Advances in pharmacotherapies for cytomegalovirus infection: what is the current state of play?

INTRODUCTION: Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV drugs are limited by toxicities and the development of resistance. Letermovir and maribavir are newly approved antivirals for the prevention and treatment of CMV. AREAS COVERED: Prior reviews have discussed use of letermovir for prevention of CMV after HCT and maribavir for resistant or refractory (R/R) CMV post HCT or SOT. Subsequent data have expanded their use including letermovir for primary CMV prophylaxis in high-risk renal transplant recipients and new recommendations for extending prophylaxis through day + 200 in certain HCT patients. Data on the use of maribavir for first asymptomatic CMV infection post-HCT has also been published. This review compares the pharmacology of anti-CMV agents and discusses the updated literature of these new drugs in the prevention and treatment of CMV. EXPERT OPINION: Letermovir and maribavir are much needed tools that spare toxicities of ganciclovir, foscarnet and cidofovir. High cost is a challenge preventing their integration into clinical practice in resource-limited countries. Transplant centers need to exercise restraint in overuse to avoid resistance, particularly in the setting of high viral loads.

Invasive Fungal Infections Associated with COVID-19.

The COVID-19 pandemic caused >6 million deaths worldwide, often from respiratory failure. Complications frequently occurred in hospitalized patients, particularly in the intensive care unit. Among these, fungal infections were a cause of high morbidity and mortality. Invasive aspergillosis, candidiasis and mucormycosis were the most serious of these infections. Risk factors included alterations in immune defense mechanisms by COVID-19 itself, as well as immunosuppression due to various therapies utilized in severely ill patients. Diagnosis was often challenging due to lack of sensitivity of current testing. Outcomes were generally poor, due to significant co-morbidities and delayed diagnosis, with mortality rates >50% in some studies. High index of clinical suspicion is needed to facilitate early diagnosis and initiation of appropriate antifungal therapy.

SARS-CoV-2 neutralizing antibodies for COVID-19: Outcomes for bamlanivimab versus bamlanivimab-etesevimab combination in a racially diverse cohort of patients with significant comorbidities.

WHAT IS KNOWN AND OBJECTIVE: Anti-spike monoclonal antibodies (MAB) including bamlanivimab (BAM) and bamlanivimab/etesevimab (BAM/E) have shown reduced hospitalization rates for non-severe coronavirus disease 2019 (COVID-19) in clinical trials. Recent data have provided real-world hospitalization rates for high-risk patients treated with BAM, however, data on a similar cohort treated with BAM/E are lacking. METHODS: This retrospective cohort study evaluated outpatients ≥18 years with laboratory-confirmed mild/moderate COVID-19 who received MAB from 1 December 2020 to 19 April 2021. Use of BAM monotherapy changed to BAM/E combination on 27 March 2021. Primary outcome was overall rate of COVID-19 related-hospitalization, including comparison of hospitalization rates between MAB-formulation groups. Secondary outcomes were 30-day mortality and length of stay (LOS). RESULTS AND DISCUSSION: The population included 643 patients (BAM and BAM/E); median age was 58 years, 43% were male, median BMI was 33 kg/m2 , and 24% self-identified as Black. Patients in the BAM/E combination group were significantly younger with higher median BMI and a longer time from symptom onset to infusion. The incidence of 30-day COVID-19 related hospitalization was similar between patients receiving either BAM or BAM/E combination (7.8% and 7.2%, respectively). WHAT IS NEW AND CONCLUSION: This study represents the first such publication of real-world BAM/E hospitalization outcomes. Hospitalization rates utilizing BAM/E were comparable to BAM in our real-world study.

A Resident-driven Quality Improvement Project to Increase Primary Care Follow-up after Congestive Heart Failure Exacerbation: Use of a Quality and Safety Award.

