Humans and the animals they have domesticated and cared for historically have been susceptible to dermal trauma and wounds. Developing healing agents for those wounds has been crucial to survival.
The emergence of antibiotic-resistant strains of pathogens in the 21st century, however, and the decrease in the production of newer antibiotics capable of fighting these often multi-antibiotic-resistant bugs has led to a revival of sorts, with renewed attention being paid to many of the older treatment methods. Many of these options were never fully researched or used previously, and they may well hold the key to being able to stay ahead of infections in the coming century (Photos 1 and 2).
"Old school" treatment options
Fresh science applied to older products and remedies may produce useful information and give equine practitioners a few more options, even though they may be "old school" options when treating dermal wounds.
Rose Cooper, PhD, a lecturer in microbiology at the Centre for Biomedical Sciences, University of Wales Institute Cardiff, U.K., has published an exhaustive review of evidence for the use of topical antimicrobial agents in wound care. She also urges caution in interpreting this information.
"Overall, the evidence concerning the efficacy of topical antimicrobial agents in the management of wounds is confusing," Cooper writes. "It must be remembered that it [published studies and evidence of effectiveness] originates from multiple sources, which are not directly comparable."
Cooper lists the following factors as variables that cloud what we know from studies of topical antimicrobial agents: concentration tested, contact time, species used for testing, temperature and number and type of organisms present. "Larger, better-designed trials to assess clinical efficiency and cost implications are necessary," says Cooper. But there's still value in reviewing what we do know—and possibly where and how this information may be used—when faced with the treatment of a dermal injury."
Chlorhexidine is still widely used as an antiseptic for hand washing, as a surgical scrub and as a navel dip for foals and wound irrigation. Discovered in the late 1940s, chlorhexidine showed rapid bactericidal activity against various nonspore-producing bacteria by damaging the outer cell layers and causing leakage of the cytoplasmic membrane. Antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa and other bacteria has been reported, but methicillin resistance has also been noted, keeping chlorhexidine from being a first choice for wound treatment.
"Despite reports of decreased bacterial counts, increased healing rates and a lack of toxicity, it was concluded that, at present, there is insufficient data to assess safety and efficacy," says Cooper, who thinks further clinical trials are required before this agent can be either recommended or condemned.
Honey is another old remedy that has been making a strong comeback, and various researchers have identified nearly 70 bacterial species susceptible to its actions, along with evidence that its use will promote healing in topical wounds. The antimicrobial action of honey arises from the osmolality, acidity and hydrogen peroxide created on the wound surface when it's used and from the presence of yet-unidentified honey phytochemicals.
Cooper cautions that "geographic location, floral origin and post-harvesting treatment conditions of individual products may also be important to its action." Published reports stress that the type of honey used is extremely important, and honey advocates and enthusiasts aggressively debate the merits of manuka honey vs. jelly bush, among others.
Particularly impressive and encouraging is honey's bactericidal action against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE), which are proving to be difficult microbes for more traditional antibiotics to handle. Honey operates by targeting multiple, nonspecific cellular sites, thus making it more difficult for microbes to overcome this agent. Multiple animal studies have identified honey's ability to promote wound healing and have documented its use in treating many types of distal limb wounds.
R. Reid Hanson, DVM, Dipl. ACVS, Dipl. ACVECC, of the Department of Clinical Sciences, College of Veterinary Medicine at Auburn University, has published extensively on the management and healing of equine wounds and burns, and he spoke about equine distal limb wounds at the 80th Western Veterinary Conference. "Honey has many useful properties, including broad-spectrum antimicrobial activity, anti-inflammatory action and stimulation of new tissue growth," reports Hanson. "The stimulatory effect of honey on wound healing may, in part, be related to up-regulation of anti-inflammatory cytokines—tissue necrosis factor, interleukin 1 beta, interleukin 6—within monocytes."
While most practitioners simply add pure honey to a nonstick wound dressing and apply this under a wrap, the development of actual wound care products containing honey is well underway. The production of standardized, purified honey and sterile dressings impregnated with honey will improve reliability, make it easier for veterinarians to use this agent and promote more controlled clinical trials that should generate more useful data on this ancient remedy.
Hydrogen peroxide is an antiseptic and disinfectant product that has also been around for a long time. It has broad-spectrum activity against bacteria, principally gram-positive species. It exerts its effect through oxidizing properties that produce free radicals to react with lipids, proteins and nucleic acids that disrupt cellular activity and kill microbes. Negative reports of air emboli and tissue irritation with hydrogen peroxide use have caused some to back off on its utilization, and there's insufficient research to make definitive statements about the place of hydrogen peroxide in wound management.
