Potential Synergy of Fluoxetine and Antibacterial Agents Against Skin and Soft Tissue Pathogens and Drug-Resistant Organisms

<b>Background/Objectives:</b> The feasibility of repurposing selective serotonin reuptake inhibitors as adjunctive antibacterial agents is an area of current investigation. We sought to evaluate if fluoxetine will achieve synergistic killing with relevant antibacterial drugs against skin and soft tissue pathogens and multidrug-resistant pathogens. <b>Methods</b>: The MIC of fluoxetine was determined using broth microdilution for a diverse isolate collection of 21 organisms. Checkerboard experiments were then conducted using fluoxetine and clinically relevant antibacterial drugs. If fluoxetine and an anti-infective agent achieved synergy denoted by a fractional inhibitory concentration index ≤ 0.5, then the combination was further evaluated in 24 h time-killing experiments. Synergy in time-killing experiments was defined as a ≥2 log₁₀ CFU/mL reduction in fluoxetine combined with an antibacterial agent at any point in the experiment in comparison to whichever agent in the combination resulted in the lowest bacterial counts individually. <b>Results</b>: The fluoxetine MICs ranged from 64 to 128 mcg/mL for Gram-positive isolates and 8-512 mcg/mL for Gram-negative organisms. Against Gram-positive isolates, vancomycin, linezolid, clindamycin, and gentamicin failed to achieve synergy in checkerboard experiments. Levofloxacin and fluoxetine were the only combination that demonstrated synergy against a Gram-positive pathogen in both checkerboard and time-killing experiments (1/6 isolates, 16.7%). Against Gram-negative organisms, the most promising combination was fluoxetine and polymyxin B, which achieved synergistic killing in both checkerboard experiments and time-killing experiments in 12/15 isolates (80%). In comparison, fosfomycin and meropenem achieved synergy in both experiments against 6/15 (40%) and 3/15 (20%) Gram-negative isolates, respectively. <b>Conclusions</b>: The combination of fluoxetine and polymyxin B may be a potential strategy for combatting difficult-to-treat Gram-negative pathogens.