Clinical presentation, antimicrobial resistance, and treatment outcomes of Aeromonas human infections: A 14-year retrospective study and comparative genomics of two isolates from fatal cases.

BACKGROUND: Aeromonas virulence may not be entirely dependent on the host immune status. Pathophysiologic determinants of disease progression and severity remain unclear. METHODS: One hundred five patients with Aeromonas infections and 112 isolates were identified, their clinical presentations and outcomes analyzed, and their antimicrobial resistance (AMR) patterns assessed. Two isolates (A and B) from fatal cases of Aeromonas dhakensis bacteremia were characterized using whole genome sequence analysis. Virulence factor- and AMR-encoding genes from these isolates were compared with a well-characterized diarrheal isolate A. dhakensis SSU, and environmental isolate A. hydrophila ATCC_7966T. RESULTS: Skin and soft tissue infections, traumatic wound infections, sepsis, burns, and intraabdominal infections were common. Diabetes, malignancy, and cirrhosis were frequent comorbidities. Male sex, age ≥ 65 years, hospitalization, burns, and intensive care were associated with complicated disease. High rates of AMR to carbapenems and piperacillin-tazobactam were found. Treatment failure was observed in 25.7% of cases. Septic shock and hospital-acquired infections were predictors of treatment failure. All four isolates harbored assorted broad-spectrum AMR genes including blaOXA, ampC, cphA, and efflux pumps. Only clinical isolates possessed both polar and lateral flagellar genes, genes for various surface adhesion proteins, type 3- and -6 secretion systems and their effectors, and toxin genes, including exotoxin A. Both isolates A and B were resistant to colistin and harbored the mobile colistin resistance-3 (mcr-3) gene. CONCLUSIONS: Empirical therapy tailored to local Aeromonas antibiograms may facilitate more favorable outcomes, while advanced diagnostic methods may aid in identifying correct Aeromonas spp. of significant clinical importance.

Implementation of a High-Value, Evidence-Based Care Program: Impact and Opportunities for Learning Organizations.

GOAL: Value-based care is not simply a matter of cost, but also one of outcomes and harms per dollar spent. This definition encompasses three key components: healthcare delivery that is organized around patients' medical conditions, costs and outcomes that are actively and consistently measured, and information technology that enables the other two components. Our objective in this project was to implement and measure a systemwide high-value, evidence-based care initiative with five pillars of high-value practices. METHODS: We performed a quasi-experimental study from September 1, 2019, to August 31, 2022, of a new care program at the University of Texas Medical Branch. Drawing from the ABIM Foundation's Choosing Wisely Campaign, the program was based on five pillars-blood management and antimicrobial, laboratory, imaging, and opioid stewardship-with interdisciplinary teams led by institutional subject matter experts (i.e., administrative leaders) accompanied by nursing, information technology, pharmacy, and clinical and nonclinical personnel including faculty and trainees. Each pillar addressed two goals with targeted interventions to assess improvements during the first three fiscal years (FYs) of implementation. The targets were set at 10% improvement by the end of each FY. Monthly measurements were recorded for each FY. PRINCIPAL FINDINGS: We tracked performance toward 30 pillar goals and determined that the teams were successful in 50%, 50%, and 70% of their goals for FY 2020, 2021, and 2022, respectively. For example, in the antimicrobial stewardship FY 2021 pillar, one goal was to decrease meropenem days of therapy (DOT) by 10% (baseline was 45 DOT/1,000 patient days; the target was 40.5 DOT/1,000 patient days). We measured quarterly DOT/1,000 patient day rates of 32.02, 30.57, and 26.9, respectively, for a cumulative rate of 26.9. Critical interventions included engaging and empowering providers and service lines (including outliers whose performance was outside norms), educational conferences, and transparent data analyses. PRACTICAL APPLICATIONS: We showed that a multidisciplinary approach to the implementation of an evidence-based, high-value care program through a partnership of engaged administrative leaders, providers, and trainees can result in sustainable and measurable high-value healthcare delivery. Specifically, structuring the program with pillars to address defined metrics resulted in progressive improvement in meeting value-based goals at the University of Texas Medical Branch. Also, challenges can be embraced as learning opportunities to inform value-based interventions that range from technological to educational tactics. The results at the University of Texas Medical Branch provide a benchmark for the implementation of a program that engages, empowers, and aligns innovative value-based care initiatives.

Extensively Drug-Resistant Acinetobacter baumannii Nosocomial Pneumonia Successfully Treated with a Novel Antibiotic Combination.

Extremely drug-resistant (XDR) Acinetobacter baumannii causes challenging nosocomial infections. We report the case of a patient with XDR A. baumannii pneumonia and septic shock successfully treated with cefiderocol and a novel antibiotic obtained via expanded access protocol. With focused research and drug development efforts, the poor outcomes associated with these infections may be mitigated.

