Gerit D. Mulder, DPM, MS; Joseph P. Cavorsi, MD; Daniel K. Lee, DPM

Disclosures

Wounds. 2007;19(7):173-182. 

In This Article

Antimicrobial Agents in Wound Care

The use of topical antimicrobial agents for wound care gained a wide acceptance in the 1960s once it was discovered that treating burns with silver nitrate decreased the number of deaths that were a result of sepsis from 60% to 28%.[12,13] Antiseptic silver sulfadiazine (SSD) was associated with additional decreases in infection, eventually making a place for itself in general wound care. Silver sulfadiazine demonstrated improved outcomes and decreased infection rates.[13] Antiseptics differ from antibiotics in that they have broad-spectrum activity and can be effective against many types of organisms including aerobic and anaerobic bacteria, yeasts, fungi, and molds. While there is concern that certain antiseptics may delay healing as a result of cytotoxicity to viable cells,14 current wound treatment products must demonstrate biocompatibility and effectiveness to reduce bioburden prior to approval for an antimicrobial indication. Antiseptics used in current wound dressings include silver, iodine, and polyhexamethylene biguanide (PHMB).

Bacterial resistance to antibiotics is extensively documented in medical literature. Resistance to antiseptics, however, has only been studied more recently. Tambe and associates15 compared the ability of Staphylococcus epidermidis to develop resistance to various antibiotics and antiseptics after 20 S epidermidis cell culture passages. Results suggested that the bacteria developed resistance to the antibiotics minocycline and rifampicin, however no evidence of resistance was observed with chlorhexidine, silver sulfadiazine, and PHMB. Minor resistance was seen with Triclosan.

Silver

Silver has been used as an antimicrobial agent for thousands of years.[13] Silver ions exert varying antimicrobial effects depending on their binding site. When binding occurs at the bacterial cell wall, ruptures can occur. When bound to proteins involved in respiration and nutrition of the organism, silver blocks these processes and the bacterium dies. When binding to DNA, silver can affect the replication and division of the organism.[16]

The activity of silver lies in its ionic form.[17] Elemental silver and silver salts demonstrate substantially less effectiveness against microbes. Previously, silver salt solutions, such as silver nitrate, were used to bathe the wound. These required large amounts of silver to achieve the desired effect.[13] Silver sulfadiazine (SSD) creams enable much lower amounts of silver to be effective and act by discharging silver ions when in contact with wound exudate. Fox and Modak18 describe the mechanism by which sulfadiazine binds the silver and releases it into the wound over time at concentrations that are bactericidal. The silver ions, however, may be rapidly neutralized and require daily or more frequent application of SSD. The amount of silver released into the wound is not always clearly defined and can be a concern for toxicity in healthy tissue.[19] More recent technological advancements have lead to methods of delivering silver to wounds over longer periods of time and at more predictable levels.

There are a variety of silver containing wound dressings available. Delivery systems vary and include polyethylene mesh (ActicoatAE, Smith and Nephew, Largo, Fla), polyurethane foam (Contreet AgAE, Coloplast, Holtedam, Denmark), activated carbon (Actisorb 220AE, Johnson and Johnson, Somerville, NJ), hydrocolloid (Contreet-HAE, Coloplast), alginate with polymers (ArglaesAE, Medline, Mundelein, Ill), alginate with carboxymethylcellulose (CMC) (SilverCelAE, Johnson and Johnson), sodium carboxymethylcellulose (Aquacel AgAE, ConvaTec, Skillman, NJ), nylon (SilverlonAE, Argentum Medical, Asheville, NC), and polyacrylate (SilvasorbAE, Medline).

Thomas and McCubbin20,21 compared the in-vitro effectiveness of various silver containing products using 3 methods-zone of inhibition, challenge testing, and microbial transmission testing to demonstrate differences in the various dressings. Results against Staphylococcus aureus, Escherichia coli, and Candida albicans suggested that polyethylene mesh had the most rapid antimicrobial effect due to its rapid release of silver. Hydrocolloid was similar but had a slower onset. Activated carbon had little activity on the surface, but organisms that were absorbed into the dressing were inactivated by the silver.[20]

Jones et al[22] found that some of the differences observed between polyethylene mesh and sodium CMC may be related to the conformability of the dressing. A greater wound bed conformability and contact correlated with an increased antimicrobial effect.

As described in the literature,6,20,21 there are a wide variety of silver dressings available and various in-vitro responses from these dressings. Well-designed and adequately powered randomized trials to support the clinical benefits of silver are lacking, are warranted, and requested by the medical community.

Iodine

Iodine is used as a disinfectant for cleaning surfaces and storage containers, in skin soaps, medicines, and for purifying water. It has been purported to have negative effects on wound healing, however some hypothesize that it may be due to the carrier.[23] Carriers for iodine have demonstrated less toxicity by releasing iodine at a slower rate, yet show the same lethality as iodine in other forms. Cadexomer iodine (IodoflexAE and IodosorbAE, marketed in the United States by Smith & Nephew, Largo, Fla) is a 3-dimensional starch lattice formed into spherical microspheres that trap iodine in the lattice. As fluid is absorbed, the pore size of the lattice increases, releasing iodine. Mertz et al[23] tested cadexomer iodine against MRSA in an in-vitro porcine model. They demonstrated significant reduction of the bacteria over a period of 72 hours.

