Overcoming phage resistance: efficacy of sequential phage-colistin therapy against carbapenem-resistant Acinetobacter baumannii

초록

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a major public health threat due to high mortality and limited treatment options. Bacteriophage (phage) therapy offers a promising alternative, but its long-term efficacy is challenged by the rapid emergence of phage-resistant bacterial populations. This study evaluates phage vB_AbaSt_W16 and whether sequential phage-antibiotic therapy enhances bacterial clearance and suppresses resistance. The optimal multiplicity of infection (MOI) for vB_AbaSt_W16 was determined across various CRAB strains. PAS was assessed in vitro using meropenem, colistin, tigecycline, rifampin, and ampicillin/sulbactam. An immunocompromised BALB/c mouse model was used to evaluate the therapeutic efficacy of phage monotherapy and combination therapy. Antibiotics were administered either concurrently with phage or sequentially 6 h after phage treatment. Bacterial clearance, survival rates, and the emergence of phage-resistant populations were monitored. Phage monotherapy inhibited bacterial growth at MOIs of 0.1-10, but high-dose treatment (MOI > 100) caused rapid regrowth within 12 h due to resistance emergence. Phage-antibiotic synergy (PAS) was observed only with tigecycline (FICI = 0.225), though the effect was transient. In the mouse model, phage monotherapy at MOIs of 0.1-1 achieved 100% survival, whereas MOI 10 reduced survival to 40%, correlating with increased bacterial burden and resistance emergence. Notably, sequential administration of colistin 6 h post-phage treatment improved survival to 100%, while colistin monotherapy resulted in survival below 40%. Sequential colistin treatment also effectively suppressed resistant bacterial populations, reducing them to nearly undetectable levels by day 4. High-dose phage treatment was limited by rapid resistance development. In contrast, sequential phage-antibiotic therapy, particularly when combined with colistin, significantly improved bacterial clearance, enhanced survival outcomes, and suppressed resistance emergence. These findings support sequential phage-antibiotic therapy as a strategy for CRAB infections.

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