Prevalence of bovine subclinical mastitis, its etiology and diagnosis of antibiotic resistance of dairy farms in four municipalities of a tropical region of Mexico.

A region-wide survey was conducted in the tropical area of Tierra Caliente, State of Guerrero, Mexico to estimate the prevalence of subclinical bovine mastitis (SCM), distribution of mastitis pathogens, and in vitro antimicrobial susceptibility of different mastitis pathogens in dairy farms. In total, 1036 quarter milk samples were obtained from 259 cows at 87 different dairy farms. Collected quarter milk samples were submitted for California Mastitis Test (CMT), bacteriological examination, and testing for antimicrobial susceptibility. Overall prevalence of SCM in the studied area was 20.5 %. Prevalence in the different regions was as follows: 28 % in Arcelia municipality, 21 % in Tlalchapa municipality, 19.4 % in Pungarabato municipality, and 14.3 % in Finch Cutzamala municipality. Of all positive isolates, 97.5 % were Gram-negative bacteria. Moreover, of all positive isolates, 37.5 % were Proteus vulgaris, 25 % Salmonella spp., 12.5 % Enterobacter aerogenes, and 10 % Escherichia coli. Klebsiella pneumonia and E. coli were sensitive for netilmicin antimicrobial. However, E. coli was sensitive for pefloxacin and gentamicin with a sensitivity for pefloxacin for E. aerogenes, while Staphylococci were sensitive for gentamicin and dicloxacillin. It could be concluded that practices such as the implementation of mastitis control programs, improved milking hygiene together with an intramammary treatment with netilmicin, pefloxacin, and gentamicin antimicrobials should be considered for mastitis prevention in the study area of Tierra Caliente, in the tropical area of Guerrero, Mexico.

Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST).

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.

A case of orbital cryptococcosis.

Purpose: This report describes a case of Cryptococcus neoformans found in an unlikely location, the orbit, in an apparently immunocompetent host. Observations: A coordinated, multi-disciplinary approach between the ophthalmology, neurosurgery, pathology, and infectious disease departments was integral to saving both vision and life. Conclusions and Importance: This is the first case of primary orbital cryptococcosis described in the medical literature, to the authors' knowledge. The case draws attention to the possibility that Cryptococcus neoformans can indeed invade the orbit and should be considered part of the differential diagnosis for patients presenting with orbital masses of uncertain etiology.

Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may lead the development of new therapeutic strategies for GISTs patients.

Structure and function of a "yellow" protein from saliva of the sand fly Lutzomyia longipalpis that confers protective immunity against Leishmania major infection.

LJM11, an abundant salivary protein from the sand fly Lutzomyia longipalpis, belongs to the insect "yellow" family of proteins. In this study, we immunized mice with 17 plasmids encoding L. longiplapis salivary proteins and demonstrated that LJM11 confers protective immunity against Leishmania major infection. This protection correlates with a strong induction of a delayed type hypersensitivity (DTH) response following exposure to L. longipalpis saliva. Additionally, splenocytes of exposed mice produce IFN-γ upon stimulation with LJM11, demonstrating the systemic induction of Th1 immunity by this protein. In contrast to LJM11, LJM111, another yellow protein from L. longipalpis saliva, does not produce a DTH response in these mice, suggesting that structural or functional features specific to LJM11 are important for the induction of a robust DTH response. To examine these features, we used calorimetric analysis to probe a possible ligand binding function for the salivary yellow proteins. LJM11, LJM111, and LJM17 all acted as high affinity binders of prohemostatic and proinflammatory biogenic amines, particularly serotonin, catecholamines, and histamine. We also determined the crystal structure of LJM11, revealing a six-bladed ß-propeller fold with a single ligand binding pocket located in the central part of the propeller structure on one face of the molecule. A hypothetical model of LJM11 suggests a positive electrostatic potential on the face containing entry to the ligand binding pocket, whereas LJM111 is negative to neutral over its entire surface. This may be the reason for differences in antigenicity between the two proteins.

Early Clinical Experience with Delafloxacin: A Case Series.

