Beyond Unplanned ICU Transfers: Linking a Revised Definition of Deterioration to Patient Outcomes.

OBJECTIVES: To develop an electronic descriptor of clinical deterioration for hospitalized patients that predicts short-term mortality and identifies patient deterioration earlier than current standard definitions. DESIGN: A retrospective study using exploratory record review, quantitative analysis, and regression analyses. SETTING: Twelve-hospital community-academic health system. PATIENTS: All adult patients with an acute hospital encounter between January 1, 2018, and December 31, 2022. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical trigger events were selected and used to create a revised electronic definition of deterioration, encompassing signals of respiratory failure, bleeding, and hypotension occurring in proximity to ICU transfer. Patients meeting the revised definition were 12.5 times more likely to die within 7 days (adjusted odds ratio 12.5; 95% CI, 8.9-17.4) and had a 95.3% longer length of stay (95% CI, 88.6-102.3%) compared with those who were transferred to the ICU or died regardless of meeting the revised definition. Among the 1812 patients who met the revised definition of deterioration before ICU transfer (52.4%), the median detection time was 157.0 min earlier (interquartile range 64.0-363.5 min). CONCLUSIONS: The revised definition of deterioration establishes an electronic descriptor of clinical deterioration that is strongly associated with short-term mortality and length of stay and identifies deterioration over 2.5 hours earlier than ICU transfer. Incorporating the revised definition of deterioration into the training and validation of early warning system algorithms may enhance their timeliness and clinical accuracy.

A Retrospective Cohort Study Comparing Dual Therapy With Ceftaroline With Vancomycin or Daptomycin Monotherapy for High-Grade or Persistent MRSA Bacteremia.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical infection associated with a high risk of mortality. Dual therapy is often used in patients with persistent bacteremia. Objective: This study aimed to compare the outcomes of vancomycin or daptomycin monotherapy with those of dual therapy with ceftaroline in high-grade or persistent MRSA bacteremia. Methods: We conducted a retrospective cohort study at a university teaching hospital between January 2014 and June 2021, involving adults initially treated with vancomycin or daptomycin. Patients were categorized into monotherapy and dual therapy groups. The primary outcome was 30-day mortality. Secondary outcomes included microbiological relapse and antibiotic-related adverse events. Results: In a group of 155 patients, 30-day mortality rates were similar between the monotherapy (23.4%) and dual therapy (22.6%) groups, with comparable microbiological relapse rates (6.5%). In inverse probability of treatment weighting analysis, we found no significant association between dual therapy and mortality (adjusted risk ratio [ARR] 1.38, 95% CI 0.64-2.41, P = 0.38) or microbiological relapse (ARR 0.95, 95% CI 0.31-2.73, P = 0.93). Dual therapy was associated with a lower risk of antibiotic-related adverse events (ARR 0.45, 95% CI 0.21-0.89, P = 0.02). Infectious diseases (ID) consultation was associated with a reduced mortality risk (ARR 0.27, 95% CI 0.07-0.95, P = 0.04). Conclusions: Dual therapy with ceftaroline did not reduce mortality risk compared with monotherapy in patients with MRSA bacteremia. However, patients with ID consultations showed a 73% reduction in mortality rates. Large-scale, prospective, and randomized controlled trials are needed to provide conclusive evidence regarding the potential benefits of dual therapy with ceftaroline for MRSA bacteremia.

Barriers to Adoption of a Secure Text Messaging System: a Qualitative Study of Practicing Clinicians.

