Standardization of an antiviral pipeline for human norovirus in human intestinal enteroids demonstrates nitazoxanide has no to weak antiviral activity.

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within 3 days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we standardized a pipeline for antiviral testing using multiple human small intestinal enteroid lines representing different intestinal segments and evaluated whether nitazoxanide inhibits replication of five HuNoV strains in vitro. Nitazoxanide did not exhibit high selective antiviral activity against any HuNoV strain tested, indicating it is not an effective antiviral for HuNoV infection. Human intestinal enteroids are further demonstrated as a model to serve as a preclinical platform to test antivirals against HuNoVs to treat gastrointestinal disease. Abstr.

Evidence of Clinical Impact Supports a New Petition for Medicare Coverage of 2-[18F]Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography in the Evaluation of Staphylococcus aureus Bacteremia: A Focused Literature Review and Call to Action.

Staphylococcus aureus bacteremia (SAB) causes considerable morbidity and mortality and requires comprehensive assessment for metastatic infection. The roles of routine imaging beyond echocardiography in SAB, including 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT), remain contentious. We performed a literature review of studies reporting impact of 18F-FDG-PET/CT on the clinical management or outcomes of SAB published through 1 March 2022. We identified 7 observational studies in which 18F-FDG-PET/CT frequently identified metastatic foci of infection, revealed foci undetected by prior investigations, led to additional source control procedures, and was associated with fewer infection relapses and lower mortality. Calculated numbers needed to treat for receipt of 18F-FDG-PET/CT were 7-9 to change antimicrobial therapy, 10-27 to lead to an additional source control procedure, and 4-8 to prevent death. These data are comparable to the evidence for clinical impact of other diagnostic modalities accepted as standard of care in SAB, and form a compelling basis for advocacy to expand access to 18F-FDG-PET/CT.

Educational Impact of #IDJClub, a Twitter-Based Infectious Diseases Journal Club.

BACKGROUND: Journal clubs have been an enduring mainstay of medical education, and hosting these on social media platforms can expand accessibility and engagement. We describe the creation and impact of #IDJClub, an infectious diseases (ID) Twitter journal club. METHODS: We launched #IDJClub in October 2019. Using the account @IDJClub, an ID physician leads a 1-hour open-access Twitter discussion of a recent publication. All participants use the hashtag #IDJClub. Sessions started monthly, but increased due to demand during the coronavirus disease 2019 (COVID-19) pandemic. We used Symplur 's Healthcare Hashtag project to track engagement of #IDJClub per 60-minute discussion plus the following 30 minutes to capture ongoing conversations. We also conducted an online anonymous survey using Likert scales and open-ended questions to assess educational impact. RESULTS: In its first 20 months, 31 journal clubs were held, with medians of 42 (interquartile range [IQR], 28.5-60) participants and 312 (IQR, 205-427.5) tweets per session. 134 participants completed the survey, of whom 39% were ID physicians, 19% pharmacists, 13% ID fellows, and 10% medical residents. Most agreed or strongly agreed that #IDJClub provided clinically useful knowledge (95%), increased personal confidence in independent literature appraisal (72%), and was more educational than traditional journal clubs (72%). The format addressed several barriers to traditional journal club participation such as lack of access, subject experts, and time. CONCLUSIONS: #IDJClub is an effective virtual journal club, providing an engaging, open-access tool for critical literature appraisal that overcomes several barriers to traditional journal club participations while fostering connectedness within the global ID community.

Dialysis Catheter-related Bloodstream Infections in Patients Receiving Hemodialysis on an Emergency-only Basis: A Retrospective Cohort Analysis.

