African hospitals are increasingly providing microbiological diagnostics, hygiene and antimicrobial stewardship (AMS) procedures in response to multidrug-resistant (MDR) bacterial diseases. However implementation within integrated, multidisciplinary hospital services is often poorly established. We first aim to assess the impact of an enhanced hospital hygiene intervention on the incidence of healthcare-associated infections (HAI) in hospitalized patients, using a stepped-wedge cluster randomised trial (SW-CRT) design. Clusters (surgical, medical wards, ICUs) in four tertiary level hospitals in Ethiopia and Ghana will be transitioned to interventions focusing on hand and instrument hygiene procedures, hygiene procedures for visitors and standardized room surface cleaning. Microbiological assessments and AMR of patients and hospital environments will be conducted, with an expected 10-15% reduction in HAI incidence. Nested within the SW-CRT, we further focus on therapeutic drug monitoring (TDM) and predicted pharmacodynamic target attainment (PTA) to optimize beta-lactam antibiotic regimens as part of AMS procedures. Patients (N=400) with severe bacterial infections (e.g. sepsis) will receive standard versus standard plus TDM/PTA based AMS assessment, with dose optimization expected in up to 50% of cases. By integrating TDM/PTA into an AMS eHealth system, we aim to generate generalizable population-based PTA support, linked with cost-effectiveness analysis to promote sustainability within routine care procedures. By shifting antibiotic treatment from an empirical to a more individualized patient management strategy, we aim to introduce optimized and affordable AMS interventions, expecting an impact on improved clinical response and reduction of AMR within hospitals. Our study consortium is built on multidisciplinary expertise. Partners have been linked for years through African-European hospital partnerships implementing high quality microbiological diagnostics.