Antimicrobial resistance is a major global health threat for humans, animals and the environment, with the highest mortality and morbidity rates in sub-Saharan Africa (SSA). The World Health Organization prioritised several carbapenem- and third-generation cephalosporin-resistant Gram-negative bacteria such as Enterobacterales as the most critical pathogens with only very limited treatment options. Bacteraemia, sepsis and other severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) give rise to excess mortality. Yet, the causative pathogens are rarely identified in patients in SSA due to a lack of microbiological diagnostics. Carbapenems and the new antibiotics ceftazidime-avibactam, cefiderocol and aztreonam-avibactam are active against different MDR GNB and could significantly reduce morbidity and mortality, but they are not widely available in SSA. The ComBac-Africa consortium has the overall goal to improve the management of severe infections due to MDR GNB in Côte d’Ivoire, Guinea-Bissau and Nigeria through the establishment of a needs-adapted diagnostic and antimicrobial stewardship (AMS) programme that provides equitable access to these novel antibiotics for targeted treatment. This will be achieved through (1) provision of high-quality and accurate microbiological diagnostics for prompt and correct identification of causative agents in bacteraemia and other severe infections; (2) a comprehensive One Health assessment of the epidemiology of GNB in humans, animal and environmental specimens; (3) tailored AMS initiatives, including early outbreak detection and infection prevention measures, to optimise the use of novel antimicrobials; (4) development of clinical algorithms for targeted diagnosis and treatment of infections due to MDR GNB; and (5) establishment of sustainable and affordable access to these antibiotics in SSA. A clinical trial will assess and quantify the impact of this multi-pronged intervention on patient outcome.