OBJECTIVES: Congestive heart failure (CHF) is the most common cause of 30-day inpatient readmission. Studies have found that early follow-up with primary care physicians (PCP) within 7 days of discharge may improve 30-day readmission rates; however, many have used a multidisciplinary discharge coordination team, which is not a resource at all centers. Here, the authors present a resident-driven quality improvement initiative using a monthly quality and safety award to increase early PCP follow-up for veterans discharged following admissions due to a CHF exacerbation. Primary outcomes were percentage of PCP follow-up within 7 days and median time to PCP follow-up. Secondary outcomes included percentage of patients attending a PCP visit within 7 days, 30-day readmission, and 30-day mortality. METHODS: This prepost quasi-experimental cohort study evaluated 3 concurrent quality improvement interventions to increase PCP follow-up after CHF exacerbation. Process maps and Ishikawa diagrams examined the discharge process. Interventions included a standardized discharge scheduling order, monthly education on the process, and monthly aggregated performance feedback for each medical resident. A patient safety and quality award was given to the team with the highest rate of PCP appointments scheduled within 7 days. Patient characteristics and outcomes were gathered for a 6-month historic period and 6-month intervention period. Test of proportions and Wilcoxon Rank-Sum test were used to compare groups. RESULTS: A total of 294 patients were discharged (161 in historic group and 133 in intervention group). Appointments scheduled within 7 days of discharge increased from 43% to 79% ( P < 0.001). Median time to PCP follow-up decreased from 8 to 6 days ( P < 0.001). Patients who completed (showed up to) a PCP appointment within 7 days increased from 16% to 41% ( P < 0.001). There was no impact on 30-day readmission or mortality; however, the number of study subjects was too small to rule out an effect. CONCLUSIONS: A standardized discharge scheduling order, more robust resident education, and a monthly patient safety and quality award resulted in a significant increase in the rate of primary care follow-up within 7 days of CHF exacerbation.

Hemophagocytic Lymphohistiocytosis Following Skin and Soft Tissue Infection in a Patient With Human Immunodeficiency Virus.

Hemophagocytic lymphohistiocytosis (HLH) is a systemic inflammatory syndrome of inappropriate immune cell activation which can be rapidly fatal if not recognized and treated. Here we discuss a case of a 26-year-old male with HIV on antiretroviral therapy who presented with sepsis secondary to soft tissue infection and ultimately progressed to multi-organ dysfunction despite broad-spectrum antibiotics and an improvement in soft tissue infection. Continued fever and pancytopenia without an explanation found during additional infectious and rheumatologic testing eventually led to bone marrow biopsy and laboratory criteria consistent with HLH. Although pancytopenia is a common finding in patients with HIV, here it marked a more rapidly progressing and fatal disease, HLH. Here we highlight the difficulty in identifying and diagnosing this rare condition, including a discussion of the characteristics, outcomes, underlying etiologies, and treatment of HLH in patients with HIV.

T2Candida for the Diagnosis and Management of Invasive Candida Infections.

Invasive candidiasis is a common healthcare-associated infection with high mortality and is difficult to diagnose due to nonspecific symptoms and limitations of culture based diagnostic methods. T2Candida, based on T2 magnetic resonance technology, is FDA approved for the diagnosis of candidemia and can rapidly detect the five most commonly isolated Candida sp. in approximately 5 h directly from whole blood. We discuss the preclinical and clinical studies of T2Candida for the diagnosis of candidemia and review the current literature on its use in deep-seated candidiasis, its role in patient management and prognosis, clinical utility in unique populations and non-blood specimens, and as an antifungal stewardship tool. Lastly, we summarize the strengths and limitations of this promising nonculture-based diagnostic test.

Ocular Toxoplasmosis Mimicking Lymphoma: Exploring the Correlation and Distinction.

We present a case of a 74-year-old woman with chronic lymphocytic leukemia (CLL) who presented with unilateral blurry vision that had progressively worsened over a few weeks. Ophthalmic examination revealed unilateral anterior chamber, vitreous body inflammation along with retinal infiltration which was initially diagnosed with posterior uveitis. Analysis of vitreous fluid aspiration was negative for bacteria, fungal and viral etiologies. Despite the broad-spectrum intraocular antibiotics, her vision continued to decline, and she later developed retinal detachment. Cytology for lymphoma was negative. However, polymerase chain reaction (PCR) with internal transcribed spacer-specific (ITS) primer set detected Toxoplasma gondii, and the patient was diagnosed with intraocular toxoplasmosis. Treatment with systemic clindamycin, pyrimethamine, leucovorin, prednisone, and topical clindamycin for four weeks successfully prevented further ocular damage.

A Physician-Driven Quality Improvement Stewardship Intervention Using Lean Six Sigma Improves Patient Care for Community-Acquired Pneumonia.

