A randomized controlled trial to evaluate outcomes with Aggrenox in patients with SARS-CoV-2 infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients. METHODS: In an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge. RESULTS: From October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05). CONCLUSION: In this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

Linezolid use for the treatment of multidrug-resistant tuberculosis, TB centers of excellence, United States, 2013-2018.

BACKGROUND: In 2019, the World Health Organization released guidelines reflecting major changes in multidrug-resistant tuberculosis (MDR-TB) management-prioritizing fluoroquinolones, bedaquiline, and linezolid (LZD) while de-emphasizing previously favored injectable agents. In some cases, linezolid use is associated with gastrointestinal intolerance, mitochondrial toxicity, and significant drug interactions. CDC's Division of Tuberculosis Elimination supports a network of regional TB Centers of Excellence, which provide medical consultation to healthcare providers. Consultations are documented in a medical consultation database (MCD) enabling evaluation of management questions and recommendations. We describe the scope of clinical inquiries and responses specific to linezolid use for MDR-TB in the US. RESEARCH QUESTION: What are the major themes of provider and patient challenges regarding the use of linezolid for the treatment of MDR-TB in the US? METHODS: We queried MCD consults categorized as "MDR/XDR-TB" from 1/1/2013 to 12/31/2018. Only linezolid-specific consultations were included; incomplete and duplicate entries were excluded as were those citing linezolid historically or theoretically. Subgroup characteristics were assessed (e.g., Center, year, provider type). A descriptive coding scheme was developed through inductive thematic analysis. RESULTS: In 2013-2018 of the 1889 consults regarding MDR/XDR-TB, 934 MDR-TB consults referenced linezolid; 137 met inclusion criteria, representing between 4 and 10% of MDR-TB consults annually. Four main themes emerged: adverse effects (71.5%); concerns about linezolid use due to co-morbidities or concurrent medication use (15.3%); dosing adjustments (8.8%); and monitoring and maintenance logistics (4.4%). INTERPRETATIONS: Linezolid consults consistently exceeded 4% of all consults annually over the 6-year period, suggesting a need for access to expert opinion for providers using linezolid to manage MDR-TB. While only a snapshot of MDR-TB in the US, this evaluation summarizes major provider concerns regarding particular adverse effects, and highlights a need for evidence-based guidance regarding linezolid dosing and toxicity management.

Revisiting John Snow to Meet the Challenge of Nontuberculous Mycobacterial Lung Disease.

Nontuberculous mycobacteria (NTM) are ubiquitous components of the soil and surface water microbiome. Disparities by sex, age, and geography demonstrate that both host and environmental factors are key determinants of NTM disease in populations, which predominates in the form of chronic pulmonary disease. As the incidence of NTM pulmonary disease rises across the United States, it becomes increasingly evident that addressing this emerging human health issue requires a bold, multi-disciplinary research framework that incorporates host risk factors for NTM pulmonary disease alongside the determinants of NTM residence in the environment. Such a framework should include the assessment of environmental characteristics promoting NTM growth in soil and surface water, detailed evaluations of water distribution systems, direct sampling of water sources for NTM contamination and species diversity, and studies of host and bacterial factors involved in NTM pathogenesis. This comprehensive approach can identify intervention points to interrupt the transmission of pathogenic NTM species from the environment to the susceptible host and to reduce NTM pulmonary disease incidence.

Deaths Related to Nontuberculous Mycobacterial Infections in the United States, 1999-2014.

RATIONALE: Unlike tuberculosis, nontuberculous mycobacterial disease is not reportable to public health authorities in the United States, and the total burden of disease is uncertain. OBJECTIVES: To estimate the mortality of nontuberculous mycobacterial disease in the United States over a 15-year period and to identify temporal trends. METHODS: The U.S. Multiple Cause of Death Files from 1999 through 2014 were searched for a listing of nontuberculous mycobacterial disease by International Classification of Diseases, Tenth Revision code as either the underlying or a contributing cause of death. Characteristics of individuals with nontuberculous mycobacteria-related deaths in the United States were summarized according to demographic characteristics. Age-adjusted mortality rates and rate ratios were calculated using bridged-race population estimates of U.S. census population data. Time trends were evaluated with negative binomial regression. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in nontuberculous mycobacteria-related deaths among individuals without a diagnosis of HIV infection (P = 0.004). Mortality rates increased with advancing age. Age-adjusted mortality rate ratios were lower for men (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.80-0.87) compared with women, and were lower for Hispanic individuals (RR, 0.53; 95% CI, 0.49-0.56) and black, non-Hispanic persons (RR, 0.83; 95% CI, 0.77-0.88) compared with white, non-Hispanic individuals. CONCLUSIONS: The mortality rate of nontuberculous mycobacterial disease among HIV-uninfected individuals has increased in the United States between 1999 and 2014. These deaths occurred disproportionately in older white women. Considering the concurrent decline in tuberculosis-related deaths, these findings demonstrate a shift in the epidemiology of fatal mycobacterial infections in the United States.

Colistin- and Carbapenem-Resistant Escherichia coli Harboring mcr-1 and blaNDM-5, Causing a Complicated Urinary Tract Infection in a Patient from the United States.

