Incidence and predictors of complications in Gram-negative bloodstream infection.

BACKGROUND: The incidence of metastatic complications in Gram-negative bloodstream infection (GN-BSI) remains undefined. This retrospective cohort study examines the incidence and predictors of complications within 90 days of GN-BSI. METHODS: Patients with GN-BSIs hospitalized at two Prisma Health-Midlands hospitals in Columbia, South Carolina, USA from 1 January 2012 through 30 June 2015 were included. Complications of GN-BSI included endocarditis, septic arthritis, osteomyelitis, spinal infections, deep-seated abscesses, and recurrent GN-BSI. Kaplan-Meier analysis and multivariate Cox proportional hazards regression were used to examine incidence and risk factors of complications, respectively. RESULTS: Among 752 patients with GN-BSI, median age was 66 years and 380 (50.5%) were women. The urinary tract was the most common source of GN-BSI (378; 50.3%) and Escherichia coli was the most common bacteria (375; 49.9%). Overall, 13.9% of patients developed complications within 90 days of GN-BSI. The median time to identification of these complications was 5.2 days from initial GN-BSI. Independent risk factors for complications were presence of indwelling prosthetic material (hazards ratio [HR] 1.73, 95% confidence intervals [CI] 1.08-2.78), injection drug use (HR 6.84, 95% CI 1.63-28.74), non-urinary source (HR 1.98, 95% CI 1.18-3.23), BSI due to S. marcescens, P. mirabilis or P. aeruginosa (HR 1.78, 95% CI 1.05-3.03), early clinical failure criteria (HR 1.19 per point, 95% CI 1.03-1.36), and persistent GN-BSI (HR 2.97, 95% CI 1.26-6.99). CONCLUSIONS: Complications of GN-BSI are relatively common and may be predicted based on initial clinical response to antimicrobial therapy, follow-up blood culture results, and other host and microbiological factors.

The prevalence of gram-negative bacteria with difficult-to-treat resistance and utilization of novel ß-lactam antibiotics in the southeastern United States.

Objective: To evaluate temporal trends in the prevalence of gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) in the southeastern United States. Secondary objective was to examine the use of novel ß-lactams for GNB with DTR by both antimicrobial use (AU) and a novel metric of adjusted AU by microbiological burden (am-AU). Design: Retrospective, multicenter, cohort. Setting: Ten hospitals in the southeastern United States. Methods: GNB with DTR including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. from 2015 to 2020 were tracked at each institution. Cumulative AU of novel ß-lactams including ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, and cefiderocol in days of therapy (DOT) per 1,000 patient-days was calculated. Linear regression was utilized to examine temporal trends in the prevalence of GNB with DTR and cumulative AU of novel ß-lactams. Results: The overall prevalence of GNB with DTR was 0.85% (1,223/143,638) with numerical increase from 0.77% to 1.00% between 2015 and 2020 (P = .06). There was a statistically significant increase in DTR Enterobacterales (0.11% to 0.28%, P = .023) and DTR Acinetobacter spp. (4.2% to 18.8%, P = .002). Cumulative AU of novel ß-lactams was 1.91 ± 1.95 DOT per 1,000 patient-days. When comparing cumulative mean AU and am-AU, there was an increase from 1.91 to 2.36 DOT/1,000 patient-days, with more than half of the hospitals shifting in ranking after adjustment for microbiological burden. Conclusions: The overall prevalence of GNB with DTR and the use of novel ß-lactams remain low. However, the uptrend in the use of novel ß-lactams after adjusting for microbiological burden suggests a higher utilization relative to the prevalence of GNB with DTR.

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications in 2022.

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor identified antimicrobial stewardship-related, peer-reviewed literature that detailed an actionable intervention during 2022. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight actionable interventions used by antimicrobial stewardship programs to capture potentially effective strategies for local implementation.

Evaluation of the diagnostic utility of metagenomic next-generation sequencing testing for pathogen identification in infected hosts: a retrospective cohort study.