BACKGROUND: An estimated 6500 undocumented immigrants with end-stage renal disease (ESRD) live in the United States. Those living in states that do not provide undocumented immigrants scheduled hemodialysis receive intermittent hemodialysis only when life-threatening conditions arise. Little is known about catheter-related bloodstream infections (CRBSIs) in this population. METHODS: We conducted a retrospective cohort study of emergency-only hemodialysis patients in the Harris Health System in Houston, Texas, between January 2012 and December 2015. We assessed CRBSI risk factors including demographics, comorbidities, and duration and frequency of hemodialysis. We investigated the microbiologic etiology of these infections, rates of recurrent CRBSI, and associated morbidity and mortality. RESULTS: The cohort included 329 patients; 90% were Hispanic, 60% had diabetes, and the average age was 51 years. A total of 101 CRBSIs occurred, with a rate of 0.84 infections per 1000 catheter-days. Cirrhosis and duration of hemodialysis during the study period were associated with increased risk of CRBSI. Seventeen CRBSIs were recurrent; infection with gram-positive bacteria predicted recurrence. Adherence to catheter-related infection guidelines was improved by infectious diseases consultation and associated with fewer recurrent infections. CRBSI was associated with prolonged hospitalization (mean, 15 days), composite complication rate of 8%, and a 4% mortality rate. CONCLUSIONS: Patients receiving emergency-only hemodialysis via tunneled catheters have a high CRBSI rate compared with infection rates previously reported in patients receiving scheduled maintenance hemodialysis. Increased CRSBI risk likely contributes to the increased morbidity and mortality seen in ESRD patients receiving emergency-only hemodialysis.

Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen.

As with many other viruses, the initial cell attachment of rotaviruses, which are the major causative agent of infantile gastroenteritis, is mediated by interactions with specific cellular glycans. The distally located VP8* domain of the rotavirus spike protein VP4 (ref. 5) mediates such interactions. The existing paradigm is that 'sialidase-sensitive' animal rotavirus strains bind to glycans with terminal sialic acid (Sia), whereas 'sialidase-insensitive' human rotavirus strains bind to glycans with internal Sia such as GM1 (ref. 3). Although the involvement of Sia in the animal strains is firmly supported by crystallographic studies, it is not yet known how VP8* of human rotaviruses interacts with Sia and whether their cell attachment necessarily involves sialoglycans. Here we show that VP8* of a human rotavirus strain specifically recognizes A-type histo-blood group antigen (HBGA) using a glycan array screen comprised of 511 glycans, and that virus infectivity in HT-29 cells is abrogated by anti-A-type antibodies as well as significantly enhanced in Chinese hamster ovary cells genetically modified to express the A-type HBGA, providing a novel paradigm for initial cell attachment of human rotavirus. HBGAs are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori and noroviruses. Our crystallographic studies show that the A-type HBGA binds to the human rotavirus VP8* at the same location as the Sia in the VP8* of animal rotavirus, and suggest how subtle changes within the same structural framework allow for such receptor switching. These results raise the possibility that host susceptibility to specific human rotavirus strains and pathogenesis are influenced by genetically controlled expression of different HBGAs among the world's population.

The VP8* domain of neonatal rotavirus strain G10P[11] binds to type II precursor glycans.

Naturally occurring bovine-human reassortant rotaviruses with a P[11] VP4 genotype exhibit a tropism for neonates. Interaction of the VP8* domain of the spike protein VP4 with sialic acid was thought to be the key mediator for rotavirus infectivity. However, recent studies have indicated a role for nonsialylated glycoconjugates, including histo-blood group antigens (HBGAs), in the infectivity of human rotaviruses. We sought to determine if the bovine rotavirus-derived VP8* of a reassortant neonatal G10P[11] virus interacts with hitherto uncharacterized glycans. In an array screen of >600 glycans, VP8* P[11] showed specific binding to glycans with the Galß1-4GlcNAc motif, which forms the core structure of type II glycans and is the precursor of H type II HBGA. The specificity of glycan binding was confirmed through hemagglutination assays; GST-VP8* P[11] hemagglutinates type O, A, and B red blood cells as well as pooled umbilical cord blood erythrocytes. Further, G10P[11] infectivity was significantly enhanced by the expression of H type II HBGA in CHO cells. The bovine-origin VP4 was confirmed to be essential for this increased infectivity, using laboratory-derived reassortant viruses generated from sialic acid binding rotavirus SA11-4F and a bovine G10P[11] rotavirus, B223. The binding to a core glycan unit has not been reported for any rotavirus VP4. Core glycan synthesis is constitutive in most cell types, and modification of these glycans is thought to be developmentally regulated. These studies provide the first molecular basis for understanding neonatal rotavirus infections, indicating that glycan modification during neonatal development may mediate the age-restricted infectivity of neonatal viruses.

