sample size, this study demonstrated a low prevalence of resistance. These results are promising in the ongoing and emerging issue of antibiotic resistance, and larger studies are needed to determine true efficacy and place in therapy for cefiderocol.

Disclosures

All Authors: No reported disclosures.
1729. Real-world Experience with Ceftazidime-avibactam Compared with Ceftolozane-tazobactam on Clinical Outcomes in Pseudomonas aeruginosa Infections
Authors: Golia Austin , Guo Yi , Chang Mei H , McSweeney Terrence D , Lee Philip J , Bao Hongkai
Published: December 2022

Background

The 2022 IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-negative Infections recommends the use of a novel beta-lactam/beta-lactamase inhibitor, such as ceftolozane-tazobactam (C/T) or ceftazidime-avibactam (C/A), as first-line for treatment of resistant Pseudomonas aeruginosa infections. C/T is often preferred for these infections due to a narrower spectrum and lower cost. However, from December 2020 to January 2022, a global shortage of C/T resulted in widespread adoption of C/A as an alternative. While in vitro susceptibilities support the use of C/A for P. aeruginosa, real-world experience comparing clinical outcomes to C/T is limited.

Methods

This multicenter, retrospective analysis was conducted at an urban, academic healthcare system in the Bronx, NY. Between January 2018 and December 2020, admitted adult patients who received C/A or C/T to treat P. aeruginosa infections were included. Patients were excluded if in vitro resistance to either drug was demonstrated or if susceptibility was missing. The primary outcome was clinical success, defined as resolution of signs and symptoms of infection, by end of treatment. Secondary outcomes included 30-day mortality, resistance to study drug after therapy, modification of therapy, 14-day microbiological failure, 90-day infection recurrence, and length of stay.

Results

A total of 46 patients received C/A and 56 patients received C/T to treat P. aeruginosa infections. Most baseline characteristics were similar between the two arms, though more patients were critically ill in the C/A arm (Table 1). Clinical success was similar between C/A and C/T patients (72% vs. 63%, p=0.33). No significant differences between arms were identified for secondary outcomes (Table 2). Development of drug resistance within 90 days of treatment occurred more frequently in the C/A arm, approaching significance. On multivariate regression analysis, vasopressor use at the time of study drug initiation was the only variable associated with reduced clinical success.

Conclusion

C/A may be an effective alternative treatment for multidrug-resistant P. aeruginosa infections with close monitoring for development of resistance. Larger comparative studies are needed to confirm these findings.

Disclosures

Yi Guo, PharmD, BCIDP, Merck: Grant/Research Support.
1739. An Exploratory Analysis to Examine Urgent Care Antibiotic Prescribing Inequities in a Vertically Integrated Healthcare System
Authors: Seibert Allan M , Stanfield Valoree K , Fino Nora , Gwiazdon Matthew , Hersh Adam , Stenehjem Edward A
Published: December 2022

Background

Previous studies have shown antibiotic prescribing differences based on patient demographics which may represent inequitable care. Our objective was to perform an exploratory analysis of antibiotic prescribing rates for respiratory conditions to better understand possible inequities and identify disparities in our health system.

Methods

This was a retrospective cohort study of urgent care encounters for respiratory conditions in the Intermountain Healthcare (IH) network from July 1st 2018 – June 30th 2019. Individual respiratory encounters were identified using a validated methodology based on ICD10 codes. Overall antibiotic prescribing rates and rates for Tier 1 (antibiotics indicated), 2 (sometimes indicated), and 3 (not indicated, eg bronchitis) conditions were assessed. Prescribing rates for categories in which inequities might exist, including age, weight, patient race/ethnicity, preferred language, provider type, and provider/patient gender combinations, were examined. We considered an absolute percentage difference between groups within a category of ≥5.0% to represent a potential disparity.

Results

93,588 (48.5%) of 193,107 respiratory urgent care encounters were associated with an antibiotic prescription. Overall antibiotic prescribing rates (Results Image 1) were higher in white compared to non-white patients (49.0% vs 38.2%) and in those reporting non-Hispanic ethnicity compared to Hispanics (49.1% vs 43.2%). Patients over 18 years-old were prescribed antibiotics more frequently than younger patients. Among Tier 3 encounters male providers prescribed antibiotics more frequently for male patients than female providers did for female patients (20.8% vs 15.6). Overweight and obese patients with Tier 3 diagnoses received antibiotic prescriptions more frequently than non-obese patients (22.8% vs 15.3%). Minimal differences between patients who preferred English and those who preferred non-English languages were observed. Results Image 1 - Table 1

Overall antibiotic prescribing rates and antibiotic prescribing rates for Tier 3 conditions for urgent care respiratory condition encounters July 1st, 2018 – June 30th, 2019*¥. *Tier 3 codes are those where antibiotics are not indicated (eg bronchitis). ¥Absolute differences of ≥5.0% between groups within each category are indicated in bold.

Conclusion

Antibiotic prescribing rates for respiratory conditions in urgent care encounters in our system differed based on race, ethnicity, age, obesity, and gender. These differences may represent biases contributing to inequities in care and may serve as potential targets for improved stewardship efforts.

Disclosures

All Authors: No reported disclosures.