ObjectivesReducing unnecessary exposure to antimicrobials and minimising preventable deaths from sepsis are in persistent tension in clinical work. Guidance documents are central to shaping clinical and organisational practice, yet there is a gap in understanding how these documents conceptualise the organisational system conditions that influence their use in practice.MethodsUsing content analysis, this qualitative document review analysed 40 national, regional, and local documents from six hospitals systems across England to examine how guidance conceptualises system conditions that influence antimicrobial use in cases of suspected or confirmed sepsis.ResultsWe identified six themes: (1) symbolic use of human factors, (2) an unclear understanding of the end user, (3) an ambiguous fit between national, regional, and local documents, (4) harmony in what is stated, (5) harmony in what is not stated, and (6) a lack of focus on management's role.ConclusionsSystem conditions within organisations will mediate how these documents are enacted in practice. Therefore, future development should consider how documents can guide a coherent fit between clinical, operational, and leadership structures via an effective operating model and the role management plays in achieving this coherence in different settings.