STeroids and Enhanced Spectrum Antibiotics for the Treatment of Patients in Africa With Refractory Sepsis

Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is the leading cause of global mortality. The World Health Organization has declared sepsis a global priority. Yet, little is known about sepsis in the global South and specifically sub-Saharan Africa where there are an estimated 17 million cases and 3.5 million attributable deaths per year. The majority of these patients are living with human immunodeficiency virus (HIV). The investigators have determined the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths occurring within the first 4-5 days of admission. Other causative pathogens include bacteria commonly or intrinsically resistant to third-generation cephalosporins which are the standard antimicrobial treatment for sepsis adopted from the global North. The investigators have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Concurrently, the investigators have also found a high burden of corticosteroid insufficiency in people with critical illness at collaborative study sites in Uganda and Tanzania. HIV and TB, independently and in combination, contribute to adrenal infection and endogenous steroid insufficiency. In further observational study, adults with sepsis at the collaborative study sites treated with corticosteroids have significantly improved survival from septic shock in-line with some, but not all, trials of adjunctive steroids in infection associated critical illness. Therefore, hypotheses are that immediate hydrocortisone administered over 7 days followed by a 7-day taper will improve 28 day mortality compared to the standard of care where corticosteroids are not administered, and that an enhanced antimicrobial regimen for 14 days to target TB and other drug-resistant bacteria of sepsis (rifampin, isoniazid, levofloxacin and linezolid) will improve 28 day mortality compared to the standard of care of immediate conventional anti-TB treatment and ceftriaxone alone. These hypotheses will be tested through a randomized 2x2 factorial clinical trial where participants hospitalized with HIV and sepsis will be randomized to 1) hydrocortisone or the standard care without hydrocortisone, and 2) the enhanced antimicrobial regimen plus ceftriaxone or the standard care with ceftriaxone alone. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan stakeholders, utilizes drugs that are available within national formularies and regional pharmacies, and if successful will be scalable for adults with sepsis in HIV endemic regions of sub-Saharan Africa. Improved understanding of the physiology and treatment alternatives for HIV related critical illness globally will have reciprocal benefit for health in the U.S.

• In-hospital mortality [Срок оценки: from enrollment through hospitalization, an average of 14 days]
• 6-month mortality [Срок оценки: From the date of randomization until death or 180 days from randomization]
• Time to death [Срок оценки: From date of randomization to death or 180 days from randomization]
• Incidence of new post-admission shock [Срок оценки: From the time of enrollment through hospital discharge, an average of 14 days]
• Duration of hospitalization [Срок оценки: From the time of randomization until date of hospital discharge up to 180 days, or death if before hospital discharge]
• Volume of IV fluids received [Срок оценки: From the date of randomization until date of hospital discharge up to 180 days, or date of death if occurring before discharge]
• Adverse drug events during the 28-day study period [Срок оценки: From date of randomization to 28 days post randomization or date of death if death occurred before 28 days]
• Time to ambulation [Срок оценки: From date of randomization until the date of first documented ambulation during hospitalization, or date of death from any cause, whichever came first, on average over 14 days, but up to 180 days]
• Time to temperature normalization [Срок оценки: From date of randomization until the date of first documented normal temperature during hospitalization, or date of death from any cause, whichever came first, on average over 14 days, but up to 180 days]
• Lactate/delta lactate [Срок оценки: From the date of randomization until the date of hospital discharge or the date of death if death occurred before discharge, on average 14 days]
• Capillary fill time/delta capillary fill time [Срок оценки: From the date of randomization until the date of hospital discharge or the date of death if death occurred before discharge, on average 14 days]
• Universal Vital Assessment score and delta Universal Vital Assessment score: component number one, heart rate [Срок оценки: From the time of randomization to 72 hours after randomization]