BACKGROUND: Secure text messaging systems (STMS) offer HIPAA-compliant text messaging and mobile phone call functionalities that are more efficient than traditional paging. Although some studies associate improved provider satisfaction and healthcare delivery with STMS use, healthcare organizations continue to struggle with achieving widespread and sustained STMS adoption. OBJECTIVE: To understand the barriers to adoption of an STMS among physicians and advanced practice providers (APPs). DESIGN: We qualitatively analyzed free-text comments that clinicians (physicians and APPs) across a large healthcare organization offered on a survey about STMS perceptions. PARTICIPANTS: A total of 1110 clinicians who provided a free-text comment in response to one of four open-ended survey questions. APPROACH: Data were analyzed using a grounded theory approach and constant comparative method to characterize responses and identify themes. KEY RESULTS: The overall survey response rate was 20.5% (n = 1254). Clinicians familiar with the STMS frequently believed the STMS was unnecessary (existing tools worked well enough) and would overburden them with more communications. They were frustrated that the STMS app had to be downloaded onto their personal mobile device and that it drained their battery. Ambiguity regarding who was reachable in the app led to missed messages and drove distrust of the STMS. Clinicians saw the exclusion of other care team members (e.g., nurses) from the STMS as problematic; however, some clinicians at hospitals with expanded STMS access complained of excessive messages. Secondhand reports of several of these barriers prevented new users from downloading the app and contributed to ongoing low use. CONCLUSIONS: Clinicians are reluctant to adopt an STMS that does not offer a clear and trustworthy communication benefit to offset its potential burden and intrusiveness. Our findings can be incorporated into STMS implementation strategies that maximize active users by targeting and mitigating barriers to adoption.

Technology acceptance and critical mass: Development of a consolidated model to explain the actual use of mobile health care communication tools.

OBJECTIVE: Secure mobile communication technologies are being implemented at an increasing rate across health care organizations, though providers' use of these tools can remain limited by a perceived lack of other users to communicate with. Enabling acceptance and driving provider utilization of these tools throughout an organization requires attention to the interplay between perceived peer usage (i.e. perceived critical mass) and local user needs within the social context of the care team (e.g. inpatient nursing access to the mobile app). To explain these influences, we developed and tested a consolidated model that shows how mobile health care communication technology acceptance and utilization are influenced by the moderating effects of social context on perceptions about the technology. METHODS: The theoretical model and questionnaire were derived from selected technology acceptance models and frameworks. Survey respondents (n = 1254) completed items measuring perceived critical mass, perceived usefulness, perceived ease of use, personal innovativeness in information technology, behavioral intent, and actual use of a recently implemented secure mobile communication tool. Actual use was additionally measured by logged usage data. Use group was defined as whether a hospital's nurses had access to the tool (expanded use group) or not (limited use group). RESULTS: The model accounted for 61% and 72% of the variance in intent to use the communication tool in the limited and expanded use groups, respectively, which in turn accounted for 53% and 33% of actual use. The total effects coefficient of perceived critical mass on behavioral intent was 0.57 in the limited use group (95% CI 0.51-0.63) and 0.70 in the expanded use group (95% CI 0.61-0.80). CONCLUSION: Our model fit the data well and explained the majority of variance in acceptance of the tool amongst participants. The overall influence of perceived critical mass on intent to use the tool was similarly large in both groups. However, the strength of multiple model pathways varied unexpectedly by use group, suggesting that combining sociotechnical moderators with traditional technology acceptance models may produce greater insights than traditional technology acceptance models alone. Practically, our results suggest that healthcare institutions can drive acceptance by promoting the recruitment of early adopters though liberal access policies and making these users and the technology highly visible to others.

Defragmenting Heart Failure Care: Medical Records Integration.

Heart failure management requires intensive care coordination. Guideline-directed medical therapies have been shown to save lives but are practically challenging to implement because of the fragmented care that heart failure patients experience. Electronic health record adoption has transformed the collection and storage of clinical data, but accessing these data often remains prohibitively difficult. Current legislation aims to increase the interoperability of software systems so that providers and patients can easily access the clinical information they desire. Novel heart failure devices and technologies leverage patient-generated data to manage heart failure patients, whereas new data standards make it possible for this information to guide clinical decision-making.