Hansson and colleagues24 compared cadexomer iodine to hydrocolloid and paraffin gauze dressings in a randomized, open, controlled, multicenter clinical trial. In the 153-patient study they demonstrated 62% reduction in ulcer size with the cadexomer iodine as compared to 41% and 24% for the hydrocolloid and paraffin gauze, respectively. Patients were treated until the wound was dry or until 12 weeks, whichever came first. The investigators also compared the cost of the dressing over the 12-week period and demonstrated cost savings with the cadexomer iodine.[24]

Studies suggest that iodine's mechanism of action is through destabilization of the bacterial cell wall and disruption of the membrane that results in leakage of the intracellular components.[25]

Polyhexamethylene Biguanide (PHMB)

Polyhexamethylene biguanide (PHMB), also known as polyhexanide and polyaminopropyl biguanide, is a commonly used antiseptic. It is used in a variety of products including wound care dressings, contact lens cleaning solutions, perioperative cleansing products, and swimming pool cleaners.

Wound care products containing PHMB include Kerlix AMD99, Excilon AMD99, and Telfa AMD99 (all from Tyco HealthCare Group, Mansfield, Mass) and XCellAE Cellulose Wound Dressing Antimicrobial (Xylos Corp, Langhorne, Pa).

A review of the literature demonstrates in-vivo and in-vitro safety and effectiveness of PHMB for a number of applications. For wound dressings, Wright and colleagues26 compared the effectiveness of a silver dressing to a dry gauze dressing containing PHMB (Kerlix AMD). Results demonstrated reduction in bioburden with both dressings when tested in an in-vitro bactericidal assay. Using a Kirby-Bauer zone of inhibition study, the gauze was not as effective. This was believed to be due to a tight bond between the dressing and PHMB, which was not released and therefore did not result in killing beyond the edge of the dressing.[26] Alternatively, Motta and associates6 demonstrated a good response using Kerlix AMD compared to gauze without PHMB in wounds where packing the dressing into the wound was required. Results suggested that the PHMB in the gauze resulted in a decrease in the number of organisms present in the wound.

The majority of literature describes effectiveness of PHMB on various microorganisms associated with contact lens disinfecting solutions. Antimicrobial effectiveness has been demonstrated on Acanthamoeba polyphaga, A castellanii, and A hatchetti.[25,27,28] Additional effectiveness was demonstrated for PHMB use in water treatment. Barker and colleagues29 tested the effect of PHMB on Legionella pneumophila. This bacterium causes Legionnaire's disease and can be found in water systems, air conditioning machinery, and cooling towers.

Gilbert and colleagues30,31 have performed numerous studies on bacteria, especially those that form biofilms, such as Klebsiella pneumoniae. In studying biofilms produced from E coli and S epidermidis, they noted that those compounds with higher activity against planktonic bacteria, including PHMB, were also the most effective agents against sessile bacteria found within biofilms. They suggested that the differences in effects of concentration of PHMB on planktonic versus sessile bacteria was due to either the mechanism of action or the number or disposition of cationic binding sites.[30–32] Kramer et al[33] have studied the effects of various antiseptics including PHMB on fibroblast proliferation and cytotoxicity. They noted that while octenidine-based products retarded wound healing, PHMB promoted contraction and aided wound closure significantly more than octenidine and placebo.

The mechanism of action of PHMB has been described in a number of articles. Broxton et al[34,35] demonstrated that maximal activity of the PHMB occurs at between pH 5-6 and that initially the biocide interacts with the surface of the bacteria and then is transferred to the cytoplasm and cytoplasmic membrane. Ikeda and colleagues36 showed that the cationic PHMB had little effect on neutral phospholipids in the bacterial membrane-its effect was mainly on the acidic negatively charged species where it induced aggregation leading to increased fluidity and permeability. This results in the release of lipopolysaccharides from the outer membrane, potassium ion efflux, and eventual organism death.[37]

Clinically, PHMB has been used as a perioperative cleansing agent,38 in mouth wash,39 in ophthalmology,38,40 and as a topical wash.[18] Hohaus et al[19] reported on the oral use of PHMB (Lavasept 1%, Fresenius-Kabi, Bad Homburg, Germany). A combination of oral terbinafine and topical ciclopirox and PHMB were used to successfully treat a deep fungal infection (Trichophyton mentagrophytes) of the throat. Petrou-Binder40 describes the germicidal effects of PHMB (Lavasept 0.02%) as eye drops prior to cataract surgery. It was well tolerated with low tissue response and minimal patient discomfort.

While there is no peer-reviewed clinical literature of PHMB used on wounds, industry literature describes the effectiveness of AMD Gauze (Kerlix) as a bacterial barrier against Staphylococcus epidermidis (penicillin resistant) on volunteers. Results suggest that clinically, this dressing was an effective barrier against bacterial colonization.[41] The studies suggested that AMD gauze did not elicit any skin reactions.[42]

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