Innate immunity and antibiotic activity in resistant bacterial infections in immunocompromised hosts

Antimicrobial resistance (AMR) is particularly difficult to manage in immunocompromised hosts, in whom impaired bacterial containment and clearance can coexist with restricted treatment options, altered drug exposure, and anatomically complex infection sites. Susceptibility testing and pharmacokinetic/pharmacodynamic (PK/PD) assessment guide antibiotic treatment, while host defenses help determine whether injured bacteria are cleared. This Review examines the host–antibiotic interface in resistant bacterial infection, with emphasis on how innate immunity contributes to antibacterial activity in immunocompromised populations. We distinguish quantitative and qualitative defects in neutrophils, monocyte hyporesponsiveness, complement impairment, barrier disruption, and combined host deficits, and consider how bacterial burden, infection compartment, and protected intracellular or extracellular populations modify drug–host interactions. Experimental studies show that immune function influences bacterial growth, clearance, and observed antibiotic exposure–response relationships. Antibiotic-induced changes in bacterial morphology, microbial-product release, and immune recognition may promote clearance or inflammatory injury depending on pathogen, burden, timing, and host state. Adjunctive approaches, including colony-stimulating factors, interferon-γ, innate agonists, pathogen-specific antibodies, antibody–antibiotic conjugates, and phage–antibiotic combinations, vary substantially in mechanism and strength of supporting evidence. Clinical assessment of adjunctive strategies requires evidence of improved infection outcomes as well as biological activity. We propose a research-oriented framework integrating antibacterial exposure, bacterial phenotype and burden, infection compartment, and host immune function to guide mechanistic investigation, while retaining effective antibiotic treatment and source control when indicated as the foundations of clinical care.