Preclinical and Clinical Investigations of Severe Infection and Critical Illness

Clinical Center

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Abstract

Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest 1990), the role of endotoxemia (J Clin Invest 1989; J Exp Med 1989; Chest 1991; N Engl J Med 1993; Infect Immun 1996), and the efficacy of various anti-endotoxin therapies (Antimicrob Agents Chemother 1989; J Clin Invest 1987; Pharm Res 1990; JAMA 1993; J Infect Dis 1994). Nitric oxide (NO) was examined as a mediator of septic shock (Crit Care Med 1993; JAMA 1996). Non-selective NO synthase inhibitors were toxic and never beneficial (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). NO production in endotoxemic volunteers was blocked by ibuprofen, but blood pressure was unaffected, as compensatory mechanisms maintained vasodilation (J Pharmacol Exp Ther 1999). Risk of death influenced 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 model of pneumonia (Intensive Care Med 2008). Intra-aortic balloon counterpulsation prolonged survival in a canine model of 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) axis unresponsiveness and high aldosterone levels identified a canine pneumonia subpopulation with poor outcomes (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 and oxygen targets in the trial 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). A survey found that diagnosing sepsis is highly subjective and variable (Critical Care 2016). A clinical surveillance definition accurately identified septic shock and suggested 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 was administered infrequently and did not 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 infusions of alteplase for submassive pulmonary embolism warrants further investigation (Blood Coagulation and Fibrinolysis 2018). Meta-analysis of transfusion in patients with cardiovascular disease demonstrated that a restrictive vs. liberal approach was associated with an increased risk of death and coronary events (Transfusion Med 2018). Difficult to Treat Resistance (DTR) to all high-efficacy, low-toxicity antibiotics, in gram-negative bloodstream infections was an independent contributor to mortality (Clin Infect Dis 2018). The DTR metric was subsequently 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 comparators agents and patient characteristics (Am J Infect Control 2019). In a meta-analysis of procalcitonin (PCT)-guided antibiotic discontinuation, benefits were primarily only seen in low quality studies without high protocol adherence (Chest 2019). Most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher 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 grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy (Clin Infect Dis 2021). Approximately one in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy. Receiving discordant empirical antibiotic therapy was associated with increased odds of mortality. Early identification of bloodstream pathogens and resistance 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). CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention (Am J Physiol Heart Circ Physiol 2021). Despite improvements in COVID-19 survival, surges in hospital COVID-19 caseloads was detrimental to survival and potentially eroded benefits gained from emerging treatments. Bolstering preventon and supporting surging hospitals can save lives (Ann Intern Med 2021). In a retrospective cohort study, among 131,773 patients with previous COVID19, 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 2021).