State-of-the-Art Review: Use of Antimicrobials at the End of Life.

Navigating antibiotics at the end of life is a challenge for infectious disease (ID) physicians who remain deeply committed to providing patient-centered care and engaging in shared decision making. ID physicians, who often see patients in both inpatient and outpatient settings and maintain continuity of care for patients with refractory or recurrent infections, are ideally situated to provide guidance that aligns with patients' goals and values. Complex communication skills, including navigating difficult emotions around end-of-life care, can be used to better direct shared decision making and assist with antibiotic stewardship.

The PEST (Pathology, Epidemiology, Severity, Treatment) approach to optimizing antimicrobial therapy.

BACKGROUND: Selecting an empiric antimicrobial regimen can be difficult for early learners and misuse of antibiotics can lead to adverse events and antimicrobial resistance. There have been few interventions that have focused on improving antibiotic decision making, as a form of therapeutic reasoning, for post-graduate trainees. We describe here an approach to aid internal medicine interns in their therapeutic reasoning, particularly when it comes to diagnosing and empirically treating infections. METHODS: The PEST (pathology, epidemiology, severity, treatment) model was created as a four-step approach to therapeutic reasoning and choosing an appropriate antimicrobial regimen for a given infectious disease syndrome. In February 2020, we conducted two independent teaching sessions for interns on the PEST approach. We assessed pre-and post-teaching responses to five clinical vignette-based questions. Results were presented as a percentage of interns who chose an appropriate antibiotic and provided sufficient therapeutic reasoning as defined by using at least three out of the four PEST criteria. Statistical analysis occurred via Fischer's exact test to determine the level of statistical significance between responses. RESULTS: Twenty-seven interns participated in the activity. At baseline, several interns had incorporated aspects of the PEST approach in their pre-teaching responses. Ten interns commented on the usefulness of such a systematic approach. While there was no statistically significant difference in antibiotic selection, the teaching session demonstrated a trend towards significance in improving therapeutic reasoning as defined by the PEST strategy. CONCLUSION: Our results suggested an improvement in using a structured cognitive tool such as the PEST approach to reinforce therapeutic reasoning, but the method did little to improve antibiotic selection. Some interns used select "PEST" concepts prior to the intervention suggesting that the PEST approach may enhance prior knowledge or clinical reasoning skills. Continued incorporation of the PEST approach using a case-based framework may solidify conceptual and practical knowledge of antimicrobial selection. Further studies are needed to assess the impact of such teaching interventions.

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

The Path of More Resistance: a Comparison of National Healthcare Safety Network and Clinical Laboratory Standards Institute Criteria in Developing Cumulative Antimicrobial Susceptibility Test Reports and Institutional Antibiograms.

In the absence of antimicrobial susceptibility data, the institutional antibiogram is a valuable tool to guide clinicians in the empirical treatment of infections. However, there is a misunderstanding about how best to prepare cumulative antimicrobial susceptibility testing reports (CASTRs) to guide empirical therapy (e.g., routine antibiogram) versus monitoring antimicrobial resistance, with the former following guidance from the Clinical and Laboratory Standards Institute (CLSI) and the latter from the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). These criteria vary markedly in their exclusion or inclusion of isolates cultured repeatedly from the same patient. We compared rates of nonsusceptibility (NS) using annual data from a large teaching health care system subset to isolates eligible by either NHSN criteria or CLSI criteria. For a panel of the three most prevalent Gram-negative pathogens in combination with clinically relevant antimicrobial agents (or priority pathogen-agent combinations [PPACs]), we found that the inclusion of duplicate isolates by NHSN criteria yielded higher NS rates than when CLSI criteria (for which duplicate isolates are not included) were applied. Patients with duplicate isolates may not be representative of antimicrobial resistance within a population. For this reason, users of CASTR data should carefully consider that the criteria used to generate these reports can impact resulting NS rates and, therefore, maintain the distinction between CASTRs created for different purposes.

Beyond the 405 and the 5: Geographic Variations and Factors Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Positivity Rates in Los Angeles County.