Background: Metagenomic next-generation sequencing (mNGS) testing identifies thousands of potential pathogens in a single blood test, though data on its real-world diagnostic utility are lacking. Objectives: Determine the diagnostic utility of mNGS testing in practice and factors associated with high clinical utility. Design: Retrospective cohort study of mNGS tests ordered from June 2018 through May 2020 at a community teaching hospital. Methods: Tests were included if ordered for diagnostic purposes in patients with probable or high clinical suspicion of infection. Exclusions included patient expiration, hospice care, or transfer outside of the institution. Utility criteria were established a priori by the research team. Two investigators independently reviewed each test and categorized it to either high or low diagnostic utility. Reviewer discordance was referred to a third investigator. The stepwise multiple regression method was used to identify clinical factors associated with high diagnostic utility. Results: Among 96 individual tests from 82 unique patients, 80 tests met the inclusion criteria for analysis. At least one potential pathogen was identified in 58% of tests. Among 112 pathogens identified, there were 74 bacteria, 25 viruses, 12 fungi, and 1 protozoon. In all, 46 tests (57.5%) were determined to be of high diagnostic utility. Positive mNGS tests were identified in 36 (78.3%) and 11 (32.4%) of high and low diagnostic utility tests, respectively (p < 0.001). Antimicrobials were changed after receiving test results in 31 (67.4%) of high utility tests and 4 (11.8%) of low utility tests (p < 0.0001). In the multiple regression model, a positive test [odds ratio (OR) = 10.9; 95% confidence interval (CI), 3.2-44.4] and consultation with the company medical director (OR = 3.6; 95% CI, 1.1-13.7) remained significantly associated with high diagnostic utility. Conclusion: mNGS testing resulted in high clinical utility in most cases. Positive mNGS tests were associated with high diagnostic utility. Consultation with the Karius® medical director is recommended to maximize utility.

Evaluating the real world utility of using a diagnostic test that uses cell-free DNA to identify bacteria, viruses, fungi and protozoa from blood in hospitalized adult and pediatric patients Our institution has utilized a meta-genomic test that identifies bacteria, DNA-based viruses, fungi and protozoa from blood sample in hospitalized patients to support diagnostics in select clinical cases. We evaluated the utility of these tests in an adult and pediatric population. We found that 58% of the 96 tests from 82 unique patients produced a pathogen. Overall, a majority (58%) of tests were deemed to be of high utility which directly resulted in changes in antimicrobial therapy, selection of duration of therapy, direction for new diagnostics, or avoidance of further need for diagnostics. Positive tests and consultation with the medical director of the laboratory were both associated with high utility of the tests.

Epidemiology and treatment of invasive Bartonella spp. infections in the United States.

OBJECTIVES: Bartonella spp., renowned for cat-scratch disease, has limited reports of dissemination. Tissue and blood cultures have limitations in detecting this fastidious pathogen. Molecular testing (polymerase chain reaction, PCR) and cell-free DNA have provided an avenue for diagnoses. This retrospective observational multicenter study describes the incidence of disseminated Bartonella spp. and treatment-related outcomes. METHODS: Inclusion criteria were diagnosis of bartonellosis via diagnosis code, serology testing of blood, polymerase chain reaction (PCR) of blood, 16/18S tests of blood or tissue, cultures of blood or tissue, or cell-free DNA of blood or tissue from January 1, 2014, through September 1, 2021. Exclusions were patients who did not receive treatment, insufficient data on treatment course, absence of dissemination, or retinitis as dissemination. RESULTS: Patients were primarily male (n = 25, 61.0%), white (n = 28, 68.3%), with mean age of 50 years (SD 14.4), and mean Charlson comorbidity index of 3.5 (SD 2.1). Diagnosis was primarily by serology (n = 34, 82.9%), with Bartonella henselae (n = 40, 97.6%) as the causative pathogen. Treatment was principally doxycycline with rifampin (n = 17, 41.5%). Treatment failure occurred in 16 (39.0%) patients, due to escalation of therapy during treatment (n = 5, 31.3%) or discontinuation of therapy due to an adverse event or tolerability (n = 5, 31.3%). CONCLUSIONS: In conclusion, this is the largest United States-based cohort of disseminated Bartonella spp. infections to date with a reported 39% treatment failure. This adds to literature supporting obtaining multiple diagnostic tests when Bartonella is suspected and describes treatment options.

