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Therapeutic Strategies for Acetic Acid for Pseudomonas Infection in the Diabetic Foot
As early as 420 BCE, Hippocrates, the “Father of Medicine,” used vinegar to manage wounds.1 While medical practice has evolved significantly since then, the fight against infection continues. Pseudomonas aeruginosa infection in diabetic foot wounds presents a unique challenge due to the complexities of the diabetic condition and pathogenicity of P aeruginosa. Diabetic foot ulcers are inherently predisposed to infection due to factors such as peripheral neuropathy, poor vascularity, and impaired immune function.
When P aeruginosa infection occurs, it can cause tissue damage, delay wound healing, and increase the risk of complications such as osteomyelitis and limb amputation. Several factors contribute to the increased risk of P aeruginosa infection including a warm, moist environment, biofilm formation, vascular compromise, and an impaired immune response.
Managing P aeruginosa infection requires a comprehensive treatment plan encompassing wound debridement, antibiotic therapy, wound care, pressure offloading, and optimized glycemic control. The growing challenge of antibiotic resistance has prompted interest in examining alternative treatment options such as topical acetic acid for potential efficacy against P aeruginosa infection. This poses a significant challenge due to infection complexity and the emergence of antibiotic-resistant strains.
Current antibiotic therapies for P aeruginosa have limitations as patients may develop resistance to these antibiotics over time and there are very few antibiotics available for serious pseudomonal infection, particularly those caused by multidrug resistant organisms (MDRO). Acetic acid, a weak organic acid, possesses potent antimicrobial properties that can assist in treating
P aeruginosa infection. Physicians can use acetic acid as an adjunctive therapy with traditional oral or intravenous antibiotics; in turn it can shorten antibiotic treatment duration and limit the risk of MDRO strains. Data from the Centers for Disease Control and Prevention suggest MDRO P aeruginosa causes roughly 13% of severe health care infection in the United States.2 While some antibiotics exist for MDRO, their use can be nephrotoxic, particularly for patients with pre-existing renal conditions like diabetes or chronic kidney disease.
The purpose of this article is to provide an overview of P aeruginosa infection, explore the potential role of topical acetic acid agent in aiding treatment, and provide insights into novel therapeutic strategies in clinical practice.
What You Should Know About Pseudomonas Aeruginosa
Pseudomonas aeruginosa, a gram-negative bacterium commonly found in soil and water, presents a significant challenge in health care due to its ability to form biofilms and develop antibiotic resistance. Biofilms are complex aggregates of bacteria encased in a self-generated matrix of extracellular polymeric substances. This protective layer allows them to survive in harsh environments with fluctuating temperature and nutrient availability.
Unfortunately, biofilms hinder the effectiveness of antibiotics and immune system response in eradicating infection.3 During taxis, neutrophils release toxic substance which delays wound healing.4 This poses a concern for developing antibiotic resistance. Acetic acid has the ability to reduce the pH of the wound and denature proteins. Many studies have shown that acetic acid can disrupt the formation of biofilms and even eradicate infection.3-6
The Role of Acetic Acid in P Aeruginosa Infection
Researchers have explored acetic acid, a weak organic acid, as a potential topical treatment for P aeruginosa infection. It works through several mechanism from disrupting cell membrane, altering the intracellular pH, inhibit biofilm formation and promote reepithelialization. Since acetic acid is a weak organic acid, it can penetrate bacterial cell walls and disrupt membrane integrity. P aeruginosa relies on an intact cell membrane for essential cellular function such as osmotic balance and regulating nutrients.
