Sepsis and meningitis account for significant mortality and long-term neurodevelopmental disability among neonates and young children in sub-Saharan Africa. There is a paucity of data on the aetiology of sepsis and meningitis in neonates and young children due to limited microbiological diagnostic capacity. As a result, clinicians often rely on recognition of a set of simple clinical signs and symptoms at admission to decide on initiation and duration of antibiotics. The use of such clinical decision rules to guide antibiotic use or identify children at high risk of poor outcomes may contribute to development of antimicrobial resistance (AMR) as neonates and young children often present to hospital with subtle and non-specific signs and symptoms. Similarly, the decision to step up, step down or stop antibiotics rarely benefits from reliable cultures or ancillary investigations such as complete blood count (CBC). Irrational antibiotic use (both over- and under-use) in the face of rising AMR and limited therapeutic options in the development pipeline threatens child survival in sub-Saharan Africa. This thesis aimed to address several related questions faced in the diagnosis and management of sepsis and meningitis in neonates and young children in resource-limited settings. The first part of this thesis investigated the causes of early-onset neonatal sepsis (EONS), while Part II assessed the performance of clinical signs in predicting serious bacterial infection or mortality among hospitalised children. The final part of the thesis investigated the safety and pharmacokinetic profile of fosfomycin in neonates hospitalised with clinical sepsis.