Infections are common in nursing home (NH) residents with advanced dementia but are often managed inappropriately. Antimicrobials are extensively prescribed, but frequently with insufficient evidence ...to support a bacterial infection, promoting the emergence of multidrug-resistant organisms. Moreover, the benefits of antimicrobials remain unclear in these seriously ill residents for whom comfort is often the goal of care. Prior NH infection management interventions evaluated in randomized clinical trials (RCTs) did not consider patient preferences and lack evidence to support their effectiveness in 'real-world' practice.
This report presents the rationale and methodology of TRAIN-AD (Trial to reduce antimicrobial use in nursing home residents with Alzheimer's disease and other dementias), a parallel group, cluster RCT evaluating a multicomponent intervention to improve infection management for suspected urinary tract infections (UTIs) and lower respiratory tract infections (LRIs) among NH residents with advanced dementia. TRAIN-AD is being conducted in 28 facilities in the Boston, USA, area randomized in waves using minimization to achieve a balance on key characteristics (N = 14 facilities/arm). The involvement of the facilities includes a 3-month start-up period and a 24-month implementation/data collection phase. Residents are enrolled during the first 12 months of the 24-month implementation period and followed for up to 12 months. Individual consent is waived, thus almost all eligible residents are enrolled (target sample size, N = 410). The intervention integrates infectious disease and palliative care principles and includes provider training delivered through multiple modalities (in-person seminar, online course, management algorithms, and prescribing feedback) and an information booklet for families. Control facilities employ usual care. The primary outcome, abstracted from the residents' charts, is the number of antimicrobial courses prescribed for UTIs and LRIs per person-year alive.
TRAIN-AD is the first cluster RCT testing a multicomponent intervention to improve infection management in NH residents with advanced dementia. Its findings will provide an evidence base to support the benefit of a program addressing the critical clinical and public health problem of antimicrobial misuse in these seriously ill residents. Moreover, its hybrid efficacy-effectiveness design will inform the future conduct of cluster RCTs evaluating nonpharmacological interventions in the complex NH setting in a way that is both internally valid and adaptable to the 'real-world'.
ClinicalTrials.gov, NCT03244917 . Registered on 10 August 2017.
Background The characteristics of co-colonization with multiple different species of multidrug-resistant gram-negative bacteria (MDRGN) have not been fully elucidated. Quantifying the prevalence of ...co-colonization and those patients at higher risk of co-colonization may have important implications for strategies aimed at limiting the spread of MDRGN. Methods To determine the prevalence of MDRGN colonization, rectal swabs were obtained from 212 residents residing in a 600-bed long-term care facility. Co-colonization was defined as colonization with ≥2 different MDRGN species. Co-colonized residents were compared with residents colonized with a single MDRGN species to identify factors associated with an increased risk for co-colonization. Molecular typing was performed to determine the contribution of cross transmission to the co-colonized state. Results A total of 53 (25%) residents was colonized with ≥1 MDRGN. Among these, 11 (21%) were colonized with ≥2 different species of MDRGN. A global deterioration score of ≥5 representing advanced dementia and an increased requirement for assistance from health care workers was significantly associated with co-colonization ( P = .05). Clonally related MDRGN strains were identified among 7 (64%) co-colonized residents. Conclusion The prevalence of co-colonization with ≥2 different MDRGN is substantial. Cross transmission of MDRGN is a major contributor to the co-colonized state.
The diagnostic accuracy of the rectal swab (RS) culture method in identifying gastrointestinal colonization with vancomycin-resistant enterococci (VRE) is not known. Serial quantitative stool ...cultures, skin cultures, and RS cultures were performed for patients with VRE infections to assess the false-negative rate of the RS and the prevalence of skin colonization, a prerequisite for cross-transmission, at varying VRE stool densities. A total of 35 stool samples were obtained from 13 patients. The sensitivity of the RS culture was 58%; it ranged from 100%, at VRE densities of ⩾7.5 log10 colony forming units (cfu) per gram of stool, to 0%, at densities of ⩽4.5 log10 cfu per gram of stool. Skin colonization was detected at these low VRE stool densities, but it was more common at higher VRE densities (P < .001). Antibiotic exposure was significantly associated with higher VRE stool densities (P < .001). The high false-negative rate of the RS may be contributing to the continued increase in the prevalence of VRE.
Abstract Resistance to antimicrobials continues to increase worldwide. Data suggest that older patients are among the main reservoirs of multidrug-resistant organisms (MDROs) in the hospital. We ...hypothesized that older patients (≥65 years of age) are more likely to harbor MDRO at hospital admission. We compared rates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and multidrug-resistant gram-negative bacteria (MDRGN) recovered from clinical cultures within the first 48 h of admission to an adult acute care hospital between the elderly (≥65 years old) and young per 1000 age-stratified admissions over a 12-year study period. Trends in antimicrobial resistance, sites of recovery and species for MDRGN were also characterized. An average of 7534 positive bacterial cultures were collected per year. The admission prevalence per 1000 age-stratified admissions was consistently higher among the elderly for all three MDRO under investigation. Among the elderly, the admission prevalence increased significantly for VRE (0.89 in 1998 to 3.62 in 2009 per 1000 admissions; p < 0.001) and MDRGN (1.41 in 1998 to 11.33 in 2009 per 1000 admissions; p < 0.001). Percentage resistant for all three MDRO increased as well. These data suggest that elderly patients are contributing substantially to the influx of MDRO into the hospital setting.
