Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense.

Summary

Under physiologically relevant conditions, colistin remains bactericidal against mcr-1+ Enterobacteriaceae, enhancing complement deposition and synergizing with human serum. It killed mcr-1+ strains in fresh human blood and was effective as monotherapy in a murine bacteremia model, challenging conventional AST-based exclusion of colistin.

Key Findings

• Colistin retained bactericidal activity against mcr-1+ E. coli, K. pneumoniae, and S. enterica in tissue culture medium with physiological bicarbonate.
• Colistin enhanced complement deposition and synergized with human serum to kill mcr-1+ pathogens.
• At clinically achievable concentrations, colistin killed mcr-1+ strains in fresh human blood and was effective as monotherapy in a murine E. coli bacteremia model.
• Conventional enriched-media AST failed to capture this activity, suggesting current testing may underestimate in vivo efficacy.

Clinical Implications

Clinicians and microbiology labs should consider physiologically relevant AST conditions; colistin may be reconsidered for select mcr-1+ infections (e.g., bacteremia/sepsis) particularly where complement activity is intact, pending prospective clinical trials.

Limitations

• No human clinical trial; translational applicability may vary with patient immune status (e.g., complement deficiencies).
• Focused on mcr-1; generalizability to other mcr variants or resistance mechanisms requires testing.

Future Directions

Redesign AST protocols to incorporate physiological buffers/serum components and conduct prospective trials of colistin (alone or in combinations) in mcr-1+ bloodstream infections/sepsis with immune phenotyping.