Optimising antimicrobial therapy for sepsis in Malawi (360G-Wellcome-109105_Z_15_A)

Mortality from severe sepsis in Malawi is extremely high – 50% compared to 20-30% in high-income settings. Guidelines on optimal use of available therapies (antimicrobials, intravenous fluids and oxygen) are extrapolated from high-income settings and/or based on expert opinion. Data to inform acute care guidelines for Malawi and sub-Saharan Africa (SSA), are urgently needed. Data from SSA suggest sepsis is caused by diverse pathogens including M. tuberculosis, not covered by current empiric therapy, and I propose that broadening the spectrum of empiric antimicrobial chemotherapy may play a role in improving outcomes. Great care must be taken with such a strategy to minimise development of antimicrobial resistance (AMR). The epidemiology of this emerging threat is not well understood in Malawi, but longitudinal surveillance reveals an alarming increase in drug resistant infection. I propose to: Conduct a prospective case-cohort study of severe sepsis patients in Malawi to provide a detailed description of sepsis, including microbiological causes and determinants of poor outcome. Use deep sequencing to study survivors and describe acquisition and duration of carriage of resistant bacteria. Ultimately, this will guide antimicrobial strategies to achieve the twin aims of improving clinical outcomes while minimising the development of AMR in Malawi.