Selective serotonergic reuptake inhibitors (SSRIs) and beta-adrenergic blockers among agents with potential to mitigate chronic wound infections.
Image credit: Towfiqu Barbhuiya, Pexels
Topical application of selective serotonergic reuptake inhibitors (SSRIs) and of beta-adrenergic antagonists (ß-AR antagonists,"beta-blockers") has demonstrated potential to mitigate wound infections by helping to overcome barriers of bacterial biofilms and antimicrobial resistance, according to a recent review of non-antibiotic approaches for hastening healing of chronic wounds.1
Rivkah Isseroff, MD, Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, and colleagues point out that persistent wound infection not only reflects microbial density and pathogen predominance exceeding commensal colonization, but a bacterial biofilm matrix that encases the robust bacterial communities.
"These biofilms escalate bacterial virulence, perpetuate chronic inflammation, are more resistant to antibiotic therapies and extend healing durations, thus complicating effective wound management," Isseroff and colleagues explain.
In their review of non-antibiotic approaches to wound healing, which includes negative pressure and light and energy-based therapies, the investigators focus on pharmacologic classes which have demonstrated promise through novel mechanisms.
They find evidence that topical SSRIs, in addition to exerting antimicrobial activity, can mitigate the "uncontrolled and self-sustaining" inflammatory response in chronic wounds that interferes with healing.
Beta-blockers might interfere with bacterial quorum sensing (QS), which Isseroff and colleagues characterize as "a sophisticated system through which bacteria coordinate critical functions such as virulence factor production and biofilm formation."They also note that topical application of these drugs has attenuated expression of virulence genes in Pseudomonas aeruginosa biofilms, and has demonstrated synergistic interactions with antibiotics.
The synergy is reflected in reduced minimum inhibitor concentration (MIC) required to inhibit pathogens such as P aeruginosa and Serratia marcescens. "This synergy suggests that ß-AR antagonists, such as timolol, can significantly enhance the effectiveness of standard antibiotic treatments, providing a multifaceted approach to managing wound infections that addresses both bacterial virulence and antibiotic resistance," Isseroff and colleagues indicate.
In studies of SSRI effect on wound healing, the investigators find evidence, particularly with fluoxetine and paroxetine, of serotonin receptor-medated fibroproliferation. They suggest that wound healing follows from increased fibroblasts and improved epithelialisation. In a study in which a gel with fluoxetine-loaded solid lipid nanoparticles was applied to a wound, there was a reported increase in hydroxyproline, cellular proliferation, angiogenesis and collagen synthesis.
In addition to promoting healing, Isseroff and colleagues find evidence that the SSRIs exert direct antimicrobial activity; with sertaline, fluoxetine and proxetine having demonstrated inhibition of bacterial cell wall efflux, and effectiveness against Gram-positive bacteria.
"This (gel with SSRI-loaded nanoparticles) may represent a practical avenue for fluoxetine and other SSRIs to be repurposed as a topical for wound healing and wound infection," Isseroff and colleagues suggest.
Topical SSRIs (e.g., fluoxetine, paroxetine) show promise in chronic wound healing by mitigating inflammation, promoting fibroproliferation, and enhancing epithelialization.
Both drug classes exhibit unique mechanisms that tackle bacterial biofilms and antimicrobial resistance, key barriers in wound management.
The data supports repurposing SSRIs and beta-blockers for topical wound care applications.
In considering the promising data with ß-AR antagonists in disrupting biofilm formation and apparent synergy with antibiotics resulting in lowered MIC, Isseroff and colleagues propose that the currently available ophthalmic solution of timolol could provide an "off-label" treatment option.
"The extensive data accumulated over recent decades highlights timolol's beneficial effects on wound healing, and given its relevant evaluation on infection mitigation, should be considered as an adjuvant therapy in wound care protocols," they recommend.
In addition to the developments with SSRIs and ß-AR antagonists, Isseroff and colleagues note the progress and challenges with other non-antibiotic therapeutics for wounds, including antiseptics, honey-based products, and benzoyl peroxide.
"These include understanding the ecological effects of such treatments on microbial communities, ensuring their safety and efficacy in clinical settings, and overcoming the hurdles in translating preclinical success to tangible clinical outcomes," observe Isseroff and colleagues.