Without an intact cell membrane, intracellular contents can leak out and eventually lead to cell death. Acetic acid lowers the pH of bacterial cytoplasm, creating an acidic environment that disrupts cellular metabolism. P aeruginosa is known for creating thick biofilm to protect the extracellular matrix, which leads to increased resistance to antibiotics making it difficult to eradicate. Acetic acid disrupts biofilm, making them more susceptible to treatment, and exhibits multifaceted antimicrobial effects, effectively inhibiting the growth of P aeruginosa infection.3,5,8,9 Studies show that physicians have used acetic acid concentration varying between 0.5% and 5% for wounds; however, physicians have frequently used 2% to overcome infection.6 Additionally, acetic acid promotes reepithelialization of chronic nonhealing wounds through various cellular processes. While numerous studies demonstrate the effectiveness of acetic acid, further research is needed to optimize its therapeutic use in clinical practice.4-9
An in-vitro study by Bjarnsholt and colleagues explored the efficacy of both liquid and salt forms of acetic acid against bacterial biofilms.6 This study tested the effects of 0.5% and 1.0% acetic acid, as well as hydrochloric acid (HCl), on biofilms formed by wild-type strains of P aeruginosa and Staphylococcus aureus (S aureus). Both concentrations of acetic acid completely eradicated P aeruginosa biofilm, while HCl had no effect. For S aureus, treatment with 0.5% had reduced number of viable cells, whereas only a higher concentration (1.0%) completely eradicated the biofilms. This study also investigated the impact of pH on acetic acid’s antimicrobial properties. The authors found that acetic acid had a significant antimicrobial effect against P aeruginosa at pH below 4.76. Above pH 5, there were only minor and nonsignificant effects. Additionally, researchers tested the effects of a salt form of acetic acid, sodium diacetate (NaHAc2), on both 20-hour and 168-hour-old biofilms. Interestingly, NaHAc2 completely eradicated biofilms on both plates, suggesting that, regardless of form (liquid or salt), acetic acid has potential as a treatment for certain biofilms, especially those formed by P aeruginosa.
Jeong and colleagues investigated the combined effects of negative pressure wound therapy (NPWT) and acetic acid on wound healing at a cellular and molecular level, specifically angiogenesis and collagen synthesis.8 Through multiple histological analysis researchers found that reepithelialization and angiogenesis are enabled by the migration of fibroblasts along fibrin network. Specifically, matrix metalloproteinases (MMPs) were activated post-treatment, which signaled the reepithelialization but diminishes once closure is complete. From this study, NPWT increases angiogenesis but adding 1% acetic acid enhances reepithelialization via upregulation of MMPs.8
A prospective randomized controlled clinical trial, conducted by Madhusudhan and colleagues evaluated efficacy of 1% acetic acid in treatment of P aeruginosa infection in chronic wounds compared with conventional normal saline dressings.6 This study included 32 patients over a 6-month period. The mean time required for eliminating P aeruginosa infection from the wounds was 5.5 days with 1% acetic acid compared to 12.25 days with saline. This statistically significant difference (P <.001) suggests that acetic acid offers valuable evidence of effectiveness in treating P aeruginosa infected chronic wounds. Overall, 1% acetic acid is a simple, safe and effective topical treatment to eliminate P aeruginosa infection.3 This study minimizes bias and strengthens evidence of study outcomes with time and concentration being used in the therapy. On the other hand, assessing wound healing rates and recurrence of infection over a long period of time would provide a comprehensive understanding of treatment effectiveness.
Nagoba and colleagues investigated the use of acetic acid to treat P aeruginosa infection across different body sites including perinephric abscesses, postoperative wound infection, gluteal abscesses, and diabetic foot ulcers.9 The study utilized 3% acetic acid to eliminate Pseudomonas infection ranging from 2 to 12 days. In one instance, physicians used 5% acetic acid to treat perinephric abscess. This portrays the importance of considering factors such as wound chronicity, size, location, and severity of infection in determining the duration and optimal concentration of acetic acid therapy. This demonstrates the versatility of acetic acid treatment across various body sites. However, this heterogeneity with varying infection sites, makes it challenging to isolate the specific effects of acetic acid on each location.
Muthuraman and colleagues conducted a randomized control trial with 80 DFU patients with P aeruginosa.10 Half received standard saline dressings while the other half received 3% acetic acid dressing. As a result, researchers found a statistically significant difference (P=.009) in eradication rates. The acetic acid group achieved a 25% higher eradication rate (87.5%) compared to the saline group (62.5%).10 This is statistically significant and suggests that acetic acid dressings are effective in managing diabetic foot ulcers infected with P aeruginosa.