Short versus long duration of ceftaroline combination therapy and outcomes in persistent or high-grade MRSA bacteremia: A retrospective single-center study.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high mortality rates. Despite antibiotic therapy, persistent bacteremia is challenging to treat. Combination therapy with ceftaroline has emerged as a potential treatment option; however, the optimal duration and clinical implications after bacteremia clearance are unknown. METHODS: This retrospective cohort study examined patients with high-grade or persistent MRSA bacteremia who were treated with ceftaroline combination therapy at the University of New Mexico Hospital between January 2014 and June 2021. Patients were categorized into short- (<7 days) or long-duration (≥7 days) groups based on the duration of combination therapy after bacteremia clearance. Outcomes included 30-day all-cause mortality, bacteremia recurrence, post-bacteremia clearance length of stay, and adverse events. RESULTS: A total of 32 patients were included in this study. The most common sources of bacteremia were bone/joint and endovascular (28.1%, 9/32 each). The median duration of combination therapy after clearance was seven days (IQR 2.8, 11). Patients in the long-duration group had a lower Charlson comorbidity index (1.0 vs 5.5, p = 0.017) than those in the short-duration group. After adjusting for confounders, there was no significant difference in the 30-day all-cause mortality between the groups (AOR 0.17, 95% CI 0.007-1.85, p = 0.18). No association was found between combination therapy duration and recurrence (OR 2.53, 95% CI 0.19-inf, p = 0.24) or adverse drug events (OR 3.46, 95% CI 0.39-74.86, p = 0.31). After controlling for total hospital length of stay, there was no significant difference in the post-bacteremia clearance length of stay between the two groups (p = 0.37). CONCLUSIONS: Prolonging ceftaroline combination therapy after bacteremia clearance did not significantly improve outcomes in patients with persistent or high-grade MRSA bacteremia. The limitations of this study warrant cautious interpretation of its results. Larger studies are needed to determine the optimal duration and role of combination therapy for this difficult-to-treat infection.

Contemporary Pharmacotherapies for Nontuberculosis Mycobacterial Infections: A Narrative Review.

Nontuberculous mycobacteria (NTM) are a group of atypical bacteria that may cause a spectrum of clinical manifestations, including pulmonary, musculoskeletal, skin and soft tissue, and cardiac infections. Antimycobacterial medication regimens for NTM infections require multiple agents with prolonged treatment courses and are often associated with poor tolerance in patients and suboptimal clinical outcomes. This review summarizes NTM pharmacotherapy, including treatment concepts, preferred medication regimens according to NTM species and site of infection, and emerging treatment methods for difficult-to-treat species.

Validation of a Proprietary Deterioration Index Model and Performance in Hospitalized Adults.

Importance: The Deterioration Index (DTI), used by hospitals for predicting patient deterioration, has not been extensively validated externally, raising concerns about performance and equitable predictions. Objective: To locally validate DTI performance and assess its potential for bias in predicting patient clinical deterioration. Design, Setting, and Participants: This retrospective prognostic study included 13 737 patients admitted to 8 heterogenous Midwestern US hospitals varying in size and type, including academic, community, urban, and rural hospitals. Patients were 18 years or older and admitted between January 1 and May 31, 2021. Exposure: DTI predictions made every 15 minutes. Main Outcomes and Measures: Deterioration, defined as the occurrence of any of the following while hospitalized: mechanical ventilation, intensive care unit transfer, or death. Performance of the DTI was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Bias measures were calculated across demographic subgroups. Results: A total of 5 143 513 DTI predictions were made for 13 737 patients across 14 834 hospitalizations. Among 13 918 encounters, the mean (SD) age of patients was 60.3 (19.2) years; 7636 (54.9%) were female, 11 345 (81.5%) were White, and 12 392 (89.0%) were of other ethnicity than Hispanic or Latino. The prevalence of deterioration was 10.3% (n = 1436). The DTI produced AUROCs of 0.759 (95% CI, 0.756-0.762) at the observation level and 0.685 (95% CI, 0.671-0.700) at the encounter level. Corresponding AUPRCs were 0.039 (95% CI, 0.037-0.040) at the observation level and 0.248 (95% CI, 0.227-0.273) at the encounter level. Bias measures varied across demographic subgroups and were 14.0% worse for patients identifying as American Indian or Alaska Native and 19.0% worse for those who chose not to disclose their ethnicity. Conclusions and Relevance: In this prognostic study, the DTI had modest ability to predict patient deterioration, with varying degrees of performance at the observation and encounter levels and across different demographic groups. Disparate performance across subgroups suggests the need for more transparency in model training data and reinforces the need to locally validate externally developed prediction models.