High Efficacy of Oral Tetracyclines in Prosthetic Joint Infection Treated With Debridement, Antibiotics, and Implant Retention (DAIR) or Resection Arthroplasty With Destination Spacer Placement.

Prosthetic joint infections are often managed with debridement and implant retention (DAIR) or resection arthroplasty with destination spacer placement. Both surgical approaches require long courses of postoperative antibiotics, for which tetracycline antibiotics have not been well-studied. In this retrospective case series, we included patients at our institution treated for staphylococcal prosthetic joint infection managed with DAIR or destination spacer placement who were switched from IV antibiotics to oral tetracycline within 12 weeks of surgery. Our primary outcome of interest was treatment failure within one year of initial surgery. Among the patients in our series, 88.2% (n = 15) of patients who underwent DAIR and 100% (n = 7) of patients who underwent resection arthroplasty with destination spacer remained event-free for one year. These results demonstrated that the use of oral tetracyclines as long-term therapy in the treatment of these infections was effective and well-tolerated.

Early switch from intravenous to oral antibiotic treatment in bone and joint infections.

OBJECTIVES: The timing of the switch from intravenous (i.v.) to oral antibiotic therapy for orthopaedic bone and joint infections (BJIs) is debated. In this narrative article, we discuss the evidence for and against an early switch in BJIs. DATA SOURCES: We performed a PubMed and internet search investigating the association between the duration of i.v. treatment for BJI and remission of infection among adult orthopaedic patients. CONTENT: Among eight randomized controlled trials and multiple retrospective studies, we failed to find any minimal duration of postsurgical i.v. therapy associated with clinical outcomes. We did not find scientific data to support the prolonged use of i.v. therapy or to inform a minimal duration of i.v. THERAPY: Growing evidence supports the safety of an early switch to oral medications once the patient is clinically stable. IMPLICATIONS: After surgery for BJI, a switch to oral antibiotics within a few days is reasonable in most cases. We recommend making the decision on the time point based on clinical criteria and in an interdisciplinary team at the bedside.

A Standardized Antiviral Pipeline for Human Norovirus in Human Intestinal Enteroids Demonstrates No Antiviral Activity of Nitazoxanide.

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within three days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we established a standardized pipeline for antiviral testing using multiple human small intestinal enteroid (HIE) lines representing different intestinal segments and evaluated whether nitazoxanide inhibits replication of 5 HuNoV strains in vitro . Nitazoxanide did not exhibit high selective antiviral activity against any HuNoV strains tested, indicating it is not an effective antiviral for norovirus infection. HIEs are further demonstrated as a model to serve as a pre-clinical platform to test antivirals against human noroviruses to treat gastrointestinal disease.

Adjunctive Rifampin Following Debridement and Implant Retention for Staphylococcal Prosthetic Joint Infection: Is it Effective if not Combined With a Fluoroquinolone?

Whether rifampin benefits retained staphylococcal prosthetic joint infection is unsettled. In a meta-analysis of 8 studies, we found greater clinical cure with fluoroquinolone-rifampin vs all other regimens (odds ratio [OR], 2.68; 95% CI, 1.43-5.02), but no greater cure with other rifampin combinations vs regimens without rifampin (OR, 1.22; 95% CI, 0.79-1.88).

Excellent Outcomes With the Selective Use of Oral Antibiotic Therapy for Bone and Joint Infections: A Single-Center Experience.

Background and objective Recent studies have challenged the notion that prolonged intravenous (IV) antibiotics are preferable to oral antibiotics for treating musculoskeletal infections. Our institution's orthopedic surgery and orthopedic infectious disease (ID) groups have established consensus criteria for the use of oral antibiotics in musculoskeletal infections. In this study, we examine one-year and two-year outcomes of the selective use of oral antibiotics for musculoskeletal infections in a real-world setting. Methods We conducted a single-center retrospective analysis of adults seen in our orthopedic ID clinic over a six-month period for the first episode of surgically managed osteomyelitis, native joint septic arthritis (NJSA), prosthetic joint infection (PJI), or other musculoskeletal hardware infection with an established microbiologic etiology who received surgical interventions and >2 weeks of antimicrobial treatment. Patients were evaluated for treatment failure at one year and two years following their index surgery, which we defined as death, unplanned surgery, or the initiation of chronic antibiotic suppression. Results One-year treatment failure rates were 0/23 (0%) in patients who switched to oral therapy versus 6/17 (35%) in patients who remained on IV treatment. Two-year treatment failure rates were 0/23 (0%) in patients who switched to oral therapy versus 8/17 (47%) in patients who remained on IV treatment. Conclusions Our consensus criteria for the switch to oral antibiotics for musculoskeletal infections identified patients who went on to have excellent outcomes at one year and two years, suggesting that these criteria can effectively identify patients at low risk for treatment failure. Collaboration between ID specialists and orthopedic surgeons to select antimicrobial regimens can avoid significant burdens, costs, and complications associated with prolonged IV therapy.