BACKGROUND: The most recently approved fluoroquinolone for use in the US and Europe, delafloxacin (DLX) provides broad-spectrum coverage, improved side effect profile, and excellent potency. Currently approved for the treatment of acute bacterial skin infections and community-acquired pneumonia, DLX may be useful in the treatment of other infections given the longstanding versatility of other fluoroquinolones. MATERIALS AND METHODS: This is a retrospective review of adult patients treated with DLX at The University of Texas Medical Branch, Galveston, TX from January 1, 2018 to February 1, 2020 using pre-existing electronic medical records. Simple statistics were calculated using Microsoft Excel. RESULTS: Five patients were prescribed DLX (median age 59 years, 40% female, 100% outpatient) with a median treatment duration of seven days. Prescriptions were initiated by infectious diseases specialists (2/5, 40%), emergency medicine physicians (2/5, 40%), and ophthalmologists (1/5, 20%).  The most common conditions treated were prosthetic joint infections (PJI) and acute skin and soft tissue infections (each n = 2). Both PJIs were caused by multi-drug-resistant Staphylococcus epidermidis. Off-label utilization was high (3/5, 60%). No patient experienced any documented treatment failure due to delafloxacin and there were zero reported adverse events. CONCLUSIONS: A new antibiotic with valuable characteristics, DLX treatment was highly successful in this case series, including with multiple off-label indications. Real-world clinical data with delafloxacin are currently scant. Prospective data would be useful for identifying future clinical niches for this new fluoroquinolone.

Antibiotic Stewardship and Inpatient Clostridioides difficile Testing in Solid Organ Transplant Recipients: The Need for Multilevel Checks and Balances.

BACKGROUND: Diarrhea among recipients of solid organ transplants is a commonly encountered problem and is often multifactorial in etiology. Owing to the combination of perioperative antibiotic administration and the immunosuppressed status of transplant recipients, a high degree of suspicion for Clostridioides difficile (C. difficile) colitis is prudent. The purpose of this study is to demonstrate the association of an institutional integrated stewardship program with C. difficile testing practices after abdominal solid organ transplantation. METHODS: Starting in July 2017, a diagnostic stewardship was enacted in our institution requiring the ordering provider to answer a series of questions within the electronic medical record before ordering a C. difficile toxin test. The charts were reviewed for all solid organ transplant recipients on whom a test was ordered between January 2016 and September 2019. RESULTS: Orders for C. difficile toxin per quarter significantly decreased in the postintervention era (18 vs 8.5, P = .038). Median cost of inpatient treatment and days of therapy per thousand patient days was significantly lower in the postintervention era (median cost, $2,944.55 vs $416.92; P = .01) (days of therapy per thousand patient days, 521.9 vs 300.5; P < .01). Quarterly rates of negative tests were similar between the pre- and postintervention eras (65% vs 73%, P = .38). CONCLUSIONS: Although no orders were blocked based on the responses, this multilevel intervention was associated with a 47% decrease in C. difficile testing without effecting the rate of negative testing. These results suggest that we have achieved significant cost savings, in testing and isolation, without sacrificing critical aspects of clinical care.

Prediction of the need for intensive oxygen supplementation during hospitalisation among subjects with COVID-19 admitted to an academic health system in Texas: a retrospective cohort study and multivariable regression model.

OBJECTIVE: SARS-CoV-2 has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming COVID-19 respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterise the likelihood of patients with COVID-19 to progress to severe hypoxemic respiratory failure are still needed. DESIGN: We conducted a retrospective cohort study to develop a model using demographic and clinical data collected in the first 12 hours of admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalised patients with COVID-19. SETTING: University-based healthcare system including six hospitals located in the Galveston, Brazoria and Harris counties of Texas. PARTICIPANTS: Adult patients diagnosed with COVID-19 and admitted to one of six hospitals between 19 March and 30 June 2020. PRIMARY OUTCOME: The primary outcome was defined as reaching a WHO ordinal scale between 6 and 9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation. RESULTS: We included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), Quick Sequential Organ Failure Assessment score (OR 2.26) and neutrophil to lymphocyte ratio (OR 1.15) were significant predictors of severe disease. The final model showed an area under the curve of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies. CONCLUSIONS: Our study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.

Comparison of Coronary Artery Involvement and Mortality in STEMI Patients With and Without SARS-CoV-2 During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis.

BACKGROUND: Cardiovascular injury with SARS-CoV-2 infection is well known. Several studies have outlined baseline characteristics in patients presenting with STEMI and SARS-CoV-2. Paucity in data exists in selective coronary involvement in patients with STEMI and SARS-CoV-2 during the COVID-19 pandemic. METHODS: A systematic search and meta-analysis of studies meeting the inclusion and exclusion criteria obtained from MEDLINE, Scopus, and Cochrane databases was performed utilizing PRISMA criteria. The main outcome was likelihood of coronary artery involvement among patients with STEMI and SARS-CoV-2 versus without SARS-CoV-2. The primary adverse outcome measured was in-hospital mortality. RESULTS: The final analysis included 5 observational studies with a total of 2,266 patients. There was no statistical significance in LM (OR 1.40; 95% CI: 0.68, 2.90), LAD (OR 1.09; 95% CI 0.83, 1.43), LCX (OR 1.17; 95% CI: 0.75, 1.85), or RCA (OR 0.59; 95% CI: 0.30, 1.17) disease among the 2 groups. LAD disease was the most prevalent coronary involvement among patients with STEMI and SARS-CoV-2 (49.6%). Higher in-hospital mortality was observed in the STEMI and SARS-CoV-2 group (OR 5.24; 95% CI: 3.63, 7.56). CONCLUSIONS: Our analysis demonstrated no statistical significance in selective coronary involvement in patients with STEMI and SARS-CoV-2 during the COVID-19 pandemic. The higher mortality among patients with SARS-CoV-2 and STEMI has been noted in prior studies with concerns being late presentation due to fear of infection, delayed care time, and poor resource allocation. Focus should be placed on identifying and managing comorbidities to reduce mortality.