Highlights • All parenteral antimicrobials administered to patients requiring chronic hemodialysis in 2 outpatient hemodialysis units over a 12-month period were quantified and assessed for ...appropriateness based on published guidelines. • A third of patients received at least 1 dose of antimicrobials, and among these, more than half received at least 1 inappropriately indicated dose. • Patients with a tunneled catheter access, a history of colonization or infection with a multidrug-resistant organism, and receiving hemodialysis during daytime shifts were more likely to receive antimicrobials. • Patients with a tunneled catheter access, receiving dialysis in unit B, and with a longer duration of hemodialysis prior to enrollment were at higher risk of receiving an inappropriately indicated antimicrobial dose. • Antimicrobial stewardship efforts in outpatient hemodialysis may focus on minimizing tunneled catheter use, incorporate prior history of multidrug-resistant organisms, and will likely require unit-specific practices.
Background. Treatment of acute human immunodeficiency virus type 1 (HIV-1) infection may have unique immunologic, virological, and clinical benefits. However, the timing of treatment, optimal ...starting regimens, and expected response to therapy have not been defined. Methods. One hundred two subjects treated during acute and early HIV-1 infection were observed prospectively to determine the effect of time elapsed before initiation of therapy on time to virological suppression and absolute CD4+ cell count. Subjects were divided into pre- and postseroconversion groups on the basis of HIV-1 antibody status at the time of initiation of treatment. Absolute CD4+ cell counts were compared between these groups and with those of historical untreated persons who had experienced seroconversion. Potential predictors of time to virological suppression and CD4+ cell count at ⩾12 months were assessed. Results. Ninety-nine (97%) of 102 subjects achieved virological suppression. The median time to suppression was 11.1 weeks (95% confidence interval, 9.4–14.9) and was independent of initial regimen. The mean CD4+ cell count at 12 months was 702 cells/mm3 (95% confidence interval, 654–750 cells/mm3) and showed an increasing trend over 60 months. Treated subjects demonstrated a statistically significant gain in the CD4+ cell count, compared with untreated historical control subjects, at ⩾12 months. Comparable virological and immunologic outcomes were seen in the pre- and postseroconversion groups. Baseline virus load and nadir CD4+ cell count predicted time to virological suppression and CD4+ cell count at ⩾12 months, respectively. Conclusions. Early treatment of HIV-1 infection is well tolerated and results in rapid and sustained virological suppression. Preservation of CD4+ cell counts may be achieved with early therapy, independent of seroconversion status. Protease inhibitor—based and nonnucleoside reverse-transcriptase inhibitor—based regimens show comparable performance in tolerability, time to virological suppression, and CD4+ cell count when used as a first regimen.
Background. The goal of this study was to develop a validated prediction rule for identification of patients harboring vancomycin-resistant enterococci (VRE) at hospital admission. Methods. A model ...for the prediction of patients harboring VRE at admission was created and validated by assigning weighted point values to independent risk factors associated with harboring VRE at admission, in 2 different cohorts of patients from 2 tertiary care hospitals in Boston, Massachusetts. Patients with VRE isolated from clinical culture samples collected within 48 h of hospital admission were compared with patients not harboring VRE. To assess the diagnostic accuracy of the prediction rule, the main outcome measures were patient demographic characteristics, comorbid illnesses, hospitalizations, and antibiotic exposure. Results. A total of 412 patients were enrolled. A risk index score was derived by using the following 6 independent risk factors associated with VRE recovery within 48 h of hospital admission: previous isolation of methicillin-resistant Staphylococcus aureus (MRSA), whether the patient was receiving long-term hemodialysis, transfer from a long-term care facility, antibiotic exposure, prior hospitalization, and age >60 years. On the basis of a point score ⩾10, the sensitivity, specificity, and positive and negative predictive values of this prediction rule were 44%, 98%, 81%, and 90%, respectively. Conclusions. This validated clinical prediction rule provides a novel strategy for the identification of patients at high risk of harboring VRE at hospital admission. Implementation of this rule may reduce the influx of VRE into health care institutions and the overall prevalence of VRE, by targeting VRE-screening measures and contact isolation precautions for these high-risk patients.
Long-term care facilities are significant reservoirs of antimicrobial-resistant organisms, and patients with advanced dementia are particularly vulnerable to multidrug-resistant organism (MDRO) ...acquisition and antimicrobial overuse. In this study, we longitudinally examined a group of patients with advanced dementia using metagenomic sequencing. We found significant inter- and intra-subject heterogeneity in microbiota composition, suggesting temporal instability. We also observed a link between the antimicrobial resistance gene density in a sample and the relative abundances of several pathobionts, particularly Escherichia coli, Proteus mirabilis, and Enterococcus faecalis, and used this relationship to predict resistance gene density in samples from additional subjects. Furthermore, we used metagenomic assembly to demonstrate that these pathobionts had higher resistance gene content than many gut commensals. Given the frequency and abundances at which these pathobionts were found in this population and the underlying vulnerability to MDRO of patients with advanced dementia, attention to microbial blooms of these species may be warranted.
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•Longitudinal analysis of the rectal microbiota of patients with advanced dementia•The microbiota was temporally unstable and characterized by pathobiont blooms•Antimicrobial resistance gene burden correlated with abundances of pathobionts•Genome assembly revealed that these species carried high levels of resistance genes
Genomics; Microbiome; Multi-Drug Resistant Organisms
T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, ...a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1
mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.
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