Optimization of Empirical Antimicrobial Therapy in Enterobacterales Bloodstream Infection Using the Extended-Spectrum Beta-Lactamase Prediction Score.

Clinical tools for the prediction of antimicrobial resistance have been derived and validated without examination of their implementation in clinical practice. This study examined the impact of utilization of the extended-spectrum beta-lactamase (ESBL) prediction score on the time to initiation of appropriate antimicrobial therapy for bloodstream infection (BSI). The quasi-experimental cohort study included hospitalized adults with BSI due to ceftriaxone-resistant (CRO-R) Enterobacterales at three community hospitals in Columbia, South Carolina, USA before (January 2010 to December 2013) and after (January 2014 to December 2019) implementation of an antimicrobial stewardship intervention. In total, 45 and 101 patients with BSI due to CRO-R Enterobacterales were included before and after the intervention, respectively. Overall, the median age was 66 years, 85 (58%) were men, and 86 (59%) had a urinary source of infection. The mean time to appropriate antimicrobial therapy was 78 h before and 46 h after implementation of the antimicrobial stewardship intervention (p = 0.04). Application of the ESBL prediction score as part of an antimicrobial stewardship intervention was associated with a significant reduction in time to appropriate antimicrobial therapy in patients with BSI due to CRO-R Enterobacterales. Utilization of advanced rapid diagnostics may be necessary for a further reduction in time to appropriate antimicrobial therapy in this population.

Cefazolin in the treatment of central nervous system infections: A narrative review and recommendation.

Infections of the central nervous system (CNS) are complex to treat and associated with significant morbidity and mortality. Historically, antistaphylococcal penicillins such as nafcillin were recommended for the treatment of methicillin-susceptible staphylococcal CNS infections. However, the use of antistaphylococcal penicillins presents challenges, such as frequent dosing administration and adverse events with protracted use. This narrative reviews available clinical and pharmacokinetic/pharmacodynamic (PK/PD) data for cefazolin in CNS infections and produces a recommendation for use. Based on the limited available evidence analyzed, dose optimized cefazolin is likely a safe and effective alternative to antistaphylococcal penicillins for a variety of CNS infections due to methicillin-susceptible Staphylococcus aureus. Given the site of infection and wide therapeutic index of cefazolin, practitioners may consider dosing cefazolin regimens of 2 g IV every 6 h or a continuous infusion of 8-10 g daily instead of 2 g IV every 8 h to optimize PK/PD properties.

Show me the data: A statewide comparative report of National Healthcare Safety Network (NHSN) Antimicrobial Use Option standardized antimicrobial administration ratios (SAARs).

The Antimicrobial Stewardship Collaborative of South Carolina created quarterly Comparative SAAR Analysis Reports based on standardized antimicrobial administration ratio (SAAR) data from the NHSN Antimicrobial Use (AU) Option. These reports provide SAAR histograms and site-specific feedback to participating facilities in South Carolina. They were created to improve antimicrobial use throughout the state, especially in rural regions.

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications for Hospitalized Patients in 2021.

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related, peer-reviewed literature that detailed an "actionable" intervention among hospitalized populations during 2021. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight "actionable" interventions used by antimicrobial stewardship programs in hospitalized populations to capture potentially effective strategies for local implementation.

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications in Non-Hospital Care Settings in 2021.

The scope of antimicrobial stewardship programs has expanded beyond the acute hospital setting. The need to optimize antimicrobial use in emergency departments, urgent, primary, and specialty care clinics, nursing homes, and long-term care facilities prompted the development of core elements of stewardship programs in these settings. Identifying the most innovative and well-designed stewardship literature in these novel stewardship areas can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network evaluated antimicrobial stewardship-related, peer-reviewed literature published in 2021 that detailed actionable interventions specific to the nonhospital setting. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for expansion of antimicrobial stewardship programs beyond the acute hospital setting.

Candida parapsilosis bloodstream infection in an immunocompromised host with discordant multiplex polymerase chain reaction and conventional blood culture results: a case report.