Mice with lung airway ciliopathy develop persistent Mycobacterium abscessus lung infection and have a proinflammatory lung phenotype associated with decreased T regulatory cells.

Introduction: Human pulmonary infection with non-tuberculous mycobacteria (NTM) such as Mycobacterium abscessus (Mabs) occurs in seemingly immunocompetent patients with underlying structural lung disease such as bronchiectasis in which normal ciliary function is perturbed. In addition to alterations in mucociliary clearance, the local immunologic milieu may be altered in patients with structural lung disease, but the nature of these changes and how they relate to NTM persistence remain unclear. Methods: We used a mouse strain containing a conditional floxed allele of the gene IFT88, which encodes for the protein Polaris. Deletion of this gene in adult mice reportedly leads to loss of cilia on lung airway epithelium and to the development of bronchiectasis. In a series of experiments, IFT88 control mice and IFT88 KO mice received different preparations of Mabs lung inocula with lung CFU assessed out to approximately 8 weeks post-infection. In addition, cytokine levels in bronchoalveolar lavage (BAL) fluid, lung T cell subset analysis, and lung histopathology and morphometry were performed at various time points. Results: Mabs embedded in agarose beads persisted in the lungs of IFT88 KO mice out to approximately 8 weeks (54 days), while Mabs agarose beads in the lungs of IFT88 control mice was cleared from the lungs of all mice at this time point. T cells subset analysis showed a decrease in the percentage of CD4+FoxP3+ T cells in the total lymphocyte population in the lungs of IFT88 KO mice relative to IFT88 control mice. Proinflammatory cytokines were elevated in the BAL fluid from infected IFT88 KO mice compared to infected IFT88 control mice, and histopathology showed an increased inflammatory response and greater numbers of granulomas in the lungs of infected IFT88 KO mice compared to the lungs of infected IFT88 control mice. Scanning lung morphometry did not show a significant difference comparing lung airway area and lung airway perimeter between IFT88 KO mice and IFT88 control mice. Discussion: Persistent lung infection in our model was established using Mabs embedded in agarose beads. The utility of using IFT88 mice is that a significant difference in Mabs lung CFU is observed comparing IFT88 KO mice to IFT88 control mice thus allowing for studies assessing the mechanism(s) of Mabs lung persistence. Our finding of minimal differences in lung airway area and lung airway diameter comparing IFT88 KO mice to IFT88 control mice suggests that the development of a proinflammatory lung phenotype in IFT88 KO mice contributes to Mabs lung persistence independent of bronchiectasis. The contribution of cilia to immune regulation is increasingly recognized, and our results suggest that ciliopathy associated with structural lung disease may play a role in NTM pulmonary infection via alteration of the local immunologic lung milieu.

Indication alerts to improve problem list documentation.

BACKGROUND: Problem lists represent an integral component of high-quality care. However, they are often inaccurate and incomplete. We studied the effects of alerts integrated into the inpatient and outpatient computerized provider order entry systems to assist in adding problems to the problem list when ordering medications that lacked a corresponding indication. METHODS: We analyzed medication orders from 2 healthcare systems that used an innovative indication alert. We collected data at site 1 between December 2018 and January 2020, and at site 2 between May and June 2021. We reviewed random samples of 100 charts from each site that had problems added in response to the alert. Outcomes were: (1) alert yield, the proportion of triggered alerts that led to a problem added and (2) problem accuracy, the proportion of problems placed that were accurate by chart review. RESULTS: Alerts were triggered 131 134, and 6178 times at sites 1 and 2, respectively, resulting in a yield of 109 055 (83.2%) and 2874 (46.5%), P< .001. Orders were abandoned, for example, not completed, in 11.1% and 9.6% of orders, respectively, P<.001. Of the 100 sample problems, reviewers deemed 88% ± 3% and 91% ± 3% to be accurate, respectively, P = .65, with a mean of 90% ± 2%. CONCLUSIONS: Indication alerts triggered by medication orders initiated in the absence of a justifying diagnosis were useful for populating problem lists, with yields of 83.2% and 46.5% at 2 healthcare systems. Problems were placed with a reasonable level of accuracy, with 90% ± 2% of problems deemed accurate based on chart review.