BACKGROUND: To highlight geographic differences and the socio-structural determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity within Los Angeles County (LAC). METHODS: A geographic information system was used to integrate, map, and analyze SARS-CoV-2 testing data reported by the LAC Department of Public Health and data from the American Community Survey. Structural determinants included race/ethnicity, poverty, insurance status, education, and population and household density. We examined which factors were associated with positivity rates, using a 5% test positivity threshold, with spatial analysis and spatial regression. RESULTS: Between 1 March and 30 June 2020 there were 843 440 SARS-CoV-2 tests and 86 383 diagnoses reported, for an overall positivity rate of 10.2% within the study area. Communities with high proportions of Latino/a residents, those living below the federal poverty line, and with high household densities had higher crude positivity rates. Age- adjusted diagnosis rates were significantly associated with the proportion of Latino/as, individuals living below the poverty line, and population and household density. CONCLUSIONS: There are significant local variations in test positivity within LAC and several socio-structural determinants contribute to ongoing disparities. Public health interventions, beyond shelter in place, are needed to address and target such disparities.

Case Report: Cardiovascular Manifestations due to Flea-Borne Typhus.

Flea-borne typhus is a vector-borne disease caused by Rickettsia typhi that occurs worldwide, except in Antarctica. In the United States, most cases are restricted to California, Hawaii, and Texas. The syndrome is characterized by nonspecific signs and symptoms: fever, headache, rash, arthralgia, cough, hepatosplenomegaly, diarrhea, and abdominal pain. Although flea-borne typhus can cause pulmonary, neurological, and renal complications, the cardiovascular system is rarely affected. We present a case of endocarditis resulting from flea-borne typhus diagnosed by blood microbial cell-free DNA testing that required valve replacement and antibiotic therapy for 6 months. In addition, we review 20 cases of presumed and confirmed cardiovascular manifestations resulting from flea-borne typhus in the literature.

Informing estimates of probability of Clostridioides difficile infection for testing and treatment: expert consensus from a modified-Delphi procedure.

Background: Clostridioides difficile infection (CDI) may be misdiagnosed if testing is performed in the absence of signs or symptoms of disease. This study sought to support appropriate testing by estimating the impact of signs, symptoms, and healthcare exposures on pre-test likelihood of CDI. Methods: A panel of fifteen experts in infectious diseases participated in a modified UCLA/RAND Delphi study to estimate likelihood of CDI. Consensus, defined as agreement by >70% of panelists, was assessed via a REDCap survey. Items without consensus were discussed in a virtual meeting followed by a second survey. Results: All fifteen panelists completed both surveys (100% response rate). In the initial survey, consensus was present on 6 of 15 (40%) items related to risk of CDI. After panel discussion and clarification of questions, consensus (>70% agreement) was reached on all remaining items in the second survey. Antibiotics were identified as the primary risk factor for CDI and grouped into three categories: high-risk (likelihood ratio [LR] 7, 93% agreement among panelists in first survey), low-risk (LR 3, 87% agreement in first survey), and minimal-risk (LR 1, 71% agreement in first survey). Other major factors included new or unexplained severe diarrhea (e.g., ≥ 10 liquid bowel movements per day; LR 5, 100% agreement in second survey) and severe immunosuppression (LR 5, 87% agreement in second survey). Conclusion: Infectious disease experts concurred on the importance of signs, symptoms, and healthcare exposures for diagnosing CDI. The resulting risk estimates can be used by clinicians to optimize CDI testing and treatment.

Changes in the timing of antiretroviral therapy initiation in HIV-infected patients with tuberculosis in Uganda: a study of the diffusion of evidence into practice in the global response to HIV/AIDS.

BACKGROUND: We aimed to determine the extent to which emerging evidence and changing guidelines regarding timing of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected patients with tuberculosis influenced "real-world" clinical practice in Uganda. METHODS: We evaluated ART-naive, HIV-infected adults starting tuberculosis therapy at 2 HIV clinics in Uganda between 26 August 2006 and 29 September 2012. We used multivariate regression to calculate associations between 4 calendar periods reflecting publication of seminal clinical studies or changes in guidelines and timing of ART after tuberculosis therapy initiation. RESULTS: For patients with CD4 counts <50 cells/µL, the fraction starting ART within 14 and 30 days of initiating tuberculosis therapy increased from 7% to 14% and from 14% to 86% over the period of observation. The fraction of patients with CD4 counts >50 cells/µL starting ART within 60 days increased from 16% to 28%. After adjustment for sociodemographic factors, when comparing the most recent with the earliest calendar period, the rate of ART initiation increased by 4.57-fold (95% confidence interval [CI], 1.76-fold to 11.86-fold) among patients with baseline CD4 counts ≤ 50 cells/µL and by 5.43-fold (95% CI, 3.16- fold to 9.31-fold) among those with baseline CD4 counts >50 cells/µL. CONCLUSIONS: We observed large changes in clinical practice during a period of emerging data and changing guidelines among HIV-infected patients with tuberculosis. Nonetheless, a significant proportion of individuals with higher CD4 cell counts do not start ART within recommended time frames. Targeted dissemination and implementation efforts are still needed to achieve target levels in practice.

