Azithromycin in crisis: antimicrobial resistance, diagnostics gaps, and vaccine-linked stewardship for enteric infections in low- and middle-income countries.

Background: Azithromycin remains an important oral treatment option for enteric infections in low- and middle-income countries (LMICs), where rising fluoroquinolone resistance, limited diagnostic capacity, and restricted access to parenteral therapy have encouraged widespread empirical use. Increasing azithromycin resistance among Objectives: This Perspective examines azithromycin resistance as a health-system challenge rather than solely a microbiological phenomenon. Diagnostic gaps, prolonged empirical prescribing, over-the-counter availability, and inadequate antimicrobial stewardship contribute to sustained selective pressure. The drug's prolonged half-life, extensive tissue and intracellular penetration, and sustained intestinal exposure may further facilitate resistance selection. Importantly, resistance mechanisms, susceptibility patterns, and clinical-microbiological relationships differ substantially among enteric pathogens, limiting the value of uniform treatment strategies. The Perspective highlights diagnostic stewardship, pathogen-specific surveillance, locally relevant susceptibility interpretation, and vaccination as complementary approaches to reducing unnecessary azithromycin exposure. Conclusion: Preserving azithromycin requires coordinated health-system interventions that integrate accessible diagnostics, pathogen-directed antimicrobial stewardship, resistance surveillance, regulation of antibiotic access, and vaccination. Such an approach is particularly important in LMICs, where azithromycin remains one of the few accessible oral options for severe enteric infections.