Deconstructing the Dogma: Systematic Literature Review and Meta-analysis of Adjunctive Gentamicin and Rifampin in Staphylococcal Prosthetic Valve Endocarditis.

Background: Based primarily on in vitro and animal models, with little data directly addressing patient outcomes, current guidelines recommend treating staphylococcal prosthetic valve endocarditis (PVE) with antibiotic combinations including gentamicin and rifampin. Here, we synthesize the clinical data on adjunctive rifampin and gentamicin in staphylococcal PVE. Methods: We conducted a systematic review and meta-analysis of PubMed- and Cochrane-indexed studies reporting outcomes of staphylococcal PVE treated with adjunctive rifampin, gentamicin, both agents, or neither (ie, glycopeptide or ß-lactam monotherapy). We recorded outcomes including mortality, relapsed infection, length of stay, nephrotoxicity, hepatotoxicity, and important drug-drug interactions (DDIs). Results: Four relevant studies were identified. Two studies (n = 117) suggested that adding gentamicin to rifampin-containing regimens did not reduce clinical failure (odds ratio [OR], 0.98 [95% confidence interval {CI}, .39-2.46]), and 2 studies (n = 201) suggested that adding rifampin to gentamicin-containing regimens did not reduce clinical failure (OR, 1.29 [95% CI, .71-2.33]). Neither gentamicin nor rifampin was associated with reduced infection relapse; 1 study found that rifampin treatment was associated with longer hospitalizations (mean, 31.3 vs 42.3 days; P < .001). Comparative safety outcomes were rarely reported, but 1 study found rifampin to be associated with hepatoxicity, nephrotoxicity, and DDIs, leading to treatment discontinuation in 31% of patients. Conclusions: The existing clinical data do not suggest a benefit of either adjunctive gentamicin or rifampin in staphylococcal PVE. Given that other studies also suggest these agents add nephrotoxicity, hepatoxicity, and risk of DDIs without benefit in staphylococcal endovascular infections, we suggest that recommendations for gentamicin and rifampin in PVE be downgraded and primarily be used within the context of clinical trials.

New Insights and Enhanced Human Norovirus Cultivation in Human Intestinal Enteroids.

Human noroviruses (HuNoVs) are the leading cause of epidemic and sporadic acute gastroenteritis worldwide. We previously demonstrated human intestinal stem cell-derived enteroids (HIEs) support cultivation of several HuNoV strains. However, HIEs did not support virus replication from every HuNoV-positive stool sample, which led us to test and optimize new medium conditions, identify characteristics of stool samples that allow replication, and evaluate consistency of replication over time. Optimization of our HIE-HuNoV culture system has shown the following: (i) a new HIE culture medium made with conditioned medium from a single cell line and commercial media promotes robust replication of HuNoV strains that replicated poorly in HIEs grown in our original culture medium made with conditioned media from 3 separate cell lines; (ii) GI.1, 11 GII genotypes (GII.1, GII.2, GII.3, GII.4, GII.6, GII.7, GII.8, GII.12, GII.13, GII.14, and GII.17), and six GII.4 variants can be cultivated in HIEs; (iii) successful replication is more likely with virus in stools with higher virus titers; (iv) GII.4_Sydney_2012 virus replication was reproducible over 3 years; and (v) HuNoV infection is restricted to the small intestine, based on replication of two viral strains in duodenal and ileal HIEs, but not colonoids, from two susceptible donors. These results improve the HIE culture system for HuNoV replication. Use of HIEs by several laboratories worldwide to study the molecular mechanisms that regulate HuNoV replication confirms the usefulness of this culture system, and our optimized methods for virus replication will advance the development of effective therapies and methods for virus control.IMPORTANCE Human noroviruses (HuNoVs) are highly contagious and cause acute and sporadic diarrheal illness in all age groups. In addition, chronic infections occur in immunocompromised cancer and transplant patients. These viruses are antigenically and genetically diverse, and there are strain-specific differences in binding to cellular attachment factors. In addition, new discoveries are being made on strain-specific differences in virus entry and replication and the epithelial cell response to infection in human intestinal enteroids. Human intestinal enteroids are a biologically relevant model to study HuNoVs; however, not all strains can be cultivated at this time. A complete understanding of HuNoV biology thus requires cultivation conditions that will allow the replication of multiple strains. We report optimization of HuNoV cultivation in human intestinal enteroid cultures to increase the numbers of cultivatable strains and the magnitude of replication, which is critical for testing antivirals, neutralizing antibodies, and methods of virus inactivation.

