Culture-negative bacteria: a blind spot in bacterial pathogen prioritization

Highlights
•Bartonella, Coxiella, Rickettsia, Orientia, and Leptospira elude standard culture.
•Culture-negative bacteria (CNB) commonly cause febrile illness in LMICs.
•Diagnostic limits and bias obscure CNB burden and delay appropriate treatment.
•CNB fulfill many WHO NTD and BPPL criteria but are excluded from pathogen lists.
•Recognizing CNB would improve surveillance and antimicrobial stewardship.

Abstract
Culture-negative bacteria (CNB), including Bartonella spp., Coxiella burnetii, Rickettsia spp., Orientia tsutsugamushi, and Leptospira spp., are frequent yet underrecognized causes of febrile illness in low- and middle-income countries (LMICs). Although these pathogens cause significant morbidity and mortality, they often remain undetected because standard culture techniques fail to identify them, resulting in systematic underdiagnosis. This narrative review examines existing criteria used in infectious disease guidelines for pathogen recognition and prioritization, applying them to CNB to assess how these organisms fit, or fail to fit, within current frameworks. We discuss the diagnostic limitations that impede CNB detection, as well as the cognitive biases that lead clinicians and public health practitioners to overlook these infections. The disproportionate impact of CNB in LMICs, where diagnostic infrastructure is limited and pathogen diversity is high, further fragments epidemiological data and constrains research investment. Collectively, these factors perpetuate the neglect of CNB in clinical practice, public health policy, and global health research agendas.