Prompt treatment of candidemia, especially in immunocompromised hosts, is known to improve outcomes. We present a case of discordance among results of Gram stain, multiplex polymerase chain reaction (PCR)-based rapid diagnostic technology, and conventional cultures that subsequently resulted in delayed therapy and hospitalization. An immunocompromised patient presented to the outpatient oncology clinic with signs and symptoms of systemic infection. Blood cultures were obtained, and Gram stain showed gram-negative rods, while multiplex PCR results (BioFire® FilmArray® BCID 1) returned positive for both Enterobacter cloacae and Candida parapsilosis. Conventional cultures only grew E. cloacae. Because of the discordant results, the primary team elected to give ertapenem monotherapy and defer antifungal therapy. The patient's symptoms progressed, and 11 days later, the patient was admitted with subsequent positive blood cultures for C. parapsilosis. The patient required a 9-day hospitalization due to complications associated with candidemia. This case highlights the value of understanding and interpretation of rapid diagnostics, shared decision-making in antimicrobial management of high-risk patients, and the important responsibility of antimicrobial stewardship teams across the continuum of care.

Impact of Clinical Pharmacy Expansion within a Rural Federally Qualified Health Center through Implementation of Pharmacist-Led Medicare Annual Wellness Visits.

Medicare Annual Wellness Visits (AWVs) are annual appointments with the primary care team to prepare personalized prevention plans and focus on gaps in care. Although beneficial, AWVs are often difficult for providers to schedule and complete due to the increased time commitments compared to other visits. The purpose of this study was to assess the clinical, economic and patient-level value of newly implemented pharmacist-led AWVs within a rural Federally Qualified Health Center (FQHC). This retrospective, cohort study included patients who completed an AWV between 1 October 2021, and 14 February 2022. The primary objective was to compare the per clinician rate of completed AWVs between pharmacists and providers. The secondary objectives were to compare revenue generated, interventions made, and patient satisfaction between pharmacist- and provider-led AWVs. During the study period, nine providers completed 139 AWVs (15.4/provider) and two pharmacists completed 116 AWVs (58/pharmacist). Proportions of interventions ordered among those due in eligible patients were similar between pharmacists and providers (47.6% vs. 44.5%; p = 0.356). Patient satisfaction was overall positive with no difference between groups. Pharmacist-led AWVs increased completion of AWVs by 83% over a 20-week period, including significantly more initial, compared to subsequent, AWVs than providers. Sustainability of pharmacist-led AWVs at this FQHC is supported by study outcomes.

Rethinking residency recruitment, application, and interview processes to benefit applicants and programs long-term.

Pharmacy residency recruitment and interviews have been significantly impacted by the COVID-19 pandemic. Many traditional recruitment events and interviews were transitioned from in-person to virtual, and new approaches to recruitment, such as virtual open houses, were developed. There are limited data on how these changes impacted pharmacy residency applicants and programs, and the future of virtual events is currently unknown. We highlight recommendations for virtual recruitment and interviews and provide suggestions for residency programs and national organizations to improve virtual processes in the future.

Break time: Examining pharmacy residency application deadlines and the potential impact of a proposed timeline shift.

INTRODUCTION: Many pharmacy residency programs set their application deadlines around the first of the calendar year, only weeks following the American Society of Health-System Pharmacists (ASHP) meeting in mid-December. This contributes to a condensed timeframe for applicants and reference writers to complete and submit materials over the winter holidays. This study examined pharmacy residency program application deadlines and respective timing of application and reference letter submissions. METHODS: This retrospective, observational study evaluated all residency programs within the ASHP residency directory. Several scenarios were examined for impact of a universal earliest deadline (UED) designation spanning early January. Subsequent analysis included compilation of application and reference submission dates from a sample of ASHP-accredited residency programs to determine timing of submission in regard to application deadline. RESULTS: A total of 2449 programs representing 4927 positions were identified for the 2018-2019 application cycle. The mean deadline was 5 January (± three days), and 11% of programs had a deadline prior to 1 January. Among the five first-year residency programs that provided application and reference submission data spanning the 2016-2020 application cycles, the average time from submission to application deadline was four days for applicants and 11 days for references. CONCLUSIONS: Most pharmacy residency programs have deadlines in early January. Implementation of a UED would cause a major shift for these programs but is only one component of change for the application process.