Do hospitals that participate in COVID-19 research differ from non-trial hospitals? A cross-sectional study of US hospitals.

OBJECTIVES: To compare hospitals that did and did not participate in clinical trials evaluating potential inpatient COVID-19 therapeutics. METHODS: We conducted a cross-sectional study of hospitals participating in trials that were registered on clinicaltrials.gov between April and August 2020. Using the 2019 RAND Hospital Dataset and 2019 American Community Survey, we used logistic regression modeling to compare hospital-level traits including demographic features between trial and non-trial hospitals. RESULTS: We included 488 hospitals that were participating in 298 interventional trials and 4232 non-participating hospitals. After controlling for demographic and other hospital traits, we found that teaching status (OR 2.11, 95% CI 1.52-2.95), higher patient acuity (OR 7.48, 4.39, 13.1), and location in the Northeast (OR 1.83, 95% CI 1.18, 2.85) and in wealthier counties (OR: 1.32, 95% CI 1.16-1.51) were associated with increased odds of trial participation, while being in counties with more White residents was associated with reduced odds (OR 0.98, 95% CI 0.98-0.99). CONCLUSIONS: Hospitals participating and not participating in COVID-19 inpatient treatment clinical trials differed in many ways, resulting in important implications for the generalizability of trial data.

Inclusion, Diversity, Access, and Equity in Infectious Diseases Fellowship Training: Tools for Program Directors.

The Infectious Diseases Society of America (IDSA) has set clear priorities in recent years to promote inclusion, diversity, access, and equity (IDA&E) in infectious disease (ID) clinical practice, medical education, and research. The IDSA IDA&E Task Force was launched in 2018 to ensure implementation of these principles. The IDSA Training Program Directors Committee met in 2021 and discussed IDA&E best practices as they pertain to the education of ID fellows. Committee members sought to develop specific goals and strategies related to recruitment, clinical training, didactics, and faculty development. This article represents a presentation of ideas brought forth at the meeting in those spheres and is meant to serve as a reference document for ID training program directors seeking guidance in this area.

Micronutrient Deficiency as a Confounder in Ascertaining the Role of Obesity in Severe COVID-19 Infection.

Food insecurity in the United States has been exacerbated due to the socioeconomic strain of the coronavirus disease 2019 (COVID-19) pandemic. Populations experiencing poverty and, as a consequence, food insecurity in the United States are disproportionately affected by obesity, which was identified early in the pandemic as a major risk factor for increased susceptibility to COVID-19 infection and mortality. Given the focus on obesity and its role in immune dysregulation, it is also important to note the role of micronutrient deficiency, another sequalae of food insecurity. Micronutrients play an important role in the ability of the immune system to mount an appropriate response. Moreover, OBESE individuals are more likely to be micronutrient deficient. This review will explore the role of micronutrients, vitamin A, vitamin D, vitamin C, and zinc in respiratory immunity and COVID-19 and how micronutrient deficiency may be a possible confounder in obesity's association with severe outcomes. By illuminating the role of micronutrients in COVID-19, this paper expands the discussion from food insecurity and obesity to include micronutrient deficiency and how all of these interact in respiratory illnesses such as COVID-19.

Neutralizing Monoclonal Antibodies for Coronavirus Disease 2019 (COVID-19) in Pregnancy: A Case Series.

OBJECTIVE: To describe outcomes associated with monoclonal antibody use in pregnant persons with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: We present a retrospective case series of pregnant patients who received anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibody infusions at a single center from April 1, 2021, through October 16, 2021. Pregnant patients who had a positive SARS-CoV-2 polymerase chain reaction (PCR) test result and mild-to-moderate COVID-19 symptoms were eligible for monoclonal antibody infusion. Exclusion criteria for administration included need for supplemental oxygen, hospitalization due to COVID-19, and positive SARS-CoV-2 PCR test result more than 7 days before screening. All patients received either bamlanivimab plus etesevimab or casirivimab plus imdevimab based on availability and dosing instructions of the product and emerging resistance patterns in the community. RESULTS: During the study period, monoclonal antibody infusions were administered to 450 individuals at our institution, of whom 15 were pregnant. Of the 15 pregnant persons receiving monoclonal antibody, six (40%) had full-vaccination status at the time of infusion. Two individuals (13%, CI 0-31%) experienced systemic reactions during the infusion, both resulting in temporary changes in the fetal heart rate tracing that recovered with maternal and intrauterine resuscitative efforts. One patient delivered after infusion for worsening maternal and fetal status; the remainder of the patients did not require admission for COVID-19. CONCLUSION: In this case series, pregnant persons who received anti-SARS-CoV-2 monoclonal antibody infusions had generally favorable outcomes.

