Preclinical and Clinical Investigations of Severe Infection and Critical Illness

Clinical Center

Investigators

Linked publications & trials

Abstract

Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest 1990), endotoxemia (J Clin Invest 1989; J Exp Med 1989; Chest 1991; N Engl J Med 1993; Infect Immun 1996), and anti-endotoxin therapies (Antimicrob Agents Chemother 1989; J Clin Invest 1987; Pharm Res 1990; JAMA 1993; J Infect Dis 1994). Nitric oxide (NO) was investigated in septic shock (Crit Care Med 1993; JAMA 1996). Non-selective NO synthase inhibitors were toxic or lacked benefit (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). NO in LPS-challenged volunteers was blocked by ibuprofen, but blood pressure was unaffected, as other pathways maintained vasodilation (J Pharmacol Exp Ther 1999). Risk of death affected the therapeutic efficacy of anti-inflammatory agents in sepsis (Am J Respir Crit Care Med 2002). L-arginine in canine septic shock was harmful (Crit Care Med 2006). Our canine sepsis model was redeveloped to balance animal welfare and relevance (Am J Physiol Heart Circ Physiol 2007). Risk of death and hydrocortisone efficacy was investigated in a mouse pneumonia model (Intensive Care Med 2008). Intra-aortic balloon counterpulsation prolonged survival in canine Staphylococcal pneumonia-induced septic shock (Crit Care Med 2009). The U.S. Critical Illness and Injury Trials Group (USCIITG; http://www.usciitg.org/) was founded to create a clinical research framework (Crit Care Med 2009). A meta-analysis of bundled care for septic shock; survival was strongly associated with early and appropriate antibiotics (Crit Care Med 2010). Inhibiting p38 improved cardiac function but worsened lung injury and survival in murine pneumonia (J Trauma 2010). Fluids and vasopressors were harmful in a rat model of anthrax lethal toxin (LeTx)-induced shock (Crit Care Med 2009). In canines, edema toxin increased mortality when added to lethal toxin (J Infect Dis 2010). Heparin failed to improve lung injury or survival in E. coli pneumonia (Crit Care Med 2011). In canines with S. aureus pneumonia, mineralocorticoid was beneficial prophylactically, while glucocorticoid was beneficial given at the onset of infection (Crit Care Med 2012). Stress dose corticosteroids were only beneficial in sepsis with a high risk for death (Intensive Care Med 2012). Tigecycline was associated with increased mortality and non-cure (Clin Infect Dis 2012). Using an aerosolized staphylococcal enterotoxin B (SEB) mouse model, gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death (PLoS One 2014). Hypothalamic-pituitary-adrenal (HPA) unresponsiveness and aldosterone levels were associated with poor outcomes in canine pneumonia (Am J Physiol Endocrinol Metab 2014). Intravenous colistin use identified a severely ill population with culture- confirmed, extensively drug-resistant bacteria (Clin Infect Dis 2015). SUPPORT consent forms incorrectly characterized the low oxygen saturation arm as usual care but it differed substantially from routine management (PLoS One 2016). Toxoplasmosis encephalitis was complicated by immune-reconstitution inflammatory syndrome (IRIS) in an allogeneic stem cell transplant patient (Bone Marrow Transplant 2016). Meningoencephalitis was characterized in Ebola virus disease (Ann Intern Med 2016). Diagnosing sepsis is highly subjective and variable (Critical Care 2016). A robust clinical surveillance definition of septic shock found that its incidence rose and mortality rates fell more slowly than previously estimated (Chest 2017). In a propensity-matched cohort with necrotizing fasciitis and shock, IVIG failed to decrease mortality (Clin Infect Dis 2017). Sepsis incidence was stable between 2009-2014 with no significant change in death and discharge to hospice (JAMA 2017). Low dose, brief duration alteplase for submassive pulmonary embolism might be useful in selected patients (Blood Coagul Fibrinolysis 2018). Meta-analysis of restrictive vs. liberal transfusion in patients with cardiovascular disease demonstrated an increased risk of death and coronary events (Transfusion Med 2018). Difficult to Treat Resistance (DTR) in gram-negative bloodstream infections was an independent contributor to mortality (Clin Infect Dis 2018). DTR metric was validated in a follow-up study (Open Forum Infect Dis 2019). Variation in completeness and accuracy of claims data for sepsis and organ dysfunction limited their usefulness (Crit Care Med 2019). Using tracer antibiotic algorithms, attributable mortality for extensively drug resistant (XDR) gram-negative infections varied by comparator agents and patient characteristics (Am J Infect Control 2019). In a meta-analysis of procalcitonin (PCT)-guided antibiotic discontinuation, benefit was only seen in low quality studies with poor protocol adherence (Chest 2019). Patients with community-onset sepsis were often treated with broad-spectrum antibiotics but infrequently had resistant pathogens. Both inadequate and unnecessarily broad empiric antibiotics were associated with mortality (JAMA Netw Open 2020). Oversight measures have been inadequate to ensure that subjects in comparative effectiveness trials are receiving usual and not unusual care (Crit Care Resusc 2020). The rarity of GNIs with no or suboptimal treatment options underscores the necessity for non-revenue-based strategies and innovative trial designs (Lancet Infect Dis 2020). Ceftazidime-avibactam use has increased, while colistin has correspondingly declined due to concerns about renal function (Clin Infect Dis 2021). One in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy, which was associated with mortality. Early identification of resistant pathogens will likely improve population-level outcomes (Lancet Infect Dis 2021). Adjunctive clindamycin improves the outcome of invasive group A -haemolytic streptococcal, but not invasive non-group A/B -haemolytic streptococcal infections (Lancet Infect Dis 2021). Cell-free hemoglobin adversely impacts sepsis outcomes through more than one mechanism and could represent a novel target for therapeutic intervention (Am J Physiol Heart Circ Physiol 2021). Despite improvements in COVID-19 survival, surges in hospital caseloads was detrimental to survival. Therefore, bolstering prevention to suppress surges and better supporting surging hospitals are effective strategies to save lives (Ann Intern Med 2021). In a retrospective cohort study, reinfection with SARS-CoV-2 was suspected in 253 (0.2%). Healthcare burden and illness severity were similar between index and reinfection encounters (Clin Infect Dis 2022). Among 1581 patients with S maltophilia infections, levofloxacin (n = 823) displayed statistically similar mortality risk (aOR, 0.76 95% confidence interval CI, .58-1.01; P = .06) compared to TMP-SMX (n = 758). Based on this observation evidence, levofloxacin was a reasonable alternative to TMP-SMX for the treatment of bloodstream and lower respiratory tract infections caused by S maltophilia (Open Forum Infect Dis 2022). Severe COVID-19 is associated with multiorgan failure and small vessel vasculopathy characterized by widespread microthrombi. However, antiplatelet therapy (Ann Intern Med commentary 2022) and aggressive anticoagulation have not had the hoped-for effect on outcome. We are examining endothelial senescence as a targetable mechanism of COVID-19 microvasculopathy.