Educational and Personal Opportunity Costs of Medical Student Preparation for the United States Medical Licensing Examination Step 1 Exam: A Single-Center Study.

Purpose To assess the degree to which medical students choose to disengage from their regular preclinical curriculum and extracurricular activities in order to focus on United States Medical Licensing Examination (USMLE) Step 1 exam preparation, as well as learner-perceived effects of Step 1 preparation on their physical, social, and mental health. Method Online survey of medical students who have taken the USMLE Step 1 exam at a single large Midwestern academic medical center. Results The response rate was 54%. Students often reported absenteeism from a variety of preclinical curricular activities, including lectures (44%) and didactics focusing on medical ethics (37%), clinical skills (28%), and encounters with actual and standardized patients (9%) in order to study for USMLE Step 1. Many students also forewent extracurricular opportunities including research (53%), elective patient care opportunities (45%), community service (39%), and healthcare advocacy experiences (38%) in order to study for USMLE Step 1. Majorities of students identified Step 1 preparation as a cause of burnout (79%) or significant anxiety or depression (61%), for which nearly a third sought mental healthcare; students also reported Step 1 preparation as a cause of engaging in dangerous behaviors such as illicit prescription stimulant use as well as driving or providing patient care while impaired by fatigue. In narrative comments, students frequently described Step 1 to be a barrier to their development into effective clinicians, the traditional medical school curriculum to be a barrier to performance on Step 1, or both. Conclusions Medical students often prioritize Step 1 exam preparation over engaging with the standard preclinical curriculum, extracurricular opportunities, and activities to promote wellbeing. These findings have implications for the emphasis residency program directors place on single high-stakes standardized exams in the resident recruitment process.

The History of Antibiotic Treatment of Osteomyelitis.

Antibiotic treatment of osteomyelitis has evolved substantially over the past 80 years. Traditional teachings (eg, that antimicrobials must be given parenterally, selected based upon ratios of achieved bone vs serum drug levels, and continued for 4-6 weeks) are supported by limited data. New studies are challenging this dogma, however. In this review, we seek to contextualize the discussion by providing a narrative, chronologic review of osteomyelitis treatment spanning the pre-antibiotic era through the present day and by describing the quality of evidence supporting each component of traditional osteomyelitis therapy.

Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges.

Noroviruses, in the genus Norovirus, are a significant cause of viral gastroenteritis in humans and animals. For almost 50 years, the lack of a cultivation system for human noroviruses (HuNoVs) was a major barrier to understanding virus biology and the development of effective antiviral strategies. This review presents a historical perspective of the development of a cultivation system for HuNoVs in human intestinal epithelial cell cultures. Successful cultivation was based on the discovery of genetically-encoded host factors required for infection, knowledge of the site of infection in humans, and advances in the cultivation of human intestinal epithelial cells achieved by developmental and stem cell biologists. The human stem cell-derived enteroid cultivation system recapitulates the multicellular, physiologically active human intestinal epithelium, and allows studies of virus-specific replication requirements, evaluation of human host-pathogen interactions, and supports the pre-clinical assessment of methods to prevent and treat HuNoV infections.