Extensively drug-resistant Salmonella Typhi in a patient returning from Pakistan, complicated by relapse with meropenem monotherapy.

In developing countries, typhoid fever is a common cause of febrile illness accompanied by abdominal pain and weakness. It is caused by Salmonella enterica serovar Typhi. Humans are the only known reservoir of infection, and typhoid fever is common in regions where access to clean water and sanitation is limited. The antimicrobials of choice for a case of typhoid fever acquired outside Pakistan are third generation cephalosporins. Lately, cases of extensively drug-resistant (XDR) Salmonella Typhi have been reported in people with a travel history to Pakistan. We present a case of XDR typhoid fever which relapsed after treatment with meropenem.

Native and Prosthetic Valve Staphylococcus capitis Endocarditis: A Review of the Literature.

Infective endocarditis (IE) is a rare but serious disease. Coagulase-negative staphylococci (CoNS) are among the least prevalent causes of IE. Staphylococcus capitis, a species of CoNS, although described in the literature before has only been seen in a few cases. Even with such few cases, complications and mortality have still been demonstrated. In our review, we look at the epidemiology, diagnosis, management, and literature prevalence of CoNS in native and prosthetic valve IE.

Neoadjuvant and adjuvant imatinib treatment in gastrointestinal stromal tumor: current status and recent developments.

PURPOSE OF REVIEW: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is a paradigm of targeted therapy for solid tumors. Elucidation of the biology of GIST enabled use of imatinib, which revolutionized the prognosis of advanced GIST. Whereas surgical resection continues to be the standard of care for primary GIST, judicious and individualized use of adjuvant and neoadjuvant imatinib may enhance the potential for cure in select patients. RECENT FINDINGS: Prospective trials utilizing adjuvant and neoadjuvant imatinib have established the safety and efficacy of these modalities adjunct to surgical resection. Correlative tissue studies derived from these trials have examined gene expression patterns, metabolic and radiographic response, and apoptosis during the first few days of imatinib therapy. As appropriate use of adjuvant and neoadjuvant imatinib requires proper patient selection, development of a predictive nomogram, and advances in mutational analysis represent progress toward individualized care. SUMMARY: Imatinib is well tolerated and beneficial as adjuvant and neoadjuvant therapy, but its utility in these settings continues to be refined. The greatest benefit will derive from an individualized approach that considers multiple patient, drug, and tumor characteristics to assess risk and likelihood of benefit for each patient.

Neoadjuvant treatment of soft-tissue sarcoma: a multimodality approach.

Unlike epithelial cancers that are both more homogeneous and easily categorized by their respective tissues of origin (e.g., breast or lung cancer), sarcomas represent a diverse class of molecularly distinct bone and soft-tissue mesenchymal neoplasms of more than 50 subtypes. This diversity, as well as the relative rarity of sarcomas as a whole, has presented challenges in conducting prospective randomized clinical trials to assess the value of neoadjuvant chemotherapy for any given subtype. Most clinical trials and meta-analyses have neglected the phenotypic and molecular heterogeneity differentiating one sarcoma subtype from another in favor of a simplified grouping that ensures timely trial completion. As the success of treating gastrointestinal stromal tumors (GISTs) with imatinib demonstrates, a decision to provide neoadjuvant chemotherapy must take into consideration both the subtype being treated and the effect such treatment would be expected to exert upon that subtype.

Life-Threatening Intraventricular Rupture of Brain Abscess in a Patient With Undiagnosed Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic condition associated with mucocutaneous and visceral arteriovenous malformations (AVMs), including pulmonary AVMs, which predispose patients to systemic paradoxical emboli that can lead to brain abscesses. Intraventricular rupture of brain abscess (IVROBA) is a feared complication with a high mortality rate. Here, we present a case with brain abscesses complicated by IVROBA and ventriculitis as the initial presentation of HHT in an undiagnosed patient. We also discuss the diagnostic and therapeutic approach that resulted in this patient's clinical improvement.