The element iodine was discovered in 1811 and was tried as a wound treatment for many years, principally during the American Civil War. In its elemental form, it inhibited bacteria but also caused pain, skin irritation and discoloration. The development of iodophors—mixtures of polyvinyl surfactant iodine complexes such as povidone-iodine—in the late 1940s made this agent safer, less painful and more effective. Iodophors release low-level concentrations of free iodine that produce multiple cellular effects by binding to proteins, nucleotides and fatty acids to block hydrogen bonding. Povidone-iodine has broad-spectrum activity against microbes, including bacteria, mycobacteria, fungi, protozoa and viruses.
"Its efficacy as a skin disinfectant is undisputed," says Cooper. "And numerous publications describe the use of iodine in cleansing wounds and as a topical agent to prevent or treat localized wound infections."
Some controversy exists regarding the use of povidone-iodine. Severe metabolic acidosis has been reported after use, and although these are isolated cases with questionable methodology, there's still a strong view in human medicine that povidone-iodine use should be restricted to brief topical application on superficial wounds, rather than long-term use on large wounds. Clearly, more research should be done in this area to increase confidence concerning iodophore use and to possibly clear the path for increased application of this treatment agent.
Of all the older antimicrobial agents enjoying renewed interest, perhaps the one with the most tremendous potential is silver. Colloidal silver is effective against bacteria in extremely low concentrations. Studies have shown 0.01 to 0.04 ppm to be effective against hundreds of types of bacteria and 3 to 5 ppm to be effective against nearly 650 different microbes.
Colloidal silver is a solution in which microscopic, electrically charged particles of silver are in suspension. Electrolysis of very pure water (less than 1 ppm of contamination) using a 99.9 percent pure silver electrode places a positive charge on silver ions and places them in solution.
The quality of the water and the silver are crucial to the production of a functional product, as is the strict control of current flow. Tap water contains roughly 100 to 300 ppm of dissolved solids, so highly distilled or deionized water must be used, but the resultant product has tremendous potential to provide veterinarians with antimicrobial agents that can take on the resistant bacteria and viruses we're increasingly encountering.
"Silver ions avidly bind to negatively charged components in proteins and nucleic acids, thereby effecting structural changes in bacterial components in proteins and in nucleic acids that affect viability," says Cooper. She adds that silver ions cause multiple deleterious events in microbes rather than specific lesions, making colloidal silver much more destructive to bacteria and viruses and much harder for pathogenic organisms to develop resistance to.
Multiple research projects have shown silver sulfadiazine (SSD) to possess broad-spectrum antibacterial, antifungal and antiviral activity. Hanson notes, "SSD's antibacterial activity includes Pseudomonas species, and contrary to what has been noted in other species, it does not decrease the rate of wound contracture in horses."
Many silver-based wound treatment products are coming into the veterinary marketplace, and there likely will be more as ongoing silver research continues to show promise.
A new company, EquiSilver, has begun using chelated silver rather than colloidal silver in an attempt to get even greater cellular penetration and antimicrobial action. This agent features a chelator bound tightly to a metal atom (silver in this case, but many minerals are commonly chelated), which forces the metal atom to go wherever the chelator goes. This combination of chelator and metal atom is called a chelate. Chelators are intended to carry atoms into the body in higher concentrations than normally would be allowed. It's proposed that the chelator is treated as a desirable molecule by the recognition system in cell walls and, consequently, the chelate is allowed entry. Research at the College of Veterinary Medicine at the University of Florida and elsewhere is underway looking at the beneficial effects of chelated silver on topical wounds but also on internal conditions of the guttural pouch, pharynx, larynx and lungs in horses.
The information presented here on topical wound agents is intended to stimulate thinking about additional ways to manage equine wounds. The development of newer, stronger antibiotics won't happen at anywhere near the pace required to keep ahead of microbial species' evolution, and more cases of antibiotic resistance are predicted for coming decades.
"The future threat of ineffectual control of wound infections caused by antibiotic-resistant strains of pathogens is sufficient reason to consider modifying our present reliance on antibiotics," says Cooper.
The intelligent use of existing antiseptic and antimicrobial agents seems warranted, as does continued research into the yet-unknown benefits of many of these compounds. Researchers are just beginning to look at the action of some of these agents against biofilm bacteria encased in slime layers that make them even more antibiotic-resistant.
"Already, some in vitro tests on biofilm with iodine show inhibition, and hydrogen peroxide (and hence peroxide-generating honeys) also offers potential," says Cooper.
Antimicrobials isolated from amphibian skin, bacteriophage therapy (i.e., viruses that specifically target pathogenic bacteria) and other therapies are being investigated.
While some of the research is new, many of these agents have been available for centuries and used, in some form or another, by past civilizations and ancient healers. The current challenge is to take these older agents and use modern technology to optimize and intensify their potential in our veterinary patients.
Dr. Marcella is an equine practitioner in Canton, Ga.