From Start to Finish: Examining Factors Associated With Higher Likelihood of Publication Among Abstracts Presented at an International Infectious Diseases Scientific Meeting.

Background: The landscape of infectious diseases research by interprofessional teams continues to change in both scope and engagement. Limited information exists regarding publication metrics and factors associated with publication of abstracts presented at professional infectious diseases meetings. Methods: This was a retrospective, observational study evaluating abstracts presented at IDWeek in 2017 and 2018. The primary endpoint was the proportion of abstracts that were subsequently published in peer-reviewed journals. Factors associated with publication were evaluated, and a description of publication metrics was reported. Results: Of the 887 abstracts analyzed from the IDWeek meetings, 236 (26.6%) were published. Significantly more abstracts were published if they were presented as a platform presentation versus poster presentation (35% vs 21%, P < .001). Inclusion of a PhD author significantly increased the likelihood of publication (P = .0014). Prospective studies, greater number of authors, and greater number of study subjects were more common among published abstracts. Median time to publication was 10.9 months, and the majority were published in infectious diseases journals, with an overall average impact factor of 7.7 across all journals. Conclusions: Abstracts from IDWeek presented as oral platforms and those including a PhD author were more likely to be published. Large, diverse authorship teams were common among published abstracts. The high quality of resulting manuscripts is evident by the destination journals and their respective impact factors. These data may be used to inform and motivate clinicians and trainees engaging in infectious diseases-related research.

Is Three Company or a Crowd? Comparing and Contrasting U.S. and European Clostridioidesdifficile Clinical Practice Guidelines.

In 2021, the American College of Gastroenterology (ACG), the Infectious Diseases Society of America in conjunction with the Society for Healthcare Epidemiology of America (IDSA/SHEA), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published updated clinical practice guidelines (CPGs) for the management of Clostridioides difficile infections. The differences, sometimes subtle, between these guideline recommendations have caused some debate among clinicians. This paper delves into select key recommendations from each respective CPG and analyzes the differences and evidence associated with each. One primary difference between the CPGs is the preference given to fidaxomicin over vancomycin for initial treatment in non-severe and severe disease endorsed by IDSA/SHEA and ESCMID guidelines, while the ACG-sponsored CPGs do not offer a preference. The emphasis on cost effective data was also a noticeable difference between the CPGs and thus interpretation of the available evidence. When using guidelines to help support local practice or institutional treatment pathways, clinicians should carefully balance CPG recommendations with local patient populations and feasibility of implementation, especially when multiple guidelines for the same disease state exist.

Evaluation of Pharmacy Residency Recruitment and Interview Processes during the COVID-19 Pandemic (2020-2021 Application Cycle).

Introduction: Due to the COVID-19 pandemic, most pharmacy residency programs changed to an all-virtual format for recruitment and interviews for the 2020-2021 application cycle. There are no data evaluating the experiences and perceptions of these changes from the perspective of pharmacy residency programs and applicants. Methods: An electronic cross-sectional survey was distributed via email to post-graduate year 1 (PGY1) and post-graduate year 2 (PGY2) pharmacy residency programs and applicants across the Southeastern United States. Results have been reported according to the Checklist for Reporting of Survey Studies (CROSS) guidelines (Enhancing the QUAlity and Transparency Of health Research [EQUATOR] Network). Results: 142 residency applicants and 104 residency programs responded to the survey. Most respondents participated in virtual recruitment and interviews. In 2020-2021, less residency programs participated in local/regional showcases and personal placement services, but social media engagement increased. Of the applicants who responded, over half felt the need to apply to more programs during this application cycle, and a corresponding increase in applications were seen by residency programs. Residency interviews appeared shorter than previous years, and less programs offered an informal time to get to know the applicants. Overall, applicants and residency programs preferred on-site interviews, but both parties reported feeling confident creating rank lists after virtual interviews. Conclusion: These results highlight the impact of COVID-19 on residency recruitment and the interview process. Residency programs should implement feedback for improving the virtual experience, as able. The ongoing pandemic may affect the 2022-2023 application cycle, and pharmacy leadership organizations should consider developing guidance for applicants and residency programs on navigating another year of virtual events.This article is protected by copyright. All rights reserved.