UNLABELLED: Colistin is increasingly used as an antibiotic of last resort for the treatment of carbapenem-resistant Gram-negative infections. The plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China and subsequently reported worldwide, including in the United States. Of particular concern is the spread of mcr-1 into carbapenem-resistant bacteria, thereby creating strains that approach pan-resistance. While several reports of mcr-1 have involved carbapenem-resistant strains, no such isolates have been described in the United States. Here, we report the isolation and identification of an Escherichia coli strain harboring both mcr-1 and carbapenemase gene blaNDM-5 from a urine sample in a patient without recent travel outside the United States. The isolate exhibited resistance to both colistin and carbapenems, but was susceptible to amikacin, aztreonam, gentamicin, nitrofurantoin, tigecycline, and trimethoprim-sulfamethoxazole. The mcr-1- and blaNDM-5-harboring plasmids were completely sequenced and shown to be highly similar to plasmids previously reported from China. The strain in this report was first isolated in August 2014, highlighting an earlier presence of mcr-1 within the United States than previously recognized. IMPORTANCE: Colistin has become the last line of defense for the treatment of infections caused by Gram-negative bacteria resistant to multiple classes of antibiotics, in particular carbapenem-resistant Enterobacteriaceae (CRE). Resistance to colistin, encoded by the plasmid-borne gene mcr-1, was first identified in animal and clinical samples from China in November 2015 and has subsequently been reported from numerous other countries. In April 2016, mcr-1 was identified in a carbapenem-susceptible Escherichia coli strain from a clinical sample in the United States, followed by a second report from a carbapenem-susceptible E. coli strain originally isolated in May 2015. We report the isolation and identification of an E. coli strain harboring both colistin (mcr-1) and carbapenem (blaNDM-5) resistance genes, originally isolated in August 2014 from urine of a patient with recurrent urinary tract infections. To our knowledge, this is the first report in the United States of a clinical bacterial isolate with both colistin and carbapenem resistance, highlighting the importance of active surveillance efforts for colistin- and carbapenem-resistant organisms.

Extrapulmonary tuberculosis presenting as a cavernous sinus syndrome: Case report with review of existing literature.

Tuberculoma involving the cavernous sinus is a rare presentation of CNS disease, with only twelve cases reported in previous literature. We report a case of a 48 year old woman who presented with a right cavernous sinus syndrome of 2 months duration. MRI showed a mass in the right cavernous sinus, and serologic workup revealed an elevated sedimentation rate and positive Quantiferon(®)-GOLD testing. 18-FDG PET-CT demonstrated a hypermetabolic 3 cm subcarinal lymph node, and lymph node biopsy showed caseating granuloma. Culture of lymphatic tissue grew drug-sensitive M. tuberculosis. The patient was treated with a non-standard 4-drug regimen and prednisone, with rapid improvement of symptoms and radiologic abnormalities. Total length of treatment was 12 months. In addition, we review the 12 cases found in literature, and discuss clinical features, diagnostic dilemmas, and approaches to treatment.

Contemporary ventilator management in patients with and at risk of ALI/ARDS.

BACKGROUND: Ventilator practices in patients at risk for acute lung injury (ALI) and ARDS are unclear. We examined factors associated with choice of set tidal volumes (VT), and whether VT < 8 mL/kg predicted body weight (PBW) relates to the development of ALI/ARDS. METHODS: We performed a secondary analysis of a multicenter cohort of adult subjects at risk of lung injury with and without ALI/ARDS at onset of invasive ventilation. Descriptive statistics were used to describe ventilator practices in specific settings and ALI/ARDS risk groups. Logistic regression analysis was used to determine the factors associated with the use of VT < 8 mL/kg PBW and the relationship of VT to ALI/ARDS development and outcome. RESULTS: Of 829 mechanically ventilated patients, 107 met the criteria for ALI/ARDS at time of intubation, and 161 developed ALI/ARDS after intubation (post-intubation ALI/ARDS). There was significant intercenter variability in initial ventilator settings, and in the incidence of ALI/ARDS and post-intubation ALI/ARDS. The median VT was 7.96 (IQR 7.14-8.94) mL/kg PBW in ALI/ARDS subjects, and 8.45 (IQR 7.50-9.55) mL/kg PBW in subjects without ALI/ARDS (P = .004). VT decreased from 8.40 (IQR 7.38-9.37) mL/kg PBW to 7.97 (IQR 6.90-9.23) mL/kg PBW (P < .001) in those developing post-intubation ALI/ARDS. Among subjects without ALI/ARDS, VT ≥ 8 mL/kg PBW was associated with shorter height and higher body mass index, while subjects with pneumonia were less likely to get ≥ 8 mL/kg PBW. Initial VT ≥ 8 mL/kg PBW was not associated with the post-intubation ALI/ARDS (adjusted odds ratio 1.30, 95% CI 0.74-2.29) or worse outcomes. Post-intubation ALI/ARDS subjects had mortality similar to subjects intubated with ALI/ARDS. CONCLUSIONS: Clinicians seem to respond to ALI/ARDS with lower initial VT. Initial VT, however, was not associated with the development of post-intubation ALI/ARDS or other outcomes.

Planning against biological terrorism: lessons from outbreak investigations.

We examined outbreak investigations conducted around the world from 1988 to 1999 by the Centers for Disease Control and Prevention's Epidemic Intelligence Service. In 44 (4.0%) of 1,099 investigations, identified causative agents had bioterrorism potential. In six investigations, intentional use of infectious agents was considered. Healthcare providers reported 270 (24.6%) outbreaks and infection control practitioners reported 129 (11.7%); together they reported 399 (36.3%) of the outbreaks. Health departments reported 335 (30.5%) outbreaks. For six outbreaks in which bioterrorism or intentional contamination was possible, reporting was delayed for up to 26 days. We confirmed that the most critical component for bioterrorism outbreak detection and reporting is the frontline healthcare profession and the local health departments. Bioterrorism preparedness should emphasize education and support of this frontline as well as methods to shorten the time between outbreak and reporting.