A randomized clinical trial of early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa

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PROJECT SUMMARY/ABSTRACT Sepsis is a syndrome of critical illness defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is a leading cause of global mortality. In May of 2017, the World Health Organization (WHO) made sepsis a global health priority. Yet, little is known about sepsis in the global South and specifically sub-Saharan Africa where there are at least 1.2-2.2 million cases of sepsis and 6.5 million deaths due to infection annually. The majority of these patients are living with HIV. We 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. However, it is difficult to identify TB sepsis clinically or with diagnostic tests which are often unavailable and have limited sensitivity. Therefore, TB can be missed and patients with TB sepsis may not receive anti-TB therapy, or if they do, it may be delayed. However, we have found that empiric treatment of TB in septic patients without a confirmed diagnosis of TB improves 28 day survival. We have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Therefore, our hypotheses are that immediate anti-TB therapy will improve 28 day survival compared to anti-TB therapy that is administered only after a diagnosis is made, and that optimized sepsis-specific dosing will improve 28 day mortality compared to conventional WHO recommended weight-based dosing regardless of the timing of administration. We will test these hypotheses through a randomized 2x2 factorial clinical trial where participants with HIV and sepsis will be randomized to 1) empiric immediate initiation of anti-TB therapy plus standard care or diagnosis dependent anti-TB therapy and standard care and 2) sepsis-specific dose anti-TB therapy plus standard care or conventional WHO weight-based recommended dose anti-TB therapy and standard care. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan community advisory boards and will be the first to determine the optimal content, dosing, and timing of the antimicrobial regimen for adult sepsis in sub-Saharan Africa.