Deletion of the mmpL4b gene in the Mycobacterium abscessus glycopeptidolipid biosynthetic pathway results in loss of surface colonization capability, but enhanced ability to replicate in human macrophages and stimulate their innate immune response.

Mycobacterium abscessus is considered to be the most virulent of the rapidly growing mycobacteria. Generation of bacterial gene knockout mutants has been a useful tool for studying factors that contribute to virulence of pathogenic bacteria. Until recently, the optimal genetic approach to generation of M. abscessus gene knockout mutants was not clear. Based on the recent identification of genetic recombineering as the preferred approach, a M. abscessus mutant was generated in which the gene mmpL4b, critical to glycopeptidolipid synthesis, was deleted. Compared to the previously well-characterized parental strain 390S, the mmpL4B deletion mutant had lost sliding motility and the ability to form biofilm, but acquired the ability to replicate in human macrophages and stimulate macrophage Toll-like receptor 2. This study demonstrates that deletion of a gene associated with expression of a cell-wall lipid can result in acquisition of an immunostimulatory, invasive bacterial phenotype and has important implications for the study of M. abscessus pathogenesis at the cellular level.

Demonstration of cord formation by rough Mycobacterium abscessus variants: implications for the clinical microbiology laboratory.

In low-income countries some infections caused by nontuberculous mycobacteria are misdiagnosed as multidrug-resistant tuberculosis. In most of these settings the observation of microscopic cords is the only technique used to identify Mycobacterium tuberculosis in the laboratory. In this article we definitively demonstrate that Mycobacterium abscessus, an emerging pulmonary pathogen, also forms microscopic cords.

Mycobacterium abscessus Glycopeptidolipids mask underlying cell wall phosphatidyl-myo-inositol mannosides blocking induction of human macrophage TNF-alpha by preventing interaction with TLR2.

Mycobacterium abscessus causes disease in patients with structural abnormalities of the lung, and it is an emerging pathogen in patients with cystic fibrosis. Colonization of the airways by nontuberculous mycobacteria is a harbinger of invasive lung disease. Colonization is facilitated by biofilm formation, with M. abscessus glycopeptidolipids playing an important role. M. abscessus can transition between a noninvasive, biofilm-forming, smooth colony phenotype that expresses glycopeptidolipid, and an invasive rough colony phenotype that expresses minimal amounts of glycopeptidolipid and is unable to form biofilms. The ability of this pathogen to transition between these phenotypes may have particular relevance to lung infection in cystic fibrosis patients since the altered pulmonary physiology of these patients makes them particularly susceptible to colonization by biofilm-forming bacteria. In this study we demonstrate that rough variants of M. abscessus stimulate the human macrophage innate immune response through TLR2, while smooth variants do not. Temperature-dependent loss or physical removal of glycopeptidolipid from the cell wall of one of the smooth variants leads to TLR2 stimulation. This response is stimulated in part through phosphatidyl-myo-inositol mannosides that are present in the cell wall of both rough and smooth variants. Mannose-binding lectins bind to rough variants, but lectin binding to an isogenic smooth variant is markedly reduced. This suggests that glycopeptidolipid in the outermost portion of the M. abscessus cell wall masks underlying cell wall lipids involved in stimulating the innate immune response, thereby facilitating colonization. Conversely spontaneous "unmasking" of cell wall lipids may promote airway inflammation.

Granulomatous interstitial nephritis in the setting of disseminated Mycobacterium simiae: a rare presentation of immune reconstitution inflammatory syndrome.

Disseminated Mycobacterium simiae is a rare opportunistic infection reported most commonly in advanced human immunodeficiency virus (HIV) infection. Treatment can be further complicated by the occurrence of severe immune reconstitution inflammatory syndrome (IRIS). We present the first case of disseminated multi-drug-resistant M. simiae in the setting of advanced HIV, complicated by IRIS in the form of granulomatous interstitial nephritis causing acute renal failure. This case highlights the importance of recognizing rare complications of IRIS, as delays in therapy can be life threatening.

A Rare Case of Neisseria animaloris Hand Infection and Associated Nonhealing Wound.