On variants and vaccines: The effectiveness of Covid-19 monoclonal antibody therapy during two distinct periods in the pandemic.

BACKGROUND: While Covid-19 monoclonal antibody therapies (Mab) have been available in the outpatient setting for over a year and a half, little is known about the impact of emerging variants and vaccinations on the effectiveness of Mab therapies. We sought to determine the effectiveness of Covid-19 Mab therapies during the first two waves of the pandemic in Los Angeles County and assess the impact of vaccines, variants, and other confounding factors. METHODS AND FINDINGS: We retrospectively examined records for 2209 patients of with confirmed positive molecular SARS-CoV2 test either referred for outpatient Mab therapy or receiving Mab treatment in the emergency department (ED) between December 2020 and 2021. Our primary outcome was the combined 30-day incidence of ED visit, hospitalization, or death following the date of referral. Additionally, SARS-CoV2 isolates of hospitalized patients receiving Mabs were sequenced. The primary outcome was significantly reduced with combination therapy compared to bamlanivimab or no treatment (aHR 0·60; 95% CI ·37, ·99), with greater benefit in unvaccinated, moderate-to-high-risk patients (aHR ·39; 95% CI ·20, ·77). Significant associations with the primary outcome included history of lung disease (HR 7·13; 95% CI 5·12, 9·95), immunocompromised state (HR 6·59; 95% CI 2·91-14·94), and high social vulnerability (HR 2·29, 95% CI 1·56-3·36). Two predominant variants were noted during the period of observation: the Epsilon variant and the Delta variant. CONCLUSIONS: Only select monoclonal antibody therapies significantly reduced ED visits, hospitalizations, and death due to COVID-19 during. Vaccination diminished effectiveness of Mabs. Variant data and vaccination status should be considered when assessing the benefit of novel COVID-19 treatments.

Tuskegee as a History Lesson, Tuskegee as Metaphor: Addressing Discrimination as a Social Determinant of Health in the Classroom.

While basic science and social medicine are fundamental to the practice of medicine, the former is often prioritized in preclinical medical education at the expense of the latter. In this perspective, we discuss ways to introduce the concept of interpersonal, institutional, and structural discrimination as social determinants of health (SDOH) into a preclinical microbiology and infectious diseases medical course. We offer 5 specific steps to creating a comprehensive curriculum on discrimination as a social determinant of health: define and use standardized terminology; integrate the concept of SDOH throughout the course; encourage critical appraisal of lay and medical resources; encourage student feedback; and provide faculty development supported by key faculty stakeholders that focuses on increasing comfort and facility with teaching such concepts. This approach offers a template for ongoing discussion in the setting of curricular reform.

Diagnostic yield of repeat testing for SARS-CoV-2: Experience from a large health system in Los Angeles.

OBJECTIVE: To determine the diagnostic yield of repeat testing for SARS-CoV-2. METHODS: A retrospective analysis was performed of all SARS-CoV-2 test results within the UCLA Health System between March 9th and April 29th, 2020. All patients with repeat test results were identified and those with discordant results were reviewed. RESULTS: Between March 9th and April 29th there were 10,165 SARS-CoV-2 test results, of which 630 (6.2%) were positive. Among the 904 patients with repeat test results, 808 (89.4%) were initially negative and 96 (10.6%) were initially positive. Among the 808 patients with an initial negative test, 15 (1.9%) subsequently tested positive. Eleven cases with an initial negative SARS-CoV-2 test and without a known prior positive SARS-CoV-2 test were reviewed; 6 were employed as healthcare workers and 10 were positive on the second test. CONCLUSIONS: We found a low diagnostic yield of repeat testing for SARS-CoV-2 in our health system. Repeat testing might prove useful in certain clinical scenarios, such as in healthcare workers, when symptoms develop after a negative test, and in hospitalized patients with a high clinical suspicion for COVID-19.