Introduction: The Infectious Diseases Society of America (IDSA) recommends a minimum of 5 days of antibiotic therapy in stable patients who have community-acquired pneumonia (CAP). However, excessive duration of therapy (DOT) is common. Define, measure, analyze, improve, and control (DMAIC) is a Lean Six Sigma methodology used in quality improvement efforts, including infection control; however, the utility of this approach for antimicrobial stewardship initiatives is unknown. To determine the impact of a prospective physician-driven stewardship intervention on excess antibiotic DOT and clinical outcomes of patients hospitalized with CAP. Our specific aim was to reduce excess DOT and to determine why some providers treat beyond the IDSA minimum DOT. Methods: A single-center, quasi-experimental quality improvement study evaluating rates of excess antimicrobial DOT before and after implementing a DMAIC-based antimicrobial stewardship intervention that included education, prospective audit, and feedback from a physician peer, and daily tracking of excess DOT on a Kaizen board. The baseline period included retrospective CAP cases that occurred between October 2018 and February 2019 (control group). The intervention period included CAP cases between October 2019 and February 2020 (intervention group). Results: A total of 123 CAP patients were included (57 control and 66 intervention). Median antibiotic DOT per patient decreased (8 versus 5 days; p < 0.001), and the proportion of patients treated for the IDSA minimum increased (5.3% versus 56%; p < 0.001) after the intervention. No differences in mortality, readmission, length of stay, or incidence of Clostridioides difficile infection were observed between groups. Almost half of the caregivers surveyed were aware that as few as 5 days of antibiotic treatment could be appropriate. Conclusions: A physician-driven antimicrobial quality improvement initiative designed using DMAIC methodology led to reduced DOT and increased compliance with the IDSA treatment guidelines for hospitalized patients with CAP reduced without negatively affecting clinical outcomes.

Outcomes of an Online Virtual Boot Camp to Prepare Fourth-Year Medical Students for a Successful Transition to Internship.

Introduction Changes in medical education and health care delivery have limited the ability of fourth-year medical students to perform the role of an intern prior to graduating from medical school. To address this issue, many schools have instituted residency preparation courses (sometimes referred to as boot camps) particularly for students entering surgical fields. Courses for students entering nonprocedural fields are less common and most assess increases in self-reported confidence without providing objective evidence of a gain in knowledge or skills improvement. Materials and Methods We used a Plan, Do, Study, Act (PDSA) model to develop and pilot cycle 1 of a nonprocedural internship preparation elective in 2019. Feedback was used to refine the course and map sessions to core competencies outlined by the Accreditation Council of Graduate Medical Education (ACGME) for PDSA cycle 2. The curriculum was adapted for remote synchronous delivery due to the coronavirus pandemic in spring 2020 using a combination of didactic lectures containing embedded polls and case-based role play responses using a chat box. Students completed anonymous surveys assessing self-perceived levels of confidence, as well as an objective comprehensive assessment after course completion. Results A total of 89 students participated in the course. Pre-session confidence was lowest for transfusion medicine, handling pages from nursing while on call, and knowledge of the role of a chief resident. A statistically significant increase in median scores for self-reported knowledge or confidence was seen in all sessions. The percentage of students reporting that they were either confident or extremely confident also increased significantly after each session (p<0.001 for all). All sessions analyzed were rated as useful or extremely useful by more than half of the students, and 94% of the students scored 70% or higher on the comprehensive course assessment. Conclusions An online virtual synchronous boot camp increased students' confidence in handling common topics encountered during residency and demonstrated an appropriate gain in knowledge using a comprehensive assessment. We were able to adapt our curriculum to a remote model and will likely keep several sessions in an online format in the future.

Exogenous glucagon-like peptide-1 for hyperglycemia in critically ill patients.

OBJECTIVE: To review literature evaluating the safety and efficacy of exogenous glucagon-like peptide-1 (GLP-1) for hyperglycemia in critically ill patients. DATA SOURCES: PubMed was queried (inception to September 3, 2011), using the search term glucagon-like peptide-1. The search was limited to studies published in English and conducted in humans. Regular and late-breaking abstracts from the American Diabetes Association Scientific Sessions in 2009 and 2010 were also searched using the same search term. STUDY SELECTION AND DATA EXTRACTION: All abstracts were screened for eligibility, which consisted of studies reporting the effects of intravenous GLP-1 administration on glycemic control in critically ill patients. Data extracted from eligible trials included study and population characteristics, measures of glycemic efficacy, and safety. DATA SYNTHESIS: Our search resulted in the identification of 2105 potentially relevant articles; of those, 7 were reviewed. All included publications evaluated the use of intravenous GLP-1 (1.2-3.6 pmol/kg/min) compared with insulin or placebo infused for 4.5-72 hours in critically ill patients. The majority (n = 4) of studies included only patients from a surgical intensive care setting, and 71% (n = 5) of trials included those with a history of diabetes. Relative to insulin or placebo, GLP-1 therapy effectively lowered blood glucose concentrations in all trials. Out of 81 total study participants receiving GLP-1, only 4 had documented hypoglycemia (<60 mg/dL), 4 reported nausea, and 2 experienced vomiting. No other serious adverse events were reported. CONCLUSIONS: All trials reviewed suggest that GLP-1 may be a promising agent for the management of hyperglycemia in critically ill patients, regardless of diabetes status. Additional studies in more heterogeneous intensive care settings comparing GLP-1 with insulin, the current standard of care, are necessary. These studies should evaluate long-term safety and effectiveness of GLP-1 therapy on morbidity and mortality outcomes in critically ill populations.