Clinical Application and Considerations
Acetic acid therapy holds promise as a potential versatile treatment option for various wound types, including burns, trauma, and puncture wounds, extending its use beyond diabetic foot infections. As a topical treatment, acetic acid offers a potential advantage: avoiding systemic side effects associated with some traditional antibiotics, particularly nephrotoxicity in patients with compromised kidney function. When employing this therapy, healthcare providers must carefully consider the duration of treatment and the concentration of acetic acid used, tailoring these parameters to the specific needs of each patient and the severity of the wound or infection.
Additionally, it is essential to explore adjunctive therapies such as antibiotics, surgical debridement, and wound vacuum-
assisted closure to optimize treatment outcomes. Introducing adjunctive therapy alongside acetic acid treatment can expedite the eradication of P aeruginosa infection and promote faster wound healing. However, one must address several challenges, including the potential development of resistance to acetic acid, variations in patient tolerance based on concentration, and the need for standardized assessment methods and treatment guidelines.
Looking ahead, acetic acid therapy holds promise for the development of innovative nanoparticle drug delivery systems. These systems could reduce the application frequency while enhancing convenience for patients. Moreover, formulating acetic acid into topical products such as wound dressings, ointments, hydrogels, or foams could further streamline application and improve patient adherence to treatment regimens.
Case Report: P Aeruginosa Treated With Acetic Acid
The patient is a 66-year-old male with a past medical history of diabetes, hypertension, hyperlipidemia, heart failure, and venous insufficiency. He presented to the emergency department with altered mental status, fever, and a right foot ulceration on the plantar lateral aspect near the proximal fifth metatarsal base. The ulcer tracked medially and posteriorly. The wound was a full-thickness ulceration measuring about 3cm x 4cm with a fibrogranular base, probed to bone, and had well-defined edges.
The patient initially underwent irrigation, debridement, and drainage with a fifth ray amputation. Due in part to multiple instances of nonadherence over the course of several months the patient underwent multiple surgeries including: irrigation, drainage, and debridement with rotational skin plasty; negative pressure wound therapy application along with acetic acid instillation; transmetatarsal amputation with full-thickness skin graft application; NEOX (BioTissue) tissue graft application with negative pressure wound therapy with acetic acid instillation; SomaGen (MTF Biologics) application; and wet-to-dry acetic acid dressing changes.
Intraoperative cultures and specimens indicated P aeruginosa, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and extended-spectrum beta lactamase Klebsiella. This resulted in broadening the patient’s antibiotics to IV vancomycin, meropenem and daptomycin for 6 weeks. Figure 1 shows progression of the surgical site post–transmetatarsal amputation and the various allograft applications. This patient currently has daily dressing changes of wet-to-dry with acetic acid to help eradicate pseudomonal infection. Figure 2, taken several weeks ago, shows significant improvement and healing.
In Conclusion
In the right patients, topical acetic acid can be a safe, economical, effective part of treatment for topical Pseudomonas infection, particularly in diabetic foot infection. Studies suggest its effectiveness in reducing P aeruginosa burden, promoting wound healing, and reducing reliance on systemic antibiotics. In addition, one can easily use acetic acid on an outpatient basis by reducing financial and social burden.
P aeruginosa infection in diabetic foot wounds poses a significant clinical challenge. Topical acetic acid emerges as a promising therapeutic option in the treatment arsenal due to its multifaceted antimicrobial effects. Studies have shown its effectiveness in eliminating Pseudomonas and promoting wound healing. However, further investigation is necessary to optimize treatment protocols, including concentration, application methods, and management of potential side effects.
Future clinical trials should explore the efficacy of acetic acid in combination with established therapies and develop standardized protocols for optimal use. The development of novel delivery systems like impregnated wound dressings and combination therapies holds promise for enhanced patient adherence and improved treatment outcomes. As the fight against antibiotic resistance continues, acetic acid warrants further exploration as a valuable tool for combating P aeruginosa infections.
Jannani Krishnan, DPM, is a second-year podiatric surgery resident at the Department of Veterans Affairs Palo Alto Health Care Systems in Palo Alto, CA,
James Brian Warne, DPM is Section Chief of Department of Podiatric Surgery, Department of Surgery at the Department of Veterans Affairs Palo Alto Health Care Systems in Palo Alto, CA.
References
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