Affective domain predictors of PharmD student pursuit of and successful matching for postgraduate pharmacy residency training.

PURPOSE: A study was conducted to identify significant associations between affective domain (AD) features identified using the Birkman Method assessment and students' likelihood to pursue and to successfully match for postgraduate residency training (PGRT), while controlling for demographic and academic variables known to impact PGRT match rates. METHODS: A retrospective analysis of 3 graduating classes of PharmD students from 2 colleges of pharmacy was performed. Data points such as PGRT match results, PGRT pursuit, student demographics, academic performance information, and AD data from the Birkman assessment were analyzed. Regression analysis was used to identify statistically significant associations between demographic, academic performance, and AD variables with both pursuit of PGRT and successful matching for PGRT. RESULTS: Data from 503 students were evaluated, with 211 (42%) pursuing PGRT. A variety of AD variables were significantly associated with pursuing PGRT and matching for PGRT. Two groups of actionable variables emerged: (1) variables associated with a lesser likelihood of pursuing PGRT but a greater likelihood of successful matching, and (2) variables associated with a greater likelihood of pursuing PGRT and a lesser likelihood of successful matching. CONCLUSION: Early identification of students' AD features along with specific interventions to promote PGRT pursuit in those less likely to pursue but more likely to match, as well as interventions to promote successful matching in students most likely to pursue but less likely to match for PGRT, is a strategy for possibly optimizing PharmD student career path planning and PGRT match success that merits further evaluation.

Increased viral load in a hospitalized patient on treatment with crushed bictegravir/emtricitabine/tenofovir alafenamide: A case report and review of the literature.

PURPOSE: To describe a case of increased viral load in a patient with HIV-1 infection receiving treatment with crushed bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF). SUMMARY: A 43-year-old man, newly diagnosed with HIV, was hospitalized due to failure to thrive, neurological changes, and hypotension. Before treatment, the HIV viral load (VL) was 769,704 copies/mL and the CD4+ T-cell count was 36 cells/µL. On hospital day (HD) 8, B/FTC/TAF by mouth daily was initiated. During the hospitalization, the patient's course was complicated by opportunistic infections, bilateral pneumothorax, seizure activity, and acute respiratory distress, requiring multiple intubations and extended time in the intensive care unit. A repeat VL measurement on HD 28 was 5,887 copies/mL after the patient had received 14 of 20 scheduled B/FTC/TAF doses. Because of a failed swallow study and continued nutritional deficits, a percutaneous endoscopic gastrostomy (PEG) tube was placed on HD 38 and continuous tube feeds via the PEG tube were initiated. Subsequently, the B/FTC/TAF order was modified to be crushed, mixed in 30 mL water, and administered daily via the PEG tube. A repeat VL measurement on HD 65 showed an increase to 8,047 copies/mL, despite receipt of 37 consecutive doses of B/FTC/TAF. B/FTC/TAF was discontinued and dolutegravir 50 mg twice daily, darunavir 800 mg plus ritonavir 100 mg (DRV/r), and tenofovir disoproxil fumarate/FTC 300 mg/200 mg were started due to virological increase, need for a viable option compatible with PEG tube delivery, and potential for integrase inhibitor resistance. At the time of regimen change (HD 67), a resistance panel showed minor mutations, E157Q and V118I. The regimen was streamlined with discontinuation of DRV/r on HD 92. The patient was discharged on HD 161. The PEG tube was removed 2 months after discharge, oral B/FTC/TAF was reinitiated, and the patient was virologically suppressed at 1 year after discharge. CONCLUSION: Controlled studies are needed to verify acceptable pharmacokinetic and pharmacodynamic metrics for crushed B/FTC/TAF given via tube, with and without tube feeds, before use in this manner.