Neisseria animaloris is a rare pathogen in humans primarily associated with dog and cat bites. Fourteen cases have been documented in the literature related to the difficulty in identifying this bacterium in the laboratory. We present a patient case demonstrating a prolonged treatment course, which is often seen as the result of misdiagnosis, and subsequent nonhealing wound requiring multiple surgeries and eventual wide excision with staged graft coverage. We discuss the clinical course, laboratory identification techniques, surgical treatment, and patient outcome.

Differential antibiotic susceptibility of Mycobacterium abscessus variants in biofilms and macrophages compared to that of planktonic bacteria.

Mycobacterium abscessus causes refractory pulmonary infections requiring surgery for cure. It exists as a smooth biofilm-forming phenotype which is noninvasive and a rough, non-biofilm-forming phenotype which can invade macrophages and cause persistent pulmonary infection in mice. We have postulated that the dissociation of the smooth phenotype to the rough phenotype may lead to invasive lung disease following initial colonization of the airways. Amikacin, cefoxitin, and clarithromycin are standard therapies for this infection. We determined the MICs of these antibiotics against this pathogen in biofilms and macrophages, the niches that it likely occupies in the human host. Our results demonstrate that even though the MICs indicate sensitivity to these antibiotics, the minimal bactericidal concentrations for amikacin and clarithromycin were substantially higher and were out of the range of the concentrations achievable in serum. Cefoxitin demonstrated only bacteriostatic activity. In addition, although amikacin had modest activity against M. abscessus in biofilms, clarithromycin demonstrated only minimal activity at the highest concentrations tested. Our results indicate that M. abscessus in mature biofilms is in a stationary-phase state and that clarithromycin is relatively inactive against stationary-phase M. abscessus. In human macrophages, all three antibiotics were only bacteriostatic for M. abscessus variants at 10 times their MICs. These results suggest why treatment failure with antibiotics alone is common in the clinical setting of M. abscessus pulmonary infection. Determination of the efficacies of new antibiotics should include an assessment of their activities against the smooth and rough M. abscessus morphotypes in biofilms and macrophages.

Mycobacterium abscessus: Shapeshifter of the Mycobacterial World.

In this review we will focus on unique aspects of Mycobacterium abscessus (MABS) which we feel earn it the designation of "shapeshifter of the mycobacterial world." We will review its emergence as a distinct species, the recognition and description of MABS subspecies which are only now being clearly defined in terms of pathogenicity, its ability to exist in different forms favoring a saprophytic lifestyle or one more suitable to invasion of mammalian hosts, as well as current challenges in terms of antimicrobial therapy and future directions for research. One can see in the various phases of MABS, a species transitioning from a free living saprophyte to a host-adapted pathogen.

Reporter-Based Assays for High-Throughput Drug Screening against Mycobacterium abscessus.

Mycobacterium abscessus is a non-tuberculous mycobacterium that causes pulmonary and non-pulmonary infections. M. abscessus is resistant to many chemotherapeutic agents and the current treatment options show poor clinical outcomes. Thus, there is a dire need to find new antimicrobials effective at killing M. abscessus. Screening drug libraries to identify potential antimicrobials has been impeded by the lack of validated HTS assays for M. abscessus. In this study, we developed two 384-well high-throughput screening assays using fluorescent and bioluminescent reporter strains of M. abscessus for drug discovery. Optimization of inoculum size, incubation time and the volume-per-well based on Z-factor and signal intensity yielded two complementary, robust tools for M. abscessus drug discovery with Z-factor > 0.8. The MIC of known drugs, amikacin and clarithromycin, as determined by bioluminescence was in agreement with the published MIC values. A proof-of-concept screen of 2,093 natural product-inspired compounds was conducted using the 384-well bioluminescent assay to identify novel scaffolds active against M. abscessus. Five active "hit" compounds identified in this pilot screen were confirmed and characterized by a CFU assay and MIC determination. Overall, we developed and validated a 384-well screen that offers simple, sensitive and fast screening of compounds for activity against this emerging pathogen. To our knowledge, this is the first reporter-based high-throughput screening study aimed at M. abscessus drug discovery.